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Review
. 2024 Feb 20;23(1):75.
doi: 10.1186/s12933-023-02097-8.

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus

Inés Valencia  1 , Jairo Lumpuy-Castillo  2   3 , Giselle Magalhaes  4 , Carlos F Sánchez-Ferrer  4   5 , Óscar Lorenzo  6   7 , Concepción Peiró  8   9
Affiliations
Review

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus

Inés Valencia et al. Cardiovasc Diabetol. .

Abstract

Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.

Keywords: COVID-19; Coagulation; Diabetes mellitus; Endothelial cells; SARS-CoV-2; Thrombosis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
COVID-19 and hemostasis regulation. SARS-CoV-2 may infect endothelial cells (EC) causing endothelitis and directly disrupting endothelial homeostasis, leading to cytokine release, and favoring a pro-coagulant micro-environment. Then, primary hemostasis can be induced by fast vasoconstriction and release of pro-inflammatory and pro-contractile endothelial factors. Activation of coagulation cascades weaves thrombin and fibrin networks that immobilize erythrocytes and activated platelets to from a blood clot in the secondary hemostasis. The resolution of coagulation (tertiary hemostasis) may be also damaged in COVID-19 by alterations in the plasminogen-plasmin and thrombin/thrombomodulin-EPCRP-aPC pathways. Hyperinflammation, hypercoagulation, and hypofibrinolysis could be responsible for thrombotic events in COVID-19 subjects. TXA2 (thromboxane A2), aPC (activated protein C), PC (protein C), EPCR (endothelial protein C receptor)
Fig. 2
Fig. 2
The EC activation and dysfunction, as a central pathophysiological mechanism of COVID-19 coagulopathy. SARS-CoV-2 infection and its concomitant local and systemic immunogenic stimuli (cytokine storm, vasoactive compounds, NETosis, and activated complement system) disrupt endothelial homeostasis leading to EC activation. This activation comprises over-inflammation, loss of endothelial barrier integrity and altered hemostasis, favoring coagulation and thrombosis. In red, specific drugs against mediators of endothelial activation. ARDS (acute respiratory distress syndrome), IL (interleukin), TNF-α (tumor necrosis factor alpha), Ang-(1-7) (angiotensin-(1-7)), NO (nitric oxide), Ang II (angiotensin II), TXA2 (thromboxane A2), MAC (membrane attack complex), TLR-4 (toll-like receptor 4)
Fig. 3
Fig. 3
Hypercoagulability and hypofibrinolysis in COVID-19 and DM. Disrupted hemostasis during COVID-19 may be further intensified under diabetic milieu, resulting in a hypercoagulant phenotype of the activated EC. Elevated levels of pro-coagulant factors (VWF, FVIII, TF/TFPI, thrombin and fibrin) and diminished or insufficient anti-coagulant mediators (ADAMST-13, tPA-plasminogen, KKS, aPC-EPCR) may alter the thrombosis and thrombolysis equilibrium towards formation of blood clots. Arrows indicate over- or down-regulation of factors in COVID-19 (blue) or in DM (green) pathology. Drugs against specific mediators are shown in red beside its target of action. VWF (von Willebrand factor), FVIII (factor VIII), TF (tissue factor), HMWK (high molecular weight kininogen), PK (plasma kallikrein), LMWH (low molecular weight heparin), FXa (activated factor X), aPC (activated protein C), EPCR (endothelial cell protein C receptor), tPA (tissue plasminogen activator), PAI-1 (tissue plasminogen activator), TAFI (thrombin activatable fibrinolysis inhibitor)
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