The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants-and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.

Keywords: COVID-19; DOACs; LMWH; Long-COVID-19; PARs; anticoagulants.

Figure 1

Interplay between SARS-CoV-2 infection, coagulation system, protease-activated receptors and inflammation. Activation of the coagulation cascade by the SARS-CoV-2 leads to the cleavage of fibrinogen into fibrin and platelet activation that can contribute to thrombosis. Platelet activation and fibrin degradation products can also enhance inflammation. Coagulation proteases can activate endothelial cells via protease-activated receptors that can increase the expression of inflammatory mediators. Drugs capable of inhibiting Factor Xa could attenuate the inflammatory response and modulate the coagulation cascade by reducing the formation of blood clots. This figure was created using the website https://app.biorender.com (accessed on 6 July 2021).

Figure 2

High resolution computed tomography (HRCT) chest, axial post-processed images, showing bilateral peripheral areas of ground-glass opacity (GGO).

Figure 3

Pathophysiological mechanism of heparin-induced thrombocytopenia (HIT). Platelet factor 4 (PF4) is a chemokine secreted from the alpha-granules of platelets, released as tetramers. They bind to heparin and other proteoglycans and inactivate them. The binding of heparin to PF4 exposes new antigen sites and hence the formation of new (IgG) antibodies. Platelet Fc receptors bind the antibody-heparin-PF4, which contribute to thrombosis. Thrombocytopenia occurs by two mechanisms: removal of platelets with bound IgG by splenic macrophages and platelet consumption caused by thrombus formation. PF4 can also bind heparin sulfate on vascular endothelial cells; subsequent binding of the pathologic antibody to this PF4-heparin sulfate complex can injure the endothelium, which further promotes thrombosis. This figure was created using the website https://app.biorender.com (accessed on 12 July 2021).

Figure 4

A 71-year-old male with sequel of COVID-19 pneumonia. Chest computed tomography (CT), axial image (A) showing bilateral peripheral areas of consolidation with surrounding ground-glass opacities (GGOs). Coronal image (B) showing bilateral peripheral area of interstitial thickening.

Figure 5

The cross-talk between coronary artery disease, diabetes, hypertension, dyslipidemia and Long-COVID-19.