Hereditary coagulation disorders

Coagulation disorders include a number of disorders that are related to defects in the clottingof blood. The best known is hemophilia, which is due to an inherited defect transmitted by the female but manifested almost exclusively in the male. The most common form of hemophilia, hemophilia A, is caused by the absence of the coagulation protein factor VIII. Of patients with hemophilia, approximately 85 percent have factor VIII deficiency. The next mostcommon form of hemophilia, hemophilia B, is due to factor IX deficiency. Both factor VIII deficiency and factor IX deficiency have signs and symptoms that are indistinguishable. Spontaneous bleeding into joints, giving rise to severe chronic arthritis, is a common problemamong patients with severe hemophilia; in addition, there is bleeding into the brain and the abdominal cavity, as well as marked bruising. In general, the greater the deficiency in either factor VIII or factor IX, the more severe the manifestations of disease. Treatment of bleeding episodes emphasizes the replacement of the missing plasma protein. In a patient with hemophilia A, factor VIII can be replaced by the infusion into a vein of plasma derived from a normal donor, the cryoprecipitate fraction of normal plasma, or a partially purified preparation of factor VIII derived from normal plasma. The peptide DDAVP (1-deamino-8-D-arginine vasopressin) is useful in treating milder forms of hemophilia A. Similarly, in a patient with hemophilia B, factor IX can be replaced by the infusion into the vein of plasma derived from a normal donor or a partially purified preparation of factor IX derived from normal plasma. Because donor plasma may be contaminated with virus particles, a number of viral diseases including hepatitis and AIDS can be transmitted by plasma protein. New methods of preparing factor VIII and factor IX, using genetic engineering techniques, should lead to the introduction of safer factor VIII and factor IX generated by recombinant DNA methods. With the current methods of medical care, hemophiliacs can live nearly normal, productive lives. Major surgery, if needed, can be accomplished by the administration of the missing protein. The life expectancy of a hemophiliac with access to quality medical care is normal.

Inherited deficiencies of other clotting proteins are also associated with clotting disorders, but these disorders are not common (see table).

Vitamin K deficiency leads to a deficiency of the proteins that require vitamin K for their synthesis: prothrombin, factor X, factor IX, factor VII, protein C, and protein S. Vitamin K deficiency is associated with obstructive jaundice, in which the flow of bile into the bowel is interrupted. Bile is necessary for the absorption of vitamin K. Similar changes may take place when absorption of vitamin K is impaired by conditions such as chronic diarrhea or with the administration of certain antibiotics. Vitamin K deficiency also occurs in the newborn infant as hemorrhagic disease of the newborn. This form of prothrombin deficiency can be prevented by administration of vitamin K to the baby during delivery. Accidental consumptionor overdoses of the medication warfarin can lead to a deficiency of the vitamin K-dependent blood-clotting proteins and a serious bleeding tendency.

Severe liver diseases such as cirrhosis and hepatitis can be associated with significant bleeding problems. The liver is the site of synthesis of the clotting proteins. When the liver tissue is diseased or replaced by other cancerous tissues, the synthesis of the clotting proteins is impaired. Often, thrombocytopenia complicates severe liver disease and adds to the bleeding tendency.

Afibrinogenemia, or hypofibrinogenemia, refers to a reduction in the amount of the clotting factor fibrinogen in the blood. This problem is seen in rare instances as an inherited disorder,but more commonly it is found as part of the syndrome of disseminated intravascular coagulation.

Von Willebrand's disease is due to the lack of von Willebrand factor, a plasma protein that binds to factor VIII and promotes the interaction of platelets with the blood vessel. This disorder is transmitted as an autosomal dominant trait, and its symptoms consist mainly of bleeding through the skin and mucous membranes. Treatment involves the infusion of plasma, the cryoprecipitate fraction of plasma, or the peptide DDAVP.

Disseminated intravascular coagulation is an acquired disorder in which the blood coagulation system is activated inappropriately, and the normal regulatory mechanisms are overwhelmed. Numerous primary problems can be responsible for this activation: bacteria and bacterial products, dead or injured cells as a result of tissue injury or surgery, cells from the placenta or a dead fetus, certain forms of cancer, and venom from snake bites. Treatment involves the removal of the inciting cause of the activation of the blood coagulation system. In this disorder, platelets and blood-clotting components are consumed until a severe deficiency exists, resulting in a bleeding disorder. In addition, the fibrinolytic system—the system that dissolves clots—is also activated, leading to the destruction of fibrinogen and fibrin clots.

General treatment of bleeding disorders consists mainly of temporary replacement therapy by transfusion. In thrombocytopenia (deficiency of platelets) or thrombocytopathy (malfunctioning platelets) transfusions of normal donor platelets can be given. The clotting deficiencies are treated with plasma or plasma proteins containing the missing factor. These agents can restore hemostatic function to normal for hours or days and, with continued treatment, allow injuries to heal or complicated surgery to be performed.