Porth's Essentials of Pathophysiology, 4e

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Hematopoietic Function

U N I T 3

Inherited Disorders Of the inherited causes of hypercoagulability, mutations in the factor V and prothrombin genes are the most common. 4,10 In persons with inherited defects in factor V, the mutant factor Va cannot be inactivated by protein C; as a result, an important antithrombotic counterreg- ulatory mechanism is lost. Approximately 2% to 5% of Caucasians carry a specific factor V mutation (referred to as the Leiden mutation, because of the Dutch city where it was first discovered). 3 The defect predisposes to venous thrombosis, and among persons with recurrent deep vein thrombosis, the frequency of the mutation may be as high as 60%. 3 It is one of the most common causes of primary and recurrent thromboembolism in pregnancy and is also associated with abruptio placen- tae (premature placental separation) and fetal growth disturbance. 10 A single nucleotide change in the prothrombin gene, which affects 1% to 2% of the population, is associated with elevated prothrombin levels and an almost three- fold increase in venous thromboses. 4 Another hereditary defect results in high circulating levels of homocyste- ine, which predisposes to venous and arterial thrombo- sis by activating platelets and altering antithrombotic mechanisms. 4 Acquired Disorders Unlike the hereditary disorders, multiple conditions often predispose persons to acquired or secondary thrombotic disorders. Stasis of blood and accumulation of platelets and activated clotting factors are common in situations such as with prolonged bed rest and immobil- ity. Hyperviscosity syndromes (e.g., polycythemia) and deformed red blood cells in sickle cell disease increase the resistance to flow and cause small vessel stasis. Hypercoagulability is associated with oral contraceptive use and the hyperestrogenic state of pregnancy, prob- ably related to the increased synthesis of coagulation factors and reduced synthesis of antithrombin III. 11 The incidence of stroke, thromboemboli, and myocardial infarction is greater in women who use oral contra- ceptives, particularly those older than 35 years of age and those who smoke tobacco. In disseminated cancer, release of procoagulant tumor products predisposes to thrombosis. Smoking and obesity promote hypercoagu- lability for unknown reasons. Antiphospholipid Syndrome. Another cause of increased venous and arterial thrombosis is the antiphospholipid syndrome . This condition is associ- ated with a family of autoantibodies directed against several negatively charged phospholipids, causing an increase in coagulation activity. It is unclear how antiphospholipid antibodies lead to hypercoagulability, but possible explanations include direct platelet activa- tion, endothelial cell activation or injury, or interfer- ence with the phospholipid-binding proteins involved in the regulation of blood coagulation (e.g., tissue fac- tor, prothrombin, antithrombin III, and protein C). 12–14 Common features of the syndrome include recurrent

CHART 12-1   Conditions Associated with Hypercoagulability States

Increased Platelet Function Increased platelet numbers

include an increase in platelet count and disturbances in blood flow, damage to the vascular endothelium, and increased sensitivity of platelets to factors that cause adhesiveness and aggregation. The term thrombocytosis is used to describe eleva- tions in the platelet count above 1,000,000/ μ L. 9 An increase in platelet count can occur as a reactive dis- order associated with iron-deficiency anemia, especially in children; splenectomy; cancer; and chronic inflamma- tory conditions such as rheumatoid arthritis and Crohn disease. Usually the only clinically apparent signs are those of the underlying disease. Myeloproliferative dis- orders such as polycythemia vera (see Chapter 14) pro- duce excess platelets that may predispose to thrombosis or, paradoxically, bleeding when the rapidly produced platelets are defective. Atherosclerotic plaques disturb blood flow, causing endothelial damage and promoting platelet adherence. Platelets adhere to the vessel wall, release growth fac- tors, cause proliferation of smooth muscle, and thereby contribute to the development of atherosclerosis (see Chapter 18). Smoking, elevated levels of blood lipids and cholesterol, hemodynamic stress, and diabetes mel- litus predispose to vessel damage, platelet adherence, and eventual thrombosis. Increased Clotting Activity Thrombus formation due to activation of the coagu- lation system can result from primary (genetic) or secondary (acquired) disorders affecting the coagula- tion components of the blood clotting process (i.e., an increase in procoagulation factors or a decrease in anti- coagulation factors). Reactive disorder (iron-deficiency anemia, splenec­ tomy, cancer, chronic inflammatory conditions) Myeloproliferative disorders (polycythemia vera) Endothelial injury Atherosclerosis Elevated blood lipid and cholesterol levels Smoking Accelerated Activity of the Clotting System Inherited disorders (primary) Mutation in the factor V gene (factor V Leiden) Mutation in the prothrombin gene Acquired (secondary) Prolonged bed rest or immobility Oral contraceptive agents and pregnancy Myocardial infarction Heart failure Malignant diseases Antiphospholipid antibody syndrome