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Sunday, April 15, 2007

Human Anticoagulant Genes

One of the most important factors in anticoagulation is antithrombin III [Inhibiting Blood Clots: Anticoagulants]. The official name of this protein is serpin peptidase inhibitor and gene for antithrombin III is called SERPINC1 [GeneID=462]. The gene is located on chromosome 1 at q23-q25.1.

Deficiencies in antithrombin III cause thrombosis, or excess clotting. Dozens of different alleles are known. The defective proteins show a variety of effects including reduced binding to heparan sulfate, reduced binding to thrombin, and decreased stability [OMIM 107300]. In most cases the affected individuals contain only one copy of the mutant allele suggesting that both copies must be active for effective anticoagulant activity.

The other anticoagulant pathway requires thrombomodulin plus protein C and protein S. The gene for thrombomodulin is called THRM [GeneID=7056] and it is found on chromosome 20 at p11.2.

Mutations in THRM are associated with mild thrombosis and increased risk of myocardial infarction (heart attacks). People with this susceptibility are heterozygous for the mutant allele. Most alleles that have a physiological phenotype are recessive lethals resulting in late fetal deaths (spontaneous abortion). The defect is associated with the formation of excessive blood clots at the region where placental blood and maternal blood vessels are in close contact [OMIM 188040].

The gene for protein C is PROC [GeneID=5624] on chromosome 2 at q13-q14.

Deficiencies in protein C cause congenital thrombotic disease or thrombphilia (due to PC deficiency). The type patient ("propositus") and his family are described on the Online Mendelian Inheritance in Man entry for PROC [OMIM 176860].

Their propositus was a 22-year-old Caucasian male with recurrent thrombophlebitis complicated by pulmonary embolism. His 56-year-old father had thrombophlebitis with pulmonary embolism following a minor leg injury at age 24, a cerebrovascular accident at age 43, and a myocardial infarction at age 45. A paternal uncle had thrombophlebitis and recurrent pulmonary emboli dating from age 20. The paternal grandfather died abruptly at age 45. He had sustained a leg injury in a fall from a horse. While he was confined to bed, pulmonary infiltrates developed. These resolved, but on his first day out of bed he collapsed and died after taking a few steps. The paternal great-grandfather died unexpectedly of a cerebrovascular accident at age 61. The propositus, his father, and his paternal uncle showed levels of plasma protein C antigen (determined immunologically by the Laurell rocket technique) 38 to 49% of normal. Clinically unaffected members of the kindred had normal levels.
There are at least 25 known variants of PROC causing increased risk of thrombosis and heat attacks.

The gene for protein S is called PROS1 [GeneID=5627], located at the centromere of chromosome 3 (3p11.1-q11.2). Deficiencies in protein S produce symptoms very similar to those desribed for protein C deficiencies. As is the case with PROC mutants, PROS1 mutant alleles are dominant although the penetrance is less than 100%. What this means is that some people who are heterozygous don’t show any increased risk of thrombosis while others do. This suggests there are other factors that are required for thrombosis [OMIM 176880].

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