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Platelets as drivers of immunothrombosis in rheumatic diseases

Nature Reviews Rheumatology volume 21, pages 478–493 (2025)Cite this article

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Abstract

Platelets are central players in inflammatory and thrombotic responses that drive the onset and progression of rheumatic diseases. In particular, they regulate immunothrombosis, a defence mechanism in which the immune and blood-clotting systems cooperate to contain infections or vascular damage. Although immunothrombosis can help to preserve blood-vessel integrity and promote healing, it becomes harmful when exaggerated or chronic. In rheumatic diseases, such as systemic lupus erythematosus, systemic sclerosis and antiphospholipid syndrome, immunothrombosis contributes to persistent inflammation, abnormal blood-clot formation and long-term damage to the small blood vessels. It has also been implicated in maintaining autoimmune responses to autoantigens released by neutrophils. Platelets are among the first responders to vascular injury and influence the activity of immune cells, particularly neutrophils, by promoting the formation of neutrophil extracellular traps. Platelets express proteins such as P-selectin and the damage-associated molecule high-mobility group box 1 (HMGB1), which have distinct and non-redundant roles, both via direct interactions locally at sites of vascular damage and systemically via the release of extracellular vesicles. Understanding how platelets contribute to vascular inflammation and clotting in autoimmune settings elucidates disease mechanisms and might lead to the identification of new therapeutic targets.

Key points

  • Immunothrombosis integrates innate immune defence with coagulation, when dysregulated, it sustains maladaptive immune responses, driving inflammation, thrombotic complications and pathological tissue remodelling — highlighting its relevance as a key therapeutic target.

  • Platelets are central orchestrators of immunothrombosis, bridging vascular injury and immune activation in rheumatic diseases.

  • Although the hallmarks of immunothrombosis are shared across rheumatic diseases, the cellular mediators and initiating pathways vary according to disease-specific inflammatory contexts.

  • Pharmacological targeting of immunothrombosis holds promise not only for reducing autoimmune-driven cardiovascular risk but also for controlling chronic inflammation and limiting tissue damage.

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Fig. 1: Acute microvascular injury drives the early interaction between activated platelets and neutrophils.
Fig. 2: Platelet-derived HMGB1 promotes neutrophil NET formation.
Fig. 3: Responses to vascular injury in healthy people and patients with systemic sclerosis.
Fig. 4: Mechanisms that link platelet activation and immunothrombosis in antiphospholipid syndrome.

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Acknowledgements

The authors acknowledge the support provided to their laboratory by the European Union — Next Generation EU — NRRP M6C2 — Investment 2.1, “Enhancement and strengthening of biomedical research in the NHS”, Project: PNRR-MR1-2022-12376638. This Review is a product of the knowledge and research environment fostered by this support.

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Authors and Affiliations

  1. Division of Immunology, Transplantation & Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Norma Maugeri & Angelo A. Manfredi

  2. Università Vita-Salute San Raffaele, Milan, Italy

    Norma Maugeri & Angelo A. Manfredi

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  1. Norma Maugeri
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  2. Angelo A. Manfredi
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Correspondence to Angelo A. Manfredi.

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Nature Reviews Rheumatology thanks Jason S. Knight, who co-reviewed with Somanathapura K.; Naveen Kumar, Marko Radic and Eric Boilard, for their contribution to the peer review of this work.

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Glossary

α-granules

Platelet granules that contain haemostatic proteins (such as fibrinogen and von Willebrand Factor), growth factors, angiogenic signals and adhesion molecules (such as P-selectin).

αIIbβ3 integrin

Also known as GPIIb/GPIIIa. Mediates platelet aggregation by binding fibrinogen and contributing to clot formation.

Dense granules

Store small molecules such as ADP, ATP, serotonin and calcium ions, which contribute to platelet aggregation and activation.

Emperipolesis

A cellular process in which one living cell (such as a neutrophil) actively enters and resides within another cell (such as a megakaryocyte) without being destroyed. In the context of haematopoiesis, emperipolesis contributes to platelet heterogeneity by enabling the transfer of membrane components from neutrophils to developing platelets.

GPIb–IX–V complex

A mechanoreceptor that interacts with von Willebrand Factor on the subendothelial matrix during platelet adhesion.

High-mobility group box 1

(HMGB1). A damage-associated molecular pattern released from platelets that amplifies inflammation and neutrophil activation in immunothrombosis.

Immunothrombosis

A physiological process in which components of the innate immune system and coagulation system, including platelets and neutrophils, cooperate to form intravascular microthrombi, which help to contain pathogens and limit their systemic spread.

Iterative fission events

A stepwise process by which megakaryocytes produce platelets, involving the repeated extension and fragmentation of proplatelet projections into the bloodstream to generate mature platelets.

ST-segment elevation myocardial infarction

(STEMI). A type of acute myocardial infarction characterized by persistent ST-segment elevation on electrocardiography, indicating complete or prolonged occlusion of a coronary artery.

Thrombocytopoiesis

The biological process by which platelets are produced from megakaryocytes, primarily in the bone marrow but also in other tissues such as the spleen and lungs during stress or inflammation.

Thromboinflammation

A pathological state that results from dysregulated or excessive immunothrombosis, in which inflammation and thrombosis amplify one another, leading to tissue damage, vascular dysfunction and organ injury.

Thromboxane A2

Promotes platelet activation, aggregation and vasoconstriction.

Von Willebrand factor

(vWF). Binds GPIb to mediate platelet adhesion under shear stress.

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Maugeri, N., Manfredi, A.A. Platelets as drivers of immunothrombosis in rheumatic diseases. Nat Rev Rheumatol 21, 478–493 (2025). https://doi.org/10.1038/s41584-025-01276-z

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