Role in Disease
Deficiencies of either protein components of the prothrombinase complex are very rare. Factor V deficiency, also called parahemophilia, is a rare autosomal recessive bleeding disorder with an approximate incidence of 1 in 1,000,000. Congenital Factor X deficiency is also extremely rare, affecting an estimated 1 in 1,000,000.
A point mutation in the gene encoding Factor V can lead to a hypercoagulability disorder called Factor V Leiden. In Factor V Leiden, a G1691A nucleotide replacement results in an R506Q amino acid mutation. Factor V Leiden increases the risk of venous thrombosis by two known mechanisms. First, activated protein C normally inactivates Factor Va by cleaving the cofactor at Arg306, Arg506, and Arg679. The Factor V Leiden mutation at Arg506 renders Factor Va resistant to inactivation by activated protein C. As a result of this resistance, the half-life of Factor Va in plasma is increased, resulting in increased thrombin production and increased risk of thrombosis. Secondly, under normal conditions, if Factor V is cleaved by activated protein C instead of thrombin, it can serve as a cofactor for activated protein C. Once bound to Factor V, activated protein C cleaves and inactivates Factor VIIIa. The mutated form of Factor V present in Factor V Leiden, however, serves as a less efficient cofactor of activated protein C. Thus, Factor VIIIa is less efficiently inactivated in Factor V Leiden, further increasing the risk of thrombosis. In fact Factor V Leiden is the most common cause of inherited thrombosis.
Heterozygous Factor V Leiden is present in approximately 5% of the white population in the United States and homozygous Factor V Leiden is found less than 1% of this population. Factor V Leiden is much more common in individuals of Northern European descent and in some Middle Eastern populations. It is less common in Hispanic populations, and rare in African, Asian, and Native American populations. Factor V Leiden is an important risk factor for venous thromboembolism, that is, deep vein thrombosis or pulmonary embolism. In fact, heterozygous Factor V Leiden increases one's risk of recurrent venous thromboembolism by 40%.
Read more about this topic: Prothrombinase
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