Proposal of the Definition for COVID-19-Associated Coagulopathy

Abstract

Thrombotic events are common complications in COVID-19 patients that include both thrombus formation in large vessels and the microvasculature of the lung and other organs. COVID-19-associated coagulopathy (CAC) and disseminated intravascular coagulation (DIC) have similarities and differences, and whether CAC is a form of DIC is the subject of debate. Reported mechanisms of CAC include activated coagulation, endotheliopathy, up-regulated innate and adaptive immunity, and activated complement system. Although the clinical features and laboratory findings of CAC and DIC seem different, there are fundamental similarities that should be considered. Basically, the pathological findings of COVID-19 fall within the scope of the definition of DIC, i.e., systemic activation of coagulation caused by or resulting from the microvascular damage. Therefore, we suggest that although CAC differs from usual infection-associated DIC, its various features indicate that it can be considered a thrombotic phenotype DIC. This review summarizes the current knowledge about CAC including differences and similarities with sepsis-associated DIC.

Keywords: COVID-19; coagulopathy; disseminated intravascular coagulation; endothelial cell; heparin.

Figure 1

The progression from COVID-19-associated coagulopathy to disseminated intravascular coagulation (DIC). Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) elicits thrombotic property by damaging the vascular endothelial cells. Activation in coagulation is initially localized in the lung microcirculation, however, when it expands systemically, it is called COVID-19-associated coagulopathy (CAC). The diagnostic criteria of CAC are proposed as (A) proven COVID-19 and (B) two or more of the following criteria: (1) decrease in platelet count (less than 150 × 10⁹/L); (2) increase in D-dimer (more than two times the upper limit of normal); (3) >1 s prolonged prothrombin time or International Normalized Ratio (INR) > 1.2; (4) decrease in fibrinogen level; (5) presence of thrombosis (macrothrombosis including deep vein thrombosis/venous thromboembolism, thrombotic stroke, acute coronary syndrome, limb artery thrombosis, mesenteric artery thrombosis, etc., and/or microthrombosis including skin, acral lesions, etc.). “Risk of CAC” is defined as one of above five criteria and one of following criteria: (i) increase in fibrinogen level; (ii) increased von Willebrand factor (VWF) (more than two times the upper normal limit); (iii) presence of lupus anticoagulant and/or high-titer antiphospholipid antibodies. CAC and risk of CAC can progress to disseminated intravascular coagulation (DIC) when the disease progresses.

Figure 2

The mechanisms of COVID-19-associated coagulopathy. The pathogenesis of COVID-19-associated coagulopathy is complex. Activated coagulation and endothelial cell (EC) damage are the two main axes. SARS-CoV-2 infects macrophage and endothelial cells via binding to angiotensin 2 receptor (ACE2). Tissue factor (TF) expressed on immune cells and excess cytokine production stimulate coagulation and damages endothelial cells. Von Willebrand factor (VWF), factor VIII, and angiopoietin 2 are released from endothelial cells. Antiphospholipid antibodies such as lupus anticoagulant antibodies and anti-β₂ glycoprotein (GP) I antibodies could initiate vasculitis. In addition, the complement system and innate immunity relate to the endothelial damage. The membrane attack complex (MAC) damages cellular membrane and activated neutrophil release neutrophil extracellular traps (NETs), damage-associated molecular patterns (DAMPs), and chemical mediators to damage the vasculature.