Platelets are versatile cells: New discoveries in hemostasis, thrombosis, immune responses, tumor metastasis and beyond

Abstract

Platelets are small anucleate blood cells generated from megakaryocytes in the bone marrow and cleared in the reticuloendothelial system. At the site of vascular injury, platelet adhesion, activation and aggregation constitute the first wave of hemostasis. Blood coagulation, which is initiated by the intrinsic or extrinsic coagulation cascades, is the second wave of hemostasis. Activated platelets can also provide negatively-charged surfaces that harbor coagulation factors and markedly potentiate cell-based thrombin generation. Recently, deposition of plasma fibronectin, and likely other plasma proteins, onto the injured vessel wall has been identified as a new “protein wave of hemostasis” that may occur even earlier than the first wave of hemostasis, platelet accumulation. Although no experimental evidence currently exists, it is conceivable that platelets may also contribute to this protein wave of hemostasis by releasing their granule fibronectin and other proteins that may facilitate fibronectin self- and non-self-assembly on the vessel wall. Thus, platelets may contribute to all three waves of hemostasis and are central players in this critical physiological process to prevent bleeding. Low platelet counts in blood caused by enhanced platelet clearance and/or impaired platelet production are usually associated with hemorrhage. Auto- and allo-immune thrombocytopenias such as idiopathic thrombocytopenic purpura and fetal and neonatal alloimmune thrombocytopenia may cause life-threatening bleeding such as intracranial hemorrhage. When triggered under pathological conditions such as rupture of an atherosclerotic plaque, excessive platelet activation and aggregation may result in thrombosis and vessel occlusion. This may lead to myocardial infarction or ischemic stroke, the major causes of mortality and morbidity worldwide. Platelets are also involved in deep vein thrombosis and thromboembolism, another leading cause of mortality. Although fibrinogen has been documented for more than half a century as essential for platelet aggregation, recent studies demonstrated that fibrinogen-independent platelet aggregation occurs in both gene deficient animals and human patients under physiological and pathological conditions (non-anti-coagulated blood). This indicates that other unidentified platelet ligands may play important roles in thrombosis and might be novel antithrombotic targets. In addition to their critical roles in hemostasis and thrombosis, emerging evidence indicates that platelets are versatile cells involved in many other pathophysiological processes such as innate and adaptive immune responses, atherosclerosis, angiogenesis, lymphatic vessel development, liver regeneration and tumor metastasis. This review summarizes the current knowledge of platelet biology, highlights recent advances in the understanding of platelet production and clearance, molecular and cellular events of thrombosis and hemostasis, and introduces the emerging roles of platelets in the immune system, vascular biology and tumorigenesis. The clinical implications of these basic science and translational research findings will also be discussed.

Keywords:

• Angiogenesis
• atherosclerosis
• fibrinogen
• fibronectin
• inflammation
• integrin
• lymphatic vessel
• metastasis
• thrombocytopenia
• venous thromboembolism

Acknowledgements

The authors would like to thank Dr. Denisa D. Wagner, Dr. John Freedman, Dr. Richard O. Hynes, Dr. Zaverio M. Ruggeri and all members of the Toronto Platelet Immunobiology Group for their long-term support for these research projects.

Declaration of interest

The authors report no declarations of interest. This work was supported in part by the Canadian Institutes of Health Research (MOP 68986, MOP 119551, MOP 97918, and 119540), the Grant-in-Aid from the Heart and Stroke Foundation of Canada (Ontario), and the equipment funds from St. Michael’s Hospital, Canadian Blood Services, and the Canada Foundation for Innovation. XRX is a recipient of the Heart and Stroke/Richard Lewar Center of Excellence Studentship award, The Meredith & Malcolm Silver Scholarship in Cardiovascular Studies, and The China National Scholarship Award. BEO is a recipient of the Canadian Blood Services Summer Research Scholarship. NC is a recipient of the Canadian Blood Services Postdoctoral Fellowship. XW is supported by the Sailing Engineering Project of Jiangxi Province, P.R. China. YH is a recipient of a State Scholarship Fund from the China Scholarship Council. CL is a recipient of the Entrance Award from the Department of Physiology, University of Toronto.