TAFIa, PAI-1 and alpha-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: 5.55). 05/2007; 5(4):812-7. DOI: 10.1111/j.1538-7836.2007.02430.x
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Factor XIII (FXIII) stabilizes thrombi against fibrinolysis by cross-linking α2-antiplasmin (α2AP) to fibrin. Cellular FXIII (FXIII-A) is abundant in platelets, but the extracellular functions of this pool are unclear, as it is not released by classical secretion mechanisms. We examined the function of platelet FXIII-A using Chandler model thrombi formed from FXIII-depleted plasma. Platelets stabilized FXIII-depleted thrombi in a transglutaminase-dependent manner. FXIII-A activity on activated platelets was unstable and was rapidly lost over 1 h. Inhibiting platelet activation abrogated the ability of platelets to stabilize thrombi. Incorporation of a neutralizing antibody to α2AP into FXIII-depleted thrombi revealed that the stabilizing effect of platelet FXIII-A on lysis was α2AP-dependent. Platelet FXIII-A activity and antigen were associated with the cytoplasm and membrane fraction of unstimulated platelets and these fractions were functional in stabilizing FXIII-depleted thrombi against lysis. Fluorescence confocal microscopy and flow cytometry revealed exposure of FXIII-A on activated membranes with maximal signal detected with thrombin and collagen stimulation. FXIII-A was evident in protruding 'caps' on the surface of phosphatidylserine-positive platelets. Our data show a functional role for platelet FXIII-A through exposure on the activated platelet membrane where it exerts antifibrinolytic function through cross-linking α2AP to fibrin.
    Blood 10/2014; 124(26). DOI:10.1182/blood-2014-06-583070 · 9.78 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Little is known, in man, in the post-thrombolytic molecular dynamics of haemostasis, particularly the effect of rt-PA on antifibrinolytic components such as alpha2 anti-plasmin and Factor XIII. The purpose of this study was to systematically determine changes in coagulation and fibrinolytic parameters after thrombolysis with rt-PA during 24h. We also aimed to correlate these parameters with different acute ischemic stroke subtypes and global outcome. Eighty consecutive patients with cerebral infarcts treated with rt-PA had their plasma levels of fibrinogen, plasminogen, alpha2-antiplasmin, Factor XIII, fibrin(ogen) degradation products (FDP) and D-Dimers measured at baseline (h0), 2 (h2) and 24h (h24) after initiation of thrombolysis. Correlations between the variations of these components were statistically studied, using the Spearman rank test or the Pearson test. These haemostatic parameters were also compared with cardioembolic and non cardioembolic patients, as well as between poor and favourable outcome patients. Between h0 and h2, a decrease in fibrinogen, plasminogen, alpha2-antiplasmin, and factor XIII was observed, while an increase in FDP and D-Dimers took place. These values returned to the initial levels at h24. At 2h, the decrease in fibrinogen was significantly correlated with that of plasminogen (0.48, p=0.01), alpha2-antiplasmin (0.48, p=0.004), and factor XIII (0.44, p=0.01); the decrease in plasminogen was significantly correlated with those of antifibrinolytic components, factor XIII (0.47, p=0.02) and alpha2-antiplasmin (r=0.77, p<0.001). These variations were independent of NIHSS. Cardioembolic infarcts showed a statistically significant greater h0-h2 decrease in plasminogen (p=0.04) and an h0-h2 increase in FDP (p=0.02). Poor outcome was linked to low plasminogen values at 2 and 24h. Supposed to be fibrin-specific, rt-PA induces a decrease in circulating fibrinogen, significantly linked to a decrease in plasminogen. A collateral increase in antifibrinolytic agents such as factor XIII and alpha2-antiplasmin is also observed. At 2h, a significant decrease in plasminogen and a significant increase in fibrin(ogen) degradation products (FDP) are observed in cardioembolic infarcts, and appear as early independent predictors of this aetiology. A low plasminogen value at 2h is potentially predictive of poor prognosis at 3months. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of the Neurological Sciences 12/2014; 349(1-2). DOI:10.1016/j.jns.2014.12.029 · 2.26 Impact Factor

Full-text (2 Sources)

Available from
Nov 2, 2014