The Hemophiliac Excessive Bleeding Diseases

The most common form of hemophilia is due to Von Willebrand disease in which VWF is mutated at the site where it binds to collagen (A3 domain) or to platelets (A1 or Cl domain). The second most common form is classical hemophilia (hemophilia A), long present in European royal families. Much of our original understanding of blood coagulation relied on identifying and studying these two forms of hemophilia. 

In hemophilia A, the protein sequence of factor VIII is mutated so that it cannot be cleaved, resulting in a blocked intrinsic pathway. Therefore, tissue factor must be activated to stop bleeding (extrinsic pathway). Because the capillaries of joints and muscles are continually damaged by crushing when the surrounding bones and muscles move, they produce small amounts of RNA that activates the intrinsic path. Because there is no tissue factor at that site and the mutation of factor VIII in hemophilia A has blocked the intrinsic path, the affected subjects bleed into the joints. The pressure in the joint eventually stops the bleeding, and reticuloendothelial cells are recruited to remove the blood cells. The pain is relieved, but the joint structure is slowly destroyed and over time surviving individuals develop arthritis. 

Hemophilia B is rarer than hemophilia A and is sometimes called Christmas disease after Stephen Christmas, the first patient described with this disease. It is due to a mutation that prevents factor IX from activating factor VIII. However, unlike hemophilia A, factor VIII can be activated by thrombin, and so hemophilia B is less severe. 

Hemophilia C occurs at 10% of the frequency of hemophilia A and is the least common form of hemophilia in the United States, where it mainly occurs in Ashkenazi lews. It is caused by a deficiency of factor XI. Unlike hemophilia A and B, there is no bleeding into joints Factor Xlla can apparently activate factor IX directly without first activating factor XI. Nevertheless, afflicted individuals suffer nosebleeds and heavy menstrual bleeding and, like all hemophiliacs, require a clotting agent to prevent excessive bleeding following a tooth extraction (Sect. 11.6.5). 

Two pathways initiate a fibrin clot. Extrinsic path is mediated by tissue factor, also called thromboplastin. This membrane protein is exposed when pericytes are damaged. It binds to factor Vila in blood. Factor Vila is a protease and the phospholipid-VIIa-TF complex activates (converts) factor X by cleaving it to Xa. Intrinsic path is initiated by factor XII (Hageman factor), whose conformation is changed to a protease (XHa) by contact with a negatively charged surface such as RNA from damaged or necrotic cells. 

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