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Platelet biology and functions: new concepts and clinical perspectives

Abstract

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.

Key points

  • 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.

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Fig. 1: Major signalling events and responses during platelet activation.
Fig. 2: Platelet alterations during ageing.
Fig. 3: Environmental and platelet factors influencing platelet heterogeneity in the thrombus.
Fig. 4: Coagulation pathways contributing to the heterogeneous nature of thrombus formation.
Fig. 5: Negative and positive priming factors influencing platelet responses.
Fig. 6: Platelets in vascular thromboinflammation.

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Acknowledgements

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.

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Nature Reviews Cardiology thanks E. Gardiner, M. Gawaz, and the other, anonymous reviewer for their contribution to the peer review of this work.

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Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Paola E. J. van der Meijden or Johan W. M. Heemskerk.

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P.E.J.v.d.M. is a consultant at Bayer AG. J.W.M.H. is a founder and shareholder of FlowChamber BV.

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Glossary

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.

α-Granules

Platelet secretion granules containing multiple stored proteins including growth factors.

δ-Granules

Platelet secretion granules with dense appearance in electron microscopy, containing Ca2+-bound nucleotides (ADP, ATP, and polyphosphates).

Plateletcrit

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.

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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

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