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      Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: Consider low volume plasma exchange and low dose steroid

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          Abstract

          We read with interest the case report by Escher [1] 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]. Escher et al. suggest therapeutic anticoagulation in severe COVID-19 patients with endothelial activation [1]. 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] and acute on chronic liver failure [4]. 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]. Plasma exchange removes molecules regardless of size. We demonstrated VWF-pheresis during plasma exchange in patients with liver failure [6]. Plasma VWF levels reduce after plasma exchange in patients with early septic shock [7]. Rising serum ferritin levels (which indicate macrophage activation/secondary hemophagocytic lymphohisticytosis) predict death in COVID-19 patients [8]. 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]. 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]. 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]. This treatment worked best in patients identified and treated early in the illness [2]. 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. Declaration of competing interest None.

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          Most cited references9

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            ISTH interim guidance on recognition and management of coagulopathy in COVID‐19

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              Severe COVID-19 infection associated with endothelial activation

              Mounting evidence supports the strong prognostic importance of D-dimers and the impact of coagulopathy in COVID-19 patients [1,2,3]. We would like to emphasize the significance of anticoagulation in severe COVID-19 disease, by adding our observation of highly pathological data on anti-phospholipid-antibodies, von Willebrand Factor (VWF) and Factor VIII. We observed a 72-year-old previously healthy male patient admitted to our hospital 6 days after the onset of respiratory symptoms and fever. Six days after admission, following a rapid deterioration of his clinical condition with development of acute respiratory distress syndrome, acute renal insufficiency and altered mental status, he was transferred to the intensive care unit (ICU). Supportive care with intubation, positive pressure ventilation and renal replacement therapy led to a stabilization of his condition. During the ICU stay, a continual increase of D-dimers was observed, from initially 0.69 mg/L to 2.55 mg/L on day 4, 2.81 mg/L on day 11 to 20.63 mg/L on day 21. At this time, IgG anti-cardiolipin antibodies (ACA) and anti-beta2-glycoprotein I (anti-β2-GPI) were negative, but IgM ACA elevated at 121.9 CU (normal <20 CU) and IgM anti-β2-GPI elevated at 275.3 CU (normal <20 CU). Furthermore, on day 21, we also observed a concurrent massive elevation of VWF, with VWF:antigen 555% (normal 42–136%) and VWF:activity 520% (normal 42–168%), accompanied by an increase of Factor VIII clotting activity of 369% (normal 55–164%). The increased VWF points towards massive endothelial stimulation and damage with release of VWF from Weibel-Palade bodies. Interestingly, endothelial cells express ACE2, the receptor for SARS-CoV-2, thus possibly mediating endothelial activation [3]. The patient received prophylactic anticoagulation with dalteparin 5000 U s.c. daily from admission to hospital. We increased the dose to therapeutic anticoagulation with unfractionated heparin on day 21, without hemorrhagic complication. Since then, the patient is steadily improving, ventilation and hemodialysis could be successfully withdrawn, and he has been transferred from the ICU to a general ward. D-dimers decreased to 6.26 mg/L on day 24 and to 1.94 mg/L on day 29. Considering the high levels of VWF and factor VIII, we strongly suggest administering higher, possibly therapeutic doses of anticoagulation to these patients. The role of antiphospholipid antibodies, VWF and FVIII needs further study. Uncited reference [4]
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                Author and article information

                Contributors
                Journal
                Thromb Res
                Thromb. Res
                Thrombosis Research
                Published by Elsevier Ltd.
                0049-3848
                1879-2472
                5 May 2020
                5 May 2020
                Affiliations
                [a ]Hepatology Department, Christian Medical College, Vellore, India
                [b ]Department of Transfusion Medicine and Immunohaematology, Christian Medical College, Vellore, India
                [c ]The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
                [d ]Research Haematology Dept., University College London, London, UK
                [e ]Liver Unit, University Hospitals Birmingham, Birmingham, UK#
                Author notes
                [* ]Corresponding author. eapen@ 123456cmcvellore.ac.in
                Article
                S0049-3848(20)30164-X
                10.1016/j.thromres.2020.05.001
                7198395
                32403033
                92048392-e455-4ae9-8052-d3fd7cd4444c
                © 2020 Published by Elsevier Ltd.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                : 1 May 2020
                : 2 May 2020
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