Genetic Disorders that Affect Blood Clotting Factors

The human blood clotting cascade consists of a tightly regulated network of enzymes designed to contain damage to the blood vessels by means of coagulation, thus restoring vascular integrity. Briefly, when a blood vessel suffers penetrating trauma, blunt force trauma, or an internal rupture, the clotting cascade swings into action. The various proteins activate one another culminating in the formation of a clot composed of a platelet plug and cross linked strands of fibrin. The clot, or thrombus, acts as damage control, stopping further loss of blood through the wound.

Physiologists divide the clotting cascade into three branches: the extrinsic pathway, consisting of Factors III and VII; the intrinsic pathway, consisting of Factors XII, XI, IX, and VIII; and the final common pathway, consisting of Factors X, V, prothrombin (II), fibrinogen (I) and XIII. Because the clotting factors were numbered in the order of their discovery, they do not follow a sequential order. (Factor IV was later discovered to be calcium, and Factor VI was omitted as a redundancy after two labs discovered the same enzyme independently).

Far and away, the most common disease involving a protein in the clotting cascade is Factor VIII deficiency, better known as Hemophilia A. An estimated 30,000 males in the U.S. are believed to have Factor VIII deficiency. Because the gene responsible for this disease is located on the X chromosome, the pattern of heredity most often observed is a female carrier giving birth to a son with hemophilia. (Males inherit a Y chromosome from their father and a single X chromosome from their mother). Rarely, females develop hemophilia. For this to occur, however, the girl's father would have to have hemophilia himself, and her mother would have to carry the defective gene. Hemophilia A is treated with injections of recombinant Factor VIII. (The term recombinant denotes any protein produced by genetically engineered bacteria.) In emergency situations, fresh frozen plasma or cryoprecipitate can be given as a substitute.

Factor IX deficiency, also known as Hemophilia B, is also an X linked disorder. It occurs about 10% as often as Hemophilia A, and affects an estimated 3,300 males in the U.S. Most cases of Factor IX deficiency come to medical attention when a patient with hemophilia fails to respond to injections of Factor VIII. Hemophilia B is treated with injections of recombinant Factor IX.

Some cases of Factor XI and XII deficiency have been reported; however these disorders are quite rare and tend to be milder than Hemophilia A or B. Another clotting disorder is Von Willebrand disease. This disorder is caused by mutations or deletions of the gene encoding a protein called VWF, or von Willebrand Factor. VWF plays two roles in the clotting cascade. First, it protects Factor VIII from degradation in the liver. In the absence of VWF, the plasma half-life of Factor VIII drops from 8 hours to around 2 hours, in essence creating a Factor VIII deficiency. Second, VWF is exposed during vascular injury when endothelial cells are sheared off blood vessel walls. It helps anchor platelets at the site of damage, speeding up clot formation. Hence, a deficiency of VWF results in an abnormally long bleeding time. In some cases, treatment with ddAVP (vasopressin) reduces bleeding episodes in patients with Von Willebrand disease; in other cases, Factor VIII injections may be helpful. 

Several genetic disorders result in a hypercoagulable state; however, unlike the above mentioned diseases, most people with these disorders are heterozygotes whose symptoms exhibit great variability. The most well characterized of these disorders include deficiencies of Antithrombin III, Protein C, Protein S, and Factor V Leiden mutation. The treatment for these disorders is heparin injections in the acute setting. Long term treatment consists of anticoagulation with warfarin for patients with Protein C, S, or Factor V Leiden deficiency. People who are homozygous for Protein C deficiency require periodic transfusions of blood plasma rather than oral warfarin therapy.