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Causes and pathogenesis of hemophilia
Last reviewed: 04.07.2025
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The immediate cause of hemophilia A and B is a mutation of the gene in the region of the long q27-q28 arm of the X chromosome. About 3/4 of patients with hemophilia have a family history of hemorrhagic syndrome in relatives, and in about 1/4 there is no traceable inheritance of the disease and in such cases a spontaneous mutation of genes in the X chromosome is assumed.
Hemophilia is inherited X-linked. All daughters of people with hemophilia are obligate carriers of the abnormal genes; all sons are healthy. The probability that the son of a carrier mother will have hemophilia is 50%, and the probability that her daughter will become a carrier of the disease is also 50%.
Hemophilia can affect girls born to a man with hemophilia and a female carrier, as well as those with Turner syndrome. In female carriers, bleeding can occur during menstruation, childbirth, operations and injuries.
Pathogenesis of hemophilia. Deficiency of plasma coagulation factors (VIII, IX, XI) causes a disturbance in the internal coagulation link of hemostasis and causes a delayed hematoma type of bleeding.
The concentration of factors VIII and IX in the blood is low (1-2 mg and 0.3-0.4 mg per 100 ml, respectively, or one factor VIII molecule per 1 million albumin molecules), but in the absence of one of them, blood clotting in its first phase along the external activation pathway slows down very sharply or does not occur at all.
Human factor VIII is a large-molecular protein with a mass of 1,120,000 daltons, consisting of a number of subunits with a mass from 195,000 to 240,000 daltons. One of these subunits has coagulation activity (VIII: K); another has the activity of von Willebrand factor, necessary for their adhesion to the damaged vascular wall (VIII: VWF); antigenic activity depends on two more subunits (VIII: Kag and VIII: VBag). The synthesis of subunits of factor VIII occurs in different places: VIII: VWF - in the vascular endothelium, and VIII: K, probably, in lymphocytes. It has been established that a single molecule of factor VIII contains several subunits of VIII: VWF. In patients with hemophilia A, the activity of VIII: K is sharply reduced. In hemophilia, abnormal factors VIII or IX are synthesized, which do not perform coagulation functions.
The gene encoding the synthesis of both proteins related to coagulation (VIII: K, VIII: Kag) is localized on the X chromosome (Xq28), while the gene determining the synthesis of VIII: VWF is on chromosome 12. Gene VIII: K was isolated in 1984; it is the largest of the known human genes, consisting of 186 thousand bases. It has been confirmed that in approximately 25% of patients, hemophilia is a consequence of spontaneous mutation. The mutation frequency for hemophilia A is 1.3x10, and for hemophilia B it is 6x10. The hemophilia B gene is fixed on the long arm of the X chromosome (Xq27); hemophilia C - on the 4th chromosome, inherited autosomal.
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