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.

Subclinical myocardial injury, coagulopathy, and inflammation in COVID-19: A meta-analysis of 41,013 hospitalized patients

“… [10] Another possible contributory mechanism associated with high fatality in COVID-19 and complications is disseminated intravascular coagulation (DIC), with the cross-talk between inflammation and coagulation mediated through protease-activated receptors (PARS); there have been recommendations for clinical use of direct oral anticoagulants to inhibit PARS in acute care of COVID-19 and in patients experiencing persisting symptoms of COVID-19. [48] …”

COVID-19, Vaccines, and Thrombotic Events: A Narrative Review

“…A summary of hypothesized thrombotic mechanisms after COVID-19 is shown in Figure 1. It is possible to find a prothrombotic state also in long COVID-19, due to residual persistence of the blood chemistry of inflammation and procoagulative states [49]. The most frequently reported coagulation abnormality, especially in the most severe patients, is the elevation of D-dimer, but there are also increases in fibrinogen and its degradation products, PAI-1, and von Willebrand factor, as well as low levels of antithrombin III and antiphospholipid antibodies, known for their thrombophilic effect [29,39,45,[50][51][52].…”

SARS-CoV-2 Infection and Lung Regeneration

“…This is presumably caused by the potential immunogenicity of stem cells and their differentiated products, which can be cleared by the host innate and/or adaptive immune systems ( 241 ). In addition, it may also be due to the altered hostile tissue environments, such as in COVID-19, inflammatory, fibrotic, and oxidative niche, which is not conducive for the implanted LSPCs or MSCs to engraft and survive ( 242 , 243 ). Although MSCs exhibit potent immunoregulatory abilities, the contribution of surviving MSCs (only a small portion of the implanted MSCs) to the therapeutic benefits for COVID-19 patients is questionable.…”