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- W2580842912 abstract "Abstract It has been documented that fibrinogen (Fg) is required for platelet aggregation. However, we recently found that platelet rich thrombi still formed in mice lacking either Fg (Fg−/−) or both Fg and vWF (Fg/vWF−/−) (Ni et al, JCI106:385–392, 2000). To explore the potential mechanisms of Fg/vWF-independent platelet aggregation, we studied platelet aggregation in vitro in platelet rich plasma (PRP). We found no platelet aggregation in Fg−/− or Fg/vWF−/− PRP induced by adenosine diphosphate (ADP) in the presence of anticoagulant reagents including divalent cation chelators (ACD, sodium citrate, and EDTA), and thrombin inhibitors (heparin, hirudin, PPACK). Since no fibrin formation occurs in Fg/vWF−/− plasma, we then induced Fg/vWF−/− platelet aggregation in non-anticoagulated platelet poor plasma (PPP). Surprisingly, robust aggregation occurred after ADP treatment. We further demonstrated that directly triggering the thrombin receptor PAR4 with thrombin receptor activation peptide (TRAP, AYPGKF-NH2) induced platelet aggregation in thrombin-inhibitor treated Fg/vWF−/− PRP and gel-filtered Fg/vWF-platelets in 1mM Ca2+ PIPES buffer. Thus Fg/vWF-independent aggregation can be induced in vitro and both divalent cations and thrombin are required for this novel platelet aggregation pathway. It is likely that ADP induced thrombin generation in Fg/vWF-/- PRP. Considering platelet aggregation has been observed in type I Glanzmann Thrombasthenic patients lacking αIIbβ3 protein, we hypothesized that Fg/vWF−/− platelet aggregation may occur in either a β3 integrin-dependent or β3 integrin independent manners. To test this hypothesis, β3 integrin deficient (β3−/−) platelets were added into the same non-anticoagulated Fg/vWF−/− plasma and no aggregation was observed after ADP treatment. β3−/− platelets also did not co-aggregate with Fg/vWF−/− platelets in vitro in aggregation assays, which were analyzed by flow cytometry with an anti-CD61 (anti-β3 integrin) antibody. Furthermore, when fluorescently labeled β3−/− platelets were injected into Fg/vWF−/− mice, β3−/− platelets did not significantly incorporate into Fg/vWF−/− thrombi under confocal intravital microscopy. The inability of β3−/− platelets to aggregate is not due to a deficiency in other adhesive receptors, since no reduction of GPIbα, β1 integrins, and P-selectin was observed on β3−/− platelets. Thus, although the GPIb complex, P-selectin, and β1 integrins may be involved in platelet aggregation, β3 integrin is essential for this Fg/vWF-independent platelet aggregation pathway. This also indicates that other alternative ligands of β3 integrin from either the plasma or platelet granules are capable of mediating platelet aggregation independent of both Fg and vWF under more physiologically relevant conditions (i.e. non anti-coagulated blood) where divalent cations and thrombin are present." @default.
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- W2580842912 date "2005-11-16" @default.
- W2580842912 modified "2023-10-16" @default.
- W2580842912 title "Fibrinogen and von Willebrand Factor-Independent Platelet Aggregation: The Essential Roles of β3 Integrin, Thrombin, and Divalent Ca2+ Cations." @default.
- W2580842912 doi "https://doi.org/10.1182/blood.v106.11.2651.2651" @default.
- W2580842912 hasPublicationYear "2005" @default.
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