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Review
. 2021 Sep;18(9):666-682.
doi: 10.1038/s41569-021-00552-1. Epub 2021 May 6.

Interplay between inflammation and thrombosis in cardiovascular pathology

Konstantin Stark  1   2   3 , Steffen Massberg  4   5   6
Affiliations
Review

Interplay between inflammation and thrombosis in cardiovascular pathology

Konstantin Stark et al. Nat Rev Cardiol. 2021 Sep.

Abstract

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The interplay between platelets and innate immune cells in host defence.
Immunothrombosis is triggered by an invasion of the bloodstream by pathogens. After activation by ADP and thromboxane A2 (TXA2), migrating platelets collect and bundle bacteria and fibrinogen (mediated by αIIbβ3 integrin) on their surface (part a). By actomyosin-dependent migration, platelets present bacteria to neutrophils and boost neutrophil activation. In addition, platelets are activated by Toll-like receptor 4 (TLR4) binding to bacterial products such as lipopolysaccharide (LPS) and pathogen-associated molecular patterns. Together with the complement system, platelets trigger the formation of neutrophil extracellular traps (NETs) through interaction between P-selectin on the platelet surface and P-selectin glycoprotein ligand 1 (PSGL1) on neutrophils. This process depends on NADPH oxidase and protein-arginine deiminase type 4 (PAD4) in neutrophils. NETs trap and kill bacteria but also promote the initiation of the coagulation cascade by activation of the intrinsic pathway (catalysing the activation of factor XII (FXII) to FXIIa) and by degrading the natural anticoagulant tissue factor (TF) pathway inhibitor. The activation of monocytes and macrophages in infection involves the process of pyroptosis (part b). These cells carry on their surface inactive TF, which is a trigger of the extrinsic coagulation pathway. A lytic cell death programme that is dependent on caspase 1, caspase 11, gasdermin D and anoctamin 6 is initiated, resulting in gasdermin pore formation and phosphatidylserine exposure in the plasma membrane. These processes together with the release of protein disulfide-isomerase (PDI) lead to TF activation and the release of TF-rich microvesicles. Finally, activation of the coagulation cascade culminates in thrombin-mediated fibrin generation and formation of an obstructive clot (part c). In parallel, a positive feedback loop is initiated by the cleavage of pro-IL-1α by thrombin into its active form, fostering the activation of innate immune cells. NETosis is counter-regulated by DNase I and DNase I-like 3, which disrupt NETs and prevent the excessive activation of immunothrombosis (part d).
Fig. 2
Fig. 2. Immunothrombosis links respiratory failure with systemic coagulopathy in COVID-19.
Immunothrombosis occurring in the lung induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers thrombotic events throughout the body. Pulmonary endothelial cells express angiotensin-converting enzyme 2 (ACE2), which is the cell-entry receptor for SARS-CoV-2 (part a). The invasion of endothelial cells by SARS-CoV-2 induces their activation and the exposure of von Willebrand factor (vWF). Platelets and neutrophils are recruited to the site of endothelial activation and engage in a mutually stimulating interplay. In patients with coronavirus disease 2019 (COVID-19), platelets are activated via pathways involving mitogen-activated protein kinase (MAPK) and interferon-induced transmembrane protein 3 (IFITM3). The release of the chemokines CCL5 and CXCL4 by platelets as well as complement activation on platelets triggers neutrophil activation and neutrophil extracellular trap (NET) formation mediated by the binding of the complement factor C5 with its receptor C5aR on neutrophils and the interaction of P-selectin on platelets with the P-selectin glycoprotein ligand 1 (PSGL1) on neutrophils. In addition, neutrophils can be directly infected by SARS-CoV-2 through ACE2 and transmembrane protease serine 2 (TMPRSS2). NETs induce microvascular thrombosis and destroy alveolar epithelial cells, thereby impairing pulmonary gas exchange and aggravating pulmonary failure (part b). Systemically, thromboinflammation is triggered, generating a prothrombotic environment characterized by activated netting neutrophils, stimulated platelets and an activated coagulation system together with elevated fibrinogen and vWF levels and decreased ADAMTS13 levels (part c). The clinical manifestations of this COVID-19-associated coagulopathy are an increased risk of ischaemic stroke, myocardial infarction and venous thromboembolism in patients with severe disease (part d). PAD4, protein-arginine deiminase type 4.
Fig. 3
Fig. 3. Platelets orchestrate the prothrombotic immune response in venous thrombosis.
Venous thrombosis is mainly triggered by a reduction in blood flow velocity. This reduced blood flow results in an aberrant activation of immunothrombosis, in which a sterile inflammatory response sets the coagulation cascade in motion (part a). Reduced blood flow activates mast cells within the venous vessel wall, which release histamine and activate endothelial cells to mobilize the adhesion molecules P-selectin and von Willebrand factor (vWF) to their surface. Innate immune cells and platelets are recruited to the endothelial surface, which is supported by the binding of all-thiol high mobility group protein B1 (HMGB1) released from platelets to the receptor for advanced glycation end products (RAGE) and Toll-like receptor 2 (TLR2) on monocytes and CXCR2 on neutrophils (part b). CXCR2 activation together with oxidized disulfide HMGB1 interacting with RAGE induce the release of neutrophil extracellular traps (NETs), which are formed in a protein-arginine deiminase type 4 (PAD4)-dependent mechanism. Monocytes are activated by platelet-derived oxidized HMGB1 to release pro-inflammatory mediators such as IL-6 and IL-1β, reinforcing innate immune cell activation (part c). In addition, monocytes release tissue factor (TF), which is activated by protein disulfide-isomerase (PDI) and unleashes the extrinsic coagulation cascade. Clot formation is triggered by TF-dependent thrombin generation and supported by the intrinsic coagulation pathway initiated by the activation of factor XII (FXII) on NETs (part d).
Fig. 4
Fig. 4. Platelet–myeloid cell crosstalk in arterial thrombosis.
Arterial thrombosis is induced by endothelial disruption caused by atherosclerotic plaque rupture or erosion. Platelets are recruited to the exposed subendothelial matrix and aggregate (part a). Neutrophils are activated by the binding of platelet-derived high mobility group protein B1 (HMGB1) to the receptor for advanced glycation end products (RAGE), by platelet P-selectin interacting with neutrophil P-selectin glycoprotein ligand 1 (PSGL1) and by α9β1 integrin ligation (part b). In parallel, platelets mediate the recruitment and activation of eosinophils in an integrin-dependent manner. Platelet-induced activation of neutrophils results in the formation of neutrophil extracellular traps (NETs), which promote the activation of the coagulation system (by degrading tissue factor (TF) pathway inhibitor (TFPI) and activating the coagulation factor XII (FXII)) (part c). In addition, platelet activation is reinforced by the release of cathelicidin antimicrobial peptides (LL37 in humans and CRAMP in mice) as well as by HMGB1 binding to platelet Toll-like receptor 4 (TLR4). Activated complement factor C3a binds to its receptor C3aR on platelets, promoting platelet activation. Activated platelets through P-selectin–PSGL1 interactions induce the formation of eosinophil extracellular traps (EETs) containing the granule protein major basic protein (MBP), which fosters platelet aggregation. Together, these processes result in the excessive activation of platelets and the coagulation system, leading to arterial occlusions in myocardial infarction and stroke. vWF, von Willebrand factor.
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