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DOI: 10.1055/s-0039-1680115
Plasmin-induced Alterations to Platelet GPIIb/IIIa Receptors Impair Secondary Blood Clot Firmness
Publikationsverlauf
Publikationsdatum:
13. Februar 2019 (online)
Background: Haemostasis involves the recruitment of platelets to the site of a vessel wall defect, the activation of plasmatic coagulation factors and the strengthening of the primary platelet plug by a network of emerging fibrin strands. About a quarter of severely injured patients present with an impairment of haemostasis, a phenomenon that has been termed trauma-induced coagulopathy (TIC). TIC is characterized by the depletion of functional coagulation factors, fibrinolytic activation and platelet dysfunction. Excessive release of tissue-plasminogen activator (t-PA) during fibrinolytic activation cannot only result in hyperfibrinolysis but can also affect platelet glycoprotein receptors. Here we investigated ex vivo, whether a global state of pro-coagulant and fibrinolytic activation can interfere with glycoprotein-mediated platelet-fibrinogen interaction and whether these conditions can affect secondary clot stability.
Methods: Whole blood of healthy donors was incubated with t-PA in the presence or absence of the antifibrinolytic tranexamic acid (TXA). Platelets were isolated, washed and transferred to a 1.5 or 3 mg/mL solution of fibrinogen in isotonic saline. Platelet-fibrin clots were formed by the addition of CaCl2 and thrombin to assess functional clot stability by thromboelastometry. Fluorescence Microscopy with fluorophore labeled fibrinogen and a monoclonal antibody against GPIIb/IIIa as well as flow cytometry (FC) were performed to assess platelet-fibrinogen interaction.
Results: Pre-incubation with t-PA resulted in a significant impairment of maximum clot firmness (MCF) and a fulminant breakdown of the platelet-fibrin clot in thromboelastometry. Both effects could be reversed by the prior co-incubation with TXA. When comparing the two fibrinogen concentrations in the t-PA group, differences in MCF and lysis onset time (LOT) were observed. Fibrinogen binding in FC and co-localization of platelet GPIIb/IIIa with fibrinogen in FM were diminished in the t-PA group. This was not the case in the group with TXA co-incubation.
Conclusions: Platelet activation in a fibrinolytic micro-environment can affect platelet GPIIb/IIIa receptors and impair their ability to contribute to a stable secondary clot. Our laboratory findings might have implications for the pathophysiology of hyperfibrinolysis, the efficacy of therapeutic fibrinogen supplementation and the significance of early tranexamic acid administration.