The coagulopathy, endotheliopathy, and vasculitis of COVID-19

Abstract

Background: COVID-19-associated coagulopathy (CAC) characterized by the elevated D-dimer without remarkable changes of other global coagulation markers is associated with various thrombotic complications and disease severity. The purpose of this review is to elucidate the pathophysiology of this unique coagulopathy.

Methods: The authors performed online search of published medical literature through PubMed using the MeSH (Medical Subject Headings) term "COVID-19," "SARS-CoV-2," "coronavirus," "coagulopathy," and "thrombus." Then, selected 51 articles that closely relevant to coagulopathy in COVID-19.

Results: The primary targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the pneumocytes, immune cells, and vascular endothelial cells. The alveolar damage and the pulmonary microvascular thrombosis are the major causes of acute lung injury in COVID-19. The endotheliopathy that occurs is due to direct SARS-CoV-2 infection and activation of other pathways that include the immune system and thromboinflammatory responses leading to what is termed CAC. As a result, both microvascular and macrovascular thrombotic events occur in arterial, capillary, venule, and large vein vascular beds to produce multiorgan dysfunction and thrombotic complications. In addition to the endothelial damage, SARS-CoV-2 also can cause vasculitis and presents as a systemic inflammatory vascular disease. Clinical management of COVID-19 includes anticoagulation but novel therapies for endotheliopathy, hypercoagulability, and vasculitis are needed.

Conclusion: The endotheliopathy due to direct endothelial infection with SARS-COV-2 and the indirect damage caused by inflammation play the predominant role in the development of CAC. The intensive control of thromboinflammation is necessary to improve the outcome of this highly detrimental contagious disease.

Keywords: COVID-19; Coagulopathy; Endotheliopathy; Thromboembolism; Vasculitis.

Fig. 1

Flow chart for identifying COVID-19-associated coagulopathy. In the typical COVID-19-associated coagulopathy, thrombocytopenia and prothrombin time (PT) prolongation are usually not remarkable in its initial phase, instead, it often shows the typical computed tomography (CT) findings of the lung and elevated levels of von Willebrand factor (VWF) and factor VIII. When both marked thrombocytopenia and prothrombin time prolongation is observed, it is the case of sepsis-induced coagulopathy (SIC)/disseminated intravascular coagulation (DIC) type and secondary bacterial infection is suspected. Hemophagocytic lymphohistiocytosis (HLH)/macrophage activated syndrome (MAS) type coagulopathy is suspected when high levels of proinflammatory cytokines are recognized. This type of coagulopathy often shows fever, splenomegaly, decreased counts in two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis. Very severe thrombocytopenia indicates the presence of thrombocytopenic purpura (TTP) and ADAMTS-13 level should be examined. Antiphospholipid syndrome (APS) type coagulopathy is suspected when high-titer IgG/IgM of anti-phospholipids (APL) antibodies such as lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein (GP) 1 antibodies are recognized

Fig. 2

Mechanisms of clot formation in COVID-19. SARS-CoV-2 infects monocyte/macrophage and vascular endothelial cell. The activated macrophage and endothelial damage are the two-wheels of the vicious cycle of the thrombus formation. The infected monocyte/macrophage expresses tissue factor on the surface and initiates coagulation cascades. The infected endothelial cell release factor VIII and von Willebrand factor (VWF) from Weibel–Palade body and accelerates coagulation. Released VWF stimulates platelet aggregation and unusually-large VWF (ULVWF) activates platelet adhesion on the endothelial cell. These multi-factorial prothrombotic changes result in arterial, venous, and microvascular thrombosis

Fig. 3

Functional change of the endothelial cell via angiopoietin pathways. Angiopoietin (Ang)-1 binds to Tie2 receptor and promotes variable actions including an anti-inflammatory through inhibiting the nuclear factor kappa B (NFκB) signaling, apoptosis, and maintain vascular permeability by through the regulating cytoskeletal architecture and VE-cadherin. Severe acute respiratory syndrome (SARS)-CoV-2 infection stimulates endothelial cells to release stored Ang2 from Weibel Palade bodies into the circulation. Ang2 competitively antagonizes Ang1/Tie2 signaling, thus turns the anticoagulant, and anti-inflammatory features of endothelial cells to the opposite ways. NO nitric oxide, PG I₂ prostaglandin I₂, ACE2 angiotensin converting enzyme 2, TMPRSS-2 transmembrane protease serine 2