Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research

Abstract

<jats:title>Abstract</jats:title><jats:p>Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.</jats:p>

Perspectives on Platelet Heterogeneity and Host Immune Response in Coronavirus Disease 2019 (COVID-19)

“…1). 41 In addition to targeting inflammation or immune responses, several trials are now underway to determine whether and how aspirin, P2Y12 inhibitors (i.e., clopidogrel, ticagrelor), and other platelet-targeted agents may benefit COVID-19 patients. Some early, small-scale studies suggest that agents such as dipyridamole may promote the clinical recovery of severe COVID-19 42 ; however, other studies find no benefit for pretreatment with antiplatelet agents in severe cases of COVID-19, 43 and large-scale extended trials are required to better understand the role of antiplatelet agents in COVID-19 as well as in vascular inflammation.…”

“…39,45,46 Intrinsic and extrinsic coagulation pathways that regulate thrombin formation and promote procoagulant platelet phenotypes are also targets of interest in COVID-19. 41,47 Platelet Phenotype and Function in COVID- 19…”

Pharmacotherapy for Prevention and Management of Thrombosis in COVID-19

“…Replacing with prasugrel in patients without contraindications and alternatively utilizing P2Y 12 platelet function assay for dose adjustment are potential management alternatives. 4,7 Cilostazol, which can be used in the management of peripheral arterial disease, may also require dose reduction if coadministered with lopinavir/ritonavir. 7 For the most part, parenteral antiplatelet agents have a safe interaction profile.…”

“…Unfractionated heparin and low-molecular-weight heparin (LMWH) are the most common parenteral anticoagulant agents used for prophylaxis and treatment of thrombotic diseases. Besides antithrombotic roles, they have been shown to have anti-inflammatory and antiviral proper-ties, 7,11 which possibly make them even more attractive in the management of COVID-19. LMWHs have the advantage of obviating the need for activated partial thromboplastin time (aPTT) monitoring, which may be difficult in COVID-19 due to considerable hemostatic derangement.…”

“…4 However, existing epidemiological studies suggest that venous thromboembolism (VTE) is the predominant form of thrombotic events, with reported rates in the literature being variable between 7% up to more than 80% (upon routine screening of critically ill patients). [5][6][7] In this setting, the optimal strategies for prevention of thrombotic events and choice of antithrombotic agents for management of pre-existing or new thrombotic events in patients with COVID-19 are of utmost importance. Herein, we provide a succinct summary of potential pharmacological options for the treatment and prevention of thrombosis in patients with COVID-19.…”