COVID-19 associated coagulopathy: Mechanisms and host-directed treatment

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is associated with specific coagulopathy that frequently occurs during the different phases of coronavirus disease 2019 (COVID-19) and can result in thrombotic complications and/or death. This COVID-19-associated coagulopathy (CAC) exhibits some of the features associated with thrombotic microangiopathy, particularly complement-mediated hemolytic-uremic syndrome. In some cases, due to the anti-phospholipid antibodies, CAC resembles catastrophic anti-phospholipid syndrome. In other patients, it exhibits features of hemophagocytic syndrome. CAC is mainly identified by: increases in fibrinogen, D-dimers, and von Willebrand factor (released from activated endothelial cells), consumption of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13), over activated and dysregulated complement, and elevated plasma cytokine levels. CAC manifests as both major cardiovascular and/or cerebrovascular events and dysfunctional microcirculation, which leads to multiple organ damage. It is not clear whether the mainstay of COVID-19 is complement overactivation, cytokine/chemokine activation, or a combination of these activities. Available data have suggested that non-critically ill hospitalized patients should be administered full-dose heparin. In critically ill, full dose heparin treatment is discouraged due to higher mortality rate. In addition to anti-coagulation, four different host-directed therapeutic pathways have recently emerged that influence CAC: (1) Anti-von Willebrand factor monoclonal antibodies; (2) activated complement C5a inhibitors; (3) recombinant ADAMTS13; and (4) Interleukin (IL)-1 and IL-6 antibodies. Moreover, neutralizing monoclonal antibodies against the virus surface protein have been tested. However, the role of antiplatelet treatment remains unclear for patients with COVID-19.

Keywords: COVID-19; Coagulopathy; Endothelial dysfunction; Microangiopathy; SARS-CoV-2.

Figure 1

Pathways leading to immunothrombotic response. Abbreviations: ADAMTS13: A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13; A1–A3: domains of von Willebrand factor; DAMPS: danger-associated molecular patterns; IL: interleukin; Gp: glycoprotein; TNF: tumor necrosis factor; ICAM: intercellular adhesion molecule; MAC: membrane attack complex; MBL: mannose binding lectin; MASP: MBL associated protease; NF-KB: nuclear factor kappa-light-chain-enhancer of activated B cells; NETs: neutrophile extracellular traps; VCAM: vascular cell adhesion molecule; vWF: von Willebrand factor.

Figure 2

Thrombus extracted from COVID-19 patient, histopathology (100x, Olympus BX 43). (A) Hematoxylin-eosin staining, thrombus with fibrin deposition and neutrophiles. (B) vWF staining, large deposition of vWf on the thrombus surface. (C) CARSTAIRS staining (fibrin-aimed staining), polymorphonuclears, neutrophiles, monocytes with large fibrin content. (D) CD68 (cluster of differentiation, protein highly expressed by monocyte lineage) staining with neutrophiles on the thrombus surface.

Figure 3

COVID-19 thrombus electron microscopy - (TEM, Jeol JEM 12 EX). (A) Polyhedrocytes with neutrophile in the center. (B) deposition of large amount of fibrin between neutrophiles, polyhedrocytes at the periphery in detailed view- high magnfication. Polyhedrocytes – deformated erytrocytes (cubic deformation with compression).

Figure 4

COVID -19 patient with Left Internal carotid artery (ICA) thrombotic occlusion,Epitifibatide recanalization. (A) Thrombosis of the left ICA bulbus origin with no distal intracranial perfusion. (B) Rapid recanalization after IIb/IIIa Eptifibatide bolus administration. (C) Distal intracranial ICA bifurcation recanalization. (D) Anterior cerebral artery (ACA) plus medial cerebral artery (MCA) reperfusion after IIb/IIIa.

Figure 5

Host-directed treatment options. Abbreviations: IL-1: interleukin 1; IL-6: interleukin-6; NF-KB: nuclear factor kappa-light-chain-enhancer of activated B cells; fXa: activated factor X; ACEIIr: angiotensin converting enzyme II receptor; vWf: von Willebrand factor; GPIb: glycoprotein Ib; Endotel: endothelium; rADAMTS13: recombinant A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13.