Chad E. Jacobs, M.D., Leonard A. Valentino, M.D., Lisa N. Boggio, M.S., M.D., Bruce C. McLeod, M.D.
1 With regard to normal hemostasis, which of the following statements is true?
A Vascular disruption is followed by vasoconstriction mediated by vasoactive substances released by activated platelets.
B Platelet adhesion is mediated by fibrin monomers.
C The endothelial surface supports platelet adhesion and thrombus formation.
D Heparin inhibits adenosine diphosphate (ADP)-stimulated platelet aggregation.
E A prolonged bleeding time may be due to thrombocytopenia, a qualitative platelet defect, or reduced amounts of von Willebrand factor.
Ref.: 1-3
Comments
Blood fluidity is maintained by the action of inhibitors of blood coagulation and by the nonthrombogenic vascular surface. Three physiologic reactions mediate initial hemostasis following vascular injury: (1) the vascular response (vasoconstriction) to injury; (2) platelet activation, adherence, and aggregation; and (3) generation of thrombin with subsequent conversion of fibrinogen to fibrin. Injury exposes subendothelial components and induces vasoconstriction independent of platelet participation, which results in decreased blood flow but an increase in local shear force. Within seconds, platelets are activated by the increase in shear force and adhere to exposed subendothelial collagen by a mechanism dependent on the participation of von Willebrand factor. Adhesion stimulates the release of platelet ADP, thereby mediating the recruitment of additional platelets. Fibrinogen binds to activated platelet receptors, and platelet aggregation follows to create a primary hemostatic plug. Formation of the plug requires calcium and magnesium and is not affected by heparin. Bleeding time measurements reflect the time that it takes to form this platelet plug. A reduction in platelet number or function, loss of vascular integrity, or a reduction in the amount or function of von Willebrand factor may prolong the bleeding time.
Answer
E
2 With regard to drug effects and platelet function, which of the following statements is true?
A Vasoconstricting agents such as epinephrine, prostaglandin G2 and H2 (PGG2 and PGH2), and thromboxane A2 reduce levels of cyclic adenosine monophosphate (cAMP) and induce platelet aggregation.
B Vasodilators such as prostaglandin E1 (PGE1), prostacyclin (PGI2), theophylline, and dipyridamole elevate cAMP levels and block platelet aggregation.
C Aspirin and indomethacin interfere with platelet release of ADP and inhibit aggregation.
D Furosemide competitively inhibits PGE2.
E The effect of aspirin is reversible in 2 to 3 days.
Ref.: 1-4
Comments
Aspirin, indomethacin, and most other nonsteroidal antiinflammatory drugs (NSAIDs) are inhibitors of prostaglandin synthesis. They block the formation of PGG2 and PGH2 from platelet arachidonic acid and, as a result, inhibit platelet aggregation. PGI2, PGE1, and thromboxane A2 stimulate cAMP production, whereas dipyridamole and theophylline derivatives block its degradation. Aspirin inhibits thromboxane production, acetylates fibrinogen, interferes with fibrin formation, and makes fibrin susceptible to accelerated fibrinolysis. The effect of aspirin begins within 2 hours, is irreversible, and lasts the 7- to 9-day life span of affected platelets. The clinical result is increased bruising and bleeding and increased risk for surgical bleeding. Platelet counts are normal, but the bleeding time is prolonged. Furosemide competitively inhibits ADP-induced platelet aggregation and reduces the response of platelets to PGG2. Furosemide may also cause thrombocytopenia. A wide variety of drugs inhibit platelet function.
Answer
B
3 With regard to blood coagulation, which of the following statements is true?
A The principal complex initiating blood coagulation is the tissue factor (TF)–factor VIIa complex.
B Coagulation is initiated in the fluid phase of blood.
C Only endothelial cells express TF.
D The factor Xa-Va complex converts fibrinogen to fibrin in quantities sufficient to activate platelets.
E Antithrombin is the main regulator of blood coagulation.
Ref.: 1, 2
Comments
Coagulation is initiated on a phospholipid surface, such as the monocyte or fibroblast membrane, following expression of TF. TF binds factor VII, which is then activated by minor proteolysis through an autocatalytic mechanism or by the action of thrombin or other serine proteases. The TF–factor VIIa complex is a potent serine protease that activates factors X and IX. Factor Xa combines with factor Va on the phospholipid surface to convert prothrombin to thrombin. The amount of thrombin generated by this reaction is insufficient for the formation of a stable fibrin clot. It is sufficient, however, to activate platelets, dissociate factor VIII from von Willebrand factor, and activate factors V, VIII, and XI. Factor IXa, formed by the action of the TF–factor VIIa complex, binds to activated platelets and associates with factor VIIIa, which then recruits circulating factor X to the platelet surface and converts it to factor Xa. Platelet-bound factor Xa and its cofactor, factor Va, generate sufficient quantities of thrombin to form a stable fibrin clot. The catalytic activity of the TF–factor VIIa–factor Xa complex is regulated by tissue factor pathway inhibitor (TFPI). TFPI binds to factor Xa, thereby limiting the activity of the complex.
Answer
A
4 With regard to fibrinolysis, which of the following statements is true?
A Plasmin is not a significant factor in fibrinolysis.
B Plasminogen deficiency results in a clinical bleeding disorder.
C Plasmin acts only on cross-linked fibrin polymers.
D Ischemia is a potent activator of the fibrinolytic system.
E Physiologic fibrinolysis does not occur.
Ref.: 1-3
Comments
Plasminogen is converted to plasmin by a number of enzymes, including blood-borne activators and tissue activators such as thrombin, streptokinase, urokinase, and kallikrein. Ischemia is also a potent stimulator of activation of the fibrinolytic system. Plasmin acts on fibrin, fibrinogen, factor V, and factor VIII. Physiologic fibrinolysis is the result of the natural affinity of plasminogen for fibrin. Plasminogen is incorporated into the clot, and fibrinolysis is locally controlled. Pathologic fibrinolysis occurs when plasminogen that is free in plasma is activated, which leads to the proteolysis of fibrinogen, fibrin, and other coagulation factors. Unrestrained fibrinolysis can result in bleeding for several reasons: small fibrin fragments are capable of interfering with normal platelet aggregation, large fibrin fragments join the clot instead of the normal monomers and produce an unstable clot, fibrin fragments interfere with cleavage of fibrinogen by thrombin, and destruction of clotting factors other than fibrin results in a consumptive coagulopathy. Blood and platelets contain antifibrinolytic substances capable of inhibition of plasminogen. Physiologic fibrinolysis plays an important role in tissue repair, cancer metastasis, ovulation, and embryo implantation. Disorders of fibrinolysis can result from excessive activity (bleeding) or insufficient activity (thrombosis).
Answer
D
5 With regard to measurement of bleeding times, which of the following statements is true?
A Spontaneous bleeding may occur with platelet counts higher than 15,000/µL.
B Platelet counts higher than 150,000/µL exclude the possibility of a primary hemostatic disorder.
C Bleeding time is a predictor of surgical bleeding.
D Platelet counts higher than 50,000/µl are usually associated with a normal bleeding time and adequate surgical hemostasis.
E Normal bleeding time excludes von Willebrand disease as a potential factor affecting surgical hemostasis.
Ref.: 1, 3
Comments
The bleeding time is a crude measure of platelet function, the number of platelets, or both. The normal value is 3 to 9 minutes and implies normal platelet function and counts greater than 50,000/µl. Spontaneous bleeding rarely occurs when the platelet count is greater than 30,000/µl. The bleeding time is prolonged in patients with normal platelet counts in whom qualitative abnormalities are present as a primary platelet disorder or one secondary to drugs, uremia, or liver disease or in those who have thrombasthenia or a variety of other defects in platelet function. Patients with defective platelets or capillaries, those with von Willebrand disease, and those with a history of recent ingestion of aspirin, NSAIDs, antibiotics (penicillins and cephalosporins), and a wide variety of miscellaneous drugs also have prolonged bleeding times. False-negative (normal) bleeding times are frequently due to the technical difficulty of performing the test and its lack of sensitivity. For example, only 60% of patients with von Willebrand disease have a prolonged bleeding time. Other tests of platelet function include assessment of platelet aggregation in response to a variety of agonists.
Answer
D
6 Which of the following conditions is associated with an isolated prothrombin time (PT) prolongation?
A von Willebrand disease
B Factor VIII deficiency (hemophilia A)
C Common pathway factor deficiencies (factors II, V, and X and fibrinogen)
D Therapeutic anticoagulation with warfarin (Coumadin)
E Therapeutic anticoagulation with heparin
Ref.: 1, 2
Comments
The one-stage prothrombin time is used to measure the function of fibrinogen and factors II, V, X, and VII. The partial thromboplastin time (PTT) reflects the function of fibrinogen and factors II, V, X, VIII, IX, XI, and XII. Fibrinogen and factors II, V, and X are common to both tests. Both tests require comparison with normal control values obtained daily in the laboratory. Because of the antithrombin effect of heparin, even trace amounts prolong the PTT and thrombin time. At least 5 hours must elapse after the last dose of intravenous heparin before the PTT can be reliably interpreted. The thrombin time is a measure of the ability to generate fibrin and is prolonged by deficiencies and abnormalities of fibrinogen or the presence of heparin or fibrinogen degradation products. The thrombin time, together with the PT and PTT, can distinguish whether factors are deficient in the first or second stage of coagulation. A normal PT and thrombin time with an abnormal PTT in the absence of clinical bleeding suggest deficiencies of factor XII, high-molecular-weight kininogen, or prekallikrein or the presence of a lupus anticoagulant. The same laboratory values obtained for a bleeding patient suggest deficiency of factor VIII, IX, or XI. A normal PTT and thrombin time with an abnormal PT suggest factor VII deficiency. A prolonged thrombin time with an abnormal PTT and PT suggests the presence of hepatocellular liver disease or a consumptive coagulopathy if the platelet count is decreased or an abnormality of fibrinogen if the platelet count is normal. Factor VIII is synthesized in the endothelial cells of the liver and is therefore not affected by hepatocellular disease. A decrease in factor VIII can be used to differentiate consumptive coagulopathy (reduced levels of all factors) from hepatocellular liver disease (reduced levels of all factors except factor VIII). The PTT is also prolonged by heparin administration and can be used to monitor its efficacy. Calculation of the international normalized ratio (INR) from the PT is the preferred method of controlling anticoagulation with warfarin (Coumadin). Vitamin K is necessary for the full function of factors II, VII, IX, and X, and therefore its deficiency is reflected by prolongation of both the PT and PTT.
Answer
D
7 All of the following statements regarding complications of transfusion are false except:
A Febrile reactions are rare.
B Gram-positive organisms are the most common contaminants of stored blood.
C Screening for minor antigens should be repeated every week when multiple transfusions are given.
D A small amount (more than 0.1 cc) of intravenous air is well tolerated.
E Malaria, Chagas disease, human T-cell leukemia virus I (HTLV-I), acquired immunodeficiency syndrome (AIDS), and hepatitis can be transmitted by blood transfusions.
Ref.: 1, 4
Comments
Febrile reactions are the most common complications of red blood cell and platelet transfusions and occur once per 100 units given. Fever and chills are the usual symptoms. If mild, these symptoms respond to antipyretics. In severe cases, they are treated with opiates. Urticarial reactions are the most common reaction to plasma transfusions. They usually respond to antihistamines. Anaphylactic reactions are rare and are treated with epinephrine and steroids. Although unusual, gram-negative organisms capable of surviving at 4° C are the most common cause of bacterial contamination of banked blood. Platelets, which are optimally stored at room temperature and are being used increasingly, are a more frequent source of sepsis, usually with gram-positive organisms. Air embolism has become rare since bottles have been replaced by collapsible plastic containers. Even small volumes of air have the potential to cause fatal complications and should be avoided whenever possible. Hepatitis viruses B and C (HBV and HCV), human immunodeficiency virus (HIV), HTLV-I and HTLV-II, malaria, Chagas disease, and other infections can be transmitted by transfusion. Specific testing of donors is available for HBV, HCV, HIV, and HTLV. Health, immigration, and travel histories are used to exclude donors who may harbor malaria or Chagas disease and are being used to control a perceived “theoretical risk” for variant Creutzfeldt-Jakob disease. Recipient alloimmunization to “minor” antigens may occur after multiple transfusions, in which case red blood cells lacking the relevant antigen must be transfused. To detect or exclude such alloimmunization, recipient serum samples should be screened for antibodies. This screening should be repeated every 48 to 72 hours if multiple transfusions are given. It can take several hours to identify the blood’s antibody specificity (e.g., anti-C and anti-K antibodies) and find donor red blood cells that lack the relevant antigen or antigens. This unavoidable delay can be problematic for same-day surgery patients who have not had a blood bank sample drawn in advance.
Answer
E
8 With regard to evaluating bleeding in surgical patients, which of the following statements is true?
A Bleeding from a resected prostatic bed indicates poor local hemostasis.
B The most common cause of surgical bleeding is incomplete mechanical hemostasis.
C ε-Aminocaproic acid is an excellent topical hemostatic agent for nonmucosal wounds.
D Bleeding from a surgical wound along with bleeding from other sites implies poor local hemostasis.
E The bleeding time is an excellent predictor of surgical bleeding.
Ref.: 1, 2, 4
Comments
Bleeding from the surgical wound suggests ineffective local hemostasis, particularly if associated wounds (e.g., drain sites, tracheostomy wounds, or intravenous infusion sites) are not bleeding. An exception is isolated bleeding from a resected prostatic bed, in which prostate-borne plasminogen activators can be activated by urokinase. Activation is inhibited by ε-aminocaproic acid. Blood transfusions can lead to bleeding via a number of mechanisms. Transfusion of more than one blood volume produces thrombocytopenia by dilution. Patients bleeding after a large number of blood transfusions should be considered thrombocytopenic and be treated as such. Nonetheless, additional evaluation is indicated because an alternative explanation for transfusion-associated bleeding is a hemolytic transfusion reaction. In such an instance, disseminated intravascular coagulopathy (DIC) is caused by thromboplastic activity of factors liberated from the stroma of lysed red blood cells. Extracorporeal circulation may induce hemostatic failure as a result of thrombocytopenia, inadequate reversal of heparinization, or overadministration of protamine. Septic surgical patients may bleed because of endotoxin-induced thrombocytopenia. Defibrination and bleeding may occur in patients with meningococcemia, Clostridium perfringens sepsis, or staphylococcal sepsis. Uncommonly, an operation on tissues rich in fibrinolytic activity, such as those of the pancreas, liver, or lungs, may lead to pathologic fibrinolysis and bleeding.
Answer
B
9 When evaluating a patient who bleeds unexpectedly, which of the following statements is true?
A The most reliable test for detecting patients at risk for bleeding is a platelet count.
B Infants who do not bleed during circumcision have normal hemostatic function.
C An isolated episode of gastrointestinal bleeding is often associated with generalized hemostatic disorders.
D Jaundice is a sign of an underlying congenital bleeding disorder.
E The presence of healthy parents and siblings does not exclude the possibility of a primary hemostatic disorder.
Ref.: 2, 3
Comments
No single test for detecting patients at risk for bleeding exists. The best protocol is a complete history and physical examination. Many normal individuals consider themselves to have a positive bleeding history. Because aspirin is contained in a wide variety of over-the-counter medications, its use is easily overlooked in the patient’s medical history. Circumcision typically involves significant trauma to tissues and activation of the TF–factor VIIa pathway. Just 30% of affected males bleed following circumcision. Only rarely do patients with a bleeding disorder undergo tooth extraction or tonsillectomy without encountering a bleeding problem. Some patients with a severe bleeding disorder experience bleeding with tooth eruption. Isolated gastrointestinal bleeding is unusual in patients with congenital bleeding disorders. Epistaxis is one of the most common symptoms of von Willebrand disease and platelet disorders. Excessive menstrual flow (menorrhagia), but not intermenstrual bleeding, is common in patients with hemostatic disorders. Because inherited bleeding defects may be autosomal dominant, autosomal recessive, or sex-linked recessive, an inquiry into the family history should account for bleeding problems in grandparents, aunts, uncles, and cousins. Since patients’ assessment of severity is subjective, objective indicators should be sought, such as need for a prolonged hospital stay for minor surgery, transfusion, and anemia. A search for ecchymosis or petechiae, particularly near pressure points, is essential. The lesions of hereditary hemorrhagic telangiectasia are found on the lips, underneath the fingernails, and around the anus. Signs of liver disease suggest the presence of an acquired deficiency of the prothrombin complex, not a predisposition to primary hemostatic disorders.
Answer
E
10 With regard to classic hemophilia, which of the following statements is true?
A The incidence in the general population is 1 in 5000.
B A given patient’s baseline factor VIII or IX level may fluctuate with stress.
C Muscle compartment bleeding is the most common orthopedic problem.
D Factor VIII replacement therapy is required before any elective surgery.
E Therapy with cryoprecipitated plasma is free of risk for hepatitis.
Ref.: 1-3
Comments
Bleeding in patients with hemophilia usually appears during early childhood. Hemarthrosis is the most common orthopedic problem. Epistaxis, hematuria, and intracranial bleeding may occur. Equinus contracture, Volkmann contracture of the forearm, and flexion contracture of the elbows or knees are sequelae of these bleeding episodes. Retroperitoneal or intramural intestinal bleeding may produce abdominal symptoms. The level of factor VIII or IX in plasma (which tends to remain stable throughout life) determines the tendency to bleed. Spontaneous bleeding is frequent in patients with severe disease, defined as less than 1% factor VIII or IX activity. Bleeding typically occurs with trauma in patients with moderately severe disease, defined as 1% to 5% factor activity. In patients with mild hemophilia A or B, defined as 6% to 25% factor activity, bleeding typically occurs only with major trauma or surgery. The factor VIII or IX level must be raised to at least 30% to achieve hemostasis and control minor hemorrhage. A level of approximately 50% is required to control joint and muscle bleeding, whereas a level of 80% to 100% is necessary to treat life-threatening hemorrhage (central nervous system, retroperitoneal, or retropharyngeal bleeding) and to prepare patients for elective surgery. After elective surgery, levels of 25% should be maintained for at least 2 weeks. Transmission of hepatitis or HIV, the development of neutralizing antibodies, and qualitative platelet dysfunction are possible complications of factor replacement therapy. Appropriate replacement includes infusions of factor VIII and factor IX. These products are available in both recombinant and highly purified concentrates that are virally inactivated. Cryoprecipitate is not optimal replacement therapy for factor VIII and von Willebrand factor, does not contain factor IX, and is associated with a risk of viral transmission.
Answer
D
11 A 12-year-old boy with known factor VIII deficiency has a painful, swollen, immobile right knee. The clinician suspects hemarthrosis. Therapeutic options include which of the following?
A Immediate aspiration and compression dressings to prevent cartilage necrosis
B Compression dressings and immobilization to prevent further bleeding
C Immediate aspiration after appropriate factor VIII replacement therapy
D Initial trial of factor VIII therapy, compression dressings, cold packs, and rest followed by active range-of-motion exercises
E None of the above is an appropriate option
Ref.: 1, 2
Comments
Treatment of hemarthrosis is aimed at preventing chronic synovitis and degenerative arthritis. Early, intensive factor VIII therapy is critical for limiting the extent of hemorrhage. Factor VIII replacement therapy is most effective when initiated before swelling of the joint capsule. Frequently, replacement therapy is initiated before the onset of any objective physical findings, when the patient perceives only subtle signs of joint hemorrhage. Factor VIII therapy, joint rest, compression dressing, and cold packs constitute the usual initial therapy. Aspiration is to be avoided. The goal of treatment of hemarthrosis is maintenance of range of motion. Active range-of-motion exercises should begin 24 hours after factor VIII therapy. Compression and cold packs should be continued for 3 to 5 days.
Answer
D
12 With regard to von Willebrand disease, which of the following statements is true?
A It is more common than hemophilia.
B It is best treated with cryoprecipitated plasma.
C Factor VIII levels are constant over time in a given patient.
D There is an associated platelet abnormality in 30% of patients.
E Bleeding after elective surgery is rare.
Ref.: 1, 2
Comments
von Willebrand disease is the most common congenital bleeding disorder, with 1% of the population being affected. The prevalence of patients with symptomatic bleeding is approximately 1 in 1000. Most patients have mild disease unless challenged by trauma or surgery. von Willebrand disease is associated with a variable deficiency of both von Willebrand factor and factor VIII. A platelet defect is also present in most patients. The severity of coagulation abnormalities varies from patient to patient and from time to time for a given patient. In all but 1% to 2% of patients, the bleeding manifestations are milder than those of classic hemophilia. In the same group of patients with type 3 von Willebrand disease, bleeding is more severe than in hemophilia. Bleeding is treated with desmopressin (DDAVP), which induces the release of von Willebrand factor from storage sites in endothelial cells and platelets. The effect of DDAVP is rapid, with maximal procoagulant effects being reached in 1 to 2 hours. The effects dissipate quickly (within 12 to 24 hours), thus necessitating repeated dosing. When more than two or three doses of DDAVP are given, the effects may diminish or are absent. DDAVP is most effective for type 1 disease and is not effective for type 3 disease. Because of a risk for thrombocytopenia, DDAVP is specifically contraindicated for type 2B disease but may be effective for other forms of type 2 disease. In type 3 and most type 2 von Willebrand disease, specific von Willebrand factor replacement product should be administered.
Answer
A
13 With regard to hereditary hemostatic disorders, which of the following statements is not true?
A Deficiencies of any of the four vitamin K–dependent factors (II, V, VII, and X) may be treated with stored plasma.
B Factor VII has the shortest intravascular half-life of any clotting factor.
C Factor IX deficiency is clinically indistinguishable from factor VIII deficiency.
D Factor V is known as a labile factor.
E Factor XI deficiency is treated with plasma.
Ref.: 2, 4
Comments
Factor V is not vitamin K dependent. Factor VIII and IX deficiencies are clinically indistinguishable. Bleeding in patients with factor IX deficiency (Christmas disease) is treated with factor IX concentrate. Prothrombin complex concentrate (PCC) contains mainly the vitamin K–dependent clotting factors. Use of PCC may be complicated by thrombosis or DIC. In older patients, administration of PCC should be accompanied by prophylactic administration of low-dose heparin. Deficiency of factor XI (Rosenthal syndrome) or factor V is treated with plasma. Because factor V is labile and activity is lost with storage, fresh plasma is necessary. Deficiency of factor VII is treated with recombinant activated factor VII (rFVIIa), and deficiency of factor X (Stuart-Prower deficiency) or II is treated with plasma or PCC. The duration and frequency of treatment with plasma-derived products are inversely proportional to the intravascular half-life.
Answer
A
14 True statements regarding acquired hypofibrinogenemia include which of the following?
A The thrombin time aids in differentiating primary fibrinolysis from DIC.
B Release of excessive plasminogen activators causes pathologic fibrinolysis.
C Primary fibrinolysis can be differentiated from DIC on the basis of the PT, PTT, and thrombin time.
D The most important aspect of the treatment of DIC is adequate heparinization.
E Thrombocytopenia is common with pure fibrinolysis.
Ref.: 1-3
Comments
DIC results from the introduction of thromboplastic material into the circulation, which leads to activation of the coagulation system and secondary “protective” fibrinolysis (Box 3-1). Transfusion reactions, crush injuries, hemorrhagic perinatal complications, disseminated cancer, and bacterial sepsis have been implicated as causes. The release of excessive plasminogen-activating substances leads to primary pathologic fibrinolysis. Shock, hypoxia, sepsis, disseminated prostate cancer, cirrhosis, portal hypertension, and peritoneovenous shunts are possible causes. The thrombin time is a measurement of the clotting time of plasma. In the absence of heparin or the by-products of fibrinolysis, fibrinogen abnormalities or deficiencies may be detected. Pathologic fibrinolysis causes a prolonged thrombin time, as well as rapid whole blood clot dissolution. Whole blood clot lysis, which normally takes as long as 48 hours, may occur in as few as 2 hours in patients with increased fibrinolysis. The presence of a paraprotein may cause false-positive results for the thrombin time and other tests based on whole blood clotting measurements. Differentiation between DIC and “protective” fibrinolysis on laboratory grounds alone is difficult, although thrombocytopenia is rarely seen with pure fibrinolysis. For both entities, treating the underlying medical or surgical problem is the most important single step. With disseminated intravascular coagulopathy, maintenance of a patent microcirculation is important. Adequate fluid volumes and heparinization may be necessary. Active bleeding should be appropriately treated with factor replacement and does not accelerate DIC. Clotting factors can be replenished with fresh frozen plasma and cryoprecipitate. Heparin alone is rarely useful for the treatment of acute DIC. Activated protein C concentrates may be beneficial. Administration of heparin to patients with primary pathologic fibrinolysis can be dangerous, as is administering ε-aminocaproic acid to patients with secondary fibrinolysis. Correction of the underlying cause is the most important component in the treatment of DIC.
BOX 3-1 Examples of Disseminated Intravascular Coagulation Syndromes
“Fast” DIC
Amniotic fluid embolism
Abruptio placentae
Septic abortion
Septicemia
Massive tissue injury
Incompatible blood transfusion
Purpura fulminans
“Slow” DIC
Acute promyelocytic leukemia
Dead fetus syndrome
Transfusion of activated prothrombin complex concentrates
Carcinomas
Kasabach-Merritt syndrome
Liver disease
Answer
B
15 With regard to polycythemia vera, which of the following statements is not true?
A Spontaneous thrombosis is a complication of polycythemia vera.
B Spontaneous hemorrhage is a possible complication of polycythemia vera.
C The reason for bleeding is a deficit in platelet function.
D A hematocrit of less than 48% and a platelet count of less than 400,000/µl are desirable before an elective operation is performed on a patient with polycythemia vera.
E Postoperative complication rates may be as high as 60%.
Ref.: 2, 3
Comments
Patients with untreated polycythemia vera are at high risk for postoperative bleeding or thrombosis. The complication rate is highest with uncontrolled erythrocytosis. Increased viscosity and platelet count, along with a tendency toward stasis, may explain the spontaneous thrombosis seen in patients with polycythemia vera. Patients most likely to bleed are those with platelet counts greater than 1.5 million/µl. Polycythemia vera may cause a qualitative defect in platelet function. When possible, surgery should be delayed until the hematocrit and platelet count can be medically reduced. Phlebotomy may help in acute situations. Complication rates as high as 46% have been reported in patients with polycythemia vera undergoing surgery. Spontaneous hemorrhage, thrombosis, a combination of hemorrhage and thrombosis, and infection are the major complications.
Answer
E
16 With regard to anticoagulation, which of the following statements is not true?
A Warfarin (Coumadin) inhibits the generation of vitamin K–dependent factors (II, VII, IX, and X).
B Heparin enhances the effect of antithrombin on thrombin-mediated conversion of fibrinogen to fibrin.
C Theoretically, 1.28 mg of protamine neutralizes 1 mg of heparin.
D The effects of vitamin K reversal take 48 hours.
E An INR of 1.5 or less is considered safe for surgery.
Ref.: 2, 5
Comments
With meticulous hemostatic technique, many operations can be performed on patients with an international normalized ratio of 1.5 or less. Exceptions include operations on the eye or the prostate, neurosurgical procedures, or blind needle aspiration. In these cases, an INR of less than 1.2 is required. Patients who are undergoing anticoagulant treatment with warfarin and require emergency surgery may be given plasma to immediately reverse the warfarin effect. Alternatively, vitamin K may be given orally or subcutaneously at least 6 hours preoperatively to reverse the effect of warfarin on vitamin K–dependent factors. The INR should be determined again before surgery, and if it is not below 1.5, plasma should be administered. The efficacy of rFVIIa and PCC in reversing the INR has been demonstrated in several clinical scenarios. These agents have the advantage of directly activating the hemostatic mechanism and generating high concentrations of thrombin. Use of rFVIIa should be reserved for patients with life-threatening hemorrhage and a significantly elevated INR (>6) in whom emergency surgery is anticipated. An INR greater than 1.5 is a contraindication to intramuscular medications.
Answer
D
17 With regard to the storage of banked blood, which of the following statements is true?
A Packed red blood cells stored in additive solution (AS-3) and kept at 4° C are suitable for transfusion for 3 months.
B Platelets in banked blood retain their function for 3 days.
C Factors II, VII, IX, and XI are stable at 4° C.
D A decrease in red blood cell oxygen affinity occurs during storage as a result of a decrease in 2,3-diphosphoglycerate (2,3-DPG) levels.
E There is a significant rate of hemolysis in stored blood.
Ref.: 4
Comments
Packed red blood cells properly collected and stored at 4° C in AS-3 additive solution are “good” for 42 days. The proportion of cells removed from the circulation within 24 hours of transfusion increases with time that the blood is in storage, with about 25% being depleted at 42 days. This percentage defines satisfactory shelf life. Any blood component that has been stored in an “open” system (e.g., frozen red blood cells after thawing and deglycerolization) has a useful life of just 24 hours because of concerns about contamination. Cells that survive the first 24 hours live out their remaining life span, and some transfused cells can be detected for up to 120 days—the life span of a normal red blood cell. Platelets in packed red blood cells become nonfunctional during the first 6 hours of storage. Red blood cell adenosine triphosphate (ATP) and 2,3-DPG levels fall during storage. Oxygen affinity is increased until 2,3-DPG levels rise again after transfusion. Factors II, VII, IX, and XI are stable at 4° C, whereas factors V and VIII are not. To maintain factor V and VIII activity, plasma must be frozen shortly after the blood is drawn (fresh frozen plasma). Lactic acid concentrations increase and the pH falls in packed red blood cells during storage, whereas potassium and ammonia concentrations rise steadily. The citrate used for preservation may reduce plasma ionized calcium if large volumes are transfused. These metabolites are especially significant in pediatric patients and in those with impaired liver or renal function (or both).
Answer
C
18 In cirrhotic patients who are actively bleeding, the coagulopathy of end-stage liver disease can be differentiated from DIC most readily by estimation of which of the following factors?
A Factor II
B Factor V
C Factor VII
D Factor VIII:C
E Factor X
Ref.: 3
Comments
Of all of the coagulation factors, only factor VIII:C is not produced by hepatocytes. It is manufactured by reticuloendothelial cells, and levels are typically increased in the presence of cirrhosis. Reductions in factor VIII:C are observed in patients with DIC because it is consumed along with the other coagulation factors.
Answer
D
19 With regard to leukocytes in cellular blood components (red blood cells and platelets), which of the following statements is true?
A Febrile reactions occur in 10% of all transfusions.
B Washing red blood cells with saline solution is the best way to remove leukocytes.
C Leukocyte reduction lowers the rate of febrile reactions to cellular components from 10% to 1%.
D Leukocyte reduction of cellular components lowers the risk of alloimmunization to HLA antigens in transfusion recipients.
E Leukocyte reduction of cellular components lowers the risk of wound infection in transfused surgical patients.
Ref.: 4
Comments
Transfused leukocytes may interact with preexisting recipient HLA antibodies. In addition, leukocytes in platelets that are stored at room temperature may elaborate pyrogenic cytokines during storage, such as interleukin-6. Either mechanism may cause a febrile reaction in a susceptible recipient. Leukocyte reduction filters are 100 to 1000 times more effective than washing for removing leukocytes from packed red blood cells. Thus, filtration is the preferred method. (Washed red blood cells are virtually free of plasma proteins and can be given safely to patients who have had severe allergic or anaphylactic reactions to plasma.) Less than 1% of transfusions cause a (usually mild) febrile reaction. Fifty percent to 70% of these reactions may be prevented by leukocyte reduction. Use of leukocyte-reduced components to avoid febrile reactions is justified only in patients who have repeated reactions despite premedication with antipyretics. A more important indication for leukocyte-reduced components is to prevent the formation of HLA antibodies in candidates for kidney, heart, or lung transplantation and in patients expected to need long-term platelet support. Despite a long-standing suspicion that transfusions may be immunosuppressive, large prospective controlled studies have not shown lower mortality rates, shorter hospital stays, or lower rates of postoperative infection in transfused surgical patients who received only leukocyte-reduced cellular components.
Answer
D
20 With regard to hemolytic transfusion reactions, which of the following statements is true?
A They are generally caused by ABO incompatibility.
B Urticaria and pruritus are the most common symptoms.
C Acidification of the urine prevents precipitation of hemoglobin.
D Intravenous diphenhydramine (Benadryl) should be given immediately.
E Laboratory findings include a negative direct hemoglobin test result and no free hemoglobin in a posttransfusion blood sample.
Ref.: 4
Comments
The most common cause of a fatal hemolytic transfusion reaction is a clerical error that results in the transfusion of red blood cells of the wrong ABO type of blood. Because the severity is proportional to the antigen dose, constant awareness, early recognition, and immediate intervention are important. Hemolytic reactions lead to complement-mediated intravascular red blood cell destruction, hemoglobinemia, and hemoglobinuria. They also lead to the release of vasoactive amines through the activation of complement. This in turn results in shock, renal ischemia, tubular necrosis, and renal failure proportional to the depth and duration of hypotension. Red blood cell lipids initiate DIC in 8% to 30% of patients in whom a full unit of mismatched blood has been transfused. However, as little as 10 mL can produce serious hypotension and DIC. Typical signs and symptoms include chills, fever, lumbar and chest pain, pain at the infusion site, and hypotension. In anesthetized patients, diffuse bleeding and continued hypotension suggest the diagnosis. Laboratory criteria are positive direct antiglobulin test results, hemoglobinemia with free hemoglobin concentrations higher than 5 mg/dL, and serologic confirmation of incompatibility. Because hemoglobin is a highly chromogenic molecule, small amounts (as little as 30 mg/dL) can be detected visually. The hemoglobin from as little as 5 mL of red blood cells makes the plasma pink and produces hemoglobinuria. Treatment includes stopping the transfusion, inserting a bladder catheter, and administering mannitol and bicarbonate to encourage excretion of alkaline urine. This helps prevent precipitation of hemoglobin in the renal tubules, which could contribute to tubular necrosis. If oliguria develops, appropriate fluid management and possibly dialysis are begun. The most important treatment is restoration of blood pressure and renal perfusion. Vasopressors may be necessary. A sample of the recipient’s blood is compared with pretransfusion samples to confirm incompatibility. Results of the direct antiglobulin test remain positive for as long as incompatible red blood cells continue to circulate. The serum bilirubin level can be monitored to chart the increase in indirect bilirubin caused by hemolysis.
Answer
A
References
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3 Colman RW, Hirsh J, Marder VJ, et al, editors. Hemostasis and thrombosis: basic principles and practice, ed 5, Philadelphia: JB Lippincott, 2006.
4 Simon TL, Snyder EL, et al, editors. Rossi’s principles of transfusion medicine, ed 4, Oxford: Wiley-Blackwell, 2009.
5 Sorensen B, Johansen P, Nielsen GL, et al. Reversal of the international normalized ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis. 2003;14:469-477.