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Eicosanoid regulation of hemostasis through concomitant signals in the human platelet
Author(s) -
Holinstat Michael,
Vesci Joanne,
Apopa Patrick,
Boutaud Olivier
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.472.1
Subject(s) - eicosanoid , platelet , chemistry , thromboxane , thrombin , receptor , hemostasis , microbiology and biotechnology , platelet activation , hirudin , thromboxane a2 , pharmacology , arachidonic acid , biochemistry , biology , medicine , immunology , enzyme
Anti‐platelet therapy has traditionally targeted the surface receptor of the human platelet. These targets often result in an increase in bleeding which in some conditions may be more deleterious to the patient than the clot itself. Recently, eicosanoid metabolites have been shown to play a crucial role in regulation and stabilization of platelet clot formation. We hypothesized that eicosanoid metabolites such as thromboxane (TxA 2 ) and 12‐HETE may play a significant role in stabilization of platelet clots. To address this question, eicosanoid formation was perturbed in washed human platelets and potential signaling deficits were measured in a number of physiological assays. TxA 2 was shown to play a significant role not only in regulating thrombin‐mediated TxA 2 formation through feedback via the TP receptor on the platelet surface, but the presence of unique regulatory mechanisms were uncovered indicating the potential for multiple pools of arachidonic acid utilized by the thrombin receptors PAR1 and PAR4. Further, inhibition of the 12‐Lipoxygenase pathway revealed novel physiological regulation of dense granules, Rap1, and GPIIbIIIa. Identification of the underlying mechanisms by which these eicosanoids regulate platelet function is the first step in the development of novel therapeutic treatment of uncontrolled clot formation. This work was supported in part by NIH grant HL089457 (MH).