Risk Management and Treatment of Coagulation Disorders Related to COVID-19 Infection

Abstract

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease. Bilateral pneumonia, acute respiratory failure, systemic inflammation, endothelial dysfunction and coagulation activation are key features of severe COVID-19. Fibrinogen and D-dimer levels are typically increased. The risk for venous thromboembolism is markedly increased, especially in patients in the intensive care unit despite prophylactic dose anticoagulation. Pulmonary microvascular thrombosis has also been described and the risk for arterial thrombotic diseases also appears to be increased while bleeding is less common than thrombosis, but it can occur. Evaluation for venous thromboembolism may be challenging because symptoms of pulmonary embolism overlap with COVID-19, and imaging studies may not be feasible in all cases. The threshold for evaluation or diagnosis of thromboembolism should be low given the high frequency of these events. Management and treatment are new challenges due to the paucity of high-quality evidence regarding efficacy and safety of different approaches to prevent or treat thromboembolic complications of the disease. All inpatients should receive thromboprophylaxis unless contraindicated. Some institutional protocols provide more aggressive anticoagulation with intermediate or even therapeutic dose anticoagulation for COVID-19 patients admitted to ICU. Therapeutic dose anticoagulation is always appropriate to treat deep venous thrombosis or pulmonary embolism, unless contraindicated. This article reviews evaluation and management of coagulation abnormalities in individuals with COVID-19.

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

“…Citrate and EDTA are also well-known for their anticoagulant activity. In this regard, a recent report demonstrated the occurrence of thrombotic complications in a high number of COVID-19 patients despite high dosages of heparin, thus indicating the need to search for a better anti-thrombotic strategy [84,94]. Notably, zinc ion has been shown to promote clot stability by binding to fibrinogen and inhibiting heparin activity, possibly providing a rationale for heparin resistance [55].…”

“…Although triggered by distinct etiological factors, severe forms of SARS-CoVs, MERS-CoV and smoke-bomb-related acute respiratory distress (ARDS) syndromes share a common liver dysfunction [3,43,58,[81][82][83]. Indeed, the elevation of hepatic procoagulant factors (e.g., C-reactive protein) and hypoalbuminemia are common underlying causes leading to thrombotic disease (distinct from disseminated intravascular coagulation [84]) and zinc toxicity, which may culminate in multi-organ dysfunction characterised by hypoxia and sudden worsening of disease-related symptoms (see Figure 1). Interestingly, circulating activity of dipeptidyl-peptidase-4 (DPP-4), the membrane receptor for MERS-CoV entry, is associated with chronic liver disease [85] and its shedding is induced by hypoxia and mediated by zinc-metalloproteases [86], thus sharing some features with ACE2 [3].…”

Serum Metabolic Profile in Patients With Long-Covid (PASC) Syndrome: Clinical Implications

“…An increase in DD correlates with mortality in severe COVID-19 infections (43), and although the clinical significance of elevated DD values has been recently reviewed and cautious interpretation is recommended (44), we postulate that the persistence of altered coagulation months after hospitalization should raise attention to the possible long term risks of thromboembolic disease in those patients, risks that have been discussed prevalently in acute settings along with the advantages and disadvantages of aggressive therapy (45). On the other hand, autopsies confirmed DD value in identifying the most serious COVID-19 dependent illnesses (46); the association between increased risk and high-dose steroid therapy has been observed (47).…”

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

“…Possible new antithrombotic strategies and similarities between COVID-19 early phase and vaccine-induced mild adverse effects . Notably, the occurrence of thrombotic events in severe COVID-19 patients despite high heparin doses indicates the need to search for a better antithrombotic strategy ( Longhitano et al, 2020 ; Zanza et al, 2021 ). In this regard, in a mouse model of microvascular thrombosis, Ang II-induced blood flow cessation was not inhibited by heparin pre-treatment; differently, antithrombin III pre-treatment was highly effective in preventing the acceleration of blood flow cessation elicited by Ang II infusion ( Senchenkova et al, 2010 ).…”

“…Moreover, administration of arginine (the NO precursor) has also been proposed to recover from coagulopathy in severe fever associated with thrombocytopenia syndrome ( Li et al, 2018 ). In this syndrome, expansion of MDSCs, which are able not only to secrete anti-inflammatory cytokines but also to express arginase, was associated with decreased NO concentration in platelet, leading to platelet hyperactivation and thrombocytopenia ( Li et al, 2018 ); curiously, both of which can occur either following SARS-CoV-2 infection ( Bhattacharjee and Banerjee, 2020 ; Zanza et al, 2021 ) or, in some rare cases, after vaccination ( Lee et al, 2021 ; Tobaiqy et al, 2021 ). Indeed, despite the current vaccines do not contain the inactivated or attenuated virus, but only the nucleic acid sequence of the SARS-CoV-2 spike glycoprotein (a small fragment of the entire viral sequence) ( Kyriakidis et al, 2021 ), SARS-CoV-2 vaccinated people may exhibit either mild to moderate COVID-19-like symptoms or, rarely, severe thrombotic-related adverse reactions ( Lee et al, 2021 ; Tobaiqy et al, 2021 ).…”