Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: Consider low volume plasma exchange and low dose steroid
Thrombosis Research(2020)
摘要
We read with interest the case report by Escher [[1]Escher R. Breakey N. Lämmle B. Severe COVID-19 infection associated with endothelial activation [published online ahead of print, 2020 Apr 15].Thromb. Res. 2020; 190: 62https://doi.org/10.1016/j.thromres.2020.04.014Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar] et al. highlighting marked endothelial activation in a COVID-19 patient with multi-organ failure. In view of raised plasma von Willebrand factor (VWF) antigen levels (4.1 fold above upper limit of normal [ULN]) and 40 fold increase in D-dimers on Day 27, he was switched from prophylactic Dalteparin to therapeutic dose unfractionated heparin with reversal of multi-organ failure. The International Society for Thrombosis and Haemostasis recommends COVID-19 patients with 3–4 fold increase in D-dimers be administered prophylactic low molecular weight heparin [[2]Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19 [published online ahead of print, 2020 Mar 25].J. Thromb. Haemost. 2020; (doi:https://doi.org/10.1111/jth.14810)https://doi.org/10.1111/jth.14810Crossref Scopus (1255) Google Scholar]. Escher et al. suggest therapeutic anticoagulation in severe COVID-19 patients with endothelial activation [[1]Escher R. Breakey N. Lämmle B. Severe COVID-19 infection associated with endothelial activation [published online ahead of print, 2020 Apr 15].Thromb. Res. 2020; 190: 62https://doi.org/10.1016/j.thromres.2020.04.014Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar]. VWF is a platelet - adhesive protein and the carrier of coagulation factor VIII synthesized by endothelial cells and megakaryocytes. Baseline VWF antigen levels were raised 3.2–4.7 fold above ULN and predicted poor outcome over the next 7–8 days in patients with acute liver injury/failure [[3]Sardar D. Mathews N. Mammen J. et al.Rodenticidal hepatotoxicity: raised plasma Von Willebrand factor levels predict in-hospital survival and preliminary report of the outcome of Von Willebrand factor reducing management protocol.Indian J. Gastroenterol. 2019; 38: 527-533Crossref PubMed Scopus (12) Google Scholar] and acute on chronic liver failure [[4]Prasanna K.S. Goel A. Amirtharaj G.J. et al.Plasma von Willebrand factor levels predict in-hospital survival in patients with acute-on-chronic liver failure.Indian J. Gastroenterol. 2016; 35: 432-440Crossref PubMed Scopus (23) Google Scholar]. The large sized high molecular weight VWF multimers (5000–10,000 kDa in size), the main circulating form in health, cannot be removed on hemodialysis, which removes molecules <60 kDa in size [[5]Goel A. Nair S.C. Zachariah U. et al.Targetting raised von Willebrand factor levels in liver diseases: opening up newer therapeutic avenues.EMJ Hepatol. 2020; (DOI/10.33590/hepatol/20-00051)https://doi.org/10.33590/hepatol/20-00051Crossref Google Scholar]. Plasma exchange removes molecules regardless of size. We demonstrated VWF-pheresis during plasma exchange in patients with liver failure [[6]Gandhi P.B. Mathews N. Mammen J. et al.von Willebrand factor (vWF)-pheresis: A possible explanation how plasma exchange is beneficial in liver failure.Hepatol. Int. 2019; 13 (S3 A): 272Google Scholar]. Plasma VWF levels reduce after plasma exchange in patients with early septic shock [[7]Stahl K. Schmidt J.J. Seeliger B. et al.Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.Crit. Care. 2020 Mar 2; 24: 71Crossref PubMed Scopus (32) Google Scholar]. Rising serum ferritin levels (which indicate macrophage activation/secondary hemophagocytic lymphohisticytosis) predict death in COVID-19 patients [[8]Mehta P. McAuley D.F. Brown M. et al.HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020 Mar 28; 395: 1033-1034Abstract Full Text Full Text PDF PubMed Scopus (6435) Google Scholar]. As VWF molecules are cleared by macrophages, it is possible that endothelial activation (reflected by raised VWF levels) contribute to macrophage activation in COVID-19. Lung capillary congestion noted in all COVID-19 patients at post mortem, was probably secondary to pulmonary arterial platelet – fibrin microthrombi (seen in 33 of 38 patients) [[9]Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: doi:https://doi.org/10.1101/2020.04.19.20054262.Google Scholar]. The main locations of macrophages in the body are in liver sinusoids and lung capillaries. It is likely that the enlarged activated macrophages and raised VWF multimer levels may contribute to sludging within the lumen of lung capillaries and impede oxygenation in COVID-19 patients [[10]Alexander V. Zachariah U. Goel A. et al.Low-volume plasma exchange and low-dose steroid to treat secondary hemophagocytic lymphohistiocytosis: a potential treatment for severe COVID-19?.Curr. Med. Issues. 2020; 18: 77-82Crossref Google Scholar]. In our preliminary experience, a treatment protocol of low volume plasma exchange and low dose steroid improved survival in patients with acute liver injury, probably by ameliorating macrophage activation and reducing VWF levels [[10]Alexander V. Zachariah U. Goel A. et al.Low-volume plasma exchange and low-dose steroid to treat secondary hemophagocytic lymphohistiocytosis: a potential treatment for severe COVID-19?.Curr. Med. Issues. 2020; 18: 77-82Crossref Google Scholar]. This treatment worked best in patients identified and treated early in the illness [2Thachil J. Tang N. Gando S. et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19 [published online ahead of print, 2020 Mar 25].J. Thromb. Haemost. 2020; (doi:https://doi.org/10.1111/jth.14810)https://doi.org/10.1111/jth.14810Crossref Scopus (1255) Google Scholar, 3Sardar D. Mathews N. Mammen J. et al.Rodenticidal hepatotoxicity: raised plasma Von Willebrand factor levels predict in-hospital survival and preliminary report of the outcome of Von Willebrand factor reducing management protocol.Indian J. Gastroenterol. 2019; 38: 527-533Crossref PubMed Scopus (12) Google Scholar]. We propose that this protocol be studied in patients with acute lung injury due to severe COVID-19 in the setting of endothelial and/or macrophage activation. None. None.
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von willebrand factor levels,macrophage activation,low volume plasma exchange
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