key: cord-0701339-83ecnff0
authors: bhogal, Pervinder; Jensen, Melanie; Collins, George; Spooner, Oliver; Makalanda, Levansri; Hart, Daniel; Jaffer, Ounali
title: Letter in response to: Coagulation markers are independent predictors of increased oxygen requirements and thrombosis in COVID‐19
date: 2020-08-26
journal: J Thromb Haemost
DOI: 10.1111/jth.15080
sha: 4a4346129de732b88bb0159ec77843e606dd2444
doc_id: 701339
cord_uid: 83ecnff0

We read with interest the recent publication by Rauche et al. and congratulate them on highlighting the potentially significant role VWF may play in the progression and prognosis of COVID19. Since SARS‐Cov2 first presented there has been an increasing recognition that the disease may trigger a widespread endotheliopathy. This fact could help to explain the highly varied presentation of patients with COVID19 from bowel ischaemia to large vessel occlusion causing strokes in addition to the more common presentation of respiratory symptoms.

We read with interest the recent publication by Rauche et al. and congratulate them on highlighting the potentially significant role VWF may play in the progression and prognosis of COVID19. Since SARS-Cov2 first presented there has been an increasing recognition that the disease may trigger a widespread endotheliopathy. This fact could help to explain the highly varied presentation of patients with COVID19 from bowel ischaemia to large vessel occlusion causing strokes in addition to the more common presentation of respiratory symptoms. At the same time there has been an increased understanding that the infection may result in microthrombosis as well as macrothrombosis both on the arterial and venous side of the circulation. Contrast enhanced ultrasound was recently used to identify microthrombi and wedge shaped perfusion defects in vivo in the pulmonary, renal, and gastrointestinal beds [1, 2] . Routine imaging methods, such as CT and CT angiography, do not have the spatial or contrast resolution to detect microvascular thrombosis and therefore, the demonstration of perfusion defects in vivo has been delayed. Post-mortem studies have also shown microthrombosis within the lungs confirming the in vivo imaging findings. In the study of Carsena et al microthrombi, in vessels <1mm in diameter, were seen in 87% of cases [3] . A further case series of COVID-19 pulmonary autopsies revealed that, alongside diffuse alveolar damage, numerous localised platelet-rich micro-thrombi, and foci of haemorrhage were present in the lungs [4] . The authors posited a pulmonary-localised thrombotic microangiopathy as key to the pathogenesis of COVID-19 with others also suggesting the micro-thrombosis is a critical driver in the disease process [5] .

Von Willebrand Factor is synthesized only in megakaryocytes and endothelial cells (ECs). The vast majority of VWF found in the plasma is derived from the VWF synthesised within the ECs, where it is stored

This article is protected by copyright. All rights reserved within the Weibel Palade Bodies (WPB). Although restricted to ECs there are differences in the synthesis of VWF within the different vascular beds of the body with the small vessels of the lung and brain expressing higher levels of VWF than similar sized vessels of the liver or kidney and higher levels in venous rather than arterial ECs [6]. A major portion of the VWF stored in the WPBs of endothelial cells is made up of ultra-large VWF (ULVWF). These larger multimers are more adhesive than the smaller multimers in the circulation and upon secretion ULVWF can spontaneously bind platelets and cause occlusion of small vessels. secretion from ECs the secreted VWF, which partly enters the circulation and partly binds to the endothelium -is sensitive to shear stress. This shear stress unfolds the VWF and exposes sites for platelet binding, selfassociation as well as for cleavage via the enzyme ADAMTS13. It has previously been shown these vWF molecules can self-associate into long 'strings' in the direction of flow, both arterial and venous, that bind to platelets and are adherent to the endothelium [7-9]. The ULVWF multimers released from the WPBs unfold at lower levels of shear stress and therefore may represent the initiating molecules for this selfassembly process which leads to hyper-adhesive strings capturing platelets. Preventing the binding of platelets to ULVWF may represent an attractive target to prevent microthrombosis formation. Inflammatory cytokines, such as IL-1 and TNF-alpha, as well as hypoxia can trigger the exocytosis of WPBs with release of their contents whilst IL-6 can inhibit the cleavage of ULVWF -platelet strings [10] . Furthermore, the synthesis of ADAMTS13, at least in cultured cells, is dramatically inhibited by a variety of cytokines including IL-6 and TNF-alpha [11] . This suggests that hypoxia, the cytokine storm and particularly IL-6, may help to propagate the microthrombosis.

One of the most interesting findings of the published work was that the 10 patients presenting with normal VWF levels were all discharged from the emergency department with out-patient follow-up. Although only a very small cohort we found it interesting that the group with normal vWF levels did not require admission or treatment with oxygen and we believe that this supports the concept that VWF plays a critical role in the pathogenesis. Furthermore, it is possible that VWF levels and the VWF:FVIII ratio could act as biomarkers for determining which patients are likely progress as well as those that are responding to treatment. The recent finding of ABO blood type and disease severity also point to a potential link with VWF with those patients with type O blood group being at lowest risk and those with type A being at highest risk [13] . Patients with type O have lower levels of VWF compared to those with non-O blood group and those with non-O blood group are at higher risk

This article is protected by copyright. All rights reserved of arterial thromboembolic disease such as a ischaemic heart disease and peripheral vascular disease. Although the exact nature of the interaction between remains unknown it has been suggested that ABO blood group determinants may be important in influencing the susceptibility of plasma VWF to proteolysis by ADAMTS13 [14] . Therefore, it is possible patients more susceptible to severe disease are already predisposed to thromboembolic diseases and that the sudden surge in VWF, particularly ULVWF, triggered by a widespread endotheliopathy overwhelms the body's innate ability to breakdown VWF via ADMTS13. Further evidence for this comes from the recent work of Ladikou et al [12] who are the first to show a marked drop in circulating ADAMTS13 levels (49.7% of normal) with the authors stating 'we speculate that excess release of VWF seen in COVID-19 patients leads to depletion of ADAMTS13 and contributes to the prothrombotic state'.

If thromboembolic complications play a significant role in the pathogenesis of the disease as it is now widely accepted then targeting this seems a natural course of action. In the recent propensity score matched study by Tremblay et al [15] there was no difference in the outcome of patients who were on prior anti-platelet or anti-coagulant medication compared to those who were not. This may suggest that that standard approaches to anti-aggregation and or anticoagulation are insufficient. This could be explained by the fact that the ULVWF strings mentioned earlier are sufficient to occlude vessels alone and this will not be inhibited by standard treatments.

Taking all of this into account we believe that there is now compelling evidence for a critical role of VWF in COVID19. Rather than merely representing a biomarker we believe it plays a pivotal role in the pathogenesis and prognosis of the disease. Targeting VWF, particularly early in the disease course, through agents such as caplacizumab or anfibatide, both of which inhibit binding of platelets to the VWF at the GPIX-Ib receptor, presents an attractive opportunity that is yet to be explored (Fig. 1) .

This article is protected by copyright. All rights reserved Author Contribution PB -originator or concept, manuscript drafting, editing MM -critical review of manuscript, editing GC -critical review of manuscript, editing OS -critical review of manuscript, editing LM -critical review of manuscript, editing DH -critical review of manuscript, editing OJ -Guarantor Conflict of Interest PB-has approached Sanofi to trial Caplacizumab in COVID +ve patients MM -None disclosed GC -None disclosed OS -None disclosed LM -None disclosed DH -has approached Sanofi to trial Caplacizumab in COVID +ve patients OJ -has approached Sanofi to trial Caplacizumab in COVID +ve patients

Contrast-enhanced ultrasound (CEUS) of the lung reveals multiple areas of microthrombi in a COVID-19 patient

Contrast enhanced ultrasonography (CEUS) to detect abdominal microcirculatory disorders in severe cases of COVID-19 infection: First experience

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a twocentre descriptive study. The Lancet Infectious Diseases

Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans

Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow

Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?

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