Summary
The incomplete penetrance of thrombosis in familial protein C deficiency suggests
disease occurs when this deficit is combined with additional abnormalities in the
hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred,
which is affected by a clinically dominant type I protein C deficiency, provides strong
evidence for a second unidentified gene that segregates independently of protein C
deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis,
thirty-four candidate genes for proteins involved in hemostasis or inflammation were
tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers
in an informative subset (n = 31) of the kindred. The genes considered are; α-fibrinogen,
β-fibrinogen, γ-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement
component 4 binding protein, factor XI, factor XII, factor XIIIa, factor Xlllb, histidine
rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor,
platelet factor 4, thrombospondin, antithrombin III, α-1-antitrypsin, thrombomodulin,
plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen
activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, α-2-plasmin
inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-β-synthase,
and methylenetetrahydrofolate reductase. Mutations in many of these genes have been
previously established as independent risk factors for thrombosis. However, linkage
analysis provided no evidence to implicate any of the candidate genes as the second
inherited factor that promotes thrombophilia in this kindred.
Keywords
Protein C - thrombophilia
