Thrombosis & Hemostasis Research

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-HT_2A; 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.