Abstract
Cross-linking of α2-plasmin inhibitor (α2-PI) to fibrin by activated factor XIII (FXIIIa) is essential for the inhibition of fibrinolysis. Little is known about the factors modifying α2-PI incorporation into the fibrin clot and whether the extent of incorporation has clinical consequences. Herein we calculated the extent of α2-PI incorporation by measuring α2-PI antigen levels from plasma and serum obtained after clotting the plasma by thrombin and Ca2+. The modifying effect of FXIII was studied by spiking of FXIII-A-deficient plasma with purified plasma FXIII. Fibrinogen, FXIII, α2-PI incorporation, in vitro clot-lysis, soluble fibroblast activation protein and α2-PI p.Arg6Trp polymorphism were measured from samples of 57 acute ischemic stroke patients obtained before thrombolysis and of 26 healthy controls. Increasing FXIII levels even at levels above the upper limit of normal increased α2-PI incorporation into the fibrin clot. α2-PI incorporation of controls and patients with good outcomes did not differ significantly (49.4 ± 4.6% vs. 47.4 ± 6.7%, p = 1.000), however it was significantly lower in patients suffering post-lysis intracranial hemorrhage (37.3 ± 14.0%, p = 0.004). In conclusion, increased FXIII levels resulted in elevated incorporation of α2-PI into fibrin clots. In stroke patients undergoing intravenous thrombolysis treatment, α2-PI incorporation shows an association with the outcome of therapy, particularly with thrombolysis-associated intracranial hemorrhage.
Highlights
Fibrinolysis is a tightly regulated process, accomplished by a wide range of cofactors, receptors and inhibitors [1]
The most important activator of the generation of plasmin is tissue plasminogen activator. This protein is used in a recombinant form as a pharmacological therapy to dissolve blood clots in patients with acute ischemic stroke (AIS), in a process known as thrombolysis [2,3]
We report that as opposed to early findings, increasing factor XIII (FXIII) levels above 8% results in elevated incorporation of α2-plasmin inhibitor (α2-PI) into fibrin clots, and the maximal extent of α2-PI incorporation is reached at FXIII levels above 100%
Summary
Fibrinolysis is a tightly regulated process, accomplished by a wide range of cofactors, receptors and inhibitors [1]. The most important activator of the generation of plasmin is tissue plasminogen activator (tPA). This protein is used in a recombinant form (rt-PA) as a pharmacological therapy to dissolve blood clots in patients with acute ischemic stroke (AIS), in a process known as thrombolysis [2,3]. Intravenous thrombolysis using rt-PA can only be successful in a short time-window after the onset of stroke symptoms (3–4.5 h). This therapy has been proven to be safe and effective in a number of clinical trials and meta-analyses, it is not a remedy for all [4,5].
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