Platelets in pulmonary vascular physiology and pathology

Abstract

Almost a trillion platelets pass through the pulmonary circulation every minute, yet little is known about how they support pulmonary physiology or contribute to the pathogenesis of lung diseases. When considering this conundrum, three questions jump out: Does platelet production in the lungs occur? Why does severe thrombocytopenia-which undercuts the principal physiological role of platelets to effect hemostasis-not lead to pulmonary hemorrhage? Why does atherothrombosis-which platelets initiate, maintain, and trigger is other critically important arterial beds-not develop in the pulmonary artery? The purpose of this review is to explore these and derivative questions by providing data within a conceptual framework that begins to organize a subject that is largely unassembled.

Keywords: cell signaling; hemostasis; platelets; thrombosis; vascular biology.

Figure 1

Scanning electron microscope images of resting, partially activated, and fully activated human platelets (from left to right). This article was originally published in the Journal of Biological Chemistry. Quantitative analysis of platelet αvβ3 binding to osteopontin using laser tweezers by Rustem I. Litvinov, Gaston Vilaire, Henry Shuman, Joel S. Bennett, and John Weisel in J Biol Chem 2003;278:51285-51290 (Cover photograph with additional credit to Chandrasekaran Nagaswami and Yevgeniya Baras). © The American Society for Biochemistry and Molecular Biology.

Figure 2

The thrombopoietic agent romiplostim induces an increase in megakaryocytes in the lungs of mice. (A) H and E-stained lung tissue of a normal mouse animal treated with romiplostim showing a representative lung megakaryocyte embolus (arrow). (B) Quantification of the emboli per capillary in lung tissue. Each bar represents the mean ± SEM of 10 animals. This figure was originally published in Blood by the American Society of Hematology (ASH). Romiplostim administration shows reduced megakaryocyte response capacity and increased myelofibrosis in a mouse model of MYH9-RD by Catherine Leon, Katja Evert, Frank Dombrowski, Fabien Pertuy, Anita Eckly, Patricia Laeuffer, Christian Gachet, and Andreas Greinacher in Blood 2012;119:3333-3341. © 2012 Reproduced with permission of ASH in the format republish in a journal via Copyright Clearance Center.

Figure 3

Adhesion and activation mechanisms supporting the hemostatic and prothrombotic function of platelets. Major ligands and receptors mediating platelet adhesion and activation at sites of vascular injury. Platelets are captured in the injured vessel wall from flowing blood through the specific interaction of the platelet GpIb-IX-V complex with collagen-bound VWF exposed on the subendothelium (top). This ligand-receptor interaction has a rapid on-off rate that supports platelet translocation at the vessel wall. Stable platelet adhesion occurs through the binding of platelet GPVI to fibrillar collagen as well as ligation of collagen to α2β1. Once firmly adherent, platelets undergo a series of biochemical changes that induce integrin αIIbβ3 activation, leading to the high affinity interaction with adhesion proteins including vWF, fibrinogen, and fibronectin. These adhesive interactions are indispensable for platelets to form stable aggregates with other activated platelets and promote thrombus growth. Activated platelets release or locally generate soluble agonists, including ADP, TXA2, and thrombin, that can induce autocrine or paracrine platelet activation (bottom). Each agonist activates specific G protein-coupled receptors on the platelet surface, including ADP-P2Y1 or ADP-P2Y12, TXA2-TP, and thrombin-PAR1 or PAR4, stimulating intracellular signaling events that include cytosolic calcium mobilization. This second messenger has a key role in promoting integrin αIIbβ3 activation, TXA2 generation, granule secretion, and the procoagulant function of platelets. This figure also shows the point of antagonism of several FDA-approved anti-platelet drugs (abciximab, eptifibatide, tirofiban, clopidogrel, prasugrel, ticagrelor, and aspirin) and two experimental PAR1 inhibitors (SCH530348 and E5555). Abbreviations: GP – glycoprotein, PAR–protease activated receptor, P – purinergic, ADP – adenosine diphosphate, TXA – thromboxane, TP– TXA2 receptor, G – heterotrimeric GTP – binding protein, FcRγ – Fc receptor gamma chain, ITAM – immunoreceptor tyrosine-based activation motif, vWF – von Willebrand factor, PLA2 – phospholipase A2, COX – cyclooxygenase, AA – arachidonic acid, PGH2 – prostaglandin H2, IP3R – inositol-1,4,5-trisphosphate receptor, DTS – dense tubular system. This figure was originally published in Nature Medicine by Nature Publishing Group. Arterial thrombosis–insidious, unpredictable and deadly by Shaun P. Jackson in Nature Medicine 2011;11:1423-1436. Reproduced with permission of Nature Publishing Group in the format reuse in a journal via Copyright Clearance Center.

Figure 4

Histone-DNA complexes are released from leukocytes and activate platelets by binding to their toll-like receptors TLR2 and TLR4. Activated or apoptotic neutrophils release histones that bind to specific platelet toll-like receptors. This results in platelet activation leading to several important antimicrobial, proinflammatory, and prothrombotic responses, including the secretion of platelet microbicidal proteins, P-selectin expression, platelet aggregation, and the expression on the platelet surface of prothrombinase activity leading to fibrin production and deposition. This figure was originally published in Blood by the American Society of Hematology (ASH). Inflammation and the platelet histone trap by Lea M. Beaulieu and Jane E. Freedman in Blood 2011;118:1714-1715. © 2012 Reproduced with permission of ASH in the format republish in a journal via Copyright Clearance Center.