Porth's Essentials of Pathophysiology, 4e

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Disorders of Hemostasis

C h a p t e r 1 2

Bleeding Associated with Vascular Disorders Bleeding resulting from vascular disorders, sometimes called nonthrombocytopenic purpura, is relatively com- mon and results in mild bleeding disorders. 3,4 These dis- orders may occur because of structurally weak vessel walls or because of damage to vessels by inflammation or immune responses. Most often they are character- ized by easy bruising and the spontaneous appearance of petechiae and purpura of the skin and mucous mem- branes. In persons with bleeding disorders caused by vascular defects, the platelet count and results of other tests for coagulation factors are normal. Among the vascular disorders that cause bleed- ing are hemorrhagic telangiectasia, vitamin C defi- ciency (scurvy), Cushing disease, and senile purpura. Hemorrhagic telangiectasia is an uncommon autosomal dominant disorder that is characterized by thin-walled, dilated capillaries and arterioles. Vitamin C is a revers- ible reducing agent that is an essential cofactor for the hydroxylation of proline in collagen synthesis. A severe vitamin C deficiency results in poor collagen synthesis and failure of capillary cells to be cemented together properly, which in turn causes a fragile vascular wall (see Fig. 12-4). Cushing disease causes protein wasting and loss of vessel tissue support because of excess cor- tisol (see Chapter 32). Senile purpura (i.e., bruising in elderly persons) is caused by impaired collagen synthesis due to the aging process. Disseminated intravascular coagulation (DIC) is a paradox in the hemostatic sequence characterized by widespread coagulation and bleeding. 28–31 It is not a primary disease but a complication of many different disorders. Disseminated intravascular coagulation begins withmassive activation of the coagulation sequence, which leads to fibrin deposition andformationofthrombiinthemicrocirculationofthebody (Fig. 12-5). The widespread deposition of fibrin leads to tissue ischemia and hemolytic anemia from fragmentation of red cells as they squeeze through the narrowed micro- vasculature. As a consequence of the thrombotic process, there is consumption of platelets and coagulation factors and the activation of plasminogen that leads to a hemor- rhagic diathesis. The disorder can be initiated by activation of the intrinsic or extrinsic pathway, or both. Activation through the extrinsic pathway occurs with liberation of tissue factors and is associated with obstetric complica- tions, trauma, bacterial sepsis, and cancer. The intrinsic pathway may be activated through extensive endothe- lial damage, with activation of factor XII. Endothelial damage may be caused by viruses, infections, immune mechanisms, stasis of blood, or temperature extremes. Impaired anticoagulation pathways are also associ- ated with reduced levels of antithrombin and the pro- tein C anticoagulant system in DIC. There is increasing Disseminated Intravascular Coagulation

concentrates from human plasma) administered at home has reduced the typical musculoskeletal damage. It is initiated when bleeding occurs or as prophylaxis with repeated bleeding episodes. The newer recombinant products and continuous-infusion pumps may allow for prevention rather than therapy for hemorrhage. The development of inhibitory antibodies to recombinant factor VIII is still a major complication of treatment; 10% to 15% of treated persons produce high titers of antibodies that bind to and inhibit factor VIII. The rate of antibody production for plasma-derived products is approximately the same. Current factor VIII products (both plasma derived and recombinant) are considered very safe as a result of technological advances over the last two decades. 27 Until the mid-1980s when routine screening of blood for HIV antibodies was instituted, thousands of patients with hemophilia received plasma-derived factor VIII that was contaminated with HIV, and many developed AIDS. Effective donor screening and development of purification and viral inactivation procedures now pro- vide a safer product. A number of recombinant factor VIII preparations are available. These products were made with the use of blood-derived additives of human or animal origin, such as albumin. These additives were needed to keep the cells viable so they could produce the factor VIII protein. With mild hemophilia A, the per- son’s endogenously produced factor VIII can be released by the administration of DDAVP. 27 In persons with moderate to severe factor VIII deficiency, the stored lev- els of factor VIII are insufficient, and DDAVP treatment is ineffective. The cloning of the factor VIII gene and progress in gene delivery systems have led to the hope that hemo- philia A may be cured by gene replacement therapy. Carrier detection and prenatal diagnosis can now be done by analysis of direct gene mutation or DNA link- age studies. Acquired Disorders Coagulation factors II, V, VII, IX, X, XI, and XII; pro- thrombin (II); and fibrinogen (I) are synthesized in the liver. In liver disease, synthesis of these clotting factors is reduced, and bleeding may result. Of the coagulation factors synthesized in the liver, factors II, VII, IX, and X and prothrombin require the presence of vitamin K for normal activity. In vitamin K deficiency, the liver produces the clotting factor, but in an inactive form. Vitamin K is a fat-soluble vitamin that is continuously being synthesized by intestinal bacteria. This means that a deficiency in vitamin K is not likely to occur unless intestinal synthesis is interrupted or absorption of the vitamin is impaired. Vitamin K deficiency can occur in the newborn infant before the establishment of the intes- tinal flora; it can also occur as a result of treatment with broad-spectrum antibiotics that destroy intestinal flora. Because vitamin K is a fat-soluble vitamin, its absorp- tion requires bile salts. Vitamin K deficiency may also result from impaired fat absorption caused by liver or gallbladder disease.