Whenever a blood vessel is broken due to injury, bleeding occurs. Bleeding soon stops, however, because the break is quickly sealed by a clot. The process by which a clot forms involves many steps and more than a dozen different proteins, or clotting factors. First, platelets adhere to the connective tissue exposed by the break in the vessel's lining. Then, the platelets and the damaged cells secrete a variety of clotting factors. These participate in a cascade of chemical reactions of which the end result is the formation of strands of fibrin, the basis of the clot. Because the factors act like links in a chain, if any one of the genetically controlled protein clotting factors is absent or deficient, the blood will clot too slowly or not at all.
Two of the disorders involve platelets. In both Glanzmanns Thrombasthenia and Bernard-Soulier Syndrome, certain glycoproteins in the cell membranes of the platelets are deficient. This prevents the platelets from adhering to the broken vessel and sealing its hole. Both of these disorders are inherited in an autosomal recessive fashion.
Perhaps the best known clotting disorder is classical hemophilia (type A), or Factor VIII deficiency. People with hemophilia have excessive bleeding into joints and muscles; bruising; and bleeding from sites of injury such as scrapes and cuts. Depending on how much Factor VIII is actually present, which in turn depends on the type and location of the mutation in the Factor VIII gene, a person's clinical phenotype is classified as mild, moderate, or severe. The treatment for this condition involves the replacement of Factor VIII either from monoclonal antibodies or from production by recombinant DNA.
The Factor VIII gene is located on the X chromosome; therefore, it is rare in females. A female heterozygous for this gene is a carrier, and each of her children has a 50% probability of inheriting a recessive allele, which does not produce Factor VIII, from her. A carrier female usually produces about 50% of the normal amount of Factor VIII, but that is sufficient for clotting. In some instances, however, due to unfavorable lyonization (random X-chromosome inactivation), in which most of the dominant alleles are by chance inactivated, a carrier female will produce less than 50% of the protein, and she will have symptoms of hemophilia. Rarely (about one time in a million), a female will have the recessive allele on each of her X chromosomes.
Factor IX deficiency, or Christmas disease (also known as hemophilia type B), has a phenotype similar to that of classical hemophilia, but is much less common. It, too, is inherited in an X-linked fashion. The deficiency of another clotting protein, Factor XI, causes the disorder hemophilia C, a milder condition that causes bleeding problems after surgery or serious injury. The Factor XI gene is located on the fourth chromosome, and the disorder is inherited in autosomal recessive fashion.
Just as failure of the blood to clot when it should is a problem, so is clotting of the blood when it should not. The protein antithrombin III inhibits several of the clotting factors so that they will not form a clot at the wrong time, damaging the heart and other organs. Deficiency of this protein allows the formation of unwanted clots. The gene for antithrombin III is located on the first chromosome. Protein C deficiency and Protein S deficiency are other disorders that prevent regulation of the clotting factors, resulting in unwanted clots. Antioagulants are used to treat bleeding and coagulation disorders.
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