151 Mini-dose heparin has been shown to be useful in the prophylaxis of postoperative venous thrombosis. Mechanism(s) by which low-dose heparin is/are thought to protect against venous thrombosis include:
a. Enhancement of antithrombin III activity
b. A decrease in thrombin availability
c. Inhibition of platelet aggregation and subsequent platelet release action
d. A mild prolongation of activated partial thromboplastin time
Answer: a, b, c
Low-dose heparin is thought to protect against venous thrombosis through three different mechanisms. First, antithrombin III activity with its inhibition of activated Factor X is enhanced by only trace amounts of heparin; second, there is a decrease in thrombin availability that prevents its activation and thus its fibrin-stabilizing effect; and third, small doses of heparin may inhibit the second wave of platelet aggregation and subsequent platelet release reaction. The standard doses of heparin administered (5000 units bid) does not affect aPTT.
152 Tests of coagulation are used to monitor anticoagulation treatment and detect intrinsic abnormalities in coagulation. Which of the following statement(s) is/are true concerning coagulation tests?
a. Prothrombin time (PT) measures both the intrinsic and extrinsic clotting pathways and fibrinogen
b. Activated partial thromboplastin time (aPTT) can be used to monitor both oral anticoagulation with Warfarin and intravenous anticoagulation with heparin
c. Thrombin clotting time (TCT) is a measurement of the time it takes for exogenously administered thrombin to turn plasma fibrinogen into fibrin clot
d. Whole blood activated clotting time (ACT) is a measurement of the ability of whole blood to clot and is used to monitor heparin levels intraoperatively during cardiovascular and peripheral vascular operations
Answer: a, c, d
Coagulation tests include prothrombin time (PT), which measures the intrinsic and extrinsic pathways of fibrinogen production and is the most common method for measuring a level of oral anticoagulant therapy. The activated partial thromboplastin time (aPTT) identifies the abnormalities of the contact and intrinsic phases of coagulation. Values of aPTT have variably been shown to correlate with heparin dosages and serum heparin levels and are therefore most commonly used in monitoring heparin therapy. It is of no value in long-term management of patients on oral Warfarin therapy. Thrombin clotting time (TCT) is the measure of the time it takes for exogenously administered thrombin to turn plasma fibrinogen into fibrin clot. It is extremely sensitive to levels of heparin and is an excellent measure of measuring the level of heparin-induced anticoagulation. The beauty of the TCT is that it is not specific for any disease condition; thus it may be used to differentiate factor deficiencies from the presence of heparin, or to separate lupus anticoagulant from abnormalities in fibrinogen levels. The whole blood activated clotting time (ACT) is a measurement of the ability of whole blood to clot, and as such, is an available technique for monitoring heparin levels intraoperatively. The ACT responds in a linear fashion to increasing heparin dosage and correlates well with the observed clinical anticoagulation. Adequate anticoagulation for extracorporeal circulation is defined as an ACT of 480 seconds or more while for peripheral vascular applications, values of 250 seconds or greater are considered appropriate.
153 Thrombolytic therapy has become a useful adjunct in the management of peripheral arterial occlusion. In this setting, direct intraarterial administration rather than intravenous has been advocated to decrease the risk of systemic bleeding. Which of the following true statement(s) concerning the use of thrombolytic agents for arterial occlusion is/are true?
a. A standard technique involves infusing high-dose urokinase, 4000 units per minute for 1–2 hours, directly into the clot by a catheter embedded in the thrombus
b. If progress is made, further fibrinolytic therapy is given at 1000 to 2000 units per minute until clot lysis has occurred
c. The usual infusion time by the above-stated technique is usually in excess of 24 hours
d. Successful clot lysis occurs more frequently in arterial graft occlusions than native arterial occlusions
e. The use of intraoperative thrombolytic therapy may be indicated for situations where complete clot evacuation cannot be accomplished surgically
Answer: a, b, e
The most popular method for intraarterial thrombolytic therapy for arterial occlusion involves passing a guidewire through the thrombus with arteriographic guidance and then infusing high-dose urokinase, 4000 units per minute for 1–2 hours, directly into the clot. If progress is made, further fibrinolytic therapy is given at 1000 to 2000 units per minute for a 6–12 hour period or until clot lysis has occurred. Using this technique, mean infusion time in a recent study was found to be 18 hours and the incidence of bleeding complications was significantly lessened. Selective intraarterial infusion of urokinase was associated with complete clot resolution in 77% of native arterial occlusions versus only 41% with arterial graft occlusion. After thrombolytic therapy has reopened an occluded vessel or graft, radiologic or surgical correction of the lesion responsible for the thrombosis in the first place must be addressed for any hope of long-term success. The use of intraoperative thrombolytic therapy is advocated in those situations where complete clot resolution cannot be accomplished (such as following balloon embolectomy for acute arterial occlusion) or when distal vasculative is occluded and precludes appropriate inflow patency.
154 Which of the following statement(s) is/are true concerning hemophilia A?
a. Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII
b. A positive family history for bleeding disorders present in all patients
c. Laboratory tests reveal a prolongation of aPTT, prothrombin time (PT), thrombin clotting time and platelet aggregation
d. Spontaneous bleeding is unusual with factor VIII levels greater than 10% of normal
Answer: a, d
Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII although 0% of cases are secondary to spontaneous mutation. The incidence of this abnormality is approximately 1/10,000 births. Laboratory screening tests usually reveal a prolongation of an aPTT but normal prothrombin time (PT), thrombin clotting time (TCT) and platelet aggregation testing. The minimum level of VIII required for hemostasis is 30% for minor bleeding, whereas spontaneous bleeding is unusual with factor levels greater than 5 to 10% of normal. In severe genetic deficiency states however, factor levels as low as 1% have been noted and patients are at risk for spontaneous bleeding.
155 Fibrinolytic therapy is based on activation of plasminogen, the inactive proteolytic enzyme of plasma that binds to fibrin during the formation of thrombosis. Activation of plasminogen to plasmin results in selective thrombolysis at the fibrin clot surface. Which of the following statement(s) is/are true concerning agents used in thrombolytic therapy?
a. Streptokinase is a bacterial protein which is antigenic in humans, resulting in allergic reactions in up to l5% of cases
b. Tissue plasminogen activator acts directly on plasmin without an intermediate drug–plasmin complex
c. The half-life of urokinase, streptokinase, and TPA all exceed 30 minutes
d. Streptokinase is significantly cheaper than urokinase or TPA
Answer: a, b, d
Streptokinase is a bacterial protein produced by group C b-hemolytic streptococci. It is therefore antigenic in humans and can be associated with allergic reaction in between 2 and 18% of cases. In addition an unusual serum sickness has been reported with streptokinase. Neither urokinase or TPA which is now manufactured with recombinant DNA technology are either associated with allergic side effects or antigenicity. Streptokinase acts through a streptokinase-plasmin complex, whereas urokinase and TPA act directly on plasmin without intermediate drug plasmin complex. The level of the lytic state is greatest with streptokinase, intermediate with urokinase, and least with TPA with the half-lives ranging all less than 1/2 hour in duration. Although the relative efficacy of the three agents has been compared in a number of studies, there appears to be no significant benefit of one agent over the other. Streptokinase however, is markedly less expensive than either urokinase or TPA.
156 Von Willebrand’s disease is a common, congenital bleeding disorder. Which of the following statement(s) is/are true concerning Von Willebrand’s disease?
a. As in hemophilia, it is much more common in men
b. A history of spontaneous bleeding is common
c. Screening laboratory tests will include a prolonged aPTT with a normal prothrombin time
d. Pre-treatment for elective surgery require administration of cryoprecipitate to achieve levels of 23–50% of normal
Answer: c, d
Von Willebrand’s factor is an adhesive protein that mediates platelet adhesion to collagen. In addition, it protects and prevents the rapid removal of factor VIII from blood. The classical deficiency state, Von Willebrand’s disease, is caused by reduction of factor VIII activity (although not as great as Hemophilia A) and the Von Willebrand factor. Clinical manifestations include epistaxis, gingival bleeding, menorrhagia, rare joint or muscle bleeding, and subcutaneous bleeding. Spontaneous bleeding is not as common as in classic Hemophilia A. The syndrome is transmitted as both autosomal dominant (heterozygous) and autosomal recessive disease (homozygous) traits. Therefore there is no sex predilection. Screening laboratory tests include a prolonged aPTT with a normal prothrombin time. In addition, because of the importance of this factor in platelet adhesion, patients display a prolonged bleeding time and have decreased level of factor VIII activity, decreased immunoreactive levels of Von Willebrand’s antigen, and abnormal platelet aggregation responses to ristocetin. The most reliable source of Von Willebrand’s factor is cryoprecipitate.
157 External pneumatic compression has been advocated for the prevention of deep venous thrombosis during operative procedures. Which of the following statement(s) concerning the use of external pneumatic compression devices is/are true?
a. Intermittent pneumatic compression is as effective as low-dose heparin in prevention of venous thrombosis
b. These devices function by compressing the lower extremities therefore augmenting venous return
c. Pneumatic compression devices may also exhibit their antithrombotic effect through stimulating local and systemic fibrinolysis
d. The length of time that intermittent pneumatic compression should be used includes through the operation and for at least several days in the postoperative period
Answer: b, c, d
In many well-controlled studies of venous prophylaxis, intermittent pneumatic compression has been found to be as effective as low-dose heparin therapy. In addition to augmentation of venous return with these devices, local and systemic fibrinolysis appears to be stimulated. Fibrinolytic activities are usually reduced for a 7–10 day period after an operation. Studies have demonstrated that the pneumatic-compression devices may exhibit their antithrombotic effect through prevention of this fibrinolytic shutdown even when applied to the upper extremity. The length of time that intermittent pneumatic compression should be used has not been adequately determined but most data suggest that devices should be used through the operation and for at least five days in the face or prolonged immobilization.
158 The standard management oral anticoagulant therapy for chronic treatment of venous thromboembolism is with the drug warfarin. Which of the following statement(s) is/are true concerning the administration of warfarin?
a. An important complication of warfarin therapy is skin necrosis in patients with protein C deficiency
b. Warfarin interferes with vitamin K dependent clotting factors II, VII, IX, X
c. For effective anticoagulation the prothrombin time (PT) should be kept at 2 control
d. It is recommended that warfarin be continued for at least one year after initial episode of deep venous thrombosis
Answer: a, b
Warfarin interferes with the vitamin K dependent clotting factors II, VII, IX and X, protein C, and protein S. An important complication of warfarin is skin necrosis with patients both with and without protein C deficiency. This syndrome usually involves full thickness skin slough over fatty areas such as the breasts and buttocks. Warfarin therapy should be monitored using the one stage prothrombin time (PT). The PT should be kept at 1.3 to 1.4 control for effective anticoagulation. At higher levels, there is a five-fold increase in the frequency of bleeding complications. Two major complications of Warfarin therapy include recurrent thrombosis and bleeding. It is recommended that Warfarin be continued four months after an initial episode of deep venous thrombosis. Between ten weeks and four to six months after deep vein thrombosis, there is a recurrent thrombosis rate of 8.3 episodes per 1000 patient months. Between four months and three years, recurrences fall to four episodes per 1000 patient-months. At four months, the risks of bleeding complications matches and exceeds the benefit from anticoagulant therapy and thus is the basis for discontinuing warfarin administration at this time.
159 Which of the following statement(s) is/are true concerning the management of a patient with hemophilia A undergoing an elective surgical operation?
a. Concentrates of factor VIII should be given several days prior to elective surgery
b. The half-life of factor VIII concentrates is less than 24 hours
c. A dose of 40–50 IU/kg of factor VIII concentrate should be given prior to the planned surgical procedure
d. Factor VIII concentration administration should be given for the first 24 hours after surgery but may then be stopped if no abnormal bleeding has been observed
e. A new recombinant preparation of factor VIII offers the advantage of being virus-free
Answer: b, c, e
Although the half-life of factor VIII is 2.9 days in normal individuals, the half-life of factor VIII concentrates is 9 to l8 hours. Levels of 80% to 100% of normal should be obtained for surgical bleeding or life-threatening hemorrhage. A dose of 40 to 50 IU/kg of factor VIII should be given with half of this dose then administered every twelve hours. After surgery, transfusion of factor VIII concentrates should be continued for at least ten days. Unfortunately, past use of concentrates of factor VIII obtained from donors has led to a high incidence of HIV infection in the hemophilia population. A new recombinant preparation of factor VIII offers the advantage of being virus-free.
160 Transfusions of blood products can be associated with a number of complications including immediate and delayed hemolytic reactions; nonhemolytic reactions; infectious disease transmission; and complications of massive transfusions. Which of the following statements are true concerning complications of blood transfusions?
a. Immediate hemolytic transfusion reactions are caused by major ABO blood group incompatibility
b. Nonhemolytic transfusion reactions are usually due to RH incompatibility and are therefore more common in women of childbearing age
c. The most common complication of massive blood transfusion is dilutional thrombocytopenia
d. Routine impaired calcium supplementation is necessary during most massive transfusion episodes
Answer: a, c
Immediate hemolytic reactions are usually caused by blood group ABO incompatibility although they may be caused by antigens of other blood group systems on the transfused red blood cells. The clinical manifestations revolve around the antigen on the red blood cell stroma and the antibody in the patient’s serum, and include production of bradykinin, compliment activation, release of vasoactive agents from platelets, and initiation of systemic clotting. Chills and fevers, chest pain and lumbar pain, tachycardia and hypotension in the conscious patient, and often diffuse bleeding in the anesthetized, unconscious patient constitute this syndrome. Although reaction occurs immediately, death related to the syndrome is uncommon, unless associated with a transfusion of more than 100 ml of blood. Death usually occurs from acute renal failure or hemorrhage due to DIC. Nonhemolytic reactions occur with the frequency of 1 to 2% of all transfusions and consist primarily of chills and fevers during the transfusion or in the first 2 to 3 hours after the transfusion is complete. Mechanism of these reactions includes the presence of antibodies to white blood cell antigens in the transfused blood, especially in the multitransfused or multiparous patient. Massive transfusion complications relate to the rate and volume of blood transfused. The most common complication is dilutional thrombocytopenia. Factor deficiency of the labile factors V and VIII rarely is of sufficient magnitude to result in problems with hemostasis. For hypocalcemia to occur with massive transfusion, citrated blood must be administered, one unit every five minutes. Routine empiric calcium supplementation is unnecessary during most massive transfusion episodes. Conversely, hypothermia is clearly a problem, especially when associated with massive transfusion during complex intraoperative procedures such as thoracoabdominal aneurysm resection.
161 A 67-year-old male with advanced cholangiocarcinoma develops gram-negative sepsis. Excessive bleeding is noted around vascular catheters and from needle puncture sites. The diagnosis of disseminated intervascular coagulation (DIC) is considered. Which of the following laboratory test(s) is/are indicative of DIC?
a. Decreased platelet count
b. Decreased fibrinogen level
c. Normal prothrombin time
d. Elevated fibrin split products
Answer: a, b, d
Disseminated intravascular coagulation (DIC) is the primary form of acute thrombosis. Causes of this syndrome include abruptio placenta, gram-positive and gram-negative sepsis, endotoxemia, malignant tumors, pelvic operations, certain snake bites, hematologic malignancies, and hepatic failure. Blood coagulation is activated by the release of tissue factor into the circulation, which activates factor VII of the extrinsic pathway to VIIa, leading to massive thrombin production and fibrin generation. This in turn activates the fibrinolytic system, leading to bleeding in the later stages of the syndrome due to consumption of coagulation factors, depletion of fibrinogen, and unchecked plasma activities. Laboratory values in DIC usually include a decline in the platelet count and fibrinogen level, along with an elevation of fibrin split products.
162 Which of the following substances, not normally present in the circulation, trigger the initiating events in the hemostatic process?
a. Thrombin
b. Platelet factor 3
c. Tissue factor
d. Collagen
Answer: c, d
The initiating agents for hemostasis involve two substances that are not normally present in the circulation—collagen and tissue factor. Tissue factor is released from injured cells, beginning the activation of the extrinsic pathway of coagulation, while disruption of the protective endothelial barrier of blood vessels exposes the underlying collagen to the activation of platelets. In the bloodstream, tissue factor complexes with factor VII which then activates factor X to factor Xa. At the same time, activated platelets change from their discoid shape with their procoagulant phospholipid (termed platelet factor 3) buried on the inner side of the surface membrane to a spreading shape to allow for the externalization of platelet factor 3 activity. Activated factor X, activated factor V, ionized calcium and factor II (prothrombin) then assemble on the platelet phospholipid surface to form the so-called prothrombinase complex which catalyzes the formation of thrombin.
163 Bleeding complications are frequently associated with fibrinolytic therapy. Which of the following statement(s) concerning complications of fibrinolytic therapy is/are true?
a. Careful monitoring of prothrombin time and aPTT time are necessary to avoid bleeding complications
b. A level of serum fibrinogen less than 100 mg/dl is associated with an increased risk of bleeding
c. Recent (less than 10 days) major surgery is a contraindication to systemic but not regional fibrinolytic therapy
d. A patient with a cerebrovascular event occurring less than two months ago can be treated with fibrinolytic therapy if head CT scan is normal
Answer: b
Fibrinolytic therapy induces a hemostatic defect through a combination of factors. Hypofibrinogenemia and fibrin degradation products inhibit fibrin polymerization and, in combination with a decrease in the clotting factors V and VIII, prolong the ability of blood to clot. However, coagulation tests in general do not correlate well with bleeding complications. A level of fibrinogen less than 100 mg/dl is associated with an increased risk of bleeding. Absolute contraindications to thrombolytic therapy include active internal bleeding, recent (less than 2 months) cerebral vascular accident, and documented left heart thrombosis. Recent (less than 10 days) major surgery, obstetric delivery, organ biopsy, or major trauma is considered a major relative contraindication to either regional or systemic thrombolytic therapy.
164 Which of the following statement(s) is/are true concerning the results of a National Institute of Health Consensus Conference on venous thrombosis and low-dose heparin prophylaxis?
a. The odds of developing deep venous thrombosis with low-dose heparin prophylaxis decreases by 67%
b. The risk of pulmonary embolism is decreased by almost 50%
c. There is no increase in mortality from other causes found in patients treated with low-dose heparin
d. There was no difference in the incidence of bleeding complications
Answer: a, b, c
In a metaanalysis of 70 randomized trials in 16,000 patients comparing low-dose heparin prophylaxis with standard therapy, the odds of developing deep venous thrombosis with low-dose heparin prophylaxis decreased 67%, whereas for pulmonary embolism (both fatal and non-fatal), the odds decreased by 47%. For fatal pulmonary embolism, the odds reduction was even greater (64%). No increase in mortality from other causes was found in those patients treated with low-dose heparin. Bleeding complications were more frequent in the heparin-treated patients, with no difference between 5000 units twice daily and 5000 units three times daily. Similarly, the effectiveness of prophylaxis was not influenced by either two or three times daily dosage.
165 Laboratory monitoring of coagulation and anticoagulation includes testing of platelet function. Which of the following statements is/are true concerning tests of platelet function?
a. A platelet count of 50,000/µL or more usually ensures hemostasis
b. Bleeding time assays assessibility of platelets to perform hemostatic plugs and is determined from a sample of blood drawn in an EDTA coated test tube
c. Aspirin therapy can be associated with a bleeding time in the range of 8–15 minutes
d. Tests of platelet aggregation should be part of the standard preoperative evaluation of patients using aspirin
Answer: a, c
Tests of platelet function include peripheral platelet counts, bleeding times, and platelet aggregation. Usually, a platelet count of 50,000/mL or more ensures adequate hemostasis, whereas counts less than 10,000/mL are dangerous and may lead to spontaneous bleeding. Bleeding time performed by observing the clotting of blood induced with a small needle stick, assesses the ability of platelets to perform hemostatic plugs and are usually shorter than eight minutes. A bleeding time between 8 and 15 minutes most often reflects a low plasma level of Von Willebrand’s Factor or the use of antiplatelet drugs. A bleeding time greater than 15 minutes is clearly prolonged and indicates severe platelet functional impairment. Platelet aggregation studies involve the use of a number of different agonists. Although a relatively straightforward technique, platelet aggregation is not available in most laboratories, probably because of the observer-dependent nature of the test.
166 As thrombin generation proceeds, the body has natural anticoagulant systems opposing further thrombus formation. Natural anticoagulants include:
a. Tissue plasminogen activator (TPA)
b. Antithrombin III
c. Activated protein C
d. Heparin cofactor II
Answer: b, c, d
Just as thrombin generation is the key to coagulation, antithrombin III is the most central anticoagulant proteins. This glycoprotein binds to thrombin, preventing its removal of fibrinoprotein A and B from fibrinogen, prevents the activation of factor V and VIII and the activation and aggregation of platelets. The second line of defense is the activated protein C, which inactivates factors Va and VIIIa. This inactivation reduces the ability of the prothrombinase complex to accelerate the rate of thrombin formation. A third natural anticoagulant is heparin cofactor II. Its concentration in plasma is estimated to be some four-fold lower than antithrombin III, and its action is primarily implicated in the regulation of thrombin formation in extravascular tissues. Tissue plasminogen activator (TPA) is a natural catalyst for the activation of plasminogen to plasmin, the main fibrinolytic enzyme in the body. Therefore, TPA is part of the fibrinolytic system rather than a natural anticoagulant.
167 Infectious disease transmission during blood transfusions is of clinical significance to surgeons and of major importance to patients contemplating surgery potentially associated with the need for blood administration. Which of the following statement(s) is/are true concerning the transmission of infectious disease during blood transfusions?
a. Post-transfusion hepatitis is usually due to hepatitis B
b. Hepatitis and HIV transmission is greatest with the administration of pooled plasma products such as serum albumin
c. The most important cause of post-transfusion disease in immunosuppressed patients is CMV infection
d. The risk of HIV transmission in blood transfusions is significantly less than the risk of hepatitis transmission
Answer: c, d
The most common infectious diseases transmitted during blood transfusions include viral hepatitis, CMV, and HIV infection. Post-transfusion hepatitis in 90% of cases consists of non-A, non-B hepatitis known as hepatitis C. All blood products except for immune serum globulin and albumin can carry and transmit this form of hepatitis. Because heat treatment eliminates the risk of viral transmission, products from pooled plasma that are heat treated such as albumin are not at risk for HIV or hepatitis transmission. CMV transmission exists in three forms—primary, reinfection, and reactivation. Primary exposure results in an IgM response to the virus. Reactivation is most commonly related to pregnancy, transplantation, and immunosuppression, and is the most important cause of post-transfusion disease accompanying immunosuppression of patients. Although the risk of the public concern for transmission of HIV disease associated with blood transfusions has significantly outweighed other infectious disease transmission, the risks of HIV transmission is markedly less than that of hepatitis.
168 There are a number of hypercoaguable states which can be associated with arterial or venous thrombosis and embolic phenomenon. These include:
a. Heparin-associated thrombocytopenia
b. Antithrombin III deficiency
c. Von Willebrand disease
d. Vitamin C deficiency
Answer: a, b
A number of hypercoaguable states are present. These include heparin-associated thrombocytopenia in which a heparin-dependent platelet antibody causes aggregation of platelets when the patient is exposed to heparin. Activation of platelets in this setting results in thrombocytopenia, thrombosis, and embolic episodes. Antithrombin III deficiency accounts for about 2% of venous thrombotic events and has been described in pulmonary embolism, mesenteric venous thrombosis, lower extremity venous thrombosis, arterial thrombosis, and dialysis fistula failure. Von Willebrand’s disease is a hereditary complex coagulation factor deficiency which is manifested by a reduction of factor VIII activity, and the Von Willebrand factor which is an adhesive protein that mediates platelet adhesion to collagen. Severe vitamin C deficiency results in a disorder in soft tissue increasing vascular permeability and fragility resulting in the potential for bleeding disorders.
169 Cytokines with clearly defined actions in acute inflammation and early tissue injury include which of the following?
a. Cysteine-X-Cysteine (C-X-C) chemokines
b. Tumor Necrosis Factor (TNFa)
c. Transforming Growth Factor-b (TGF-b)
d. Interleukin-6 (IL-6)
e. Platelet Derived Growth Factor (PDGF)
Answer: a, b, c, d, e
Polypeptide mediators, such as TNFa and IL-1, are considered “early response” cytokines and are actively involved in the initiation of the cascade of events which precipitate acute inflammation. In addition to being important triggers for the induction of other cytokines important inflammatory network, TNFa and IL-1 appear to be key mediators in promoting the adherence of inflammatory cells to the endothelium. IL-1 is a complex, multifunctional molecule that shares many overlapping biological properties with TNFa. In addition, both IL-1 and TNFa potentiate the effects of one another. The most important function of IL-6 appears to be the regulation of the hepatic acute phase response. Following injury, a number of physiologic changes develop within several hours. IL-6 is one of the primary stimuli for the production of acute phase proteins from the liver. Endotoxin, IL-1, TNFa and PDGF are capable of causing significant induction of IL-6 synthesis.
Over the last decade, at least 12 different C-X-C chemokines have been identified. These include IL-8, one of the most potent mediators of chemotaxis known. TNFa and IL-1 are key molecules for the induction of IL-8, which in turn is important for the induction of neutrophil recruitment and activation.
Similar properties are apparent for other members of this chemokine family.
Platelet activation and degranulation occur during coagulation following injury, leading to the deposition of a number of cytokines into the provisional matrix. These cytokines include transforming growth factor-a, (TGFa), transforming growth factor b (TGF-b), platelet-derived growth factor (PDGF), and neutrophil activating peptide-2 (NAP-2). These cytokines are either important growth factors or chemotaxis for leukocytes, endothelial cells, fibroblasts, and keratinocytes which are key components in the process of tissue repair. Thus, coagulation and platelet activation provide the initial foundation for subsequent cellular recruitment.
170 Which of the following statements regarding transforming growth factor b (TGF-b) are true?
a. TGF-b expression is autoregulated
b. TGF-b enhances collagen synthesis
c. TGF-b inhibits extracellular matrix production
d. TGF-b may inhibit or promote cellular proliferation
Answer: a, b, d
TGF-b appears to be one of the key cytokines in control of tissue repair. TGF-b is strongly chemotactic for neutrophils, T cells, monocytes, and fibroblasts. TGF-b activates inflammatory cells to elaborate fibroblast growth factor, TNFa, IL-1 and increase their synthesis of extracellular matrix proteins. TGF-b also induces both the infiltrating cells and resident cells to produce more TGF-b. This auto-induction amplifies its biological effects at the site of injury and may play an important role in the development of chronic fibrosis in a variety of pathologic states. TGF-b enhances collagen synthesis as well. Lastly, TGF-b may function as a mitogen or growth inhibitor for a wide variety of cell types, including selected cell types of mesenchymal origin. Whether TGF-b stimulates or inhibits proliferation depends on the presence of other growth factors, the concentration of TGF-b, and the cell density. Thus, at low doses, TGF-b stimulates the proliferation of densely plated human marrow fibroblasts, but is inhibitory at high concentrations.
171 Leukocyte activation and adhesion to vascular endothelial cells is a critical step in the inflammatory process. This process is regulated by which of the following molecules?
a. The selectins
b. The b5 integrins
c. The immunoglobulin supergene family
d. Nitric oxide
e. IL-8
Answer: a, c, d, e
The temporal events that initiate and propagate neutrophil recruitment and inflammation include endothelial cell activation and expression of endothelial-derived neutrophil adhesion molecules, neutrophil-endothelial cell adherence, and neutrophil transendothelial migration via established neutrophil chemotactic gradients. There are three major families of adhesion molecules which are expressed on the surface of leukocytes and endothelial cells and are important for leukocyte-endothelial cell interactions. These include the immunoglobin supergene family (ICAM-1, VCAM-1, and PECAM-1), the selectins (E-selectin, P-selectin and L-selectin), and the integrins. The leukocyte b2 integrin adhesion molecule family consists of three members with heterodimeric glycoproteins displayed as a variable alpha and a constant beta chain. Nitric oxide regulates the adhesion process both by direct influence on leukocyte binding as well as by regulation of regional blood flow. IL-8 is one of the most potent mediators of chemotaxis in the C-X-C chemokine family. It serves an important role in neutrophil recruitment and activation, and the continued propagation of the inflammatory response.
172 A 65-year old patient has colon carcinoma metastatic to the liver and lungs. He has had a weight loss of 10 kg. Cytokine-dependent tumor cachexia is attributable to which of the following?
a. Increased glucose uptake and increased glycogen breakdown occur in this circumstance.
b. Suppressed activity of lipoprotein lipase results from TNFa
c. TNFa stimulates lipolysis
d. The differentiation process of pre-adipocytes is impaired
e. Partial reversal of differentiated adipocytes to pre-adipocyte morphology and gene expression occurs
Answer: a, b, c, d, e
Tumor cachexia appears to be mediated by TNFa. Lipopolysaccharide (LPS), as well as other cytokines, activate a variety of inflammatory cells, most importantly macrophages, to produce TNFa. Both the chronic administration of TNFa to rats and implantation of tumors secreting TNFa in mice induce a syndrome of cachexia. In vitro, higher TNFa concentrations alter glucose metabolism in cultured myotubules by increasing glucose uptake and glycogen breakdown. It has also been demonstrated that purified TNFa suppresses lipoprotein lipase activity and stimulates lipolysis in cultured adipocytes. Further, TNFa not only inhibits the differentiation process of preadipocytes, but partially reverses differentiated adipocytes to a preadipocyte morphology and pattern of gene expression. All of these metabolic effects at least partially explain the chronic syndromes of anorexia, weight loss, and cachexia that are associated with both chronic infection and malignancy.
173 Which of the following statements regarding fibroblasts and their function in wound healing are true?
a. IL-1 has both inhibitory and promotional effects on fibroblast growth
b. TNFa stimulates fibroblast collagen synthesis
c. IL-1 and TNFa have opposite effects on the healing of bone
d. In human clinical trials, EGF (epithelial growth factor) has been demonstrated to accelerate epidermal regeneration in cutaneous wounds
Answer: a, d
IL-1 appears to be important in the process of normal wound repair. IL-1 has been shown to stimulate skin fibroblast and keratinocyte growth, as well as fibroblast collagen synthesis and keratinocyte chemotaxis. IL-1 also promotes increased transcription of the matrix degradative enzymes collagenase and stromelysin. These are important and potent tissue degrading proteinases. Other studies have demonstrated that IL-1 inhibits fibroblast growth and matrix synthesis, and stimulates collagenase production. These actions are at least partly due to the ability of IL-1 to upregulate prostaglandin E2 production which results in the down regulation of matrix synthesis. IL-1 has both promoting and inhibiting effects on fibroblast collagen synthesis, therefore, the overall activity in this area is somewhat unclear in comparison to other well-defined fibroblast growth-promoting cytokines. TNFa inhibits fibroblast collagen synthesis, however it also has potent mitogenic effects. The mitogenic response correlates well with an increased stimulation of tyrosine phosphorylation. Both IL-1 and TNFa have similar effects upon bone. Both stimulate cartilage resorption, the release of proteoglycans from cartilage by limited proteolytic degradation, and both inhibit proteoglycan synthesis. Recent studies have also demonstrated that TNFa inhibits fracture healing in experimental animals. This is due to the inhibition of cartilage formation and new bone synthesis, and the inhibition of mesenchymal cell differentiation into chondroblasts. The family of epithelial growth factor (EGF)-like molecules induce mitogenesis and play a role in wound healing. In human clinical trials, EGF has been demonstrated to accelerate epidermal regeneration in cutaneous wounds. In vitro data show that recombinant EGF enhances keratinocyte migration. EGF is also a potent chemoattractant for granulation tissue fibroblasts.
174 Neutrophil chemotaxis is a fundamental aspect of inflammatory injury in conditions such as the Adult Respiratory Distress Syndrome (ARDS). Neutrophil chemotaxis is directly attributable to which of the following molecules?
a. C5a
b. TNFa
c. LPS
d. IL-1
e. ENA-78 (Epithelial Neutrophil Activating Protein)
Answer: a, e
There is a large collection of peptide, polypeptide and lipid mediators which have chemotactic properties. Although TNF a, IL-1 and LPS were initially reported to have direct neutrophil chemotactic activity, recent studies have demonstrated that these molecules are not directly chemotactic for neutrophils. This finding suggests that cytokine networks may be operative in vivo and depend on the initial expression of early response cytokines. This initial interaction is followed by the generation of more distal inflammatory mediators that directly influence neutrophil chemotaxis and activation. There is a particularly important group of novel chemotactic cytokines which share significant homology with the presence of four conserved cysteine amino acid residues. These cytokines in their monomeric forms are all less than 10 kD, are characteristically basic heparin-binding proteins, have specific neutrophil chemotactic activity and display four highly conserved cysteine amino acid residues, with the first two cysteines separated by one non-conserved amino acid residue. Because of their chemotactic properties and the presence of C-X-C cysteine motif, these have been designated the C-X-C chemokine family. Twelve different chemokines have been identified in the last decade. These include IL-8, epithelial neutrophil activating protein (ENA-78), and others. Among the other endogenous chemoattractants are several complement-derived peptides. Perhaps, the most potent of these is the short-lived C5a peptide.
175 Which of the following statements regarding angiogenesis are true?
a. Angiogenesis is a seminal biologic event with clinical relevance limited to its effect upon tumor growth
b. C-X-C chemokines regulate angiogenesis
c. PF-4 has angiogenic properties
d. Sites of atherosclerosis demonstrate chronic angiogenic activity
Answer: b, d
An important component of tissue repair and wound healing is the process of angiogenesis. This normal, physiologic process is a local, transient event which is regulated strictly. A biological imbalance in the production of angiogenic and angiostatic factors contributes to the pathogenesis of several angiogenesis-dependent disorders. These include both malignant and nonmalignant disorders such as rheumatoid arthritis, scleroderma, psoriasis, atherosclerosis, and idiopathic pulmonary fibrosis. Persistent neovascularization in these benign disorders is a prerequisite for the perpetuation of fibroproliferation. IL-8 and potentially other C-X-C chemokines are involved with the angiogenesis process. IL-8 is a potent angiogenic factor. In contrast, another member of the C-X-C chemokine family, PF-4 has angiostatic properties. This suggests that the C-X-C chemokines may function as either angiostatic or angiogenic factors, and the biologic balance that is maintained between these factors may govern overall angiogenic potential in a variety of physiological and pathophysiological states.
176 Which of the following statements regarding IL-1 are correct?
a. While IL-1 and TNFa share many biologic effects, IL-1 appears to be more potent
b. IL-1 expression is in part autoregulated
c. IL-1 inhibits prostaglandin production
d. The ability of IL-1 to upregulate endothelial cell-neutrophil adhesion molecules is relatively limited
Answer: b
IL-1 and TNFa share many biologic properties. In addition, each potentiates the effects of the other one when given concurrently. Overall, IL-1 alone probably has weaker effects than TNFa with respect to the induction of shock; its role is likely to be important with respect to its marked potentiating abilities as it relates to TNFa. IL-1 expression is regulated by a host of factors including IL-2, granulocyte macrophage colony stimulating factor (GM-CSF), transforming growth factor b (TGF-b), TNFa, all of the interferons, and IL-1 itself. Other endogenous stimuli for IL-1 production include antigen-antibody complex, the Fc region of IgG, and C5a; other nonspecific exogenous stimuli include silica particles and UV irradiation.
One of the key proinflammatory features of IL-1-induced inflammation is the stimulation of arachadonic acid metabolism. IL-1 stimulates the release of pituitary stress hormones and increases the synthesis of collagenases, resulting in the destruction of cartilage, bone and other collagen-rich structures. IL-1 stimulates prostaglandin production.
One of the most important properties of IL-1 involves its interaction with the vascular endothelium. This includes the adherence of neutrophils, basophils, eosinophils, monocytes, and lymphocytes to the vascular endothelium via interaction between adhesion molecules on leukocytes and adhesion-receptor complex on the endothelial cells. By inducing the expression of ICAM-1, E-selectin, and VCAM-1 on endothelial cells, IL-1 provides a key step in the extravasation of leukocytes to sites of local inflammation and injury.
177 Which of the following statements regarding TNFa are true?
a. TNFa has a marked procoagulant effect
b. Passive immunization of patients with neutralizing antibodies to TNFa improves survival from multi-organ system failure
c. TNFa upregulates E-selectin expression
d. The most potent known stimulus for TNFa production and release is IL-1
Answer: a, c
TNFa has a marked procoagulant effect on endothelial cells, precipitating intravascular thrombosis. TNFa causes endothelial cells to release procoagulant activity (tissue factor), platelet activating factor, and von Willebrand factor, all of which favor thrombosis. TNFa also down regulates the expression of thrombomodulin, which has the potential to block the assembly of protein C and protein S complexes, further decreasing the anticoagulant properties of the endothelial cell surfaces.
Administration of recombinant TNFa to experimental animals produces a clinical syndrome similar to that seen in septic shock and multi-organ system failure in humans. Passive immunization of animals with neutralizing antibodies against TNFa, prior to the infusion of TNFa or endotoxin, has been shown to prevent the development of this syndrome. No such evidence exists in human patients.
TNFa upregulates a variety of leukocytic adhesion molecules including ICAM-1, PECAM-1, VCAM-1, E-selectin and P-selectin. A variety of exogenous and endogenous factors (including IL-1) are capable of inducing cells to produce TNFa, however the most potent stimulus for TNFa production and release is endotoxin.
178 Which of the following belong to the family of C-X-C chemokines?
a. IL-8
b. IL-10
c. Growth Related Oncogene-a
d. Leukotreine B4
e. b Thromboglobulin
Answer: a, c, e
A particularly important group of novel chemotactic cytokines has been elucidated over the last decade. Twelve are known and are listed below.
C-X-C Chemokines
Connective Tissue Activating Protein III
b-Thromboglobulin
Growth Related Oncogene-a
Growth Related Oncogene-b
Related Oncogene-g
Interleukin-8
Epithelial Neutrophil Activating Protein
Granulocyte Chemotactic Protein-2
Platelet Factor-4
g-Interferon-inducible Protein
Monokine-induced by g-Interferon
Each has unique biologic functions. There appear to be important in vivo cytokine networks involving these molecules which regulate chemotaxis, and other fundamental aspects of inflammation.
179 Which of the following statements regarding the complement system are true?
a. Complement activation yields products which are directly cytotoxic as well as products which act indirectly via activated leukocytes
b. Complement products referred to as anaphylatoxins include C1, C3a, C4a, and C5a
c. The principal role of C5a is in bacterial opsonization
d. The alternative and classical pathways converge proximal to generating the membrane attack complex (C5b-9)
Answer: a, d
The complement system is composed of two different but linked sequences, the classic and alternative pathways. The pathways involve serum proteins that act to amplify the inflammatory-immune response as well as to directly mediate tissue injury. Complement activation by either pathway has been associated with a cascade of events, some of which are mediated directly at a physiologic level by complement products and some of which occur indirectly via activated leukocytes. The direct physiologic effects mediated by C3a and C5a, and to a lesser extent C4a, include increased vascular permeability and contraction of smooth muscle. These are key elements of anaphylaxis. C1 is not an anaphylatoxin as it is the initial complement component which binds to antigen-antibody complex to initiate classical pathway activation. C5a acts principally to alter the behavioral characteristics of leukocytes. Effects include enhanced adherence, enhanced chemotactic activity, release of proteinases, and production of toxic metabolites of oxygen. C3, on the other hand, plays a key role in bacterial opsonization, resulting in enhanced phagocytosis of invading microorganisms. The alternative and classical complement pathways converge at the C5 level proximal to generating the membrane attack complex (C5b-9) (Figure 6-3).
180 Which of the following statements regarding neutrophils are true?
a. The neutrophil undergoes final maturation after release into the circulation
b. Patients with chronic granulomatous disease have a defective neutrophil H-oxidase system
c. Neutrophil killing of bacteria is achieved by oxidants, proteinases and cationic proteins
d. The normal human neutrophil circulates in the blood for 7–10 days
Answer: b, c
The neutrophil is a migratory phagocytic cell that defends the host against bacteria and eliminates necrotic tissue. The neutrophil matures in the bone marrow and is released into the circulation as a fully differentiated cell. It is loaded with granules containing a variety of proteinases, hydrolases, antimicrobial agents and cationic proteins. The cell phagocytoses material and the granules fuse with the phagocytic vacuoles to degrade the foreign material. When the cells are challenged with a large amount of material, the granule contents may be released into the extracellular space where damage to surrounding tissue occurs. The neutrophil normally circulates in the human bloodstream for 7 to 10 hours. Thereafter, neutrophils are thought to exist for 1 to 2 days in the tissues before being cleared from the system. Granule constituents are formed during differentiation and replenishment of spent granules does not occur once the cells are in the circulation. Hence, the neutrophil is a fully differentiated end-cell poised to respond rapidly to stimuli, but it is rapidly spent in the process. Neutrophils have a NADPH-oxidase enzyme system on the plasma membrane which can be activated to produce toxic oxygen species including the superoxide anion (02–). Patients with chronic granulomatous disease (CGD) have a defective NADPH-oxidase system in their neutrophils, and are thus unable to generate 02–. Although neutrophils from patients with CGD are able to phagocytose bacteria, they are unable to kill the intracellular microbes and chronic, unresolved infections result.
181 Which of the following statements regarding the alternative complement pathway are true?
a. C1, C4 and C2 are involved
b. NH3 apparently activates complement via this pathway
c. Factors B and D are involved
d. Endotoxin activates complement via the alternative pathway
Answer: b, c, d
The alternative pathway differs from the classic pathway in that the first steps involving C1, C4 and C2 are bypassed. (See Figure 6-3 previously reproduced.) This pathway can be directly activated by agents other than antigen–antibody complex (e.g., complex polysaccharides like endotoxin and zymosan). Other serum protein factors (e.g., factors B and D) are involved in the activation sequence. Ammonia can attack the thiol-ester, producing amidated C3 and activate the alternative pathway. This leads to membrane attack complex formation (C5b-9) and activation of a number of phagocytic cell functions including toxic oxidant production. This phenomenon may have relevance to several in vivo disease states. In animal models of renal failure, elevated levels of renal vein NH3 have been correlated with impaired renal function and the presence of complement components at the sites of renal injury.
182 Platelet activating factor is:
a. Generated by the action of phospholipase A2 on membrane phospholipids
b. Antiinflammatory in most of its actions
c. Synthesized by endothelial and other cells
d. Exerts a variety of biologic effects which are platelet-independent
Answer: a, c, d
Like the eicosanoids, platelet-activating factor (PAF) is not stored in cells but is rapidly produced during inflammation. PAF exerts a variety of biologic effects that are platelet-independent. The synthesis of PAF is initiated by the activation of phospholipase A2. Activation of phospholipase A2 releases arachidonic acid in addition to lyso-PAF. Hence, PAF synthesis and eicosanoid production are coordinately regulated. PAF is synthesized on activation of a variety of inflammatory cells including platelets, neutrophils, basophils, mast cells, mononuclear phagocytes, eosinophils and vascular endothelium. PAF is a stimulatory agonist for many inflammatory cells, as well as for smooth muscle cells, vascular endothelium and others. PAF enhances the ability of neutrophils to respond to challenge with N-formylpeptides and LTB4. There is considerable overlap and redundancy in the effects produced by PAF and eicosanoids.
183 Platelets have a wide array of functions in inflammation. Which of the following are among these?
a. Synthesis and release of vasoactive eicosanoids
b. Release of chemotactic factors
c. Adherence to and coating of bacterial and tumor cells
d. Increase of vascular permeability
e. Phagocytosis of bacteria
Answer: a, b, c, d
Platelets are anucleated cells derived from megakaryocytes in the bone marrow. Their central role in hemostasis is well known. Platelets possess a wide array of functions in inflammation, including the following:
Synthesis and release of vasoactive eicosanoids
Release of chemotactic factors
Interaction with other inflammatory cells
Interaction with endothelial cells
Adherence to and coating of bacterial and tumor cells
Platelets are not capable of phagocytosis.
Few of the factors released or the functions carried by platelets during inflammation are unique to this cell type. Other inflammatory cells often have the same or similar capabilities. Indeed, some platelet functions may reflect vestigial functions inherited from a primitive precursor inflammatory cell. Platelets serve primarily as an amplifier or modulator of the inflammatory response.
184 Eicosanoids mediate inflammation in a variety of ways. Of the following statements, which are true with regard to this?
a. Eicosanoids are stored in cytoplasmic granules for release after receptor mediated signaling
b. Eicosanoids include prostaglandins, thromboxanes, leukotrienes and lipoxins
c. Eicosanoids generally have a plasma half-life measured in hours
d. Physiologic responses to eicosanoids include vasodilatation, vasoconstriction, increased vascular permeability and both chemotaxis and chemoattractant inhibition
Answer: b, d
The eicosanoids are derived from arachidonic acid (eicosatetraenoic acid) and consist of prostaglandins, thromboxanes, leukotrienes and lipoxins. The eicosanoids are not stored in cells but are rapidly synthesized by cells in response to a variety of stimuli. They have potent effects on vascular and bronchial smooth muscle including vasodilatation, vasoconstriction, bronchodilation and bronchoconstriction. In addition, they directly regulate vascular permeability. LTB4 is a potent, neutrophil chemoattractant whereas lipoxin A4 inhibits other chemoattractants. It appears that eicosanoids are important regulators of the endogenous inflammatory response. The rapid destruction of eicosanoids in the circulation limits their role primarily to that of mediators of local inflammatory changes. The local effects can be substantial. In general, the eicosanoids are rapidly metabolized or are so chemically unstable that they primarily exert their effects near the site of synthesis. Arachidonic acid does not exist in cells but is esterified to membrane phospholipids. Thus, the first step in the production of eicosanoids is phospholipase action, which liberates arachidonic acid. (Figure 6-6)
185 Which of the following statements are true?
a. Eosinophils are the major, if not sole, source of histamine in the blood
b. Basophils are effector cells in allergic reactions by virtue of IgE receptors
c. Mast cells are the major source of tissue histamine except in the stomach and central nervous system
d. Mononuclear phagocytes release a variety of proinflammatory cytokines and growth factors
Answer: b, c, d
Eosinophils constitute 1% to 3% of the leukocyte population of the bloodstream. They also reside in tissues and they exhibit phagocytic capabilities. They are less effective as bactericidal cells than neutrophils, but play a major role in defense against parasites. Eosinophils are primary effectors in allergic reactions by virtue of IgE receptors (which are not found on neutrophils).
Basophils are fully differentiated cells released into the circulation from bone marrow. Basophils are the major, if not sole, source of histamine in the blood. Histamine is a vasoactive amine and the major mediator of the IgE-mediated immediate hypersensitivity response. Histamine release from basophils is induced by complement products as well as by IgE receptors.
Mast cells are formed from bone marrow precursors that differentiate and proliferate in connective tissue. Mast cell granules contain histamine and proteoglycans. They represent the major source of histamine in most tissues except the stomach and central nervous system.
The monocyte–macrophage system consists of phagocytic cells scattered throughout the body. During acute inflammation, monocytes respond to chemoattractants released and are recruited to the site of inflammation. Mononuclear phagocytes respond to inflammatory stimuli by releasing M-CSF, GM-CSF, IL-1, and TNF, in addition to a variety of growth factors. These factors increase the production of mononuclear phagocytes and several of these factors enhance the ability of effector cells to respond to chemotactic stimuli released at the site of injury. Thus, the mononuclear phagocytes are important in initiating and augmenting the cycle of events that result in recruitment and activation of inflammatory cells at sites of inflammation.
186 Cellular injury from oxidants may be manifest by which of the following?
a. Cell membrane lipid peroxidation
b. DNA strand breaks
c. Cytoskeletal disassembly
d. ATP depletion
Answer: a, b, c, d
Free oxygen radicals are chemical species that are intermediates in the normal process of cellular respiration. Oxidants that are free radicals have been implicated as initiators of reactions which lead to a variety of cellular injuries. Oxidants are derived from several sources, notably phagocytes. Among the effects of oxygen free radicals are membrane lipid peroxidation, DNA strand breaks, cytoskeletal disassembly and inhibition of glucose metabolism leading to decreased cellular ATP concentrations. (Figure 6-16)
187 Which of the following acute-phase protein levels are increased in human plasma following acute inflammation?
a. C-reactive protein
b. Serum amyloid
c. a -Proteinase inhibitor
d. Fibrinogen
e. Albumin
Answer: a, b, c, d
The acute-phase response is a series of homeostatic responses of the organism to tissue injury in infection and inflammation. After an inflammatory stimulus occurs, a number of events occur within hours. These reflect altered set-points for various physiologic parameters including thermoregulation (fever), nitrogen balance (negative), and levels of various plasma proteins (increased or decreased). The erythrocyte sedimentation rate, which increases with inflammatory states, is an example of this phenomenon. The increased sedimentation rate is due to increased levels of fibrinogen and some of the other acute-phase reactants in plasma. Some proteins show a large increase (about 1000-fold), some a 4-to 5-fold increase, and others about a 50% increase over resting nonstressed levels.
Note that albumin is an acute-phase reactant. Levels of albumin drop after an inflammatory stimulus, usually 30% to 50% of the level before injury. The reason for the decrease in production is poorly understood.
188 Which of the following statements regarding endothelial cells in acute inflammation are true?
a. Endothelial cells are characterized by phenotypic homogeneity
b. Specific patterns of receptor expression regulate leukocyte adherence
c. Endothelial cell nitric oxide generation regulates regional blood flow and leukocyte adhesion
d. Endothelial cells may be capable of phagocytosis
Answer: b, c, d
Endothelial cells are increasingly recognized to be phenotypically heterogeneous. Specific receptor molecules are expressed at various sites where they help to direct lymphocytes and other leukocytes to their appropriate target organ. In the high endothelial venues, these receptor molecules are known as vascular addressing. Endothelial cells play a major role in regulating vascular tone. This is the result of angiotensin-converting enzyme on the cell surface as well as the production of both endothelia (a potent vasoconstrictor) and nitric oxide (a potent vasodilator). Both play important physiologic roles in determining the distribution of blood flow. In addition, recent evidence suggests that NO may have direct effects upon the expression of a variety of leukocyte adhesion molecules. Under unusual circumstances, endothelial cells can exhibit macrophage-like properties in that they can act as antigen-presenting cells and also phagocytose particles. They may also be a significant source of oxidants in inflammatory reactions after ischemic injury. Endothelial cells are not passive participants in inflammatory processes; rather, they possess the ability to direct and focus many aspects of an inflammatory event.
189 The first line of host defense is the barrier presented to the external environment. Which of the following statement(s) is/are true concerning host barriers?
a. Sebaceous glands secrete chemical compounds that maintain a relatively high pH, providing effective bacterial stasis
b. Within the respiratory tract, ciliary function serves to extrude microorganisms trapped within the mucus secretion layer
c. The low pH within the stomach markedly decreases bacterial content of the upper gastrointestinal tract
d. Gut peristalsis serves to prevent microbial adherence and invasion
Answer: b, c, d
The skin, mucus membranes, and epithelial layers of various organs of the body constitute effective physical barriers against microbial invasion. In certain portions of the body, these barriers have developed ancillary adaptations to increase the effectiveness of the barrier functions. Skin structures such as sebaceous glands secrete chemical compounds that serve to maintain a relatively low pH, providing effective bacterial stasis. Mucus secretion by specialized glands within the bronchi and gut provide a mucus layer that represents a physical and chemical barrier to microbial invasion. Within the respiratory tract, ciliary function serves to extrude microorganisms trapped within this mucus layer. In the alimentary track, the very low pH within the stomach and gut peristalsis both serve to prevent microbial adherence and invasion.
190 Which of the following statement(s) is/are true concerning the antibody response to an invading antigen?
a. All antibodies are composed of one type of heavy and one type of light protein chain
b. The carboxyl terminus of the heavy chain is the antigen binding site
c. Antibody of the immunoglobulin G class is the initial antibody produced in response to an antigenic stimulus
d. Immunoglobulins A, D, and E play an active role in the circulating humoral response
Answer: a
Humoral defenses consist of antibody (immunoglobulin; Ig) and complement. All Ig classes (IgM, IgG, IgA, IgE, IgD) and IgG subclasses are composed of one type (M, G, A, E, D) of heavy and one type (K and g ) of light protein chains that consist of several domains both structurally and functionally. Each Ig molecule contains one or more units that consist of two heavy and two light chains linked by disulfide bonds. The amino terminus of both heavy and light chains contain several hypervariable regions that fold in three dimensions to produce the antigen-binding site. The carboxyl terminus of the heavy chains contain regions that activate complement and bind Fc receptors, by which direct adherence to polymorphonuclear leukocytes and macrophages take place after antigen binding occurs.
Initially, antibody of the IgM class is produced in response to an antigenic stimulus. A second exposure to the same antigen, or a cross-reactive antigen, leads to the so-called second set response, in which antibody of the IgG class with two binding sites is produced more rapidly and in larger quantity compared to the initial IgM primary response. Immunoglobulin of the IgA class is secreted by gut-associated lymphoid tissue and is combined with secretory components of protein to form a dimer termed secretory IgA. This antibody acts at a variety of epithelial sites to prevent microbial adherence and invasion. IgD and IgE exist in smaller amounts in the circulation and do not appear to play a major role as host defense components.
191 Increasing evidence has implicated gram-negative bacterial lipopolysaccharide (LPS endotoxin) as the portion of the gram-negative bacterial cell membrane responsible for many, if not all the toxic effects that occur during gram-negative bacterial sepsis. The following statement(s) is/are true concerning LPS and the host response.
a. The LPS molecule can in itself cause physiologic responses similar to that seen during gram-negative bacterial sepsis
b. LPS triggers host macrophages to release a variety of cytokines including TNF-a, IL-1a, and IL-1b, IL-6, and IFN-a
c. Excessive cytokine production is not associated with detrimental consequences
d. TNFa and IL-1b appear to be the primary mediators within the host, exerting deleterious effects on the host when excessive amounts reach the systemic circulation
Answer: a, b, d
The LPS molecule exerts diverse effects on the mammalian host. Immunologic responses to LPS include nonspecific polyclonal B-cell proliferation, macrophage activation and cytokine secretion, tolerance to subsequent LPS or bacterial challenge, and production of antibody directed against various portions of the LPS molecule after repeated challenge. Physiologic responses similar to those seen during gram-negative bacterial sepsis occur during LPS administration alone and include hypotension, hypoxemia, acidosis, bacterial translocation across the gut, complement and coagulation cascade activation, white blood cell and platelet margination, and death. Indirect effects result from LPS-triggering of host macrophages. Activated macrophages secrete a wide array of cytokines that include TNF-a, IL-1a, and IL-1b, IL-6 and interferon-a (IFNa). Excessive secretion of cytokines produce substantial systemic effects in the mammalian host. TNFa and IL-1b appear to be the primary mediators within the local host milieu, exerting deleterious effects on the host only after large amounts are secreted and reach the systemic circulation.
192 Which of the following statement(s) concerning the gut microflora is/are correct?
a. Gut microflora evolves constantly throughout development
b. The gut microflora can contribute to the physical and chemical barriers at the mucus membrane level
c. Most of the microorganisms found in the oropharynx eventually pass into the intestine
d. In the colon, anaerobic organisms outnumber aerobic organisms in a ratio in excess of 100:1
Answer: b, d
The composition of the gut microflora is established in neonates after ingestion of microbes that are acquired during contamination from the birth canal and during initial feeding, and remain relatively constant thereafter. Although this flora acts to promote development of the immune system, the specific interactions that produce this effect have not been fully elucidated. The microflora also contributes to physical and chemical barriers at the mucus membrane level, in that many autochthonous microbes possess adhesion proteins by which they can bind to certain areas of the mucosal cell or to specific types of bacteria, occupying potential binding sites for pathogenic organisms and producing a substantial physical mucobacterial layer. The oropharynx contains a number of aerobic and anaerobic microorganisms, however, these microbial inhabitants do not usually pass into the intestine, because the stomach itself represents a significant barrier to invading microorganisms by virtue of its low pH, which kills most microbes. The upper small intestine contains few organisms, mainly gram-positive aerobes and lactobacilli. Conversely, the lower small intestine contains a large number of aerobes and anaerobic forms, especially in patients in whom the ileocecal valve allows free backwash of cecal contents into the terminal ileum. Within the colon, a wide diversity and a large number of facultative and strict anaerobic isolates are present. Only a small number of aerobes are present, these microbes being outnumbered 100–300 to 1 by anaerobes.
193 The use of antibiotics can be based on either the clinical course of a patient without the benefit of well-defined microbiologic data (empiric therapy), or targeted at specific identified pathogens once sensitivity reports are available (directed therapy). The following statement(s) is/are true concerning these therapies.
a. The issue of toxic side effects of antibiotics is only important in dealing with emperic therapy
b. Single agent therapy is generally inferior to specific multi-drug therapy (aminoglycoside plus an antianaerobic agent) for the treatment of secondary bacterial peritonitis due to appendicitis, diverticulitis, penetrating gastrointestinal injury, or anastomotic leak
c. With the empiric use of antibiotics, a diligent search for the septic source should be undertaken and continued until identified
d. In clinical situations in which polymicrobial infection is identified, specifically-directed treatment for the predominant organism is satisfactory
Answer: c
The use of empiric therapy without the benefit of well-defined microbiologic data is appropriate when there is sufficient clinical evidence to support the diagnosis such that it would be imprudent to withhold antimicrobial therapy. In this setting, however, a diligent search for the septic focus source should be undertaken and continued (cultures, radiographic procedures, etc.), and initial limits should be placed in the course of empiric therapy with continued reevaluation based on the clinical course of the patient. The choice of antibiotic agents should be based on the clinical situation and known activity patterns within the given institution. Single broad-spectrum agents, although suffering slightly from a lack of individual pathogen specificity, are useful in this setting in that they provide a broad coverage against several groups of pathogens and may avoid some of the toxic effects with specific combined modality regimens. Similarly, for directed therapy, single-agent therapy has been demonstrated to be equivalent to combined therapy and should be chosen in an attempt to select agents with appropriate sensitivities which retain suitable clinical efficacy but exhibit minimal toxicity. After review of cultural reports, many patients have demonstrated polymicrobial infection. Because experimental clinical evidence supports the concept of aerobic-anaerobic synergy, therapy should be directed against all potential components of the infection if the body site is such that these microorganisms may be present.
194 The following statement(s) is/are true concerning newer detection methods of systemic infection.
a. Enzyme-linked immunosorbent assay (ELISA) is a rapid immunologic assay used for both antigen and antibody detection
b. Southern, northern, and western immunoblot techniques are used to detect DNA, RNA, or proteins, respectively
c. Polymerase chain reaction (PCR) is a sensitive assay used to detect small amounts of microbial DNA, thus detecting infection at its early stages
d. Infectious agents currently detected using advanced molecular techniques include cytomegalovirus (CMV) and human immunodeficiency virus (HIV)
Answer: a, b, c, d
Although the classic detection of infection based on clinical signs of infection and bacterial culture remain the most common clinical tools, increasing reliance has been placed on assays that do not employ cultural data. Specifically, the antibody and cytokine host responses are being intensely examined and extremely sensitive amplified assays that rely on antigen, antibody or microbial DNA detection are employed in the clinical setting. Enzyme-linked immunosorbent assay (ELISA) is a rapid, antigen-based, immunologic assay that can be used for both antigen and antibody detection, for determination of antibody titer, as well as for screening for monoclonal antibody production. Transblot techniques are being used increasingly in the clinical setting. These include southern, northern, and western immunotransblot techniques used to detect DNA, RNA, or proteins, respectively. The polymerase chain reaction (PCR) is being used in some centers as a sensitive assay to detect small amounts of microbial DNA. This technique involves extraction of the DNA from the test sample with in vitro amplification through repeated nucleic acid denaturing and polymerization so that the gene copy number increases exponentially. This marked amplification of the gene copy number results in extremely sensitive tests which can detect infection at its early stages.
Clinically, these detection methods are being used to detect a wide variety of infectious agents including CMV and HIV. Furthermore, preliminary investigations into possible detection of fungal pathogens are underway.
195 Cytokines are low-molecular-weight polypeptides exerting a wide variety of biologic effects at both local and systemic levels. Which of the following statement(s) is/are true concerning the production and actions of cytokines?
a. Cytokines are produced solely by macrophages
b. Cytokines act only on other cells within the same local environment
c. Cytokines may have both protective and deleterious effects on the host
d. Each specific cytokine is produced by a single cell type
Answer: c
Macrophages, endothelial cells, lymphocytes, and other cells secrete a large number of different compounds, termed cytokines, that are most probably evolved for the purpose of local intercellular and intracellular signaling. Cytokines frequently are secreted after initial lymphocyte or macrophage activation, and may act on the secreting cell itself (autocrine activation) or on other cells within the same local environment (paracrine activation) to cause increased secretion of the same cytokine or other cytokines, respectively. Some cytokines are produced by several cell types, and most produce a wide array of effects. The duality of the effects of the cytokine component of host defenses, exerting both salutatory and deleterious effects on the host, has become increasingly evident.
196 The following statement(s) is/are true concerning cellular defense mechanisms.
a. Macrophages function solely as antigen processing cells in the initial reaction to exposure to an antigen
b. Macrophages may become activated and secrete cytokines
c. Macrophages serve as phagocytic cells in the tissues but not within the bloodstream
d. Polymorphonucleocytes (PMNS) are normally present in only small numbers within the tissue and enter an area of infection through diapedesis
Answer: b, d
A wide variety of cell types serve to provide host defense at several levels. Macrophages act as the initial antigen processing cell that serves to present antigen to help T cells, thus initiating the immune response. Macrophages, however, are pluripotent cells that, in the process of engulfing and processing antigen, may become activated. Activated macrophages secrete a variety of cytokines. Macrophages also act as phagocytic cells in the tissues and within the bloodstream, and because of their resident nature in many tissues, also represent the first line of host defenses in many areas of the body, even before activation. PMNS are present within the bloodstream, but only in small numbers within the tissue, and enter an area of infection through diapedesis after chemotactic stimuli are excluded by macrophages, bacterial breakdown products, and complement activation.
197 A diabetic develops a severe perineal infection with skin necrosis, subcutaneous crepitance, and drainage of a thin, watery, grayish and foul-smelling fluid. Management should consist of:
a. Gram stain of the fluid, which will likely demonstrate multiple bacteria including predominantly gram-positive rods
b. A CT scan is indicated in a stable patient to define the extent of the disease
c. Broad spectrum antibiotics followed with prompt extensive debridement is indicated
d. A safe guideline is to resect infected necrotic tissue so that a several centimeter margin of grossly normal, healthy tissue can be achieved
e. A colostomy is of little benefit in this situation
Answer: a, b, c, d
The presence of severe perineal infection (referred to as Fournier gangrene when this process involves the perineum and scrotum in males) is associated with a continued high mortality despite aggressive and appropriate therapy. The clinical description provided would suggest an underlying soft tissue necrosis. In a stable patient radiologic studies including a CT scan to define the extent of the disease and the presence of pelvic infection is indicated. Gram stain will likely show evidence of polymicrobial organisms but the presence of Clostridia marked by gram-positive rods would suggest involvement with this organism. Prompt, aggressive and extensive debridement to remove all devitalized and affected tissue and the addition of broad spectrum antibiotics, fluid resuscitation, hemodynamic monitoring, and nutritional support would appear to afford the patient the best chance of survival. The clearest guidelines to determine the limits of resection involve removal of clearly infected, necrotic tissue so that margins several centimeters into grossly normal, healthy tissue are achieved. Because the entire perineal region and buttocks are frequently involved in these patients, performance of a fecal stream diversion by means of a colostomy often provides improved wound care and patient management, although it is not invariably a positive outcome.
198 The use of prophylactic antibiotics has become commonplace. Which of the following statement(s) is/are true concerning the prophylactic use of antibiotics?
a. The appropriate use of prophylactic antibiotics must include the initiation of the agent prior to the surgical procedure
b. Continuing the antibiotic into the postoperative period has led to improved results in antibiotic prophylaxis
c. The prophylactic administration of broad-spectrum agents (third-generation cephalosporins) has been shown to be particularly advantageous
d. The topical use of antimicrobial agents is of no advantage in the prophylactic setting
Answer: a
Intravenous administration of an antibiotic is clearly indicated for patients undergoing clean contaminated operations. These antibiotics should be administered prior to surgery to obtain adequate tissue levels at the time of potential contamination. However, there has been no added benefit demonstrated for the postoperative use of antibiotics with regard to prophylaxis. The choice of antibiotic is a complex issue which remains unresolved largely because both superficial and deep wound infections can occur as a result of either or both skin (superficial wound) flora (e.g., Staphylococcus aureus) and body site (deep wound) infection. For this reason, the administration of agents which possess activity directed against these expected agents is reasonable. Although administration of a first-generation cephalosporin is acceptable, second-generation cephalosporins or extended-spectrum penicillins with gram-positive and gram-negative activity and biliary tract excretion may be more suitable for patients undergoing gastrointestinal or biliary tract procedures. Similarly, the use of agents with additional anaerobic activity for patients undergoing gastrointestinal procedures involving the small bowel or colon should be considered. The administration of broad-spectrum agents such as third-generation cephalosporins for prophylaxis does not seem to provide additional benefit in comparison to the above-mentioned type antibiotics and may foster the development of resistant organisms within a given institution or superinfection within a given patient. There is evidence that in some cases the topical use of antimicrobial agents is equivalent to the administration of intravenous antimicrobial agent antibiotics.
199 If a necrotizing soft tissue infection is considered, therapy mandates:
a. Empiric administration of antibiotics active against gram-positive, gram-negative, and anaerobic bacteria
b. Due to usually resistant species, penicillin is not indicated
c. Immediate operative intervention and aggressive resection of all involved tissues is mandatory
d. The use of hyperbaric oxygen has been demonstrated to be clearly advantageous
Answer: a, c
Identification of a necrotizing, soft tissue infection mandates immediate operative intervention with aggressive resection of all involved tissues and empiric administration of antibiotics active against gram-positive, gram-negative, and anaerobic bacteria. In most cases, this involves the use of several antimicrobial antibiotics in combination. Because of concern in all cases for the presence of Clostridia infection, high doses of aqueous penicillin G are administered. Gram-positive organisms are treated with vancomycin or a semisynthetic penicillin and gram-negative organisms are treated with an aminoglycoside or a monobactam. Anaerobic coverage is typically achieved by use of metronidazole of clindamycin. The use of hyperbaric oxygen therapy is controversial and unfortunately due to the rarity of the disease, prospective randomized data is not available so that the literature remains without controlled trials demonstrating any additional benefits derived from hyperbaric oxygen therapy.
200 Wounds are classified according to the likelihood of bacterial contamination. Which of the following statement(s) is/are true concerning wound classifications?
a. A clean-contaminated wound would be that associated with an elective colon resection with adequate mechanical and antibiotic bowel preparation
b. A contaminated wound would include a resection of obstructed bowel with gross spillage of intestinal contents
c. In a clean wound, no viscus is entered
d. Antibiotic prophylaxis should be administered for all clean-contaminated and contaminated wounds and selectively in patients involving a clean wound
Answer: a, b, c, d
Wounds are classified under three classes according to the likelihood of bacterial contamination: 1) clean (no viscus is entered; e.g., herniorrhaphy); 2) clean-contaminated (minimal contamination; e.g., elective colon resection with adequate mechanical and antibiotic bowel preparation, and 3) contaminated (heavily contaminated surgery; e.g., resection of unprepared, obstructed bowel with gross spillage of intestinal contents or stool, drainage of abscesses, debridement of traumatic neglected wounds). Antibiotic prophylaxis generally should be administered for class 2 and 3 types of wounds, but patients undergoing clean surgery do not always require antimicrobial antibiotic prophylaxis. An exception to this tenet involves cases in which a prosthetic material may be used (artificial joint, heart valve, tissue patch).
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a. Enhancement of antithrombin III activity
b. A decrease in thrombin availability
c. Inhibition of platelet aggregation and subsequent platelet release action
d. A mild prolongation of activated partial thromboplastin time
Answer: a, b, c
Low-dose heparin is thought to protect against venous thrombosis through three different mechanisms. First, antithrombin III activity with its inhibition of activated Factor X is enhanced by only trace amounts of heparin; second, there is a decrease in thrombin availability that prevents its activation and thus its fibrin-stabilizing effect; and third, small doses of heparin may inhibit the second wave of platelet aggregation and subsequent platelet release reaction. The standard doses of heparin administered (5000 units bid) does not affect aPTT.
152 Tests of coagulation are used to monitor anticoagulation treatment and detect intrinsic abnormalities in coagulation. Which of the following statement(s) is/are true concerning coagulation tests?
a. Prothrombin time (PT) measures both the intrinsic and extrinsic clotting pathways and fibrinogen
b. Activated partial thromboplastin time (aPTT) can be used to monitor both oral anticoagulation with Warfarin and intravenous anticoagulation with heparin
c. Thrombin clotting time (TCT) is a measurement of the time it takes for exogenously administered thrombin to turn plasma fibrinogen into fibrin clot
d. Whole blood activated clotting time (ACT) is a measurement of the ability of whole blood to clot and is used to monitor heparin levels intraoperatively during cardiovascular and peripheral vascular operations
Answer: a, c, d
Coagulation tests include prothrombin time (PT), which measures the intrinsic and extrinsic pathways of fibrinogen production and is the most common method for measuring a level of oral anticoagulant therapy. The activated partial thromboplastin time (aPTT) identifies the abnormalities of the contact and intrinsic phases of coagulation. Values of aPTT have variably been shown to correlate with heparin dosages and serum heparin levels and are therefore most commonly used in monitoring heparin therapy. It is of no value in long-term management of patients on oral Warfarin therapy. Thrombin clotting time (TCT) is the measure of the time it takes for exogenously administered thrombin to turn plasma fibrinogen into fibrin clot. It is extremely sensitive to levels of heparin and is an excellent measure of measuring the level of heparin-induced anticoagulation. The beauty of the TCT is that it is not specific for any disease condition; thus it may be used to differentiate factor deficiencies from the presence of heparin, or to separate lupus anticoagulant from abnormalities in fibrinogen levels. The whole blood activated clotting time (ACT) is a measurement of the ability of whole blood to clot, and as such, is an available technique for monitoring heparin levels intraoperatively. The ACT responds in a linear fashion to increasing heparin dosage and correlates well with the observed clinical anticoagulation. Adequate anticoagulation for extracorporeal circulation is defined as an ACT of 480 seconds or more while for peripheral vascular applications, values of 250 seconds or greater are considered appropriate.
153 Thrombolytic therapy has become a useful adjunct in the management of peripheral arterial occlusion. In this setting, direct intraarterial administration rather than intravenous has been advocated to decrease the risk of systemic bleeding. Which of the following true statement(s) concerning the use of thrombolytic agents for arterial occlusion is/are true?
a. A standard technique involves infusing high-dose urokinase, 4000 units per minute for 1–2 hours, directly into the clot by a catheter embedded in the thrombus
b. If progress is made, further fibrinolytic therapy is given at 1000 to 2000 units per minute until clot lysis has occurred
c. The usual infusion time by the above-stated technique is usually in excess of 24 hours
d. Successful clot lysis occurs more frequently in arterial graft occlusions than native arterial occlusions
e. The use of intraoperative thrombolytic therapy may be indicated for situations where complete clot evacuation cannot be accomplished surgically
Answer: a, b, e
The most popular method for intraarterial thrombolytic therapy for arterial occlusion involves passing a guidewire through the thrombus with arteriographic guidance and then infusing high-dose urokinase, 4000 units per minute for 1–2 hours, directly into the clot. If progress is made, further fibrinolytic therapy is given at 1000 to 2000 units per minute for a 6–12 hour period or until clot lysis has occurred. Using this technique, mean infusion time in a recent study was found to be 18 hours and the incidence of bleeding complications was significantly lessened. Selective intraarterial infusion of urokinase was associated with complete clot resolution in 77% of native arterial occlusions versus only 41% with arterial graft occlusion. After thrombolytic therapy has reopened an occluded vessel or graft, radiologic or surgical correction of the lesion responsible for the thrombosis in the first place must be addressed for any hope of long-term success. The use of intraoperative thrombolytic therapy is advocated in those situations where complete clot resolution cannot be accomplished (such as following balloon embolectomy for acute arterial occlusion) or when distal vasculative is occluded and precludes appropriate inflow patency.
154 Which of the following statement(s) is/are true concerning hemophilia A?
a. Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII
b. A positive family history for bleeding disorders present in all patients
c. Laboratory tests reveal a prolongation of aPTT, prothrombin time (PT), thrombin clotting time and platelet aggregation
d. Spontaneous bleeding is unusual with factor VIII levels greater than 10% of normal
Answer: a, d
Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII although 0% of cases are secondary to spontaneous mutation. The incidence of this abnormality is approximately 1/10,000 births. Laboratory screening tests usually reveal a prolongation of an aPTT but normal prothrombin time (PT), thrombin clotting time (TCT) and platelet aggregation testing. The minimum level of VIII required for hemostasis is 30% for minor bleeding, whereas spontaneous bleeding is unusual with factor levels greater than 5 to 10% of normal. In severe genetic deficiency states however, factor levels as low as 1% have been noted and patients are at risk for spontaneous bleeding.
155 Fibrinolytic therapy is based on activation of plasminogen, the inactive proteolytic enzyme of plasma that binds to fibrin during the formation of thrombosis. Activation of plasminogen to plasmin results in selective thrombolysis at the fibrin clot surface. Which of the following statement(s) is/are true concerning agents used in thrombolytic therapy?
a. Streptokinase is a bacterial protein which is antigenic in humans, resulting in allergic reactions in up to l5% of cases
b. Tissue plasminogen activator acts directly on plasmin without an intermediate drug–plasmin complex
c. The half-life of urokinase, streptokinase, and TPA all exceed 30 minutes
d. Streptokinase is significantly cheaper than urokinase or TPA
Answer: a, b, d
Streptokinase is a bacterial protein produced by group C b-hemolytic streptococci. It is therefore antigenic in humans and can be associated with allergic reaction in between 2 and 18% of cases. In addition an unusual serum sickness has been reported with streptokinase. Neither urokinase or TPA which is now manufactured with recombinant DNA technology are either associated with allergic side effects or antigenicity. Streptokinase acts through a streptokinase-plasmin complex, whereas urokinase and TPA act directly on plasmin without intermediate drug plasmin complex. The level of the lytic state is greatest with streptokinase, intermediate with urokinase, and least with TPA with the half-lives ranging all less than 1/2 hour in duration. Although the relative efficacy of the three agents has been compared in a number of studies, there appears to be no significant benefit of one agent over the other. Streptokinase however, is markedly less expensive than either urokinase or TPA.
156 Von Willebrand’s disease is a common, congenital bleeding disorder. Which of the following statement(s) is/are true concerning Von Willebrand’s disease?
a. As in hemophilia, it is much more common in men
b. A history of spontaneous bleeding is common
c. Screening laboratory tests will include a prolonged aPTT with a normal prothrombin time
d. Pre-treatment for elective surgery require administration of cryoprecipitate to achieve levels of 23–50% of normal
Answer: c, d
Von Willebrand’s factor is an adhesive protein that mediates platelet adhesion to collagen. In addition, it protects and prevents the rapid removal of factor VIII from blood. The classical deficiency state, Von Willebrand’s disease, is caused by reduction of factor VIII activity (although not as great as Hemophilia A) and the Von Willebrand factor. Clinical manifestations include epistaxis, gingival bleeding, menorrhagia, rare joint or muscle bleeding, and subcutaneous bleeding. Spontaneous bleeding is not as common as in classic Hemophilia A. The syndrome is transmitted as both autosomal dominant (heterozygous) and autosomal recessive disease (homozygous) traits. Therefore there is no sex predilection. Screening laboratory tests include a prolonged aPTT with a normal prothrombin time. In addition, because of the importance of this factor in platelet adhesion, patients display a prolonged bleeding time and have decreased level of factor VIII activity, decreased immunoreactive levels of Von Willebrand’s antigen, and abnormal platelet aggregation responses to ristocetin. The most reliable source of Von Willebrand’s factor is cryoprecipitate.
157 External pneumatic compression has been advocated for the prevention of deep venous thrombosis during operative procedures. Which of the following statement(s) concerning the use of external pneumatic compression devices is/are true?
a. Intermittent pneumatic compression is as effective as low-dose heparin in prevention of venous thrombosis
b. These devices function by compressing the lower extremities therefore augmenting venous return
c. Pneumatic compression devices may also exhibit their antithrombotic effect through stimulating local and systemic fibrinolysis
d. The length of time that intermittent pneumatic compression should be used includes through the operation and for at least several days in the postoperative period
Answer: b, c, d
In many well-controlled studies of venous prophylaxis, intermittent pneumatic compression has been found to be as effective as low-dose heparin therapy. In addition to augmentation of venous return with these devices, local and systemic fibrinolysis appears to be stimulated. Fibrinolytic activities are usually reduced for a 7–10 day period after an operation. Studies have demonstrated that the pneumatic-compression devices may exhibit their antithrombotic effect through prevention of this fibrinolytic shutdown even when applied to the upper extremity. The length of time that intermittent pneumatic compression should be used has not been adequately determined but most data suggest that devices should be used through the operation and for at least five days in the face or prolonged immobilization.
158 The standard management oral anticoagulant therapy for chronic treatment of venous thromboembolism is with the drug warfarin. Which of the following statement(s) is/are true concerning the administration of warfarin?
a. An important complication of warfarin therapy is skin necrosis in patients with protein C deficiency
b. Warfarin interferes with vitamin K dependent clotting factors II, VII, IX, X
c. For effective anticoagulation the prothrombin time (PT) should be kept at 2 control
d. It is recommended that warfarin be continued for at least one year after initial episode of deep venous thrombosis
Answer: a, b
Warfarin interferes with the vitamin K dependent clotting factors II, VII, IX and X, protein C, and protein S. An important complication of warfarin is skin necrosis with patients both with and without protein C deficiency. This syndrome usually involves full thickness skin slough over fatty areas such as the breasts and buttocks. Warfarin therapy should be monitored using the one stage prothrombin time (PT). The PT should be kept at 1.3 to 1.4 control for effective anticoagulation. At higher levels, there is a five-fold increase in the frequency of bleeding complications. Two major complications of Warfarin therapy include recurrent thrombosis and bleeding. It is recommended that Warfarin be continued four months after an initial episode of deep venous thrombosis. Between ten weeks and four to six months after deep vein thrombosis, there is a recurrent thrombosis rate of 8.3 episodes per 1000 patient months. Between four months and three years, recurrences fall to four episodes per 1000 patient-months. At four months, the risks of bleeding complications matches and exceeds the benefit from anticoagulant therapy and thus is the basis for discontinuing warfarin administration at this time.
159 Which of the following statement(s) is/are true concerning the management of a patient with hemophilia A undergoing an elective surgical operation?
a. Concentrates of factor VIII should be given several days prior to elective surgery
b. The half-life of factor VIII concentrates is less than 24 hours
c. A dose of 40–50 IU/kg of factor VIII concentrate should be given prior to the planned surgical procedure
d. Factor VIII concentration administration should be given for the first 24 hours after surgery but may then be stopped if no abnormal bleeding has been observed
e. A new recombinant preparation of factor VIII offers the advantage of being virus-free
Answer: b, c, e
Although the half-life of factor VIII is 2.9 days in normal individuals, the half-life of factor VIII concentrates is 9 to l8 hours. Levels of 80% to 100% of normal should be obtained for surgical bleeding or life-threatening hemorrhage. A dose of 40 to 50 IU/kg of factor VIII should be given with half of this dose then administered every twelve hours. After surgery, transfusion of factor VIII concentrates should be continued for at least ten days. Unfortunately, past use of concentrates of factor VIII obtained from donors has led to a high incidence of HIV infection in the hemophilia population. A new recombinant preparation of factor VIII offers the advantage of being virus-free.
160 Transfusions of blood products can be associated with a number of complications including immediate and delayed hemolytic reactions; nonhemolytic reactions; infectious disease transmission; and complications of massive transfusions. Which of the following statements are true concerning complications of blood transfusions?
a. Immediate hemolytic transfusion reactions are caused by major ABO blood group incompatibility
b. Nonhemolytic transfusion reactions are usually due to RH incompatibility and are therefore more common in women of childbearing age
c. The most common complication of massive blood transfusion is dilutional thrombocytopenia
d. Routine impaired calcium supplementation is necessary during most massive transfusion episodes
Answer: a, c
Immediate hemolytic reactions are usually caused by blood group ABO incompatibility although they may be caused by antigens of other blood group systems on the transfused red blood cells. The clinical manifestations revolve around the antigen on the red blood cell stroma and the antibody in the patient’s serum, and include production of bradykinin, compliment activation, release of vasoactive agents from platelets, and initiation of systemic clotting. Chills and fevers, chest pain and lumbar pain, tachycardia and hypotension in the conscious patient, and often diffuse bleeding in the anesthetized, unconscious patient constitute this syndrome. Although reaction occurs immediately, death related to the syndrome is uncommon, unless associated with a transfusion of more than 100 ml of blood. Death usually occurs from acute renal failure or hemorrhage due to DIC. Nonhemolytic reactions occur with the frequency of 1 to 2% of all transfusions and consist primarily of chills and fevers during the transfusion or in the first 2 to 3 hours after the transfusion is complete. Mechanism of these reactions includes the presence of antibodies to white blood cell antigens in the transfused blood, especially in the multitransfused or multiparous patient. Massive transfusion complications relate to the rate and volume of blood transfused. The most common complication is dilutional thrombocytopenia. Factor deficiency of the labile factors V and VIII rarely is of sufficient magnitude to result in problems with hemostasis. For hypocalcemia to occur with massive transfusion, citrated blood must be administered, one unit every five minutes. Routine empiric calcium supplementation is unnecessary during most massive transfusion episodes. Conversely, hypothermia is clearly a problem, especially when associated with massive transfusion during complex intraoperative procedures such as thoracoabdominal aneurysm resection.
161 A 67-year-old male with advanced cholangiocarcinoma develops gram-negative sepsis. Excessive bleeding is noted around vascular catheters and from needle puncture sites. The diagnosis of disseminated intervascular coagulation (DIC) is considered. Which of the following laboratory test(s) is/are indicative of DIC?
a. Decreased platelet count
b. Decreased fibrinogen level
c. Normal prothrombin time
d. Elevated fibrin split products
Answer: a, b, d
Disseminated intravascular coagulation (DIC) is the primary form of acute thrombosis. Causes of this syndrome include abruptio placenta, gram-positive and gram-negative sepsis, endotoxemia, malignant tumors, pelvic operations, certain snake bites, hematologic malignancies, and hepatic failure. Blood coagulation is activated by the release of tissue factor into the circulation, which activates factor VII of the extrinsic pathway to VIIa, leading to massive thrombin production and fibrin generation. This in turn activates the fibrinolytic system, leading to bleeding in the later stages of the syndrome due to consumption of coagulation factors, depletion of fibrinogen, and unchecked plasma activities. Laboratory values in DIC usually include a decline in the platelet count and fibrinogen level, along with an elevation of fibrin split products.
162 Which of the following substances, not normally present in the circulation, trigger the initiating events in the hemostatic process?
a. Thrombin
b. Platelet factor 3
c. Tissue factor
d. Collagen
Answer: c, d
The initiating agents for hemostasis involve two substances that are not normally present in the circulation—collagen and tissue factor. Tissue factor is released from injured cells, beginning the activation of the extrinsic pathway of coagulation, while disruption of the protective endothelial barrier of blood vessels exposes the underlying collagen to the activation of platelets. In the bloodstream, tissue factor complexes with factor VII which then activates factor X to factor Xa. At the same time, activated platelets change from their discoid shape with their procoagulant phospholipid (termed platelet factor 3) buried on the inner side of the surface membrane to a spreading shape to allow for the externalization of platelet factor 3 activity. Activated factor X, activated factor V, ionized calcium and factor II (prothrombin) then assemble on the platelet phospholipid surface to form the so-called prothrombinase complex which catalyzes the formation of thrombin.
163 Bleeding complications are frequently associated with fibrinolytic therapy. Which of the following statement(s) concerning complications of fibrinolytic therapy is/are true?
a. Careful monitoring of prothrombin time and aPTT time are necessary to avoid bleeding complications
b. A level of serum fibrinogen less than 100 mg/dl is associated with an increased risk of bleeding
c. Recent (less than 10 days) major surgery is a contraindication to systemic but not regional fibrinolytic therapy
d. A patient with a cerebrovascular event occurring less than two months ago can be treated with fibrinolytic therapy if head CT scan is normal
Answer: b
Fibrinolytic therapy induces a hemostatic defect through a combination of factors. Hypofibrinogenemia and fibrin degradation products inhibit fibrin polymerization and, in combination with a decrease in the clotting factors V and VIII, prolong the ability of blood to clot. However, coagulation tests in general do not correlate well with bleeding complications. A level of fibrinogen less than 100 mg/dl is associated with an increased risk of bleeding. Absolute contraindications to thrombolytic therapy include active internal bleeding, recent (less than 2 months) cerebral vascular accident, and documented left heart thrombosis. Recent (less than 10 days) major surgery, obstetric delivery, organ biopsy, or major trauma is considered a major relative contraindication to either regional or systemic thrombolytic therapy.
164 Which of the following statement(s) is/are true concerning the results of a National Institute of Health Consensus Conference on venous thrombosis and low-dose heparin prophylaxis?
a. The odds of developing deep venous thrombosis with low-dose heparin prophylaxis decreases by 67%
b. The risk of pulmonary embolism is decreased by almost 50%
c. There is no increase in mortality from other causes found in patients treated with low-dose heparin
d. There was no difference in the incidence of bleeding complications
Answer: a, b, c
In a metaanalysis of 70 randomized trials in 16,000 patients comparing low-dose heparin prophylaxis with standard therapy, the odds of developing deep venous thrombosis with low-dose heparin prophylaxis decreased 67%, whereas for pulmonary embolism (both fatal and non-fatal), the odds decreased by 47%. For fatal pulmonary embolism, the odds reduction was even greater (64%). No increase in mortality from other causes was found in those patients treated with low-dose heparin. Bleeding complications were more frequent in the heparin-treated patients, with no difference between 5000 units twice daily and 5000 units three times daily. Similarly, the effectiveness of prophylaxis was not influenced by either two or three times daily dosage.
165 Laboratory monitoring of coagulation and anticoagulation includes testing of platelet function. Which of the following statements is/are true concerning tests of platelet function?
a. A platelet count of 50,000/µL or more usually ensures hemostasis
b. Bleeding time assays assessibility of platelets to perform hemostatic plugs and is determined from a sample of blood drawn in an EDTA coated test tube
c. Aspirin therapy can be associated with a bleeding time in the range of 8–15 minutes
d. Tests of platelet aggregation should be part of the standard preoperative evaluation of patients using aspirin
Answer: a, c
Tests of platelet function include peripheral platelet counts, bleeding times, and platelet aggregation. Usually, a platelet count of 50,000/mL or more ensures adequate hemostasis, whereas counts less than 10,000/mL are dangerous and may lead to spontaneous bleeding. Bleeding time performed by observing the clotting of blood induced with a small needle stick, assesses the ability of platelets to perform hemostatic plugs and are usually shorter than eight minutes. A bleeding time between 8 and 15 minutes most often reflects a low plasma level of Von Willebrand’s Factor or the use of antiplatelet drugs. A bleeding time greater than 15 minutes is clearly prolonged and indicates severe platelet functional impairment. Platelet aggregation studies involve the use of a number of different agonists. Although a relatively straightforward technique, platelet aggregation is not available in most laboratories, probably because of the observer-dependent nature of the test.
166 As thrombin generation proceeds, the body has natural anticoagulant systems opposing further thrombus formation. Natural anticoagulants include:
a. Tissue plasminogen activator (TPA)
b. Antithrombin III
c. Activated protein C
d. Heparin cofactor II
Answer: b, c, d
Just as thrombin generation is the key to coagulation, antithrombin III is the most central anticoagulant proteins. This glycoprotein binds to thrombin, preventing its removal of fibrinoprotein A and B from fibrinogen, prevents the activation of factor V and VIII and the activation and aggregation of platelets. The second line of defense is the activated protein C, which inactivates factors Va and VIIIa. This inactivation reduces the ability of the prothrombinase complex to accelerate the rate of thrombin formation. A third natural anticoagulant is heparin cofactor II. Its concentration in plasma is estimated to be some four-fold lower than antithrombin III, and its action is primarily implicated in the regulation of thrombin formation in extravascular tissues. Tissue plasminogen activator (TPA) is a natural catalyst for the activation of plasminogen to plasmin, the main fibrinolytic enzyme in the body. Therefore, TPA is part of the fibrinolytic system rather than a natural anticoagulant.
167 Infectious disease transmission during blood transfusions is of clinical significance to surgeons and of major importance to patients contemplating surgery potentially associated with the need for blood administration. Which of the following statement(s) is/are true concerning the transmission of infectious disease during blood transfusions?
a. Post-transfusion hepatitis is usually due to hepatitis B
b. Hepatitis and HIV transmission is greatest with the administration of pooled plasma products such as serum albumin
c. The most important cause of post-transfusion disease in immunosuppressed patients is CMV infection
d. The risk of HIV transmission in blood transfusions is significantly less than the risk of hepatitis transmission
Answer: c, d
The most common infectious diseases transmitted during blood transfusions include viral hepatitis, CMV, and HIV infection. Post-transfusion hepatitis in 90% of cases consists of non-A, non-B hepatitis known as hepatitis C. All blood products except for immune serum globulin and albumin can carry and transmit this form of hepatitis. Because heat treatment eliminates the risk of viral transmission, products from pooled plasma that are heat treated such as albumin are not at risk for HIV or hepatitis transmission. CMV transmission exists in three forms—primary, reinfection, and reactivation. Primary exposure results in an IgM response to the virus. Reactivation is most commonly related to pregnancy, transplantation, and immunosuppression, and is the most important cause of post-transfusion disease accompanying immunosuppression of patients. Although the risk of the public concern for transmission of HIV disease associated with blood transfusions has significantly outweighed other infectious disease transmission, the risks of HIV transmission is markedly less than that of hepatitis.
168 There are a number of hypercoaguable states which can be associated with arterial or venous thrombosis and embolic phenomenon. These include:
a. Heparin-associated thrombocytopenia
b. Antithrombin III deficiency
c. Von Willebrand disease
d. Vitamin C deficiency
Answer: a, b
A number of hypercoaguable states are present. These include heparin-associated thrombocytopenia in which a heparin-dependent platelet antibody causes aggregation of platelets when the patient is exposed to heparin. Activation of platelets in this setting results in thrombocytopenia, thrombosis, and embolic episodes. Antithrombin III deficiency accounts for about 2% of venous thrombotic events and has been described in pulmonary embolism, mesenteric venous thrombosis, lower extremity venous thrombosis, arterial thrombosis, and dialysis fistula failure. Von Willebrand’s disease is a hereditary complex coagulation factor deficiency which is manifested by a reduction of factor VIII activity, and the Von Willebrand factor which is an adhesive protein that mediates platelet adhesion to collagen. Severe vitamin C deficiency results in a disorder in soft tissue increasing vascular permeability and fragility resulting in the potential for bleeding disorders.
169 Cytokines with clearly defined actions in acute inflammation and early tissue injury include which of the following?
a. Cysteine-X-Cysteine (C-X-C) chemokines
b. Tumor Necrosis Factor (TNFa)
c. Transforming Growth Factor-b (TGF-b)
d. Interleukin-6 (IL-6)
e. Platelet Derived Growth Factor (PDGF)
Answer: a, b, c, d, e
Polypeptide mediators, such as TNFa and IL-1, are considered “early response” cytokines and are actively involved in the initiation of the cascade of events which precipitate acute inflammation. In addition to being important triggers for the induction of other cytokines important inflammatory network, TNFa and IL-1 appear to be key mediators in promoting the adherence of inflammatory cells to the endothelium. IL-1 is a complex, multifunctional molecule that shares many overlapping biological properties with TNFa. In addition, both IL-1 and TNFa potentiate the effects of one another. The most important function of IL-6 appears to be the regulation of the hepatic acute phase response. Following injury, a number of physiologic changes develop within several hours. IL-6 is one of the primary stimuli for the production of acute phase proteins from the liver. Endotoxin, IL-1, TNFa and PDGF are capable of causing significant induction of IL-6 synthesis.
Over the last decade, at least 12 different C-X-C chemokines have been identified. These include IL-8, one of the most potent mediators of chemotaxis known. TNFa and IL-1 are key molecules for the induction of IL-8, which in turn is important for the induction of neutrophil recruitment and activation.
Similar properties are apparent for other members of this chemokine family.
Platelet activation and degranulation occur during coagulation following injury, leading to the deposition of a number of cytokines into the provisional matrix. These cytokines include transforming growth factor-a, (TGFa), transforming growth factor b (TGF-b), platelet-derived growth factor (PDGF), and neutrophil activating peptide-2 (NAP-2). These cytokines are either important growth factors or chemotaxis for leukocytes, endothelial cells, fibroblasts, and keratinocytes which are key components in the process of tissue repair. Thus, coagulation and platelet activation provide the initial foundation for subsequent cellular recruitment.
170 Which of the following statements regarding transforming growth factor b (TGF-b) are true?
a. TGF-b expression is autoregulated
b. TGF-b enhances collagen synthesis
c. TGF-b inhibits extracellular matrix production
d. TGF-b may inhibit or promote cellular proliferation
Answer: a, b, d
TGF-b appears to be one of the key cytokines in control of tissue repair. TGF-b is strongly chemotactic for neutrophils, T cells, monocytes, and fibroblasts. TGF-b activates inflammatory cells to elaborate fibroblast growth factor, TNFa, IL-1 and increase their synthesis of extracellular matrix proteins. TGF-b also induces both the infiltrating cells and resident cells to produce more TGF-b. This auto-induction amplifies its biological effects at the site of injury and may play an important role in the development of chronic fibrosis in a variety of pathologic states. TGF-b enhances collagen synthesis as well. Lastly, TGF-b may function as a mitogen or growth inhibitor for a wide variety of cell types, including selected cell types of mesenchymal origin. Whether TGF-b stimulates or inhibits proliferation depends on the presence of other growth factors, the concentration of TGF-b, and the cell density. Thus, at low doses, TGF-b stimulates the proliferation of densely plated human marrow fibroblasts, but is inhibitory at high concentrations.
171 Leukocyte activation and adhesion to vascular endothelial cells is a critical step in the inflammatory process. This process is regulated by which of the following molecules?
a. The selectins
b. The b5 integrins
c. The immunoglobulin supergene family
d. Nitric oxide
e. IL-8
Answer: a, c, d, e
The temporal events that initiate and propagate neutrophil recruitment and inflammation include endothelial cell activation and expression of endothelial-derived neutrophil adhesion molecules, neutrophil-endothelial cell adherence, and neutrophil transendothelial migration via established neutrophil chemotactic gradients. There are three major families of adhesion molecules which are expressed on the surface of leukocytes and endothelial cells and are important for leukocyte-endothelial cell interactions. These include the immunoglobin supergene family (ICAM-1, VCAM-1, and PECAM-1), the selectins (E-selectin, P-selectin and L-selectin), and the integrins. The leukocyte b2 integrin adhesion molecule family consists of three members with heterodimeric glycoproteins displayed as a variable alpha and a constant beta chain. Nitric oxide regulates the adhesion process both by direct influence on leukocyte binding as well as by regulation of regional blood flow. IL-8 is one of the most potent mediators of chemotaxis in the C-X-C chemokine family. It serves an important role in neutrophil recruitment and activation, and the continued propagation of the inflammatory response.
172 A 65-year old patient has colon carcinoma metastatic to the liver and lungs. He has had a weight loss of 10 kg. Cytokine-dependent tumor cachexia is attributable to which of the following?
a. Increased glucose uptake and increased glycogen breakdown occur in this circumstance.
b. Suppressed activity of lipoprotein lipase results from TNFa
c. TNFa stimulates lipolysis
d. The differentiation process of pre-adipocytes is impaired
e. Partial reversal of differentiated adipocytes to pre-adipocyte morphology and gene expression occurs
Answer: a, b, c, d, e
Tumor cachexia appears to be mediated by TNFa. Lipopolysaccharide (LPS), as well as other cytokines, activate a variety of inflammatory cells, most importantly macrophages, to produce TNFa. Both the chronic administration of TNFa to rats and implantation of tumors secreting TNFa in mice induce a syndrome of cachexia. In vitro, higher TNFa concentrations alter glucose metabolism in cultured myotubules by increasing glucose uptake and glycogen breakdown. It has also been demonstrated that purified TNFa suppresses lipoprotein lipase activity and stimulates lipolysis in cultured adipocytes. Further, TNFa not only inhibits the differentiation process of preadipocytes, but partially reverses differentiated adipocytes to a preadipocyte morphology and pattern of gene expression. All of these metabolic effects at least partially explain the chronic syndromes of anorexia, weight loss, and cachexia that are associated with both chronic infection and malignancy.
173 Which of the following statements regarding fibroblasts and their function in wound healing are true?
a. IL-1 has both inhibitory and promotional effects on fibroblast growth
b. TNFa stimulates fibroblast collagen synthesis
c. IL-1 and TNFa have opposite effects on the healing of bone
d. In human clinical trials, EGF (epithelial growth factor) has been demonstrated to accelerate epidermal regeneration in cutaneous wounds
Answer: a, d
IL-1 appears to be important in the process of normal wound repair. IL-1 has been shown to stimulate skin fibroblast and keratinocyte growth, as well as fibroblast collagen synthesis and keratinocyte chemotaxis. IL-1 also promotes increased transcription of the matrix degradative enzymes collagenase and stromelysin. These are important and potent tissue degrading proteinases. Other studies have demonstrated that IL-1 inhibits fibroblast growth and matrix synthesis, and stimulates collagenase production. These actions are at least partly due to the ability of IL-1 to upregulate prostaglandin E2 production which results in the down regulation of matrix synthesis. IL-1 has both promoting and inhibiting effects on fibroblast collagen synthesis, therefore, the overall activity in this area is somewhat unclear in comparison to other well-defined fibroblast growth-promoting cytokines. TNFa inhibits fibroblast collagen synthesis, however it also has potent mitogenic effects. The mitogenic response correlates well with an increased stimulation of tyrosine phosphorylation. Both IL-1 and TNFa have similar effects upon bone. Both stimulate cartilage resorption, the release of proteoglycans from cartilage by limited proteolytic degradation, and both inhibit proteoglycan synthesis. Recent studies have also demonstrated that TNFa inhibits fracture healing in experimental animals. This is due to the inhibition of cartilage formation and new bone synthesis, and the inhibition of mesenchymal cell differentiation into chondroblasts. The family of epithelial growth factor (EGF)-like molecules induce mitogenesis and play a role in wound healing. In human clinical trials, EGF has been demonstrated to accelerate epidermal regeneration in cutaneous wounds. In vitro data show that recombinant EGF enhances keratinocyte migration. EGF is also a potent chemoattractant for granulation tissue fibroblasts.
174 Neutrophil chemotaxis is a fundamental aspect of inflammatory injury in conditions such as the Adult Respiratory Distress Syndrome (ARDS). Neutrophil chemotaxis is directly attributable to which of the following molecules?
a. C5a
b. TNFa
c. LPS
d. IL-1
e. ENA-78 (Epithelial Neutrophil Activating Protein)
Answer: a, e
There is a large collection of peptide, polypeptide and lipid mediators which have chemotactic properties. Although TNF a, IL-1 and LPS were initially reported to have direct neutrophil chemotactic activity, recent studies have demonstrated that these molecules are not directly chemotactic for neutrophils. This finding suggests that cytokine networks may be operative in vivo and depend on the initial expression of early response cytokines. This initial interaction is followed by the generation of more distal inflammatory mediators that directly influence neutrophil chemotaxis and activation. There is a particularly important group of novel chemotactic cytokines which share significant homology with the presence of four conserved cysteine amino acid residues. These cytokines in their monomeric forms are all less than 10 kD, are characteristically basic heparin-binding proteins, have specific neutrophil chemotactic activity and display four highly conserved cysteine amino acid residues, with the first two cysteines separated by one non-conserved amino acid residue. Because of their chemotactic properties and the presence of C-X-C cysteine motif, these have been designated the C-X-C chemokine family. Twelve different chemokines have been identified in the last decade. These include IL-8, epithelial neutrophil activating protein (ENA-78), and others. Among the other endogenous chemoattractants are several complement-derived peptides. Perhaps, the most potent of these is the short-lived C5a peptide.
175 Which of the following statements regarding angiogenesis are true?
a. Angiogenesis is a seminal biologic event with clinical relevance limited to its effect upon tumor growth
b. C-X-C chemokines regulate angiogenesis
c. PF-4 has angiogenic properties
d. Sites of atherosclerosis demonstrate chronic angiogenic activity
Answer: b, d
An important component of tissue repair and wound healing is the process of angiogenesis. This normal, physiologic process is a local, transient event which is regulated strictly. A biological imbalance in the production of angiogenic and angiostatic factors contributes to the pathogenesis of several angiogenesis-dependent disorders. These include both malignant and nonmalignant disorders such as rheumatoid arthritis, scleroderma, psoriasis, atherosclerosis, and idiopathic pulmonary fibrosis. Persistent neovascularization in these benign disorders is a prerequisite for the perpetuation of fibroproliferation. IL-8 and potentially other C-X-C chemokines are involved with the angiogenesis process. IL-8 is a potent angiogenic factor. In contrast, another member of the C-X-C chemokine family, PF-4 has angiostatic properties. This suggests that the C-X-C chemokines may function as either angiostatic or angiogenic factors, and the biologic balance that is maintained between these factors may govern overall angiogenic potential in a variety of physiological and pathophysiological states.
176 Which of the following statements regarding IL-1 are correct?
a. While IL-1 and TNFa share many biologic effects, IL-1 appears to be more potent
b. IL-1 expression is in part autoregulated
c. IL-1 inhibits prostaglandin production
d. The ability of IL-1 to upregulate endothelial cell-neutrophil adhesion molecules is relatively limited
Answer: b
IL-1 and TNFa share many biologic properties. In addition, each potentiates the effects of the other one when given concurrently. Overall, IL-1 alone probably has weaker effects than TNFa with respect to the induction of shock; its role is likely to be important with respect to its marked potentiating abilities as it relates to TNFa. IL-1 expression is regulated by a host of factors including IL-2, granulocyte macrophage colony stimulating factor (GM-CSF), transforming growth factor b (TGF-b), TNFa, all of the interferons, and IL-1 itself. Other endogenous stimuli for IL-1 production include antigen-antibody complex, the Fc region of IgG, and C5a; other nonspecific exogenous stimuli include silica particles and UV irradiation.
One of the key proinflammatory features of IL-1-induced inflammation is the stimulation of arachadonic acid metabolism. IL-1 stimulates the release of pituitary stress hormones and increases the synthesis of collagenases, resulting in the destruction of cartilage, bone and other collagen-rich structures. IL-1 stimulates prostaglandin production.
One of the most important properties of IL-1 involves its interaction with the vascular endothelium. This includes the adherence of neutrophils, basophils, eosinophils, monocytes, and lymphocytes to the vascular endothelium via interaction between adhesion molecules on leukocytes and adhesion-receptor complex on the endothelial cells. By inducing the expression of ICAM-1, E-selectin, and VCAM-1 on endothelial cells, IL-1 provides a key step in the extravasation of leukocytes to sites of local inflammation and injury.
177 Which of the following statements regarding TNFa are true?
a. TNFa has a marked procoagulant effect
b. Passive immunization of patients with neutralizing antibodies to TNFa improves survival from multi-organ system failure
c. TNFa upregulates E-selectin expression
d. The most potent known stimulus for TNFa production and release is IL-1
Answer: a, c
TNFa has a marked procoagulant effect on endothelial cells, precipitating intravascular thrombosis. TNFa causes endothelial cells to release procoagulant activity (tissue factor), platelet activating factor, and von Willebrand factor, all of which favor thrombosis. TNFa also down regulates the expression of thrombomodulin, which has the potential to block the assembly of protein C and protein S complexes, further decreasing the anticoagulant properties of the endothelial cell surfaces.
Administration of recombinant TNFa to experimental animals produces a clinical syndrome similar to that seen in septic shock and multi-organ system failure in humans. Passive immunization of animals with neutralizing antibodies against TNFa, prior to the infusion of TNFa or endotoxin, has been shown to prevent the development of this syndrome. No such evidence exists in human patients.
TNFa upregulates a variety of leukocytic adhesion molecules including ICAM-1, PECAM-1, VCAM-1, E-selectin and P-selectin. A variety of exogenous and endogenous factors (including IL-1) are capable of inducing cells to produce TNFa, however the most potent stimulus for TNFa production and release is endotoxin.
178 Which of the following belong to the family of C-X-C chemokines?
a. IL-8
b. IL-10
c. Growth Related Oncogene-a
d. Leukotreine B4
e. b Thromboglobulin
Answer: a, c, e
A particularly important group of novel chemotactic cytokines has been elucidated over the last decade. Twelve are known and are listed below.
C-X-C Chemokines
Connective Tissue Activating Protein III
b-Thromboglobulin
Growth Related Oncogene-a
Growth Related Oncogene-b
Related Oncogene-g
Interleukin-8
Epithelial Neutrophil Activating Protein
Granulocyte Chemotactic Protein-2
Platelet Factor-4
g-Interferon-inducible Protein
Monokine-induced by g-Interferon
Each has unique biologic functions. There appear to be important in vivo cytokine networks involving these molecules which regulate chemotaxis, and other fundamental aspects of inflammation.
179 Which of the following statements regarding the complement system are true?
a. Complement activation yields products which are directly cytotoxic as well as products which act indirectly via activated leukocytes
b. Complement products referred to as anaphylatoxins include C1, C3a, C4a, and C5a
c. The principal role of C5a is in bacterial opsonization
d. The alternative and classical pathways converge proximal to generating the membrane attack complex (C5b-9)
Answer: a, d
The complement system is composed of two different but linked sequences, the classic and alternative pathways. The pathways involve serum proteins that act to amplify the inflammatory-immune response as well as to directly mediate tissue injury. Complement activation by either pathway has been associated with a cascade of events, some of which are mediated directly at a physiologic level by complement products and some of which occur indirectly via activated leukocytes. The direct physiologic effects mediated by C3a and C5a, and to a lesser extent C4a, include increased vascular permeability and contraction of smooth muscle. These are key elements of anaphylaxis. C1 is not an anaphylatoxin as it is the initial complement component which binds to antigen-antibody complex to initiate classical pathway activation. C5a acts principally to alter the behavioral characteristics of leukocytes. Effects include enhanced adherence, enhanced chemotactic activity, release of proteinases, and production of toxic metabolites of oxygen. C3, on the other hand, plays a key role in bacterial opsonization, resulting in enhanced phagocytosis of invading microorganisms. The alternative and classical complement pathways converge at the C5 level proximal to generating the membrane attack complex (C5b-9) (Figure 6-3).
180 Which of the following statements regarding neutrophils are true?
a. The neutrophil undergoes final maturation after release into the circulation
b. Patients with chronic granulomatous disease have a defective neutrophil H-oxidase system
c. Neutrophil killing of bacteria is achieved by oxidants, proteinases and cationic proteins
d. The normal human neutrophil circulates in the blood for 7–10 days
Answer: b, c
The neutrophil is a migratory phagocytic cell that defends the host against bacteria and eliminates necrotic tissue. The neutrophil matures in the bone marrow and is released into the circulation as a fully differentiated cell. It is loaded with granules containing a variety of proteinases, hydrolases, antimicrobial agents and cationic proteins. The cell phagocytoses material and the granules fuse with the phagocytic vacuoles to degrade the foreign material. When the cells are challenged with a large amount of material, the granule contents may be released into the extracellular space where damage to surrounding tissue occurs. The neutrophil normally circulates in the human bloodstream for 7 to 10 hours. Thereafter, neutrophils are thought to exist for 1 to 2 days in the tissues before being cleared from the system. Granule constituents are formed during differentiation and replenishment of spent granules does not occur once the cells are in the circulation. Hence, the neutrophil is a fully differentiated end-cell poised to respond rapidly to stimuli, but it is rapidly spent in the process. Neutrophils have a NADPH-oxidase enzyme system on the plasma membrane which can be activated to produce toxic oxygen species including the superoxide anion (02–). Patients with chronic granulomatous disease (CGD) have a defective NADPH-oxidase system in their neutrophils, and are thus unable to generate 02–. Although neutrophils from patients with CGD are able to phagocytose bacteria, they are unable to kill the intracellular microbes and chronic, unresolved infections result.
181 Which of the following statements regarding the alternative complement pathway are true?
a. C1, C4 and C2 are involved
b. NH3 apparently activates complement via this pathway
c. Factors B and D are involved
d. Endotoxin activates complement via the alternative pathway
Answer: b, c, d
The alternative pathway differs from the classic pathway in that the first steps involving C1, C4 and C2 are bypassed. (See Figure 6-3 previously reproduced.) This pathway can be directly activated by agents other than antigen–antibody complex (e.g., complex polysaccharides like endotoxin and zymosan). Other serum protein factors (e.g., factors B and D) are involved in the activation sequence. Ammonia can attack the thiol-ester, producing amidated C3 and activate the alternative pathway. This leads to membrane attack complex formation (C5b-9) and activation of a number of phagocytic cell functions including toxic oxidant production. This phenomenon may have relevance to several in vivo disease states. In animal models of renal failure, elevated levels of renal vein NH3 have been correlated with impaired renal function and the presence of complement components at the sites of renal injury.
182 Platelet activating factor is:
a. Generated by the action of phospholipase A2 on membrane phospholipids
b. Antiinflammatory in most of its actions
c. Synthesized by endothelial and other cells
d. Exerts a variety of biologic effects which are platelet-independent
Answer: a, c, d
Like the eicosanoids, platelet-activating factor (PAF) is not stored in cells but is rapidly produced during inflammation. PAF exerts a variety of biologic effects that are platelet-independent. The synthesis of PAF is initiated by the activation of phospholipase A2. Activation of phospholipase A2 releases arachidonic acid in addition to lyso-PAF. Hence, PAF synthesis and eicosanoid production are coordinately regulated. PAF is synthesized on activation of a variety of inflammatory cells including platelets, neutrophils, basophils, mast cells, mononuclear phagocytes, eosinophils and vascular endothelium. PAF is a stimulatory agonist for many inflammatory cells, as well as for smooth muscle cells, vascular endothelium and others. PAF enhances the ability of neutrophils to respond to challenge with N-formylpeptides and LTB4. There is considerable overlap and redundancy in the effects produced by PAF and eicosanoids.
183 Platelets have a wide array of functions in inflammation. Which of the following are among these?
a. Synthesis and release of vasoactive eicosanoids
b. Release of chemotactic factors
c. Adherence to and coating of bacterial and tumor cells
d. Increase of vascular permeability
e. Phagocytosis of bacteria
Answer: a, b, c, d
Platelets are anucleated cells derived from megakaryocytes in the bone marrow. Their central role in hemostasis is well known. Platelets possess a wide array of functions in inflammation, including the following:
Synthesis and release of vasoactive eicosanoids
Release of chemotactic factors
Interaction with other inflammatory cells
Interaction with endothelial cells
Adherence to and coating of bacterial and tumor cells
Platelets are not capable of phagocytosis.
Few of the factors released or the functions carried by platelets during inflammation are unique to this cell type. Other inflammatory cells often have the same or similar capabilities. Indeed, some platelet functions may reflect vestigial functions inherited from a primitive precursor inflammatory cell. Platelets serve primarily as an amplifier or modulator of the inflammatory response.
184 Eicosanoids mediate inflammation in a variety of ways. Of the following statements, which are true with regard to this?
a. Eicosanoids are stored in cytoplasmic granules for release after receptor mediated signaling
b. Eicosanoids include prostaglandins, thromboxanes, leukotrienes and lipoxins
c. Eicosanoids generally have a plasma half-life measured in hours
d. Physiologic responses to eicosanoids include vasodilatation, vasoconstriction, increased vascular permeability and both chemotaxis and chemoattractant inhibition
Answer: b, d
The eicosanoids are derived from arachidonic acid (eicosatetraenoic acid) and consist of prostaglandins, thromboxanes, leukotrienes and lipoxins. The eicosanoids are not stored in cells but are rapidly synthesized by cells in response to a variety of stimuli. They have potent effects on vascular and bronchial smooth muscle including vasodilatation, vasoconstriction, bronchodilation and bronchoconstriction. In addition, they directly regulate vascular permeability. LTB4 is a potent, neutrophil chemoattractant whereas lipoxin A4 inhibits other chemoattractants. It appears that eicosanoids are important regulators of the endogenous inflammatory response. The rapid destruction of eicosanoids in the circulation limits their role primarily to that of mediators of local inflammatory changes. The local effects can be substantial. In general, the eicosanoids are rapidly metabolized or are so chemically unstable that they primarily exert their effects near the site of synthesis. Arachidonic acid does not exist in cells but is esterified to membrane phospholipids. Thus, the first step in the production of eicosanoids is phospholipase action, which liberates arachidonic acid. (Figure 6-6)
185 Which of the following statements are true?
a. Eosinophils are the major, if not sole, source of histamine in the blood
b. Basophils are effector cells in allergic reactions by virtue of IgE receptors
c. Mast cells are the major source of tissue histamine except in the stomach and central nervous system
d. Mononuclear phagocytes release a variety of proinflammatory cytokines and growth factors
Answer: b, c, d
Eosinophils constitute 1% to 3% of the leukocyte population of the bloodstream. They also reside in tissues and they exhibit phagocytic capabilities. They are less effective as bactericidal cells than neutrophils, but play a major role in defense against parasites. Eosinophils are primary effectors in allergic reactions by virtue of IgE receptors (which are not found on neutrophils).
Basophils are fully differentiated cells released into the circulation from bone marrow. Basophils are the major, if not sole, source of histamine in the blood. Histamine is a vasoactive amine and the major mediator of the IgE-mediated immediate hypersensitivity response. Histamine release from basophils is induced by complement products as well as by IgE receptors.
Mast cells are formed from bone marrow precursors that differentiate and proliferate in connective tissue. Mast cell granules contain histamine and proteoglycans. They represent the major source of histamine in most tissues except the stomach and central nervous system.
The monocyte–macrophage system consists of phagocytic cells scattered throughout the body. During acute inflammation, monocytes respond to chemoattractants released and are recruited to the site of inflammation. Mononuclear phagocytes respond to inflammatory stimuli by releasing M-CSF, GM-CSF, IL-1, and TNF, in addition to a variety of growth factors. These factors increase the production of mononuclear phagocytes and several of these factors enhance the ability of effector cells to respond to chemotactic stimuli released at the site of injury. Thus, the mononuclear phagocytes are important in initiating and augmenting the cycle of events that result in recruitment and activation of inflammatory cells at sites of inflammation.
186 Cellular injury from oxidants may be manifest by which of the following?
a. Cell membrane lipid peroxidation
b. DNA strand breaks
c. Cytoskeletal disassembly
d. ATP depletion
Answer: a, b, c, d
Free oxygen radicals are chemical species that are intermediates in the normal process of cellular respiration. Oxidants that are free radicals have been implicated as initiators of reactions which lead to a variety of cellular injuries. Oxidants are derived from several sources, notably phagocytes. Among the effects of oxygen free radicals are membrane lipid peroxidation, DNA strand breaks, cytoskeletal disassembly and inhibition of glucose metabolism leading to decreased cellular ATP concentrations. (Figure 6-16)
187 Which of the following acute-phase protein levels are increased in human plasma following acute inflammation?
a. C-reactive protein
b. Serum amyloid
c. a -Proteinase inhibitor
d. Fibrinogen
e. Albumin
Answer: a, b, c, d
The acute-phase response is a series of homeostatic responses of the organism to tissue injury in infection and inflammation. After an inflammatory stimulus occurs, a number of events occur within hours. These reflect altered set-points for various physiologic parameters including thermoregulation (fever), nitrogen balance (negative), and levels of various plasma proteins (increased or decreased). The erythrocyte sedimentation rate, which increases with inflammatory states, is an example of this phenomenon. The increased sedimentation rate is due to increased levels of fibrinogen and some of the other acute-phase reactants in plasma. Some proteins show a large increase (about 1000-fold), some a 4-to 5-fold increase, and others about a 50% increase over resting nonstressed levels.
Note that albumin is an acute-phase reactant. Levels of albumin drop after an inflammatory stimulus, usually 30% to 50% of the level before injury. The reason for the decrease in production is poorly understood.
188 Which of the following statements regarding endothelial cells in acute inflammation are true?
a. Endothelial cells are characterized by phenotypic homogeneity
b. Specific patterns of receptor expression regulate leukocyte adherence
c. Endothelial cell nitric oxide generation regulates regional blood flow and leukocyte adhesion
d. Endothelial cells may be capable of phagocytosis
Answer: b, c, d
Endothelial cells are increasingly recognized to be phenotypically heterogeneous. Specific receptor molecules are expressed at various sites where they help to direct lymphocytes and other leukocytes to their appropriate target organ. In the high endothelial venues, these receptor molecules are known as vascular addressing. Endothelial cells play a major role in regulating vascular tone. This is the result of angiotensin-converting enzyme on the cell surface as well as the production of both endothelia (a potent vasoconstrictor) and nitric oxide (a potent vasodilator). Both play important physiologic roles in determining the distribution of blood flow. In addition, recent evidence suggests that NO may have direct effects upon the expression of a variety of leukocyte adhesion molecules. Under unusual circumstances, endothelial cells can exhibit macrophage-like properties in that they can act as antigen-presenting cells and also phagocytose particles. They may also be a significant source of oxidants in inflammatory reactions after ischemic injury. Endothelial cells are not passive participants in inflammatory processes; rather, they possess the ability to direct and focus many aspects of an inflammatory event.
189 The first line of host defense is the barrier presented to the external environment. Which of the following statement(s) is/are true concerning host barriers?
a. Sebaceous glands secrete chemical compounds that maintain a relatively high pH, providing effective bacterial stasis
b. Within the respiratory tract, ciliary function serves to extrude microorganisms trapped within the mucus secretion layer
c. The low pH within the stomach markedly decreases bacterial content of the upper gastrointestinal tract
d. Gut peristalsis serves to prevent microbial adherence and invasion
Answer: b, c, d
The skin, mucus membranes, and epithelial layers of various organs of the body constitute effective physical barriers against microbial invasion. In certain portions of the body, these barriers have developed ancillary adaptations to increase the effectiveness of the barrier functions. Skin structures such as sebaceous glands secrete chemical compounds that serve to maintain a relatively low pH, providing effective bacterial stasis. Mucus secretion by specialized glands within the bronchi and gut provide a mucus layer that represents a physical and chemical barrier to microbial invasion. Within the respiratory tract, ciliary function serves to extrude microorganisms trapped within this mucus layer. In the alimentary track, the very low pH within the stomach and gut peristalsis both serve to prevent microbial adherence and invasion.
190 Which of the following statement(s) is/are true concerning the antibody response to an invading antigen?
a. All antibodies are composed of one type of heavy and one type of light protein chain
b. The carboxyl terminus of the heavy chain is the antigen binding site
c. Antibody of the immunoglobulin G class is the initial antibody produced in response to an antigenic stimulus
d. Immunoglobulins A, D, and E play an active role in the circulating humoral response
Answer: a
Humoral defenses consist of antibody (immunoglobulin; Ig) and complement. All Ig classes (IgM, IgG, IgA, IgE, IgD) and IgG subclasses are composed of one type (M, G, A, E, D) of heavy and one type (K and g ) of light protein chains that consist of several domains both structurally and functionally. Each Ig molecule contains one or more units that consist of two heavy and two light chains linked by disulfide bonds. The amino terminus of both heavy and light chains contain several hypervariable regions that fold in three dimensions to produce the antigen-binding site. The carboxyl terminus of the heavy chains contain regions that activate complement and bind Fc receptors, by which direct adherence to polymorphonuclear leukocytes and macrophages take place after antigen binding occurs.
Initially, antibody of the IgM class is produced in response to an antigenic stimulus. A second exposure to the same antigen, or a cross-reactive antigen, leads to the so-called second set response, in which antibody of the IgG class with two binding sites is produced more rapidly and in larger quantity compared to the initial IgM primary response. Immunoglobulin of the IgA class is secreted by gut-associated lymphoid tissue and is combined with secretory components of protein to form a dimer termed secretory IgA. This antibody acts at a variety of epithelial sites to prevent microbial adherence and invasion. IgD and IgE exist in smaller amounts in the circulation and do not appear to play a major role as host defense components.
191 Increasing evidence has implicated gram-negative bacterial lipopolysaccharide (LPS endotoxin) as the portion of the gram-negative bacterial cell membrane responsible for many, if not all the toxic effects that occur during gram-negative bacterial sepsis. The following statement(s) is/are true concerning LPS and the host response.
a. The LPS molecule can in itself cause physiologic responses similar to that seen during gram-negative bacterial sepsis
b. LPS triggers host macrophages to release a variety of cytokines including TNF-a, IL-1a, and IL-1b, IL-6, and IFN-a
c. Excessive cytokine production is not associated with detrimental consequences
d. TNFa and IL-1b appear to be the primary mediators within the host, exerting deleterious effects on the host when excessive amounts reach the systemic circulation
Answer: a, b, d
The LPS molecule exerts diverse effects on the mammalian host. Immunologic responses to LPS include nonspecific polyclonal B-cell proliferation, macrophage activation and cytokine secretion, tolerance to subsequent LPS or bacterial challenge, and production of antibody directed against various portions of the LPS molecule after repeated challenge. Physiologic responses similar to those seen during gram-negative bacterial sepsis occur during LPS administration alone and include hypotension, hypoxemia, acidosis, bacterial translocation across the gut, complement and coagulation cascade activation, white blood cell and platelet margination, and death. Indirect effects result from LPS-triggering of host macrophages. Activated macrophages secrete a wide array of cytokines that include TNF-a, IL-1a, and IL-1b, IL-6 and interferon-a (IFNa). Excessive secretion of cytokines produce substantial systemic effects in the mammalian host. TNFa and IL-1b appear to be the primary mediators within the local host milieu, exerting deleterious effects on the host only after large amounts are secreted and reach the systemic circulation.
192 Which of the following statement(s) concerning the gut microflora is/are correct?
a. Gut microflora evolves constantly throughout development
b. The gut microflora can contribute to the physical and chemical barriers at the mucus membrane level
c. Most of the microorganisms found in the oropharynx eventually pass into the intestine
d. In the colon, anaerobic organisms outnumber aerobic organisms in a ratio in excess of 100:1
Answer: b, d
The composition of the gut microflora is established in neonates after ingestion of microbes that are acquired during contamination from the birth canal and during initial feeding, and remain relatively constant thereafter. Although this flora acts to promote development of the immune system, the specific interactions that produce this effect have not been fully elucidated. The microflora also contributes to physical and chemical barriers at the mucus membrane level, in that many autochthonous microbes possess adhesion proteins by which they can bind to certain areas of the mucosal cell or to specific types of bacteria, occupying potential binding sites for pathogenic organisms and producing a substantial physical mucobacterial layer. The oropharynx contains a number of aerobic and anaerobic microorganisms, however, these microbial inhabitants do not usually pass into the intestine, because the stomach itself represents a significant barrier to invading microorganisms by virtue of its low pH, which kills most microbes. The upper small intestine contains few organisms, mainly gram-positive aerobes and lactobacilli. Conversely, the lower small intestine contains a large number of aerobes and anaerobic forms, especially in patients in whom the ileocecal valve allows free backwash of cecal contents into the terminal ileum. Within the colon, a wide diversity and a large number of facultative and strict anaerobic isolates are present. Only a small number of aerobes are present, these microbes being outnumbered 100–300 to 1 by anaerobes.
193 The use of antibiotics can be based on either the clinical course of a patient without the benefit of well-defined microbiologic data (empiric therapy), or targeted at specific identified pathogens once sensitivity reports are available (directed therapy). The following statement(s) is/are true concerning these therapies.
a. The issue of toxic side effects of antibiotics is only important in dealing with emperic therapy
b. Single agent therapy is generally inferior to specific multi-drug therapy (aminoglycoside plus an antianaerobic agent) for the treatment of secondary bacterial peritonitis due to appendicitis, diverticulitis, penetrating gastrointestinal injury, or anastomotic leak
c. With the empiric use of antibiotics, a diligent search for the septic source should be undertaken and continued until identified
d. In clinical situations in which polymicrobial infection is identified, specifically-directed treatment for the predominant organism is satisfactory
Answer: c
The use of empiric therapy without the benefit of well-defined microbiologic data is appropriate when there is sufficient clinical evidence to support the diagnosis such that it would be imprudent to withhold antimicrobial therapy. In this setting, however, a diligent search for the septic focus source should be undertaken and continued (cultures, radiographic procedures, etc.), and initial limits should be placed in the course of empiric therapy with continued reevaluation based on the clinical course of the patient. The choice of antibiotic agents should be based on the clinical situation and known activity patterns within the given institution. Single broad-spectrum agents, although suffering slightly from a lack of individual pathogen specificity, are useful in this setting in that they provide a broad coverage against several groups of pathogens and may avoid some of the toxic effects with specific combined modality regimens. Similarly, for directed therapy, single-agent therapy has been demonstrated to be equivalent to combined therapy and should be chosen in an attempt to select agents with appropriate sensitivities which retain suitable clinical efficacy but exhibit minimal toxicity. After review of cultural reports, many patients have demonstrated polymicrobial infection. Because experimental clinical evidence supports the concept of aerobic-anaerobic synergy, therapy should be directed against all potential components of the infection if the body site is such that these microorganisms may be present.
194 The following statement(s) is/are true concerning newer detection methods of systemic infection.
a. Enzyme-linked immunosorbent assay (ELISA) is a rapid immunologic assay used for both antigen and antibody detection
b. Southern, northern, and western immunoblot techniques are used to detect DNA, RNA, or proteins, respectively
c. Polymerase chain reaction (PCR) is a sensitive assay used to detect small amounts of microbial DNA, thus detecting infection at its early stages
d. Infectious agents currently detected using advanced molecular techniques include cytomegalovirus (CMV) and human immunodeficiency virus (HIV)
Answer: a, b, c, d
Although the classic detection of infection based on clinical signs of infection and bacterial culture remain the most common clinical tools, increasing reliance has been placed on assays that do not employ cultural data. Specifically, the antibody and cytokine host responses are being intensely examined and extremely sensitive amplified assays that rely on antigen, antibody or microbial DNA detection are employed in the clinical setting. Enzyme-linked immunosorbent assay (ELISA) is a rapid, antigen-based, immunologic assay that can be used for both antigen and antibody detection, for determination of antibody titer, as well as for screening for monoclonal antibody production. Transblot techniques are being used increasingly in the clinical setting. These include southern, northern, and western immunotransblot techniques used to detect DNA, RNA, or proteins, respectively. The polymerase chain reaction (PCR) is being used in some centers as a sensitive assay to detect small amounts of microbial DNA. This technique involves extraction of the DNA from the test sample with in vitro amplification through repeated nucleic acid denaturing and polymerization so that the gene copy number increases exponentially. This marked amplification of the gene copy number results in extremely sensitive tests which can detect infection at its early stages.
Clinically, these detection methods are being used to detect a wide variety of infectious agents including CMV and HIV. Furthermore, preliminary investigations into possible detection of fungal pathogens are underway.
195 Cytokines are low-molecular-weight polypeptides exerting a wide variety of biologic effects at both local and systemic levels. Which of the following statement(s) is/are true concerning the production and actions of cytokines?
a. Cytokines are produced solely by macrophages
b. Cytokines act only on other cells within the same local environment
c. Cytokines may have both protective and deleterious effects on the host
d. Each specific cytokine is produced by a single cell type
Answer: c
Macrophages, endothelial cells, lymphocytes, and other cells secrete a large number of different compounds, termed cytokines, that are most probably evolved for the purpose of local intercellular and intracellular signaling. Cytokines frequently are secreted after initial lymphocyte or macrophage activation, and may act on the secreting cell itself (autocrine activation) or on other cells within the same local environment (paracrine activation) to cause increased secretion of the same cytokine or other cytokines, respectively. Some cytokines are produced by several cell types, and most produce a wide array of effects. The duality of the effects of the cytokine component of host defenses, exerting both salutatory and deleterious effects on the host, has become increasingly evident.
196 The following statement(s) is/are true concerning cellular defense mechanisms.
a. Macrophages function solely as antigen processing cells in the initial reaction to exposure to an antigen
b. Macrophages may become activated and secrete cytokines
c. Macrophages serve as phagocytic cells in the tissues but not within the bloodstream
d. Polymorphonucleocytes (PMNS) are normally present in only small numbers within the tissue and enter an area of infection through diapedesis
Answer: b, d
A wide variety of cell types serve to provide host defense at several levels. Macrophages act as the initial antigen processing cell that serves to present antigen to help T cells, thus initiating the immune response. Macrophages, however, are pluripotent cells that, in the process of engulfing and processing antigen, may become activated. Activated macrophages secrete a variety of cytokines. Macrophages also act as phagocytic cells in the tissues and within the bloodstream, and because of their resident nature in many tissues, also represent the first line of host defenses in many areas of the body, even before activation. PMNS are present within the bloodstream, but only in small numbers within the tissue, and enter an area of infection through diapedesis after chemotactic stimuli are excluded by macrophages, bacterial breakdown products, and complement activation.
197 A diabetic develops a severe perineal infection with skin necrosis, subcutaneous crepitance, and drainage of a thin, watery, grayish and foul-smelling fluid. Management should consist of:
a. Gram stain of the fluid, which will likely demonstrate multiple bacteria including predominantly gram-positive rods
b. A CT scan is indicated in a stable patient to define the extent of the disease
c. Broad spectrum antibiotics followed with prompt extensive debridement is indicated
d. A safe guideline is to resect infected necrotic tissue so that a several centimeter margin of grossly normal, healthy tissue can be achieved
e. A colostomy is of little benefit in this situation
Answer: a, b, c, d
The presence of severe perineal infection (referred to as Fournier gangrene when this process involves the perineum and scrotum in males) is associated with a continued high mortality despite aggressive and appropriate therapy. The clinical description provided would suggest an underlying soft tissue necrosis. In a stable patient radiologic studies including a CT scan to define the extent of the disease and the presence of pelvic infection is indicated. Gram stain will likely show evidence of polymicrobial organisms but the presence of Clostridia marked by gram-positive rods would suggest involvement with this organism. Prompt, aggressive and extensive debridement to remove all devitalized and affected tissue and the addition of broad spectrum antibiotics, fluid resuscitation, hemodynamic monitoring, and nutritional support would appear to afford the patient the best chance of survival. The clearest guidelines to determine the limits of resection involve removal of clearly infected, necrotic tissue so that margins several centimeters into grossly normal, healthy tissue are achieved. Because the entire perineal region and buttocks are frequently involved in these patients, performance of a fecal stream diversion by means of a colostomy often provides improved wound care and patient management, although it is not invariably a positive outcome.
198 The use of prophylactic antibiotics has become commonplace. Which of the following statement(s) is/are true concerning the prophylactic use of antibiotics?
a. The appropriate use of prophylactic antibiotics must include the initiation of the agent prior to the surgical procedure
b. Continuing the antibiotic into the postoperative period has led to improved results in antibiotic prophylaxis
c. The prophylactic administration of broad-spectrum agents (third-generation cephalosporins) has been shown to be particularly advantageous
d. The topical use of antimicrobial agents is of no advantage in the prophylactic setting
Answer: a
Intravenous administration of an antibiotic is clearly indicated for patients undergoing clean contaminated operations. These antibiotics should be administered prior to surgery to obtain adequate tissue levels at the time of potential contamination. However, there has been no added benefit demonstrated for the postoperative use of antibiotics with regard to prophylaxis. The choice of antibiotic is a complex issue which remains unresolved largely because both superficial and deep wound infections can occur as a result of either or both skin (superficial wound) flora (e.g., Staphylococcus aureus) and body site (deep wound) infection. For this reason, the administration of agents which possess activity directed against these expected agents is reasonable. Although administration of a first-generation cephalosporin is acceptable, second-generation cephalosporins or extended-spectrum penicillins with gram-positive and gram-negative activity and biliary tract excretion may be more suitable for patients undergoing gastrointestinal or biliary tract procedures. Similarly, the use of agents with additional anaerobic activity for patients undergoing gastrointestinal procedures involving the small bowel or colon should be considered. The administration of broad-spectrum agents such as third-generation cephalosporins for prophylaxis does not seem to provide additional benefit in comparison to the above-mentioned type antibiotics and may foster the development of resistant organisms within a given institution or superinfection within a given patient. There is evidence that in some cases the topical use of antimicrobial agents is equivalent to the administration of intravenous antimicrobial agent antibiotics.
199 If a necrotizing soft tissue infection is considered, therapy mandates:
a. Empiric administration of antibiotics active against gram-positive, gram-negative, and anaerobic bacteria
b. Due to usually resistant species, penicillin is not indicated
c. Immediate operative intervention and aggressive resection of all involved tissues is mandatory
d. The use of hyperbaric oxygen has been demonstrated to be clearly advantageous
Answer: a, c
Identification of a necrotizing, soft tissue infection mandates immediate operative intervention with aggressive resection of all involved tissues and empiric administration of antibiotics active against gram-positive, gram-negative, and anaerobic bacteria. In most cases, this involves the use of several antimicrobial antibiotics in combination. Because of concern in all cases for the presence of Clostridia infection, high doses of aqueous penicillin G are administered. Gram-positive organisms are treated with vancomycin or a semisynthetic penicillin and gram-negative organisms are treated with an aminoglycoside or a monobactam. Anaerobic coverage is typically achieved by use of metronidazole of clindamycin. The use of hyperbaric oxygen therapy is controversial and unfortunately due to the rarity of the disease, prospective randomized data is not available so that the literature remains without controlled trials demonstrating any additional benefits derived from hyperbaric oxygen therapy.
200 Wounds are classified according to the likelihood of bacterial contamination. Which of the following statement(s) is/are true concerning wound classifications?
a. A clean-contaminated wound would be that associated with an elective colon resection with adequate mechanical and antibiotic bowel preparation
b. A contaminated wound would include a resection of obstructed bowel with gross spillage of intestinal contents
c. In a clean wound, no viscus is entered
d. Antibiotic prophylaxis should be administered for all clean-contaminated and contaminated wounds and selectively in patients involving a clean wound
Answer: a, b, c, d
Wounds are classified under three classes according to the likelihood of bacterial contamination: 1) clean (no viscus is entered; e.g., herniorrhaphy); 2) clean-contaminated (minimal contamination; e.g., elective colon resection with adequate mechanical and antibiotic bowel preparation, and 3) contaminated (heavily contaminated surgery; e.g., resection of unprepared, obstructed bowel with gross spillage of intestinal contents or stool, drainage of abscesses, debridement of traumatic neglected wounds). Antibiotic prophylaxis generally should be administered for class 2 and 3 types of wounds, but patients undergoing clean surgery do not always require antimicrobial antibiotic prophylaxis. An exception to this tenet involves cases in which a prosthetic material may be used (artificial joint, heart valve, tissue patch).
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