Role of von Willebrand Factor in COVID-19 Associated Coagulopathy

Abstract

Background COVID-19, the disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can present with symptoms ranging from none to severe. Thrombotic events occur in a significant number of patients with COVID-19, especially in critically ill patients. This apparent novel form of coagulopathy is termed COVID-19-associated coagulopathy (CAC), and endothelial derived von Willebrand factor (vWF) may play an important role in its pathogenesis. Content vWF is a multimeric glycoprotein molecule that is involved in inflammation, primary and secondary hemostasis. Studies have shown that patients with COVID-19 have significantly elevated levels of vWF antigen and activity, likely contributing to an increased risk of thrombosis seen in CAC. The high levels of both vWF antigen and activity have been clinically correlated with worse outcomes. Furthermore, the severity of a COVID-19 infection appears to reduce molecules that regulate vWF level and activity such as ADAMTS-13 and high-density lipoproteins (HDL). Finally, studies have suggested that patients with group O blood (a blood group with lower baseline levels of vWF) have a lower risk of infection and disease severity compared to other ABO blood groups; however, more studies are needed to elucidate the role of vWF. Summary CAC is a significant contributor to morbidity and mortality. Endothelial dysfunction with the release of prothrombotic factors, such as vWF, needs further examination as a possible important component in the pathogenesis of CAC.

Plasma Fibrinogen Independently Predicts Hypofibrinolysis in Severe COVID-19

“…Elevated vWF levels, as we also observed in our own cohort, imply activated or damaged endothelium [35]. It would be anticipated that damaged endothelium would result in the release of ultra-large vWF multimers capable of interacting with platelets, leading to platelet activation, microthrombi, and platelet consumption [5]. In accordance, we also found positive correlations between vWF antigen and activity and H-IPF (%) among patients with high on-aspirin platelet reactivity.…”

“…There is a great body of evidence that COVID-19 significantly affects the coagulation system, contributing to hypercoagulable states and thrombotic events. The reason for such alterations is multifactorial, including the activation of the thrombo-inflammatory cascade and endothelial dysfunction [4,5]. There is a great need to identify novel markers to stratify disease severity and predict the outcome of disease.…”

Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor

“…The COVID-19 disease caused by the SARS-CoV-2 (CoV-2) virus starts with an early infectious stage, but it may be followed by viral pneumonia and systemic inflammation that could potentially lead to respiratory failure and multiple organ dysfunction [ 122 , 123 , 124 , 125 ]. It is now well established that the COVID-19 is also associated with hypercoagulation and severe thrombotic complications—‘Corona virus-associated coagulopathy’ (CAC) [ 126 , 127 , 128 ]. Several studies have reported incidence of ischemic stroke, deep vein thrombosis, pulmonary thromboembolism, and thrombosis in small brain vessels leading to cerebral microbleeds in 20–30% of COVID-19 patients admitted to the intensive care unit (ICU).…”

“…Multiple hematological abnormalities are observed in COVID-19 patients including elevated levels of fibrinogen and D-Dimer in critically ill patients [ 127 , 136 , 137 ]. However, hematological analyses of these patients have also found that VWF levels and activities were elevated five to six folds beyond the upper normal limit [ 128 , 138 ].…”

Cumulative Evidence for the Association of Thrombosis and the Prognosis of COVID-19: Systematic Review and Meta-Analysis

“…There were four types of thrombosis found in patients with COVID-19: pale thrombus, mixed thrombus (arterial and venous thrombosis), red thrombus, and hyaline thrombus (microvascular thrombosis). A hypercoagulable state in the critically ill patients with COVID-19 was found due to the following mechanisms: severe hypofibrinolysis ( 10 ), endothelial dysfunction ( 11 , 12 ), platelet activation ( 12 , 13 ), endothelial-derived von Willebrand factor (vWF) activation ( 14 ), elevated soluble (s) P-selectin ( 13 , 15 ), gene expression ( 13 , 16 ), inflammatory cytokine activation ( 17 , 18 ), and mannose-binding lectin (MBL)-related complement activation ( 19 , 20 ). Serious adverse events, such as thrombosis and thrombocytopenia syndrome, after COVID-19 vaccination are rare ( 21 ) and are associated with a high mortality rate ( 22 ).…”