Porth's Essentials of Pathophysiology, 4e

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Hematopoietic Function

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aggregation lasts for the life of the platelet—approxi- mately 8 or 9 days. In contrast to the effects of aspirin, the inhibition of cyclooxygenase by other NSAIDs is reversible and lasts only for the duration of drug action. Aspirin (81 mg daily) commonly is used to prevent for- mation of arterial thrombi and thus reduce the risk of cardiovascular (i.e., myocardial infarction) or cerebro- vascular (i.e., stroke) accidents. Coagulation Disorders Blood coagulation defects can result from deficiencies or impaired function of one or more of the clotting factors, including vWF. Deficiencies can arise because of inher- ited disease or because of defective synthesis or increased consumption of the clotting factors. Bleeding resulting from clotting factor deficiencies typically occurs after injury or trauma. Large bruises (ecchymoses), hemato- mas, and prolonged bleeding into the gastrointestinal or urinary tracts or joints are common. Inherited Disorders Hemophilia A and von Willebrand disease are two of the most common inherited disorders of bleeding. 21,22 Hemophilia A (factor VIII deficiency) affects 1 in 5000 male live births and von Willebrand disease about 1 in 1000 persons. 21 Hemophilia B (Factor IX deficiency) is clinically similar to hemophilia A and affects approxi- mately 1 in 20,000 persons, accounting for 15% of peo- ple with hemophilia. 4 Hemophilia A and von Willebrand disease are caused by defects involving the factor VIII–vWF complex. Von Willebrand factor, which is synthesized by the endothe- lium and megakaryocytes, is required for platelet adhe- sion to the subendothelial matrix of the blood vessel. It also serves as the carrier for factor VIII and it is impor- tant for the stability of factor VIII in the circulation by preventing its proteolysis. Factor VIII coagulant protein, the functional portion of factor VIII, is produced by the liver and endothelial cells. Thus, factor VIII and vWF, synthesized separately, come together and circulate in the plasma as a unit that serves to promote clotting and adhesion of platelets to the vessel wall. Von Willebrand Disease. Von Willebrand disease is a relatively common hereditary bleeding disorder charac- terized by a deficiency or defect in vWF. It affects both men and women and is typically diagnosed in adult- hood. 23,24 In most cases, it is transmitted as an autosomal dominant disorder, but several rare autosomal recessive variants have been identified. As many as 20 variants of von Willebrand disease have been described. 4 These variants can be grouped into two categories: types 1 and 3, which are associ- ated with reduced levels of vWF; and type 2, which is characterized by defects in vWF. 4 Type 1, an autosomal dominant disorder, accounts for approximately 75% of cases and is relatively mild. Type 2, also an autosomal dominant disorder, accounts for about 20% of cases and is associated with mild to moderate bleeding. Type 3,

which is a relatively rare autosomal recessive disorder, is associated with extremely low levels of functional vWF and correspondingly severe clinical manifestations. Persons with von Willebrand disease have a com- pound defect involving platelet function and the coagulation pathway. Clinical manifestations include spontaneous bleeding from the nose, mouth, and gas- trointestinal tract; excessive menstrual flow; and a pro- longed bleeding time in the presence of a normal platelet count. Most cases (i.e., types 1 and 2) are mild and the disorder is diagnosed when surgery or dental extraction results in prolonged bleeding. In severe cases (i.e., type 3), life-threatening gastrointestinal bleeding and joint hem- orrhage may be similar to that seen in hemophilia. The bleeding associated with von Willebrand disease is usually mild, and no treatment is routinely admin- istered other than avoidance of aspirin. Desmopressin acetate (DDAVP), a synthetic analog of the hormone vasopressin, is used in the treatment of type 1 von Willebrand disease and for establishing hemostasis dur- ing surgical or dental procedures. 22,23 DDAVP stimulates the endothelial cells to release stored vWF and plasmin- ogen activator. The drug is available as an intranasal spray. A vWF-containing factor VIII concentrate may be used for treatment of persons with excessive bleeding. 21 Hemophilia A. Hemophilia A is an X-linked recessive disorder that primarily affects males. 3,4,22,24,25 Although it is a hereditary disorder, there is no family history of the disorder in approximately 30% of newly diagnosed cases, suggesting that it has arisen as a new mutation in the factor VIII gene. Approximately 90% of persons with hemophilia produce insufficient quantities of the factor and 10% produce a defective form. The per- centage of normal factor VIII activity in the circulation depends on the genetic defect and determines the sever- ity of hemophilia (i.e., 6% to 30% in mild hemophilia, 2% to 5% in moderate hemophilia, and 1% or less in severe forms of hemophilia). In mild or moderate forms of the disease, bleeding usually does not occur unless there is a local lesion or trauma such as surgery or a den- tal procedure. The mild disorder may not be detected in childhood. In severe hemophilia, bleeding usually occurs in childhood (e.g., it may be noticed at the time of circumcision) and is spontaneous and severe, often occurring several times a month. Characteristically, bleeding occurs in soft tissues, the gastrointestinal tract, and the hip, knee, elbow, and ankle joints. Spontaneous joint bleeding usually begins when a child begins to walk, with the target joint often prone to recurrent incidences. The bleeding causes inflammation of the synovium, with acute pain and swelling. Without proper treatment, chronic bleeding and inflammation cause joint fibrosis and contractures, resulting in major disability. Muscle hematomas may be present in 30% of episodes, and intracranial hemorrhage, although uncommon, is an important cause of death. 22,26 The prevention of trauma is important in per- sons with hemophilia. Aspirin and other NSAIDs that affect platelet function should be avoided. Factor VIII replacement therapy (either recombinant or heat-treated