Foley J H, Nesheim M E
Department of Biochemistry, Queen's University, Kingston, ON, Canada.
J Thromb Haemost. 2009 Mar;7(3):453-9. doi: 10.1111/j.1538-7836.2008.03261.x. Epub 2008 Dec 13.
Previous work by others has shown that premature clot lysis occurs in plasmas deficient in components of the intrinsic pathway, due to a failure to activate thrombin activatable fibrinolysis inhibitor (TAFI). This suggests the hypothesis that bleeding in hemophilia is due not only to defective coagulation but also enhanced fibrinolysis. These studies were carried out to quantify the extent of TAFI activation over time in normal plasma (NP) and factor VIII deficient plasma (FVIII-DP) and to determine whether soluble thrombomodulin (sTM) can correct the lysis defect in FVIII-DP.
The time courses of TAFI activation in both NP and FVIII-DP were monitored after clotting with thrombin, PCPS and Ca(2+), +/- sTM. Clotting and lysis were measured turbidometrically and TAFIa using a functional assay.
Premature lysis that occurs in FVIII-DP is corrected by mixing deficient plasma with 10% NP. However, this does not fully correct the defect in TAFI activation. FVIII-DP must be mixed with up to 50% NP to attain the same TAFIa potential as NP. In FVIII-DP, sTM can correct the defect in TAFIa-dependent prolongation of lysis at low tPA concentrations and partially correct this defect at high tPA concentrations.
TAFI activation increases as the concentration of FVIII increases. FVIII at a level of 10% fully corrects the lysis defect in spite of the extent of TAFI activation being only one half that obtained with 100% FVIII. In addition, sTM increases TAFI activation sufficiently to correct the premature lysis defect in FVIII-DP.
其他人之前的研究表明，由于无法激活凝血酶激活的纤维蛋白溶解抑制剂（TAFI），在内源性途径成分缺乏的血浆中会发生过早的凝块溶解。这提示了一种假说，即血友病出血不仅是由于凝血缺陷，还由于纤维蛋白溶解增强。进行这些研究是为了量化正常血浆（NP）和因子VIII缺乏血浆（FVIII-DP）中TAFI随时间的激活程度，并确定可溶性血栓调节蛋白（sTM）是否可以纠正FVIII-DP中的溶解缺陷。
用凝血酶、PCPS和Ca(2+)（±sTM）使NP和FVIII-DP凝血后，监测TAFI激活的时间进程。通过比浊法测量凝血和溶解，并使用功能测定法测量TAFIa。
将缺乏血浆与10%NP混合可纠正FVIII-DP中发生的过早溶解。然而，这并不能完全纠正TAFI激活缺陷。FVIII-DP必须与高达50%NP混合才能达到与NP相同的TAFIa潜力。在FVIII-DP中，sTM可以在低tPA浓度下纠正TAFIa依赖性溶解延长的缺陷，并在高tPA浓度下部分纠正该缺陷。
TAFI激活随着FVIII浓度的增加而增加。尽管TAFI激活程度仅为100%FVIII时的一半，但10%水平的FVIII可完全纠正溶解缺陷。此外，sTM可充分增加TAFI激活，以纠正FVIII-DP中的过早溶解缺陷。
