Current Overview on Hypercoagulability in COVID-19

Namrata Singhania; Saurabh Bansal; Divya P. Nimmatoori; Abutaleb A. Ejaz; Peter A. McCullough; Girish Singhania


Am J Cardiovasc Drugs. 2020;20(5):393-403. 

In This Article


The pathogenesis of hypercoagulability in COVID-19 is ill-defined. Figure 1 summarizes the proposed pathogenesis of hypercoagulability in COVID-19; all three components of Virchow's triad appear to be involved, including endothelial injury, stasis, and hypercoagulable state. Endothelial injury is evident from the direct invasion of endothelial cells by SARS-CoV-2;[4] endothelial cells have a high number of angiotensin-converting enzyme 2 (ACE-2) receptors. SARS-CoV-2 enters the cell through the ACE-2 receptor.[4] In the study by Varga et al., viral elements were found inside the endothelial cells, suggesting direct invasion.[4] Increased angiogenesis was also seen in these patients.[5] Increased cytokines are released, such as interleukin (IL)-6, and various acute-phase reactants in COVID-19 can lead to endothelial injury.[6] Reports also suggest activation of alternate and lectin complement pathways (C5b-9 [membrane attack complex], C4d, and mannose-binding protein-associated serine protease 2 [MASP2]), leading to further endothelial cell injury.[7] The use of intravascular catheters can cause direct endothelial cell injury. Stasis is due to immobilization in all hospitalized patients, especially those who are critically ill. A hypercoagulable state is seen due to several coagulation abnormalities from elevated circulating prothrombotic factors such as elevated von Willebrand factor (vWF), factor VIII, D-dimer, fibrinogen, neutrophil extracellular traps, prothrombotic microparticles, and anionic phospholipids.[8] Elevated levels of D-dimer have been observed to correlate with illness severity and 28-day mortality.[9] Fibrinogen levels were also significantly (p = 0.003) associated with IL-6 levels at baseline, according to a logarithmic regression.[8]

Figure 1.

Pathogenesis of coagulopathy in COVID-19. Endothelial injury (endotheliitis) is caused by direct invasion of endothelial cells by the SARS-CoV-2 virus via ACE-2 receptors, release of inflammatory cytokines such as IL-6, acute-phase reactants, complement activation, and direct injury from intravascular catheters. Stasis is due to immobilization in all hospitalized patients. The hypercoagulable state is due to elevated circulating prothrombotic factors such as elevated vWF activity, factor VIII, D-dimer, fibrinogen, neutrophil extracellular traps, prothrombotic microparticles, and anionic phospholipids. TEG findings showed shortened R (increased early thrombin burst), shortened K (increased fibrin generation), increased MA (greater clot strength), and reduced LY30 (reduced fibrinolysis). ACE-2 angiotensin-converting enzyme 2, C4d complement 4d, C5b-9 complement 5b-9, COVID-19 coronavirus disease 2019, IL interleukin, K clot formation time, LY30 clot lysis at 30 min, MA maximum amplitude, MAC membrane attack complex, MASP2 mannose-binding protein-associated serine protease 2, R reaction time, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, TEG thromboelastography, vWF von Willebrand factor

Upon autopsy, most patients showed macro- and microvascular thrombosis.[10] Gross examination of the lungs showed small and firm thrombi in peripheral parenchyma.[5] The pathological hallmark of COVID-19 is diffuse, small-vessel platelet–fibrin thrombi and intravascular megakaryocytes in all major organs, including the heart, lungs, kidneys, liver, and mesenteric fat.[10] Microscopic findings demonstrated pauci-inflammatory capillary injury, capillary congestion with luminal fibrin deposition, and angiogenesis.[5,10] The density of intussusceptive angiogenic features (mean ± standard error [SE]) 60.7 ± 11.8 features per field) was significantly higher in the lungs from patients with COVID-19 than from patients with influenza (22.5 ± 6.9) or from uninfected controls (2.1 ± 0.6) [p < 0.001 for both comparisons].[5] The degree of intussusceptive angiogenesis correlated significantly with the duration of hospitalization (p < 0.001). Endotheliitis is visible by electron microscopy in the endothelium of the heart, lung, small bowel, and kidneys.[4] Autopsy of the kidneys showed diffuse tubular injury, interstitial edema, and fibrin thrombi in the glomerular capillaries.[11]

Routine laboratory testing was performed in 24 critically ill COVID-19 patients and identified several abnormalities, including normal or slightly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), normal or increased platelet count, and increased D-dimer and fibrinogen levels.[12] Further testing also showed increased factor VIII activity and vWF antigens. Thromboelastography (TEG) showed a shortened reaction time (R), consistent with an increased early thrombin burst, in 50% of patients; shortened clot formation time (K), consistent with increased fibrin generation, in 83% of patients; increased maximum amplitude (MA), consistent with greater clot strength, in 83% of patients; and reduced clot lysis at 30 min (LY30), consistent with reduced fibrinolysis, in 100% of patients.[12] Similarly, in another viscoelastic test, increased platelet and fibrinogen contribution to clot strength was found.[8] In patients with severe disease and a positive lupus anticoagulant test, thrombocytopenia and marked prolongation of PT and aPTT can be seen.[13]

Although disseminated intravascular coagulation (DIC) has been rarely reported in severely ill patients with COVID-19, there are several features that distinguish CAC from DIC (Table 1). The major clinical finding in CAC is thrombosis, whereas in acute decompensated DIC, bleeding is the predominant feature. Pathological bleeding is not a commonly observed feature of COVID-19. Furthermore, COVID-19 has a few findings similar to DIC, including a marked increase in D-dimer levels and, in some cases, mild thrombocytopenia.[14] However, other coagulation parameters such as fibrinogen and factor VIII activity are high in CAC, while acute decompensated DIC is associated with low fibrinogen, which suggests that consumption of clotting factors is less likely in CAC. Regardless of the above similarities or differences, the basic principle of management in both CAC and DIC is treatment of the underlying condition.