Increased von willebrand factor (VWF) and factor VIII (FVIII) levels in severe acute respiratory syndrome SARS-CoV2-positive pneumonia compared with severe acute respiratory syndrome SARS-CoV2-negative: A case-control study

Background : The SARS-COV-2 direct interaction with Angiotensin-Converting-Enzyme-2 (ACE2) membrane receptor on pulmonary epithelial and endothelial cells, impairs angiotensin 1-7 production and its vasculoprotective role, promoting an upregulation of the ACE/angiotensinII/angiotensinII receptor type-1 pathway. The consequent endothelial activation and increasing secretion of VWF and FVIII levels contributes to complement activation and leukocyte extravasation, leading to local microcirculation damage. Aims : Our case-control study is aimed to investigate the characteristics of thrombotic microangiopathies (TMA)-like syndromes in COVID-19 evaluating VWF, FVIII and ADAMTS-13 levels, because the complement-mediated TMA and multiorgan microvascular lesions, observed in COVID-19 patients, seem not attributable to typical TMA. Methods : Ten COVID-19 cases presenting fever, cough and sore throat, admitted to the Fondazione Policlinico Gemelli IRCCS, Rome, and diagnosed by RT-PCR, were compared to ten control patients with non-SARS-CoV-2 interstitial pneumonia, diagnosed by chest Xray/computerized tomography;notably no patient needed mechanical ventilation. ADAMTS-13 activity was measured by a FRET-based assay;FVIII levels by a two-stage clotting assay, while VWF:antigen and VWF:activity were evaluated by chemiluminescence assays. Platelet count, schistocytes, D-dimer, C-reactive protein were centrally measured. Results : COVID-19 pneumonia patients compared with controls showed a marked elevation of both VWF:Ag (median values: 324.1 Vs 139.5%, P < 0.0001) and VWF:act levels (median values: 341.5 Vs 133%, P < 0.001), as well as FVIII levels (median values: 202.5 Vs 123%, P < 0.0001), consistent with the presence of a thrombophilic condition;without significant differences in ADAMTS-13 activity (median values: 69 Vs 76%, P = 0.473). In both groups, D-dimer and C-reactive protein levels were elevated, but not statistically different, platelet counts were normal, and schistocytes, a typical TMAs hallmark, were not observed Conclusions : The increased VWF/FVIII levels in COVID-19 pneumonia cases compared with non-COVID-19 controls cannot be fully explained by the inflammatory state alone and was likely caused by SARS-CoV-2-mediated downregulation of the ACE2 axis, resulting in damage to the local microcirculation and increased leukocyte extravasation.