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TTT-101. The answer is D.(Chap. 116) The hemophilias are X-linked inherited disorders that cause deficiency of factor VIII (hemophilia A) or factor 9 (hemophilia B). The hemophilias affect about one in 10,000 males worldwide with hemophilia A responsible for 80% of cases. Clinically, there is no difference between hemophilia A and B. The disease presentation largely depends on the residual activity of factor VIII or factor IX. Severe disease is typically seen when factor activity is less than 1%, and moderate disease appears when the levels range between 1% and 5%. The clinical manifestation of moderate and severe disease is commonly bleeding into the joints, soft tissues, and muscles that occurs after minimal trauma or even spontaneously. When factor activity is greater than 25%, bleeding would occur only after major trauma or surgery, and the diagnosis may not be made unless a prolonged

activated partial thromboplastin time is seen on routine laboratory examination. To make a definitive diagnosis, one would need to measure specific levels of factor VIII and IX. Without treatment, life expectancy is limited, but given the changes in therapy since the 1980s, life span is about 65 years. Early treatment of hemophilia required the use of pooled plasma that was used to make factor concentrates. Given the large number of donors required to generate the factor concentrates and the frequent need for transfusion in some individuals, bloodborne pathogens such as HIV and hepatitis С are among the leading cause of death in patients with hemophilia. In the 1990s, recombinant factor VIII and IX were developed. Primary prophylaxis is given to individuals with baseline factor activity levels of less than 1% to prevent spontaneous bleeding, especially hemarthroses. Although this strategy is highly recommended, only about 50% of eligible patients receive prophylactic therapy because of the high costs and need for regular intravenous infusions. When an individual is suspected of having a bleed, the treatment should begin as soon as possible and not delayed until factor activity levels return. Factor concentrates should be given to raise the activity level to 50% for large hematomas or deep muscle bleeds, and an individual may require treatment for a period of 7 days or more. For milder bleeds, including uncomplicated hemarthrosis, the goal factor activity level is 30% to 50% with maintenance of levels between 15% and 25% for 2 to 3 days after the initial transfusions. In addition to treatment with factor concentrates, care should be taken to avoid medications that inhibit platelet function. DDAVP, a desmopressin analogue, can be given as adjunctive therapy for acute bleeding episodes in hemophilia A because this may cause a transient rise in factor VIII levels and von Willebrand factor because of release from endothelial cells. This medication is typically only useful in mild to moderate disease. Antifibrinolytic drugs such as tranexamic acid or e-amino caproic acid are helpful in promoting hemostasis for mucosal bleeding.

TTT-102. The answer is D.(Chap. 116) Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy that is characterized by diffuse intravascular fibrin formation that overcomes the body's natural anticoagulant mechanisms. DIC is most commonly associated with sepsis, trauma, or malignancy or in obstetric complications. The pathogenesis of DIC is not completely elucidated, but it involves intravascular exposure to phospholipids from damaged tissue, hemolysis, and endothelial damage. This leads to stimulation of procoagulant pathways with uncontrolled thrombin generation and micro vascular ischemia. A secondary hyperfibrinolysis subsequently occurs. The primary clinical manifestations of DIC are bleeding at venipuncture sites, petechiae, and ecchymoses. Severe gastrointestinal and pulmonary hemorrhage can occur. The clinical diagnosis of DIC is based on laboratory findings in the appropriate clinical setting, such as severe sepsis. Although there is no single test for DIC, the common constellation of findings is thrombocytopenia (<100,000/uL), elevated prothrombin time and activated partial thromboplastin time, evidence of micro-angiopathic hemolytic anemia, and elevated fibrin degradation productions and D-dimer. The fibrinogen level may be less than 100 mg/dLbut often does not decrease acutely unless the DIC is very severe. The primary treatment of DIC is to treat the underlying cause, which in this case would be antibiotic therapy directed against Neisseria meningitidis. For patients such as this one who are experiencing bleeding related to the DIC, attempts to correct the coagulopathy should be undertaken. Platelet transfusions and fresh-frozen plasma (FFP) should be given. In addition, cryoprecipitate is indicated as the fibrinogen level is less than 100 mg/dL. In general, 10 U of cryoprecipitate are required for every 2 to 3 units of FFP. In acute DIC, heparin is not been demonstrated to be helpful and may increase bleeding. Low-dose heparin therapy (5-10 U/kg) is used for chronic low-grade DIC such as that seen in acute promyelocytic leukemia or removal of a dead fetus.

ТТТ-103. The answer is E.(Chap. 116) Vitamin К is a fat-soluble vitamin that plays an essential role in hemostasis. It is absorbed in the small intestine and stored in the liver. It serves as a cofactor in the enzymatic carboxylation of glutamic acid residues on prothrombin-complex proteins. The three major causes of vitamin К deficiency are poor dietary intake, intestinal malabsorption, and liver disease. The prothrombin complex proteins (factors II, VII, IX, and X and protein С and protein S) all decrease with vitamin К deficiency. Factor VII and protein С have the shortest half-lives of these factors and therefore decrease first. Therefore, vitamin К deficiency manifests with prolongation of the prothrombin time first. With severe deficiency, the activated partial thromboplastin time will be prolonged as well. Factor VIII is not influenced by vitamin K.

TTT-104. The answer is E.(Chap. 116) Hemophilia A results from a deficiency of factor VIII. Replacement of factor VIII is the centerpiece of treatment. Cessation of aspirin or nonsteroidal anti-inflammatory drugs is highly recommended. Fresh-frozen plasma (FFP) contains pooled plasma from human sources. Cryoprecipitate refers to FFP that is cooled, resulting in the precipitation of material at the bottom of the plasma. This product contains about half the factor VIII activity of FFP in a tenth of the volume. Both agents are therefore reasonable treatment options. DDAVP (desmopressin) causes the release of a number of factors and von Willebrand factor from the liver and endothelial cells. This may be useful for patients with mild hemophilia. Recombinant or purified factor VIII (i.e., Humate P) is indicated in patients with more severe bleeding. Therapy may be required for weeks, with levels of factor VIII kept at 50%, for postsurgical or severe bleeding. Plasmapheresis has no role in the treatment of patients with hemophilia A.

Ш-105. The answer is C.(Chap. 116) Lupus anticoagulants (Las) cause prolongation of coagulation tests by binding to phospholipids. Although most often encountered in patients with systemic lupus erythematosus, they may also develop in normal individuals. The diagnosis is first suggested by prolongation of coagulation tests. Failure to correct with incubation with normal plasma confirms the presence of a circulating inhibitor. Contrary to the name, patients with LA activity have normal hemostasis and are not predisposed to bleeding. Instead, they are at risk for venous and arterial thromboembolisms. Patients with a history of recurrent unplanned abortions or thrombosis should undergo lifelong anticoagulation. The presence of LAs or anticardiolipin antibodies without a history of thrombosis may be observed because many of these patients will not go on to develop a thrombotic event.

TTT-106. The answer is D.(Chap. 116) The activated partial thromboplastin time (aPTT) involves the factors of the intrinsic pathway of coagulation. Prolongation of the aPTT reflects either a deficiency of one of these factors (factor VIII, IX, XI, XII, and so on) or inhibition of the activity of one of the factors or components of the aPTT assay (i.e., phospholipids). This may be further characterized by the "mixing study" in which the patient's plasma is mixed with pooled plasma. Correction of the aPTT reflects a deficiency of factors that are replaced by the pooled sample. Failure to correct the aPTT reflects the presence of a factor inhibitor or phospholipid inhibitor. Common causes of a failure to correct include the presence of heparin in the sample, factor inhibitors (factor VIII inhibitor being the most common), and the presence of antiphospholipid antibodies. Factor VII is involved in the extrinsic pathway of coagulation. Inhibitors to factor VII would result in prolongation of the prothrombin time.

TTT-107. The answer is D.(Chap. 116) This patient presents with a significant upper gastrointestinal

(GI) bleed with a prolonged prothrombin time (PT). Hemophilia should not cause a prolonged PT. This and the presence of ascites raise the possibility of liver disease and cirrhosis. The contamination of blood products in the 1970s and 1980s resulted in widespread transmission of HIV and hepatitis С virus (HCV) within the hemophilia population receiving factor infusions. It is estimated in 2006, that more than 80% of hemophilia patients older than 20 years old are infected with HCV Viral inactivation steps were introduced in the 1980s, and recombinant factor VIII and IX were first produced in the 1990s. HCV is the major cause of morbidity and the second leading cause of death in patients exposed to older factor concentrates. Patients develop cirrhosis and complications that include ascites and variceal bleeding. End-stage liver disease requiring a liver transplant is curative for the cirrhosis and the hemophilia (the liver produces factor VIII). Hepatitis В was not transmitted in significant numbers to patients with hemophilia. Diverticular disease or peptic ulcer disease would not explain the prolonged PT. Patients with inadequately repleted factor VIII levels are more likely to develop hemarthroses than GI bleeds, and the slightly prolonged activated partial thromboplastin time makes this unlikely.

TTT-108. The answer is E.(Chap. 116) The differentiation between disseminated intravascular coagulation (DIC) and severe liver disease is challenging. Both entities may manifest with similar laboratory findings, which are elevated fibrinogen degradation products, prolonged activated partial thromboplastin time and prothrombin time, anemia, and thrombocytopenia. When suspecting DIC, these tests should be repeated over a period of 6 to 8 hours because abnormalities may change dramatically in patients with severe DIC. In contrast, these test results should not fluctuate as much in patients with severe liver disease. Bacterial sepsis with positive blood cultures is a common cause of DIC but is not diagnostic.

TTT-109. The answer is B.(Chap. 117) Venous thrombosis occurs through activation of the coagulation cascade primarily through the exposure to tissue factor, and the genetic factors that contribute to a predisposition to venous thrombosis typically are polymorphisms affecting procoagulant or fibrinolytic pathways. In contrast, arterial thrombosis occurs in the setting a platelet activation, and the genetic predisposition for arterial thrombosis includes mutations that affect platelet receptors or redox enzymes. The most common inherited risk factors for venous thrombosis are the factor V Leiden mutation and prothrombin 20210 mutation. Other mutations predisposing an individual to venous thrombosis include inherited deficiency of protein С or S and mutations of fibrinogen, tissue plasminogen activator, thrombomodulin, or plasminogen activator inhibitor. The glycoprotein lb platelet receptor mutation would increase the risk of arterial, but not venous, thrombosis.

TTT-110. The answer is A.(Chap. 117) D-Dimer is a degradation product of cross-linked fibrin and is elevated in conditions of ongoing thrombosis. Low concentrations of D-dimer are considered to indicate the absence of thrombosis. Patients older than the age of 70 years frequently have elevated D-dimers in the absence of thrombosis, making this test less predictive of acute disease. Clinical symptoms are often not present in patients with deep venous thrombosis (DVT) and do not affect interpretation of a d-dimer. Tobacco use, although frequently considered a risk factor for DVT, and previous DVT should not affect the predictive value of D-dimer. Homan's sign, calf pain elicited by dorsiflexion of the foot, is not predictive of DVT and is unrelated to D-dimer.

TTT-111. The answer is E.(Chaps. 117 and 262) The clinical probability of pulmonary embolism (PE) can be delineated into low to high likelihood using the clinical decision rule shown in Table III- 111

below. In those with a score of 3 or less, PE is low or moderately likely, and a D-dimer test should be performed. A normal D-dimer result combined with a low to moderate clinical probability of PE identifies patients who do not need further testing or anticoagulation therapy. Those with either a likely clinical probability (score >3) or an abnormal D-dimer (with unlikely clinical probability) require an imaging test to rule out PE. Currently, the most attractive imaging method to detect PE is the multislice computed tomography (CT). It is accurate and, if the result is normal, safely rules out PE. This patient has a clinical probability score of 4.5 because of her resting tachycardia and the lack of an alternative diagnosis at least as likely as PE. Therefore, there is no indication for measuring D-dimer, and she should proceed directly to multislice CT of the chest. If this cannot be performed expeditiously, she should receive one dose of low-molecular-weight heparin while awaiting the test.

Date: 2016-04-22; view: 1128