Soluble thrombomodulin partially corrects the premature lysis defect in FVIII-deficient plasma by stimulating the activation of thrombin activatable fibrinolysis inhibitor.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Foley
J H
JH
Department of Biochemistry, Queen's University, Kingston, ON, Canada.
Nesheim
M E
ME
D025901:Carboxypeptidase B2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005169:Factor VIII / Q000032:analysis / Q000502:physiology*; D005342:Fibrinolysis; D006467:Hemophilia A / Q000097:blood* / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D012995:Solubility; D018180:Thrombomodulin / Q000502:physiology*
D018180:Thrombomodulin; D005169:Factor VIII; D025901:Carboxypeptidase B2