ABSTRACT
Introduction: Coronavirus disease 2019 (COVID-19) is accompanied by a hypercoagulable state with micro- and macrovascular thrombotic complications. In plasma samples from COVID-19 patients, von Willebrand factor (vWF) levels were shown to be highly elevated and, like the relative lack of its counterpart, ADATMS13 (a disintegrin-like and metalloprotease with thrombospondin repeats 13), predictive of adverse outcomes, especially mortality. However, vWF is usually not included in routine coagulation analyses, and histologic evidence of its involvement in thrombus formation in COVID-19 is lacking. Moreover, since vWF is also an acute phase protein it needs to be determined whether it is a bystander, i.e. a biomarker reflective of endothelial dysfunction, or a causal factor in the pathogenesis of COVID-19. Method(s): We compared lung, lymph node and heart autopsy samples from 28 patients with lethal COVID-19 (B.1 virus-lineage) to controls, and systematically assessed for vWF and platelets (CD42b) by immunohistochemistry. Controls comprised of 24 lungs, 23 lymph nodes, and 9 hearts, and did not differ significantly from the COVID-19 group respecting age, sex, BMI, blood group, or anticoagulant use. Result(s): Compact platelet-rich microthrombi were more frequent in patients, who died of COVID-19 (36% vs. 8%, p = 0.02;staining for CD42b). This difference was more pronounced when lungs were analyzed for vWF: in normal lungs, vWF is physiologically present in vascular endothelial cells (Figure 1A). A completely normal pattern of vWF was rare in both groups (controls vs. COVID-19: 25% vs. 7%;p = 0.081), but vWF-rich thrombi were exclusive to COVID-19 (39% vs. 0%, p <0.01), as were NETosis thrombi enriched for vWF (25% vs. 0%, p <0.01). 46% of COVID-19 patients had either vWF-rich thrombi, NETosis thrombi, or both (Figures 1B&C). Such trends were also seen in pulmonary draining lymph nodes (35% vs. 17%, p = 0.147), where the overall presence of vWF was very high (Figure 1C). Conclusion(s): We bring in situ evidence of vWF-rich thrombi that we context as likely attributable to COVID-19. In line with the growing evidence that increased plasma vWF correlates with adverse outcomes, this supports the hypothesis that high levels of vWF and a dysregulation of the vWF/ADAMTS13 ratio contribute to COVID-19 morbidity and mortality. Hence, vWF may be a therapeutic target in severe COVID-19, warranting further studies.