Porth's Essentials of Pathophysiology, 4e

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Disorders of Hemostasis

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ITP do well without treatment. Corticosteroids are used as initial therapy; other effective initial treatment includes intravenous immune globulin. However, this treatment is expensive and the beneficial effect may last only one to two weeks. Because the spleen is the major site of antibody formation and platelet destruction, sple- nectomy is the traditional second-line treatment for per- sons who relapse or do not respond to medications. 18 Immunosuppressive therapy (i.e., azathioprine or cyclo- phosphamide) may be used in patients who are refrac- tory to other forms of treatment. Drug-Induced Thrombocytopenia. Some drugs, such as quinine, quinidine, and certain sulfa-containing anti- biotics, may induce thrombocytopenia. 19 These drugs act as haptens to induce an antigen–antibody response and formation of immune complexes that cause platelet destruction by complement-mediated lysis (see Chapter 15). In persons with drug-associated thrombocytopenia, there is a fall in platelet count 7 or more days after ini- tiating therapy with a given drug for the first time (i.e., the needed to mount an immune response) or 2 to 3 days after resuming therapy with the same drug. The platelet count rises rapidly after the drug is discontinued. The anticoagulant drug heparin has been increasingly implicated in thrombocytopenia and, paradoxically, in thrombosis. The complications typically occur five days after the start of therapy and result from heparin- dependent antiplatelet antibodies that cause aggregation of platelets and their removal from the circulation. The antibodies often bind to vessel walls, causing complica- tions such as deep vein thrombosis, pulmonary embo- lism, myocardial infarction, and stroke. 20 The treatment of heparin-induced thrombocytopenia (HIT) requires the immediate discontinuation of heparin therapy and the use of alternative anticoagulants (i.e., argatroban, fondaparinux) to prevent thrombosis recurrence. The use of low–molecular-weight heparin appears to have reduced the incidence of HIT, though there have only been a limited number of large, randomized, controlled studies. Thrombotic Microangiopathies. The term throm- botic microangiopathies encompasses a spectrum of clinical syndromes that include thrombotic thrombocy- topenic purpura (TTP) and hemolytic-uremic syndrome (HUS). 3 As originally described, TTP is associated with a combination of manifestations that includes fever, thrombocytopenia, microangiopathic hemolytic ane- mia, renal failure, and transient neurologic abnormali- ties. Hemolytic-uremic syndrome is also associated with microangiopathic hemolytic anemia and thrombocy- topenia, but it is distinguished from TTP by the domi- nance of acute renal failure and absence of neurologic manifestations. Fundamental to both conditions is the widespread formation of hyaline thrombi in the micro- circulation that are composed primarily of dense aggre- gates of platelets surrounded by fibrin. The consumption of platelets leads to thrombocytopenia, and the narrow- ing of the blood vessels by the platelet-rich thrombi results in the microangiopathic hemolytic anemia.

The pathogenesis of TTP is elusive but likely results from introduction of platelet-aggregating substances into the circulation. The underlying cause of many cases is the deficiency of an enzyme (ADAMTS 13, formerly known as vWF-cleaving protease) that degrades very high–molecular–weight multimers of vWF, allowing them to accumulate and cause platelet aggregation and adhesion to the endothelium. 3,4 The enzyme deficiency may be inherited or acquired as a result of antibody directed against the enzyme. Although TTP usually occurs in previously healthy persons, it may also com- plicate collagen vascular diseases (rheumatoid arthri- tis and systemic lupus erythematosus), drug-induced hypersensitivities, cancer chemotherapy, bone marrow transplantation, infections such as HIV, and pregnancy. 4 Thrombotic thrombocytopenic purpura occurs at virtually every age, but is most common in women in their fourth or fifth decades. It can be chronic and recur- rent, but more frequently the onset is abrupt and the outcome may be fatal. Widespread vascular occlusions result from thrombi in the arterioles and capillaries of many organs, including the heart, brain, and kidneys. The clinical manifestations include purpura, petechiae, vaginal bleeding, and neurologic symptoms ranging from headache to seizures and altered consciousness. Anemia is universal and may be marked. About half of patients have azotemia due to renal failure. 4 Emergency treatment for TTP includes plasmapher- esis, a procedure that involves removal of plasma from withdrawn blood and replacement with fresh-frozen plasma. Plasma infusion provides the deficient enzyme. With plasmapheresis and plasma infusion treatment, there is a complete recovery in 80% of cases. 4 Although clinically similar to TTP, there is no under- lying enzyme deficiency in HUS because ADAMTS 13 levels are normal. HUS in children and the elderly usu- ally occurs following infectious gastroenteritis caused by Escherichia coli O157:H7 14 (see Chapter 29). The organism elaborates a toxin that damages endothelial cells, which initiates platelet activation and aggregation. Affected individuals often present with bloody diarrhea, which is followed a few days later by HUS. With sup- portive care and plasma exchange, recovery is possible, but irreversible renal damage and death can occur in severe cases. Impaired Platelet Function Impaired platelet function (also called thrombocyto- pathia ) may result from inherited disorders of adhesion (e.g., von Willebrand disease) or acquired defects caused by drugs, disease, or surgery involving extracorporeal circulation (i.e., cardiopulmonary bypass). Defective platelet function is also common in uremia, presumably because of non-eliminated waste products. The use of aspirin and other nonsteroidal anti- inflammatory drugs (NSAIDs) is the most common cause of platelet dysfunction. Aspirin produces irrevers- ible acetylation of platelet cyclooxygenase activity, and consequently the synthesis of TXA 2 , which is required for platelet aggregation. The effect of aspirin on platelet