Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases

Abstract

Platelets are essential for clotting in the blood and maintenance of normal hemostasis. Under pathologic conditions such as atherosclerosis, vascular injury often results in hyperactive platelet activation, resulting in occlusive thrombus formation, myocardial infarction, and stroke. Recent work in the field has elucidated a number of platelet functions unique from that of maintaining hemostasis, including regulation of tumor growth and metastasis, inflammation, infection, and immune response. Traditional therapeutic targets for inhibiting platelet activation have primarily been limited to cyclooxygenase-1, integrin α_IIbβ₃, and the P2Y₁₂ receptor. Recently identified signaling pathways regulating platelet function have made it possible to develop novel approaches for pharmacological intervention in the blood to limit platelet reactivity. In this review, we cover the newly discovered roles for platelets as well as their role in hemostasis and thrombosis. These new roles for platelets lend importance to the development of new therapies targeted to the platelet. Additionally, we highlight the promising receptor and enzymatic targets that may further decrease platelet activation and help to address the myriad of pathologic conditions now known to involve platelets without significant effects on hemostasis.

Fig. 1.

The physiologic and pathophysiological roles of platelets. Platelets participate in hemostasis to prevent blood loss by forming a hemostatic plug following a vascular insult. In contrast, platelets can also partake in arterial and venous thrombosis, increasing the likelihood of vessel occlusion. The pathophysiological mechanisms of arterial and venous thrombus formation are distinct by which arterial thrombosis normally occurs following an atherosclerotic plaque rupture, leading to damaged endothelial cells, whereas, in venous thrombosis, the endothelial cells remained intact.

Fig. 2.

The role of platelets in immune response. Platelets can directly or indirectly interact with components of the virus, bacteria, or even drugs such as heparin to induce platelet activation and interaction with neutrophils or other phagocytes, resulting in neutrophil–platelet aggregate formation or thrombocytopenia.

Fig. 3.

GPCR signaling in platelet function. Platelets express thrombin (PAR1/PAR4) and purinergic (P2Y₁ and P2Y₁₂) receptors. Each receptor is coupled to either G_i, G_q, or G₁₃, which is involved in platelet activation (granule release, integrin activation).

Fig. 4.

Prostanoid receptors on human platelets. Each prostanoid receptor, IP, DP, EP_1–4, and TPα, is uniquely defined by its lipid ligands as well as its associated G proteins. Depending on the type of oxylipins or doses, platelet function can either be inhibited or activated. This is dictated by their cognate receptor activation, which is coupled to either inhibitory Gα_s or activating Gα₁₃, Gα_q, and Gα_i.

Fig. 5.

ITAM and integrin receptors on platelets. GPVI, FcγIIa, and CLEC-2 belong to a class of hemi(ITAM) receptors that are involved in platelet activation. Whereas GPVI and α₂β₁ are activated by collagen, FcγIIa recognizes IgG immune complexes to induce integrin α_IIbβ₃ activation. CLEC-2 contains a single YxxL motif that is activated by podoplanin. Ligand binding to GPVI or FcγIIa results in Syk and subsequent PLCγ2 activation, leading to platelet aggregation, mediated by the active conformation of integrin α_IIbβ₃.

Fig. 6.

The major antiplatelet targets. Drugs inhibit surface receptors, GPCRs (PAR1/4, P2Y12) and glycoproteins (integrin α_IIbβ₃, GPVI, and GIb-IX-V), oxygenases (COX-1, 12-LOX), and phosphodiesterases to regulate platelet function. Agents coded in black are currently FDA approved, whereas drugs labeled as blue are under investigation in preclinical or clinical phases.