Causes and pathogenesis of hemophilia

The immediate cause of hemophilia A and B is the 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 about 1/4 do not trace the inheritance of the disease and in such cases suggest a spontaneous mutation of genes in the X chromosome.

Inheritance of hemophilia is X-linked. All daughters of patients with hemophilia are obligate carriers of abnormal genes; all sons are healthy. The likelihood that the son of the carrier mother will be sick with hemophilia is 50%, and the likelihood that her daughter will become the carrier of the disease is also 50%.

Hemophilia can suffer girls born from a hemophiliac patient and a woman carrier, as well as with Turner syndrome. In female carriers, bleeding can occur during menstruation, childbirth, during surgery and trauma.

Pathogenesis of hemophilia. The lack of plasma coagulation factors (VIII, IX, XI) causes a disruption in the internal coagulation unit of hemostasis and causes a delayed hematoma type of bleeding.

The concentration of VIII and IX factors in the blood is low (1-2 mg and 0.3-0.4 mg per 100 ml or one molecule of factor VIII per million albumin molecules, respectively), but in the absence of one of them, blood coagulation in its first phase on the external path of activation very rapidly slows down or does not happen at all.

The human factor VIII is a large-molecular protein with a mass of 1 120 000 daltons, consisting of a number of subunits with a weight of 195,000 to 240,000 daltons. One of these subunits has coagulation activity (VIII: K); the other is the activity of the vWF factor necessary for their adhesion to the damaged vascular wall (VIII: FV); antigenic activity depends on two more subunits (VIII: Kar and VIII: FABag). Synthesis of subunits of factor VIII occurs in different places: VIII: PV in the vascular endothelium, and VIII: K, probably in lymphocytes. It is established that in a single molecule of VIII factor of subunits VIII: PV is somewhat. In patients with hemophilia A, activity VIII: K is sharply reduced. In hemophilia, an abnormal VIII or IX factor is synthesized that do not perform coagulation functions.

The gene that codes for the synthesis of both proteins related to coagulation (VIII: K, VIII: Kag) is localized on the X chromosome (Xq28), whereas the gene that determines the synthesis of VIII: PV is on the 12th chromosome. Gene VIII: K isolated in 1984, it is the largest of the known human genes, consisting of 186 thousand bases. It was confirmed that about 25% of patients have haemophilia - a consequence of spontaneous mutation. The mutation frequency for haemophilia A is 1.3 × 10, and hemophilia B is 6 × 10. The hemophilia B gene is fixed on the long arm of the X chromosome (Xq27); hemophilia C - on the 4th chromosome, is inherited autosomally.

[1], [2], [3], [4], [5], [6], [7]