Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Turecek, Peter L.; Peck, Rachel C; Rangarajan, Savita; Reilly‐Stitt, Christopher; Laffan, Michael; Kazmi, Rashid; James, Izabela; Dushianthan, Ahilanandan; Schrenk, Gerald; Gritsch, Herbert; Ewenstein, Bruce M.; Mellgård, Björn; Erdlenbruch, Wolfhard; Jain, Nisha; Binder, Nikolaus B.; Mumford, Andrew D

doi:10.1016/j.thromres.2021.02.012

Cited by 44 publications

(45 citation statements)

References 49 publications

(41 reference statements)

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“…Interestingly, previous studies have reported that increases in qualitative VWF ristocetin cofactor activity (VWF:RCo) in COVID-19 patients are consistently lower compared to increases in quantitative plasma VWF:Ag levels in the same patients. 6,8,11,12,14,15 Together, these data suggest that COVID-19 infection is not only associated with a marked quantitative increase in plasma VWF levels, but also impacts VWF functional activity.…”

Section: Me Thodsmentioning

confidence: 76%

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Ward

Fogarty

Karampini

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID‐19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS‐13)‐‐mediated proteolysis. Objectives This study investigated the hypothesis that ADAMTS‐13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) infection contributing to the observed microvascular thrombosis. Patients and Methods Patients with COVID‐19 ( n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS‐13 activity, and known inhibitors thereof were assessed. Results We observed markedly increased VWF collagen‐binding activity in patients with severe COVID‐19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS‐13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS‐13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID‐19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS‐13 and other proteases. We observed that both N‐ and O‐linked sialylation were altered in severe COVID‐19. Furthermore, plasma levels of the ADAMTS‐13 inhibitors interleukin‐6, thrombospondin‐1, and platelet factor 4 were significantly elevated. Conclusions These findings support the hypothesis that SARS‐CoV‐2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down‐regulation in ADAMTS‐13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS‐13‐VWF multimer dysfunction may be useful in COVID‐microvascular thrombosis and angiopathy.

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Section: Me Thodsmentioning

confidence: 76%

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Ward

Fogarty

Karampini

et al. 2021

Journal of Thrombosis and Haemostasis

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“…Given recent safety concerns of therapeutic systemic anticoagulation in critically ill COVID-19 patients 33 , speci cally replenishing ADAMTS13 in patients with low levels could provide a safer, targeted, and potentially more effective strategy for preventing vascular thrombosis in patients with severe COVID-19. Notably, recombinant ADAMTS13 has demonstrated safety in patients with congenital TTP, 28 and recent pilot testing of ex vivo plasma samples from patients with severe COVID-19 suggests it can effectively reduce the heightened vWF activity and increased ultra-high molecular weight vWF multimers observed in COVID-19 34 . Based on our collective ndings in humans and animals with COVID-19, we propose that targeted ADAMTS13 repletion warrants evaluation as a tailored approach to preventing myocardial injury and possibly other thromboembolic complications in patients with severe COVID-19 and reduced ADAMTS13 levels.…”

Section: Discussionmentioning

confidence: 99%

Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics

Roh

Kitchen

Guseh

et al. 2021

Preprint

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Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFβ signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (β = 0.4;padj=4.6x10− 7), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (β=-0.4;padj=8x10− 7). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

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“…Accordingly, Turecek et al reported abnormal persistence of highly thrombogenic ultra-high-molecular-weight VWF multimers in a cohort of 36 severely ill COVID-19 patients. Moreover, in vitro incubation of plasma samples from patients with recombinant ADAMTS13 substantially reduced VWF HMWM in a time- and concentration-dependent manner [ 121 ]. In contrast, Doevelaar et al reported decreased VWF HMWM in 75 patients with confirmed COVID-19 of mild to critical severity [ 122 ], an observation shared by Mancini et al in a cohort of 50 hospitalized COVID-19 patients [ 123 ].…”

Section: Covid-19 Is An Endothelial Diseasementioning

confidence: 99%

“…Recombinant ADAMTS13 (rADAMTS13) has been developed for the treatment of thrombotic thrombocytopenic purpura and has been shown to be effective in degradation of thrombi in animal models of stroke [ 174 ]. Thus, a trial of rADAMTS13 in COVID-19 may be both clinically beneficial and a useful confirmation of the microthrombus hypothesis [ 175 ]. Recent studies have also reported benefit from the use of antiplatelet agents [ 176 ].…”

Section: Microthrombosis and Mechanisms Of Vascular Damage In Covid-19mentioning

confidence: 99%

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

et al. 2021

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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

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Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Cited by 44 publications

References 49 publications

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

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