The main hypothesis of this retrospective study is that VWF biomarkers are associated with coagulation in COVID-19. It was performed a balanced retrospective study of COVID-19 hospitalized patients with similar demographics and comorbidities and a wide range of D-dimer levels to study how VWF biomarkers correlate with coagulation, intravascular hemolysis, and outcome. Indeed, we show a clear association of elevated VWF antigen and activity levels with high D-dimer and FM levels.

It was also shown that mild ADAMTS13 activity deficiency is common in COVID-19 inpatients. Elevated VWF antigen and activity levels have been documented in COVID-19. Likewise, inflammatory markers such as CRP and IL-6 are known to be elevated in COVID-19. Thus, a potential explanation for elevated VWF antigen and activity levels in COVID-19 could be that this represents an acute phase response.

However, the magnitude of increases in D-dimer, FM levels, and VWF antigen and activity cannot be explained solely by acute phase response and/or inflammation. In addition, ADAMTS13 activity is not expected to significantly decrease in acute inflammation, yet the majority of COVID-19 patients had decreased ADAMTS13 activity, indicating a profound endothelial dysregulation or an intrinsic ADAMTS13 activity deficiency. Possible mechanisms of ADAMTS13 activity deficiency include decreased production, inhibition, or consumption of ADAMTS13.

12% of patients in cohort had ADAMTS13 activity levels less than 30% but none had detectable anti-ADAMTS13 antibodies. Many of these patients had increased IL-6 levels, but the IL-6 level did not correlate linearly with reduced ADAMTS13 activity, thus favoring consumption or decreased production rather than inhibition. ADAMTS13 antigen levels were also reduced and >80% of patients with ADAMTS13 activity levels <30% had albumin levels below normal reference range, thus liver dysfunction may explain a low ADAMTS13 activity in these patients.

In addition, consumption of ADAMTS13 due to excess of its substrate, VWF, or excess of plasmin, has been observed in sepsis, disseminated intravascular coagulopathies (DICs), and thrombotic microangiopathy (TMA). Indeed, elevated VWF antigen and activity levels, D-dimer levels, FM levels along with moderately reduced ADAMTS13 activity levels is a repertoire of hallmarks shared by critical illnesses that result in severe microvascular endothelial cell injuries. Thrombocytopenia is not common in COVID-19 and was not directly associated with low ADAMTS13 activity levels in our cohort.31 Also, lack of severe ADAMTS13 activity deficiency (only two patients had ADAMTS13 activity <10%) and lack of anti-ADAMTS13 antibodies in our patients excludes thrombotic thrombocytopenic purpura (TTP) and may be
more suggestive of secondary TMA, sepsis, or DIC.

Many other studies have shown that despite anticoagulation, certain COVID-19 patients still thrombose. Anticoagulation alone is not an effective treatment for DIC.

Nafamostat, a synthetic serine protease inhibitor, used to treat DIC and pancreatitis, has been shown as beneficial in COVID-19 treatment in several case reports. Additional treatment may be required to decrease high levels of VWF antigen and activity and increase ADAMTS13 activity. A nanobody, caplacizumab, that inhibits the binding of VWF to gp-1b on platelets has been effective in treating TMAs.

ADAMTS13 replacement via plasma exchange is a standard TTP treatment. Although the main rationale of convalescent plasma (CP) treatment is to provide passive immunity to acutely ill COVID-19 patients, replacement of ADAMTS13, and other plasma proteins can possibly contribute to benefits attributed to CP.

Although we did not measure complement levels in our cohort, as serum samples were not preserved, we noticed ghost cells in several cases, which suggest complement activation of RBCs. Eculizumab, a monoclonal antibody, binds C5, inhibiting the terminal complement complex, and has been shown to be effective in treating COVID-19 in several case reports.

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