Platelets — blood cells continuously produced from megakaryocytes mainly in the bone marrow — are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood. Genetic approaches have provided information on multiple genes related to normal haemostasis, such as those encoding receptors and signalling or secretory proteins, that determine platelet count and/or responsiveness. As highly responsive and secretory cells, platelets can alter the environment through the release of growth factors, chemokines, coagulant factors, RNA species, and extracellular vesicles. Conversely, platelets will also adapt to their environment. In disease states, platelets can be positively primed to reach a pre-activated condition. At the inflamed vessel wall, platelets interact with leukocytes and the coagulation system, interactions mediating thromboinflammation. With current antiplatelet therapies invariably causing bleeding as an undesired adverse effect, novel therapies can be more beneficial if directed against specific platelet responses, populations, interactions, or priming conditions. On the basis of these novel concepts and processes, we discuss several initiatives to target platelets therapeutically.
Multiomic approaches combined with functional testing of platelets have greatly advanced the understanding of genetic factors of platelet-related haemorrhagic disorders, but to a lesser extent the understanding of the causes of platelet hyper-reactivity.
Negative and positive platelet priming alter the threshold for platelet activation in the circulation, with consequences for diagnostic assays.
The diverse pathways of information transfer by platelets through release of bioactive molecules and extracellular vesicles are still incompletely understood.
Platelets contribute to thromboinflammatory processes by their capacity to interact functionally with the activated endothelium, leukocytes, and coagulation proteins; the mechanisms are multivariate.
Platelet populations and specific platelet responses are promising targets for new antithrombotic treatment of patients with cardiovascular disease.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Quach, M. E., Chen, W. & Li, R. Mechanisms of platelet clearance and translation to improve platelet storage. Blood 131, 1512–1521 (2018).
Lefrancais, E. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544, 105–109 (2017).
Stegner, D. et al. Thrombopoiesis is spatially regulated by the bone marrow vasculature. Nat. Commun. 8, 127 (2017).
Grozovsky, R., Giannini, S., Falet, H. & Hoffmeister, K. M. Regulating billions of blood platelets: glycans and beyond. Blood 126, 1877–1884 (2015).
Kaser, A. et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 98, 2720–2725 (2001).
den Dekker, E. et al. Cell-to-cell variability in the differentiation program of human megakaryocytes. Biochim. Biophys. Acta 1643, 85–94 (2003).
Moreau, T. et al. Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Nat. Commun. 7, 11208 (2016).
Machlus, K. R. & Italiano, J. E. Jr. The incredible journey: From megakaryocyte development to platelet formation. J. Cell Biol. 201, 785–796 (2013).
Bender, M. et al. Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein. Blood 125, 860–868 (2015).
Josefsson, E. C. et al. Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Nat. Commun. 5, 3455 (2014).
Semeniak, D. et al. Proplatelet formation is selectively inhibited by collagen type I through Syk-independent GPVI signaling. J. Cell Sci. 129, 3473–3484 (2016).
Abbonante, V. et al. A new path to platelet production through matrix sensing. Haematologica 102, 1150–1160 (2017).
Shi, D. S. et al. Proteasome function is required for platelet production. J. Clin. Invest. 124, 3757–3766 (2014).
McArthur, K., Chappaz, S. & Kile, B. T. Apoptosis in megakaryocytes and platelets: the life and death of a lineage. Blood 131, 605–610 (2018).
Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).
Alhasan, A. A. et al. Circular RNA enrichment in platelets is a signature of transcriptome degradation. Blood 127, e1–e11 (2016).
Male, R., Moon, D. G., Garvey, J. S., Vannier, W. E. & Baldeschwieler, J. D. Organ distributions of liposome-loaded rat platelets. Biochem. Biophys. Res. Commun. 195, 276–281 (1993).
Karpatkin, S. Heterogeneity of human platelets. I. Metabolic and kinetic evidence suggestive of young and old platelets. J. Clin. Invest. 48, 1073–1082 (1969).
Vicic, W. J. & Weiss, H. J. Evidence that platelet α-granules are a major determinant of platelet density: studies in storage pool deficiency. Thromb. Haemost. 50, 878–880 (1983).
Savage, B., McFadden, P. R., Hanson, S. R. & Harker, L. A. The relation of platelet density to platelet age: survival of low- and high-density 111indium-labeled platelets in baboons. Blood 68, 386–393 (1986).
Freson, K. et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98, 85–92 (2001).
Baaten, C. C. F. M. J., Ten Cate, H., van der Meijden, P. E. J. & Heemskerk, J. W. M. Platelet populations and priming in hematological diseases. Blood Rev. 31, 389–399 (2017).
Heemskerk, J. W. M., Mattheij, N. & Cosemans, J. M. E. M. Platelet-based coagulation: different populations, different functions. J. Thromb. Haemost. 11, 2–11 (2013).
Jackson, S. P. & Schoenwaelder, S. M. Procoagulant platelets — are they necrotic? Blood 116, 2011–2018 (2010).
Mattheij, N. J. et al. Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII. Haematologica 101, 427–436 (2016).
Agbani, E. O. et al. Coordinated membrane ballooning and procoagulant spreading in human platelets. Circulation 132, 1414–1424 (2015).
Vogler, M. et al. BCL2/BCL-XL inhibition induces apoptosis, disrupts cellular calcium homeostasis and prevents platelet activation. Blood 117, 7145–7154 (2011).
Schubert, S., Weyrich, A. S. & Rowley, J. W. A tour through the transcriptional landscape of platelets. Blood 124, 493–502 (2014).
Pleines, I. et al. Extended platelet in vivo survival results in exhausted platelets. Blood 126, 416 (2015).
Pleines, I. et al. Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion. Blood 132, 197–209 (2018).
McManus, D. D. & Freedman, J. E. MicroRNAs in platelet function and cardiovascular disease. Nat. Rev. Cardiol. 12, 711–717 (2015).
Rowley, J. W. et al. Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. Blood 127, 1743–1751 (2016).
Clancy, L., Beaulieu, L. M., Tanriverdi, K. & Freedman, J. E. The role of RNA uptake in platelet heterogeneity. Thromb. Haemost. 117, 948–961 (2017).
Burkhart, J. M. et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 120, e73–82 (2012).
Zeiler, M., Moser, M. & Mann, M. Copy number analysis of the murine platelet proteome spanning the complete abundance range. Mol. Cell. Proteom. 13, 3435–3445 (2014).
Solari, F. A. et al. Combined quantification of the global proteome, phosphoproteome and protein cleavage to characterize altered platelet functions in the human Scott syndrome. Mol. Cell. Proteom. 15, 3154–3169 (2016).
Schoenwaelder, S. M. et al. 14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. Nat. Commun. 7, 12862 (2016).
Versteeg, H. H., Heemskerk, J. W. M., Levi, M. & Reitsma, P. S. New fundamentals in hemostasis. Physiol. Rev. 93, 327–358 (2013).
Jackson, S. P. Arterial thrombosis: insidious, unpredictable and deadly. Nat. Med. 17, 1423–1436 (2011).
Mastenbroek, T. G., van Geffen, J. P., Heemskerk, J. W. M. & Cosemans, J. M. E. M. Acute and persistent platelet and coagulant activities in atherothrombosis. J. Thromb. Haemost. 13 (Suppl. 1), S272–S280 (2015).
Shekhonin, B. V., Domogatsky, S. P., Muzykantov, V. R., Idelson, G. L. & Rukosuev, V. S. Distribution of type I, III, IV and V collagen in normal and atherosclerotic human arterial wall: immunomorphological characteristics. Coll. Relat. Res. 5, 355–368 (1985).
De Witt, S. M. et al. Identification of platelet function defects by multi-parameter assessment of thrombus formation. Nat. Commun. 5, 4257 (2014).
Swieringa, F., Spronk, H. M. H., Heemskerk, J. W. M. & van der Meijden, P. E. J. Integrating platelet and coagulation activation in fibrin clot formation. Res. Pract. Thromb. Haemost. 2, 450–460 (2018).
Dubois, C., Panicot-Dubois, L., Merrill-Skoloff, G., Furie, B. & Furie, B. C. Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. Blood 107, 3902–3906 (2006).
Zhu, S., Lu, Y., Sinno, T. & Diamond, S. L. Dynamics of thrombin generation and flux from clots during whole human blood flow over collagen/tissue factor surfaces. J. Biol. Chem. 291, 23027–23035 (2016).
Zilberman-Rudensko, J. et al. Coagulation factor XI promotes distal platelet activation and single platelet consumption in the bloom stream under shear flow. Arterioscler. Thromb. Vasc. Biol. 36, 510–517 (2016).
Morowski, M. et al. Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice. Blood 121, 4938–4947 (2013).
Boulaftali, Y., Hess, P. R., Kahn, M. L. & Bergmeier, W. Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity. Circ. Res. 114, 1174–1184 (2014).
Van Gestel, M. et al. Real-time detection of activation patterns in individual platelets during thromboembolism in vivo: differences between thrombus growth and embolus formation. J. Vasc. Res. 39, 534–543 (2002).
Stalker, T. J. et al. A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus transport and local thrombin activity. Blood 124, 1824–1831 (2014).
Brass, L. F. & Stalker, T. J. Minding the gaps—and the junctions, too. Circulation 125, 2414–2416 (2012).
Vaiyapuri, S. et al. Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. Circulation 125, 2479–2491 (2012).
Swieringa, F., Kuijpers, M. J., Lamers, M. M., van der Meijden, P. E. J. & Heemskerk, J. W. M. Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow. Haematologica 100, 748–756 (2015).
Mammadova-Bach, E. et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 126, 683–691 (2015).
Van der Meijden, P. E. J. et al. Dual role of collagen in factor XII-dependent thrombus and clot formation. Blood 114, 881–890 (2009).
Verhoef, J. J. et al. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood 129, 1707–1717 (2017).
Payne, H., Ponomaryov, T., Watson, S. P. & Brill, A. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 129, 2013–2020 (2017).
Stefanini, L. et al. RASA3 s a critical inhibitor of RAP1-dependent platelet activation. J. Clin. Invest. 125, 1419–1432 (2015).
Golebiewska, E. M. et al. Syntaxin 8 regulates platelet dense granule secretion, aggregation, and thrombus stability. J. Biol. Chem. 290, 1536–1545 (2015).
Mattheij, N. J. A. et al. Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling and protein cleavage. FASEB. J. 30, 727–737 (2016).
Schaff, M. et al. Integrin α6β1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation 128, 541–552 (2013).
Bunimov, N., Fuller, N. & Hayward, C. P. Genetic loci associated with platelet traits and platelet disorders. Semin. Thromb. Hemost. 39, 291–305 (2013).
Nurden, A. T. & Nurden, P. Inherited disorders of platelet function: selected updates. J. Thromb. Haemost. 13, S2–S9 (2015).
Bianchi, E., Norfo, R., Pennucci, V., Zini, R. & Manfredini, R. Genomic landscape of megakaryopoiesis and platelet function defects. Blood 127, 1249–1259 (2016).
Tijssen, M. R. et al. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev. Cell 20, 597–609 (2011).
Freson, K. & Turro, E. High-throughput sequencing approaches for diagnosing hereditary bleeding and platelet disorders. J. Thromb. Haemost. 15, 1262–1272 (2017).
Simeoni, L. et al. A comprehensive high-throughput sequencing test for the diagnosis of inherited bleeding, thrombotic and platelet disorders. Blood 127, 2791–2803 (2016).
Bastida, J. M. et al. Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. Haematologica 103, 148–162 (2018).
Lentaigne, C. et al. Inherited platelet disorders: toward DNA-based diagnosis. Blood 127, 2814–2823 (2016).
Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429 (2016).
Gieger, C. et al. New gene functions in megakaryopoiesis and platelet formation. Nature 480, 201–207 (2011).
Petersen, R. et al. Platelet function is modified by common sequence variation in megakaryocyte super enhancer. Nat. Commun. 8, 16058 (2017).
Nagy, M. et al. Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies. Haematologica 103, 540–549 (2018).
Snoep, J. D. et al. The minor alleleof GP6 T13254C is associated with decreased platelet activation and a reduced risk of recurrent cardiovascular events and mortality: results from the SMILE-Platelets project. J. Thromb. Haemost. 8, 2377–2384 (2010).
Williams, M. S. et al. Genetic regulation of platelet receptor expression and function: application in clinical practice and drug development. Arterioscler. Thromb. Vasc. Biol. 30, 2372–2384 (2010).
Joshi, S. & Whiteheart, S. W. The nuts and bolts of the platelet release reaction. Platelets 28, 129–137 (2017).
Golebiewska, E. M. & Poole, A. W. Platelet secretion: from haemostasis to wound healing and beyond. Blood Rev. 29, 153–162 (2015).
Adam, F. et al. Kinesin-1 is a new actor involved in platelet secretion and thrombus stability. Arterioscler. Thromb. Vasc. Biol. 38, 1037–1051 (2018).
Meng, R. et al. Defective release of α granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models. Blood 125, 1623–1632 (2015).
Sharda, A. et al. Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood 125, 1633–1642 (2015).
Battinelli, E. M., Markens, B. A. & Italiano, J. E. Jr. Release of angiogenesis regulatory proteins from platelet α granules: modulation of physiologic and pathologic angiogenesis. Blood 118, 1359–1369 (2011).
Sobota, J. A., Ferraro, F., Back, N., Eipper, B. A. & Mains, R. E. Not all secretory granules are created equal: partitioning of soluble content proteins. Mol. Biol. Cell 17, 5038–5052 (2006).
Eckly, A. et al. Respective contributions of single and compound granule fusion to secretion by activated platelets. Blood 128, 2538–2549 (2016).
King, S. M. et al. Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. Circulation 120, 785–791 (2009).
Deppermann, C. et al. Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice. J. Clin. Invest. 123, 3331–3342 (2013).
O’Donnell, V. B., Murphy, R. C. & Watson, S. P. Platelet lipidomics: modern day perspective on lipid discovery and characterization in platelets. Circ. Res. 114, 1185–1203 (2014).
Edelstein, L. C. The role of platelet microvesicles in intercellular communication. Platelets 28, 222–227 (2017).
Melki, I., Tessandier, N., Zufferey, A. & Boilard, E. Platelet microvesicles in health and disease. Platelets 28, 214–221 (2017).
Dinkla, S. et al. Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin. Blood 127, 1976–1986 (2016).
Duchez, A. C. et al. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. Proc. Natl Acad. Sci. USA 112, E3564–E3573 (2015).
Vasina, E. M. et al. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am. J. Blood Res. 3, 107–123 (2013).
Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).
Best, M. G. et al. RNA-seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell 28, 666–676 (2015).
Gidlof, O. et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 121, 3908–3917 (2013).
Michael, J. V. et al. Platelet microparticles infiltrating solid tumors transfer mi-RNAs that suppress tumor growth. Blood 130, 567–580 (2017).
Keularts, I. M., van Gorp, R. M., Feijge, M. A., Vuist, W. M. & Heemskerk, J. W. α2A-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels. J. Biol. Chem. 275, 1763–1772 (2000).
Blair, T. A. et al. Phosphoinositide 3-kinases p110α and p110β have differential roles in insulin-like growth factor-1-mediated Akt phosphorylation and platelet priming. Arterioscler. Thromb. Vasc. Biol. 34, 1681–1688 (2014).
Cosemans, J. M. E. M. et al. Potentiating roles for Gas6 and Tyro, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization. J. Thromb. Haemost. 8, 1797–1808 (2010).
Kuijpers, M. J. et al. Platelet CD40L modulates thrombus growth via phosphatidylinositol 3-kinase β, and not via CD40 and IκB kinase α. Arterioscler. Thromb. Vasc. Biol. 35, 1374–1381 (2015).
Westein, E. et al. Atherosclerotic geometries spatially confine and exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner. Proc. Natl Acad. Sci. USA 110, 1357–1362 (2013).
Blair, T. A., Moore, S. F. & Hers, I. Circulating primers enhance platelet function and induce resistance to antiplatelet therapy. J. Thromb. Haemost. 13, 1479–1493 (2015).
Swieringa, F., Kuijpers, M. J. E., Heemskerk, J. W. M. & van der Meijden, P. E. J. Targeting platelet receptor function in thrombus formation: the risk of bleeding. Blood Rev. 28, 9–21 (2014).
Naseem, K. M. & Roberts, W. Nitric oxide at a glance. Platelets 22, 148–152 (2011).
Tourdot, B. E. et al. 12-HETrE inhibits platelet reactivity and thrombosis in part through the prostacyclin receptor. Blood Adv. 1, 1124–1131 (2017).
Kraakman, M. J. et al. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. J. Clin. Invest. 127, 2133–2147 (2017).
Von Hundelshausen, P. et al. Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Sci. Transl Med. 9, 384 (2017).
Ferroni, P. et al. Biomarkers of platelet activation in acute coronary syndromes. Thromb. Haemost. 108, 1109–1123 (2012).
Ho-Tin-Noe, B., Demers, M. & Wagner, D. D. How platelets safeguard vascular integrity. J. Thromb. Haemost. 9 (Suppl. 1), 56–65 (2011).
Chatterjee, M. & Gawaz, M. Platelet-derived CXCL12 (SDF-1α): basic mechanisms and clinical implications. J. Thromb. Haemost. 11, 1954–1967 (2013).
Ho-Tin-Noe, B., Boulaftali, Y. & Camerer, E. Platelets and vascular integrity: how platelets prevent bleeding in inflammation. Blood 131, 277–288 (2018).
Croce, K. & Libby, P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr. Opin. Hematol. 14, 55–61 (2007).
Nieswandt, B., Kleinschnitz, C. & Stoll, G. Ischaemic stroke: a thrombo-inflammatory disease? J. Physiol. 589, 4115–4123 (2011).
Maiocchi, S., Alwis, I., Wu, M. C. L., Yuan, Y. & Jackson, S. P. Thromboinflammatory functions of platelets in ischemia-reperfusion injury and its dysregulation in diabetes. Semin. Thromb. Hemost. 44, 102–113 (2018).
Kleinschnitz, C. et al. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 115, 2323–2330 (2007).
Bierings, R. & Voorberg, J. Up or out: polarity of VWF release. Blood 128, 154–155 (2016).
Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).
Gerdes, N. et al. Platelet CD40 exacerbates atherosclerosis by transcellular activation of endothelial cells and leukocytes. Arterioscler. Thromb. Vasc. Biol. 36, 482–490 (2016).
Wang, Y. et al. Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat. Commun. 8, 15559 (2017).
Koenen, R. R. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat. Med. 15, 97–103 (2009).
Vajen, T., Mause, S. F. & Koenen, R. R. Microvesicles from platelets: novel drivers of vascular inflammation. Thromb. Haemost. 114, 228–236 (2015).
Ekdahl, K. N. et al. Thromboinflammation in therapeutic medicine. Adv. Exp. Med. Biol. 865, 3–17 (2015).
Martinod, K. et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc. Natl Acad. Sci. USA 110, 8674–8679 (2013).
Muller, K. A., Chatterjee, M., Rath, D. & Geisler, T. Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD. Thromb. Haemost. 114, 498–518 (2015).
Chatterjee, M. & Geisler, T. Inflammatory contribution of platelets revisited: new players in the arena of inflammation. Semin. Thromb. Hemost. 42, 205–214 (2016).
Koupenova, M., Clancy, L., Corkrey, H. A. & Freedman, J. E. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ. Res. 122, 337–351 (2018).
Virmani, R., Burke, A. P., Farb, A. & Kolodgie, F. D. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol. 47, C13–C18 (2006).
Hechler, B. & Gachet, C. Comparison of two murine models of thrombosis induced by atherosclerotic plaque injury. Thromb. Haemost. 105 (Suppl. 1), S3–12 (2011).
Kuijpers, M. J. E. et al. Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model. J. Thromb. Haemost. 7, 152–161 (2009).
Farb, A. et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 93, 1354–1363 (1996).
Sato, Y. et al. Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. Heart 91, 526–530 (2005).
Xing, L. et al. EROSION study (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion): a 1-year follow-up report. Circ. Cardiovasc. Interv. 10 (2017).
Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008).
Olie, R. H., van der Meijden, P. E. J. & Ten Cate, H. The coagulation system in atherothrombosis: implications for new therapeutic strategies. Res. Pract. Thromb. Haemost. 2, 188–198 (2018).
Patrono, C. et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J. Am. Coll. Cardiol. 70, 1760–1776 (2017).
Halvorsen, S. et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J. Am. Coll. Cardiol. 64, 319–327 (2014).
McFadyen, J. D., Schaff, M. & Peter, K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat. Rev. Cardiol. 15, 181–191 (2018).
Cattaneo, M. P2Y12 receptors: structure and function. J. Thromb. Haemost. 13 (Suppl. 1), S10–S16 (2015).
Claessen, B. E. et al. Stent thrombosis: a clinical perspective. JACC Cardiovasc. Interv. 7, 1081–1092 (2014).
Torrado, J. et al. Restenosis, stent thrombosis, and bleeding complications: navigating between Scylla and Charybdis. J. Am. Coll. Cardiol. 71, 1676–1695 (2018).
Levine, G. N. et al. 2016 ACC/AHA Guideline Focused Update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 68, 1082–1115 (2016).
Jones, B. M. et al. Matching patients with the ever-expanding range of TAVI devices. Nat. Rev. Cardiol. 14, 615–626 (2017).
Nishimura, R. A. et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 70, 252–289 (2017).
Raheja, H. et al. Comparison of single versus dual antiplatelet therapy after TAVR: a systematic review and meta-analysis. Catheter Cardiovasc. Interv. 00, 1–9 (2018).
Baumann Kreuziger, L. M., Kim, B. & Wieselthaler, G. M. Antithrombotic therapy for left ventricular assist devices in adults: a systematic review. J. Thromb. Haemost. 13, 946–955 (2015).
Bergmeijer, T. O. et al. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am. Heart. J. 198, 152–159 (2018).
Gilio, K. et al. Non-redundant roles of phosphoinositide 3-kinase isoforms α and β in glycoprotein VI-induced platelet signaling and thrombus formation. J. Biol. Chem. 284, 33750–33762 (2009).
Nylander, S., Wagberg, F., Andersson, M., Skarby, T. & Gustafsson, D. Exploration of efficacy and bleeding with combined phosphoinositide 3-kinase β inhibition and aspirin in man. J. Thromb. Haemost. 13, 1494–1502 (2015).
Tullemans, B. M. E., Heemskerk, J. W. M. & Kuijpers, M. J. E. Acquired platelet antagonism: off-target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors. J. Thromb. Haemost. 16, 1–14 (2018).
Busygina, K. et al. Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans. Blood 131, 2605–2616 (2018).
Moeckel, D. et al. Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk. Sci. Transl. Med. 6, 248ra105 (2014).
Tardif, J. C. et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J. Am. Coll. Cardiol. 61, 2048–2055 (2013).
Pasalic, L. et al. Novel assay demonstrates that coronary artery disease patients have heightened procoagulant platelet response. J. Thromb. Haemost. 16, 1198–1210 (2018).
Eikelboom, J. W. et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N. Engl. J. Med. 377, 1319–1330 (2017).
Bye, A. P., Unsworth, A. J. & Gibbins, J. M. Platelet signaling: a complex interplay between inhibitory and activatory networks. J. Thromb. Haemost. 14, 918–930 (2016).
The authors thank the Cardiovascular Centre (HVC) of Maastricht University Medical Centre, The Netherlands, for support. We thank C. Baaten and J. van Geffen (Maastricht University, The Netherlands) for their help in preparing the figures before submission.
Nature Reviews Cardiology thanks E. Gardiner, M. Gawaz, and the other, anonymous reviewer for their contribution to the peer review of this work.
P.E.J.v.d.M. is a consultant at Bayer AG. J.W.M.H. is a founder and shareholder of FlowChamber BV.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Fibrin coat
Fibrin-coated platelets are a subpopulation of phosphatidylserine-exposing platelets that bind fibrin via transglutaminase activity and activated integrin αIIbβ3. Fibrin is ‘coated’ on the platelet surface.
- Membrane ballooning
Adherent platelets on a collagen surface form phosphatidylserine-exposing, balloon-like membrane structures as a result of salt and water entry into the platelets.
- Procoagulant platelet
Platelet swollen to a balloon shape, with surface exposure of phosphatidylserine and displaying greatly increased capacity for coagulation factor activation.
- Pseudopod formation
Cytoplasm-filled projection of the platelet membrane following platelet activation.
Platelet secretion granules containing multiple stored proteins including growth factors.
Platelet secretion granules with dense appearance in electron microscopy, containing Ca2+-bound nucleotides (ADP, ATP, and polyphosphates).
Product of mean platelet volume and platelet count in blood.
- Negative or positive platelet priming
Suppression or promotion of platelet activation by bioactive molecules in the blood.
- Exhausted platelets
Also known as refractive platelets; platelets with reduced secretion capacity owing to previous activation.
- Weibel–Palade bodies
Storage granules of endothelial cells that store ultralarge von Willebrand factor multimers.
About this article
Cite this article
van der Meijden, P.E.J., Heemskerk, J.W.M. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol 16, 166–179 (2019). https://doi.org/10.1038/s41569-018-0110-0
Mendelian randomization analysis of the association between human blood cell traits and uterine polyps
Scientific Reports (2021)
Use of Intra-uterine Injection of Platelet-rich Plasma (PRP) for Endometrial Receptivity and Thickness: a Literature Review of the Mechanisms of Action
Reproductive Sciences (2021)
The association between platelet indices and cardiovascular events in chronic kidney disease patients without dialysis
International Urology and Nephrology (2021)
Role of Neurons and Glia Cells in Wound Healing as a Novel Perspective Considering Platelet as a Conventional Player
Molecular Neurobiology (2021)
A deep network designed for segmentation and classification of leukemia using fusion of the transfer learning models
Complex & Intelligent Systems (2021)