Genome scan of clot lysis time and its association with thrombosis in a protein C‐deficient kindred

Summary Background:Previously, we found increased clot‐lysis time (CLT), as measured with a plasma‐based assay, to increase the risk of venous thrombosis in two population‐based case–control studies. The genes influencing CLT are as yet unknown. Patients/Methods:We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis. Results:Protein C‐deficient family members had shorter CLTs than non‐deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4‐fold in non‐deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9‐fold. Combining both risk factors yielded a 27.8‐fold increased risk. The heritability of CLT was 42–52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin‐activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT. Conclusion:Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13.