Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
J Thromb Haemost. 2011 Jul;9(7):1383-90. doi: 10.1111/j.1538-7836.2011.04343.x.
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.
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.
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.
此前，我们在两项基于人群的病例对照研究中发现，一种基于血浆的测定方法检测到的凝块溶解时间（CLT）增加会增加静脉血栓形成的风险。影响 CLT 的基因尚不清楚。
患者/方法：我们在Kindred Vermont II（n = 346）中测试了 CLT 作为静脉血栓形成的危险因素，这一家系患有高血栓形成风险，部分归因于 I 型蛋白 C 缺乏症。此外，我们使用方差成分连锁分析方法测试了 CLT 的定量性状基因座（QTL）。
蛋白 C 缺乏的家族成员的 CLT 比非缺乏的家族成员短（中位数 CLT 为 67 分钟 vs. 75 分钟）。CLT 增加一个标准差会使非缺乏的家族成员患静脉血栓形成的风险增加 2.4 倍。无 CLT 升高的蛋白 C 缺乏症使风险增加 6.9 倍。同时结合这两个危险因素可使风险增加 27.8 倍。CLT 的遗传率为 42-52%。我们在 11 号染色体（62cM）上发现了与 CLT 相关的提示性证据，部分原因是凝血酶原 20210A 突变，在 13 号染色体（52cM）上也发现了与 CLT 相关的提示性证据。凝血酶激活的纤维蛋白溶解抑制剂基因型不能解释 CLT 的变异。
该家族中低纤维蛋白溶解似乎会增加血栓形成的风险，尤其是与蛋白 C 缺乏症相结合时。蛋白 C 缺乏症与 CLT 缩短有关。CLT 部分受遗传调控。在 11 号和 13 号染色体上发现了提示性 QTL。
