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

ABSTRACT: Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.

SUBMITTER: Turecek PL

PROVIDER: S-EPMC7890348 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Turecek Peter L PL Peck Rachel C RC Rangarajan Savita S Reilly-Stitt Christopher C Laffan Michael A MA Kazmi Rashid R James Izabela I Dushianthan Ahilanandan A Schrenk Gerald G Gritsch Herbert H Ewenstein Bruce M BM Mellgard Bjorn B Erdlenbruch Wolfhard W Jain Nisha N Binder Nikolaus B NB Mumford Andrew D AD

Thrombosis research 20210218

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF ...[more]

PMID: 33662796

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Project description:Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.

Project description:To improve outcome in pulmonary arterial hypertension, earlier diagnosis and better prognostic assessments are required. We aimed to investigate the diagnostic and prognostic potential of plasma proteins related to pathways recognized in pulmonary arterial hypertension including coagulation, inflammation, and metabolism. Forty-two proteins were analysed with proximity extension assay from plasma of 20 healthy controls and 150 patients, including (pulmonary arterial hypertension, n = 48, whereof 33 also during early treatment follow-ups); chronic thromboembolic pulmonary hypertension (CTEPH, n = 20); pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF-PH, n = 31); PH due to HF with reduced ejection fraction (HFrEF-PH, n = 36); and HF without PH (Dyspnoea/HF-non-PH, n = 15). Patients' haemodynamics were assessed by right heart catheterization. Plasma ADAMTS13 in incident pulmonary arterial hypertension was lower compared to the healthy controls (p = 0.055), as well as CTEPH (p < 0.0001), HFrEF-PH (p < 0.0001), HFrEF-PH (p < 0.0001), and Dyspnoea/HF-non-PH (p < 0.0001). Adjusted for age and sex, ADAMTS13 discriminated pulmonary arterial hypertension from the other disease groups with an AUC of 0.91 (sensitivity = 87.5%, and specificity = 78.4%). Higher plasma von Willebrand factor was associated with worse survival (log-rank p = 0.0029), and a higher mortality rate (adjusted hazard ratio 1.002, 95% confidence interval 1-1.004; p = 0.041). Adjusted for age, sex, and combined with the ESC/ERS risk score, von Willebrand factor predicted mortality (median follow-up 3.6 years) in pulmonary arterial hypertension with an AUC of 0.94 (sensitivity = 81.3%, and specificity=93.8%). ADAMTS13 may be a promising biomarker for early detection of PAH and von Willebrand factor as a candidate prognostic biomarker. The putative additional value of von Willebrand factor to the European multiparametric risk assessment strategy remains to be elucidated.

Dataset Information

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

Publications

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

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