TAFIa, PAI-1 and α2-antiplasmin: Complementary roles in regulating lysis of thrombi and plasma clots

Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 05/2007; 5(4):812-7. DOI: 10.1111/j.1538-7836.2007.02430.x
Source: PubMed


PAI-1 and alpha(2)-antiplasmin (alpha(2)AP) are the principal direct inhibitors of fibrinolytic proteases. Thrombin activatable fibrinolysis inhibitor (TAFI), a plasma procarboxypeptidase activated by thrombin-thrombomodulin to form TAFIa, also regulates fibrinolysis by modulating fibrin. In this study, the relative contributions of PAI-1, alpha(2)AP and TAFIa to inhibition of lysis were assessed. In platelet-poor plasma clots, alpha(2)AP, TAFIa and PAI-1 all inhibited lysis, as shown by the addition of neutralizing antibodies to alpha(2)AP and PAI-1 +/- CPI, a potato carboxypeptidase inhibitor. alpha(2)AP played the largest role in regulating plasma clot lysis, but neutralization of inhibitors in combinations was more effective in shortening lysis times, with a maximal effect when all three inhibitors were neutralized. In platelet-rich clots, a larger contribution of PAI-1 was evident. Tissue plasminogen activator induced lysis of model thrombi, made from whole blood, was approximately doubled on incorporation of CPI, illustrating a substantial contribution of TAFIa to inhibition of thrombus lysis. Similar increases in thrombus lysis were observed on inclusion of neutralizing antibodies to PAI-1 and alpha(2)AP, with alpha(2)AP playing the dominant role. Maximal thrombus lysis occurred upon neutralization of all three inhibitors. These observations suggest that, despite the differences in concentrations and activities of inhibitors, and the different modes of action, the roles of the three are complementary in both plasma clot lysis and thrombus lysis.

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Available from: Nicola J Mutch, Nov 01, 2014
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    • "Complement and haemostatic mechanisms also interact at the inhibitor level, for instance, C1-inhibitor inhibits complement factors C1r, C1s, MASP1, and MASP2, as well as coagulation factors XIIa and XIa [153]. TAFI not only inhibits fibrinolysis by cleaving terminal lysine residues from fibrin, thereby preventing plasminogen binding and plasmin generation [154], but TAFI also cleaves terminal arginine residues from C3a and C5a to downregulate their proinflammatory activities [155]. Cross-talk between complement and coagulation cascades therefore occurs at multiple levels and appears to be important in coordination to haemostatic and immune responses. "
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    • "Different explanations have been given for these discrepancies [8,15], but there is a need for a quantitative method that reveals the effect of cross-linking on fibrinolysis. Whole blood model thrombi formed under flow show a similar structure and protein distribution to thrombi formed in vivo [23], and have revealed the complementary nature of α2AP, PAI-1 and TAFI [24]. Here, we used model thrombi, and show that fibrinolysis is dramatically increased in FXIII deficiency, an effect that could be recapitulated by incorporating a non-reversible inhibitor of TGs. "
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    • "In addition, the crosslinking of a2AP to fibrin by activated factor XIII also inhibits the initiation of fibrinolysis in vivo (Mutch et al., 2007; Reed et al., 1990a) Studies comparing the effects of PAI-1, thrombin-activated fibrinolysis inhibitor and a2AP indicated that all three molecules exert regulatory effects, but a2AP had the greatest influence on fibrinolysis (Mutch et al., 2007). While the effects of a2AP inactivation on cerebrovascular thrombi have not been previously examined, a2AP inactivation synergistically amplifies fibrinolysis by endogenous and pharmacologic TPA in vitro and increases dissolution of venous and pulmonary emboli thrombi in vivo without causing bleeding (Butte et al., 1997; Lijnen et al., 1999; Matsuno et al., 2003; Reed et al., 1990a,1990b). "
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