-Contributed by Abi Kasberg, PhD
One of the many complicated outcomes associated with severe cases of COVID-19 is the high occurrence of thrombotic and microthrombotic events. SARS-CoV-2-induced endothelial injury drives elevated inflammatory responses that promote dysregulated coagulation systems, in a condition named COVID-19-associated coagulopathy (CAC). The severity of CAC is associated with the onset of thromboembolisms and thrombotic microangiopathies (TMAs). Additional clinical findings have highlighted the occurrences of microvascular thrombi and hypercoagulability in COVID-19 patients. This suggests that vascular endothelia and microvasculature may be experiencing dysregulated hemostasis following SARS-CoV-2 infection. Given the recent emergence and worldwide impact of COVID-19, it is of great importance to identify and understand the mechanisms that are driving microthrombotic complications in COVID-19 patients.
Two components that are critical for the maintenance of microvascular hemostasis are von Willebrand factor (vWF) and the vWF protease ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13). Inflammatory conditions trigger changes to the relative levels of vWF antigen and ADAMTS-13 activity, such that imbalanced vWF to ADAMTS-13 ratios are associated with organ failure and death (Katneni et al. 2020). Recent COVID-19 clinical studies suggest that altered ratios of vWF antigen levels to ADAMTS-13 activity (vWF/ADAMTS-13) are associated with and predictive of acute kidney injury and COVID-19 disease severity (Henry et al. 2020 and Mancini et al. 2020). This post discusses recent clinical research findings and the proposed roles that the vWF-ADAMTS-13 axis may have during SARS-CoV-2 pathogenesis in COVID-19.
The functional relationship between vWF and ADAMTS-13
vWF is an acute phase protein, meaning that vWF plasma concentrations fluctuate in response to systemic inflammation. Increased inflammation promotes the release of vWF from vascular endothelial cells and platelets, which result in elevated plasma vWF levels found in the form of ultra large multimers (ULVWF). Under normal shear flow conditions, vWF multimers and platelets coexist without contributing to thrombus formation. However, high shear stress conditions following vascular injury enable vWF multimers to accumulate in the blood which in turn activate platelet adhesion and platelet aggregation.
To prevent ULVWF accumulation in the blood, the protease ADAMTS-13 specifically cleaves vWF multimers to the extent that circulating ULVWF multimers are marginally detectable in healthy individuals. ADAMTS-13 deficiency, whether hereditary or acquired, can result in the onset of thrombotic thrombocytopenic purpura (TTP), which is caused by the accumulation of ULVWF multimers that promote platelet aggregation and uncontrolled microthrombi formation.
During systemic inflammation, vWF plasma levels are elevated accompanied by a decrease in ADAMTS-13 activity. This suggests that the ratio of ADAMTS-13 activity to vWF antigen levels are sensitive to inflammation and are important for maintaining healthy hemostasis and vascular integrity. Variation to the high molecular weight vWF/ADAMTS-13 ratio can drive a prothrombotic state, as seen with disseminated intravascular coagulation (DIC).
The vWF to ADAMTS-13 axis is imbalanced during COVID-19
Clinical studies of COVID-19 patients have reported that vWF antigen levels are elevated accompanied by a decrease in ADAMTS-13 activity levels (Mancini et al. 2020). Increased vWF levels are likely due to their release as acute phase reactants in response to endothelial injury caused by SARS-CoV-2 infection. It is suggested that decreased ADAMTS-13 activity is due to substrate consumption and inflammation-mediated degradation (Henry et al. 2020). Together, these changes create a dramatic increase in the vWF antigen to ADAMTS-13 activity ratios in severe COVID-19 patients, at levels three to seven times higher than normal (Mancini et al. 2020). These described alterations to the vWF/ADAMTS-13 ratio enables vWF to accumulate in the blood at levels that ADAMTS-13 is unable to overcome, creating an environment receptive to microthrombosis formation and hypercoagulability.
An interesting difference to highlight is between TTP and COVID-19 microangiopathy. TTP is the result of decreased ADAMTS13 enzymatic activity and is characterized by the accumulation of ULVWF multimers. In contrast, there have been no reports of ULVWF multimers in the plasma of COVID-19 patients despite changes to the vWF/ADAMTS-13 ratio (Mancini et al, 2020). Instead, COVID-19 microangiopathy more closely resembles sepsis-induced thrombotic microangiopathy, a condition where ADAMTS-13 levels are depleted as a secondary effect to cytokines produced during sepsis.
An additional clinical study also describes the association of the vWF/ADAMTS-13 ratio to the severity of clinical outcomes of COVID-19, including acute kidney injury (Henry et al. 2020). Together with elevated LDH levels and low hemoglobin, authors conclude that these results indicate a TMA-like phenomenon instead of infection-driven coagulopathy (Henry et al. 2020). Changes to the vWF/ADAMTS-13 ratio correlate with patient age, which is interesting to consider given that age may contribute to prothrombic states, and thus higher COVID-19 mortality rates among the elderly. Due to the important roles and dynamics of vWF and ADAMTS-13 in COVID-19 and thrombosis, research is critically needed to further investigate the vWF/ADAMTS-13 ratio and its contribution to COVID-19 progression and outcomes.
Proposed mechanisms of the vWF to ADAMTS-13 axis during COVID-19
Pulmonary endothelial cells are believed to function as initial sites of severe COVID-19 complications. Local injury and inflammation in the lungs drive endothelial activation and the substantial release of vWF into the blood. This causes the relative levels of vWF, platelets, and ADAMTS-13 activity to be altered, which gives rise to thrombosis. The vWF/ADAMTS-13 ratio imbalance contributes to a state of hypercoagulability and increases risk of microthrombosis, acute kidney injury, and microangiopathy (Henry et al. 2020 and Mancini et al. 2020). This is supported by evidence of TMAs in the small vasculature of the lungs of COVID-19 patients (Mancini et al. 2020).
Systemic inflammation can extend these complications throughout the body, promoting microthrombosis in other organs (Mancini et al. 2020). The observed COVID-19 microangiopathy does not appear to be TTP, likely due to ADAMTS-13 activity being reduced due to consumption instead of being deficient (Mancini et al. 2020). These clinical studies suggest that the vWF-ADAMTS-13 axis is a potential novel research biomarker to predict COVID-19 severity and shed light on the pathways that promote inflammatory microthrombosis formation (Mancini et al. 2020). Further research studies are needed to provide insight into the mechanisms of the vWF-ADAMTS-13 axis during COVID-19 to guide research efforts and improve therapeutic outcomes.
Future Research Directions to Consider
The function is vWF is regulated by multiple factors, including vWF concentration, vWF multimer size, the amount of circulating platelets, and blood flow rate (shear stress). How do these factors impact the vWF-ADAMTS-13 axis during COVID-19?
vWF is proteolytically cleaved by other enzymes in addition to ADAMTS-13, such as plasmin, neutrophil released proteases, and possibly ADAM10 and ADAM17. Are the ratios of these enzymes to vWF impacted during COVID-19?
Could therapeutics aimed at restoring the vWF/ADAMTS-13 ratio be strategies for treating microthrombi in COVID-19 and preventing acute kidney injury? Potential treatments to consider would be anti-vWF caplacizumab, antiplatelet agents, ADAMTS-13 therapies, and plasma exchange (Henry et al. 2020).
ADAMTS-13 is expressed in the hepatic stellate cells of the liver. Liver function abnormalities have been reported in COVID-19 patients. Are expression levels of ADAMTS-13 antigen in the liver impacted by SARS-CoV-2 infection? If so, could downregulated ADAMTS-13 liver expression contribute to the reported decrease of ADAMTS-13 activity in the blood during COVID-19?
Henry BM, Benoit SW, Santos de Oliveira MH, Lippi G, Favaloro EJ, Benoit JL. 2020 ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: Evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy. Int J Lab Hematol. 2020 Dec 3;10.1111/ijlh.13415. doi: 10.1111/ijlh.13415.
Katneni UK, Aikaterini A, Hunt RC, Schiller T, DiCuccio M, Buehler PW, Ibla JC, Kimchi-Sarfaty, C. Coagulopathy and Thrombosis as a Result of Severe COVID-19 Infection: A Microvascular Focus. Thromb Haemost. 2020 Dec;120(12):1668-1679. doi: 10.1055/s-0040-1715841.
Mancini I, Baronciani L, Artoni A, Colpani P, Biganzoli M, Cozzi G, Novembrino C, et al. The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost. 2020 Nov 23;10.1111/jth.15191. doi: 10.1111/jth.15191.