Genetic Aspects of Hemostasis

Summary

Hereditary defects resulting in inadequate syntheses of fibrinogen, prothrombin, factors V, VII, VIII, IX and X are quantitatively transmitted, therefore all affected members of a family are identical genetically. The concentration of the clotting factor in the blood is determined by the balance of the rate of synthesis to the rate of consumption or turnover. The required concentrations of these clotting factors to maintain hemostasis are strikingly low but below a critical level, traumatic bleeding occurs. The bleeding time is normal, and capillary or mucous membrane bleeding such as spontaneous epistaxis is uncommon or even absent. These states are transmitted as either autosomal or sex-linked recessives.

Hereditary purpuric bleeding states are usually attributable to abnormal platelet function, to a defect in the autonomic nervous system that maintains the tonus of the microcirculation, or to the telangiectatic state in which the abnormality resides either in the structure of the capillaries or the mesenchymal matrix in which the micro vessels are imbedded. The thrombopathies constitute a group with various types of hereditary transmission. The Minot-von Willebrand syndrome and telangiectasia are transmitted as autosomal dominants. In most affected subjects, the bleeding is mild and superficial, usually from mucous membranes such as nosebleeds. In many the bleeding tendency is almost subclinical. Traumatic bleeding such as intramuscular hemorrhage and hemarthrosis is absent. The bleeding time in the severe cases is prolonged but may be normal in the mild bleeder unless prolonged by the ingestion of a drug such as aspirin.

The clinical severity in the hereditary bleeding diseases is determined by: (1) the functional capacity of the gene responsible for the synthesis of the specific hemostatic factor, (2) the superimposition of a secondary hemostatic defect either hereditary or acquired, and (3) environmental factors which per se do not affect hemostasis. Hemophilia serves as the illustration. No severe bleeding occurs in pure factor VIII deficiency until the concentration is below the range of 1 to 2% of normal. On superimposition, for instance of telangiectasia on a mild hemophilia, the clinical manifestations are markedly accentuated. The simultaneous occurrence of even very mild Minot-von Willebrand syndrome in the hemophiliac will intensify the bleeding tendency, especially after the ingestion of aspirin. Environmental factors illustrated by trauma such as mild contusions, which in the normal do not even cause a bruise, may bring about intramuscular hemorrhages and hemarthroses, and thereby sometimes initiate a bleeding cycle.

• References

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