Thrombosis & Hemostasis Research

Thrombosis is a crucial hemostatic process for maintaining blood volume (hemostasis) following injury, yet aberrant thrombosis can trigger pathological conditions including myocardial infarction and stroke. Therefore the initiation of thrombosis is tightly controlled under physiological conditions.

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Mechanisms of Thrombosis and Hemostasis

Platelets are a central component of thrombosis and exhibit a rapid, exponential activation in the event of tissue damage. Produced in the bone marrow, platelets are anucleate cell fragments of megakaryocytes. Despite having no nucleus, platelets possess two different types of granules within the cytoplasm - alpha granules and dense granules - and also express a number of different receptors on their plasma membranes. Both alpha and dense granules contain a variety of bioactive mediators including ADP, calcium and 5-HT as well as growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1) and transforming growth factor (TGF) β1. Upon activation, platelets undergo degranulation; this releases granule contents into the surrounding environment and promotes the activation and aggregation of neighboring platelets.

Receptors present on the platelet plasma membrane include the purinergic P2X receptor P2X1; the puringergic P2Y receptors P2Y1 and P2Y12; the 5-HT receptor 5-HT2A; the thromboxane A2 (TXA2) receptor TP; and the protease-activated receptors PAR1 and PAR4. Platelet signaling may also be activated by exposure to collagen via the glycoprotein receptor, GPVI. Key downstream mediators of these receptors include the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), which is cleaved by phospholipase C to form inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 receptor (InsP3R) activation triggers the efflux of calcium ions from intracellular calcium stores such as the endoplasmic reticulum, leading to a rise in intracellular calcium and subsequent platelet aggregation through the activation of integrin receptors.

Agonist stimulation of platelets also initiates the production of arachidonic acid from membrane phospholipids in a reaction catalyzed by cytosolic phospholipase A2 (cPLA2). Arachidonic acid can be utilized by both cyclooxygenases (COX) to form prostaglandin H2 (PGH2), and also by lipoxygenases (LOX) to form the lipid mediator hydroperoxyeicosatetraenoic acid (HPETE). PGH2 is further metabolized to form prothrombotic eicosanoids including TXA2.