Background Severe coronavirus disease 2019 (COVID‐19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients. Objectives To investigate the mechanism of microthrombosis in COVID‐19 progression. Patients/Methods We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin‐cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross‐sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high‐flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19). Results Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID‐19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high‐to‐low molecular‐weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care. Conclusions We found a significant alteration of the VWF‐ADAMTS13 axis in COVID‐19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID‐19 patients and their risk of microthrombosis.
Introduction von Willebrand disease (VWD) diagnosis starts with first level tests: factor VIII coagulant activity, VWF antigen (VWF:Ag) and platelet‐dependent VWF activity (VWF:RCo, VWF:Ab, VWF:GPIbR or VWF:GPIbM). The VWF collagen binding (VWF:CB) assay measures the binding capacity of von Willebrand factor (VWF) to collagen. Aim To assess, in previously diagnosed VWD patients, the performance of a fully automated chemiluminescent test panel including VWF:Ag, VWF:GPIbR and VWF:CB assays. Methods The patients, historically evaluated using in‐house VWF:Ag and VWF:CB assays and an automated latex enhanced immunoassay VWF:GPIbR method, were re‐evaluated using the VWF test panel HemosIL AcuStar. Results The VWF:GPIbR/VWF:Ag and VWF:CB/VWF:Ag obtained by means of AcuStar showed an overall good concordance with the corresponding data obtained at the time of the historical diagnosis. When discrepancies occurred, these were generally due to the lower VWF:CB/VWF:Ag obtained with AcuStar as compared with that obtained with the historical methods and this affected particularly the diagnosis of VWD type 2M. Together, the AcuStar VWF:GPIbR/VWF:Ag and VWF:CB/VWF:Ag were able to distinguish type 1 from types 2A, 2B and 2M, whereas no distinction was possible between type 2A and 2B. Conclusion The AcuStar panel offers a good performance in the differential diagnosis between VWD type 1 and 2A/2B patients. A high rate of coincidence with historical diagnosis was obtained for VWD types 3, 2A/2B and 1. Even though in some cases more tests (eg, RIPA/multimeric analysis) are needed to complete an accurate VWD classification, the AcuStar panel is considered a sensitive, rapid and reliable tool to diagnose VWD patients.
von Willebrand disease (VWD) type 2 is caused by qualitative abnormalities of von Willebrand factor (VWF). This study aimed to determine the genotype and phenotype characterization of a large VWD type 2 cohort from Milan. We included 321 patients (54% females) within 148 unrelated families from 1995-2021. Patients were fully characterized using laboratory phenotype tests and the genotype diagnosis was confirmed by target genetic analysis using Sanger sequencing. Patients were diagnosed with type 2A (n= 98, 48 families), 2B (n= 85, 38 families), 2M (n= 112, 50 families), and 2N (n= 26, 12 families). Eighty-two unique VWF variants including 8 novels were found. The potential pathogenic effect of novel variants was assessed by in silico analysis. Most patients were heterozygous for a single variant (n= 259, 81%), whereas 37 cases (11%) had 2 variants (4 homozygous, 9 in trans and 24 in cis). Twenty-five patients (8%) had 3 or more variants, mainly due to gene conversions. Among the 82 distinct variants identified, five different types including missense (n= 64), gene conversion (n= 10), synonymous (n= 1), deletion (n= 4) and splice (n= 3) were observed. The results of this large cohort showed that VWD type 2 is invariably due to variants that do not prevent the synthesis of the protein and the vast majority of patients (88%) had missense variants. Given the complexity of type 2 diagnosis and the necessity of performing several phenotypic tests, genetic analysis for patients suspected of type 2 is beneficial to establish the correct diagnosis.
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