<scp>VWF</scp> collagen (types <scp>III</scp> and <scp>VI</scp>)‐binding defects in a cohort of type 2M <scp>VWD</scp> patients – a strategy for improvement of a challenging diagnosis

Fidalgo, Teresa; Oliveira, Ana Catarina Lima de; Pinto, Carla; Martinho, Patrícia; Ferreira, Gisela; Salvado, Ramón; Sevivas, Teresa; Catarino, Cristina; Ribeiro, Maria Letı́cia

doi:10.1111/hae.13156

Cited by 6 publications

(6 citation statements)

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“…According to previous reports, 12,45,46 our type 2A and 2M patients carrying the same DCV showed variable bleeding scores not only in the same family but also among families. Accordingly, it seems reasonable to speculate on the involvement of modifier genes 13,47 on the clinical phenotype of these patients.…”

Section: Discussionmentioning

confidence: 99%

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Woods

Paiva

Primrose

et al. 2021

Semin Thromb Hemost

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Type 2A and 2M von Willebrand disease (VWD) broadly show similar phenotypic parameters, but involve different pathophysiological mechanisms. This report presents the clinical and laboratory profiles of type 2A and type 2M patients genotypically diagnosed at one large center. Higher bleeding score values and a higher incidence of major bleeding episodes were observed in type 2A compared with type 2M, potentially reflective of the absence of large and intermediate von Willebrand factor (VWF) multimers in 2A. In type 2A, most of disease-causing variants (DCVs) appeared to be responsible for increased VWF clearance and DCV clustered in the VWF-A1 domain resulted in more severe clinical profiles. In type 2M, DCV in the VWF-A1 domain showed different laboratory patterns, related to either reduced synthesis or shortened VWF survival, and DCV in the VWF-A2 domain showed patterns related mainly to shortened survival. VWF-type 1 collagen binding/Ag (C1B/Ag) showed different patterns according to DCV location: in type 2A VWD, C1B/Ag was much lower when DCVs were located in the VWF-A2 domain. In type 2M with DCV in the VWF-A1domain, C1B/Ag was normal, but with DCV in the VWF-A2 domain, C1B/Ag was low. The higher frequency of major bleeding in VWD 2M patients with DCV in the VWF-A2 domain than that with DCV in the VWF-A1 domain could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF-GPIb binding. In silico modeling suggests that DCV impairing the VWF-A2 domain somehow modulates collagen binding to the VWF-A3 domain. Concomitant normal FVIII:C/Ag and VWFpp/Ag, mainly in type 2M VWD, suggest that other nonidentified pathophysiological mechanisms, neither related to synthesis/retention nor survival of VWF, would be responsible for the presenting phenotype.

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Section: Discussionmentioning

confidence: 99%

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Woods

Paiva

Primrose

et al. 2021

Semin Thromb Hemost

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“…Fidalgo et al 1. described a VWD2M patient with heterozygous compound genotype for p.Arg1315Hys associated with type 1 VWD, and another mutation in the splicing site c.7464C>T in exon 44, who presented reduced RCo/Ag and CB6/Ag, but normal CB1/Ag.…”

Section: Resultsmentioning

confidence: 99%

“…22 Reduced binding to type VI collagen has been reported in VWD2M patients in the presence of four mutations located in VWF-A1 domain. 23 Fidalgo et al 1 Compound heterozygosity would result in a severe clinical phenotype, similar to a homozygous VWD2M behavior, despite it is not the case. Heterozygous p.Arg1426Cys in proband's mother suggests possible type 1 VWD, and p.Pro1648fs*45 has been described as responsible for type 1 VWD.…”

Section: Resultsmentioning

confidence: 99%

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Combined effects of two mutations in von Willebrand disease 2M phenotype

Woods

Paiva

Kempfer

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Compound heterozygosity causes a VWD2M phenotype in a child with severe bleeding symptoms.p.P1648fs*45 changes the folding of A2 domain altering VWF binding to GPIbα and type VI collagen.p.P1648fs*45 was considered as an apparent de novo mutation; AS‐PCR revealed paternal mosaicism.Bleeding score and DDAVP's response were worse than those seen in VWD2M heterozygous controls. BackgroundType 2M von Willebrand disease (VWD2M) is usually characterized by VWF:RCo/VWF:Ag<0.6 and normal multimeric profile; desmopressin (DDAVP) challenge test commonly shows poor response of VWF:RCo.ObjectiveWe describe the bleeding tendency and the laboratory phenotype in a patient carrying two heterozygous mutations affecting VWF‐A1 domain and VWF‐A2 domain.Subjects/methodsA 12‐year‐old patient (O blood group) with severe hemorrhagic tendency was phenotypically and genotypically analyzed; his parents were also studied.ResultsThe proband showed decrease FVIII:C, VWF:RCo/VWF:Ag, and VWF:CB6/VWF:Ag ratios, but normal platelet count, VWF:CB1/VWF:Ag ratio, VWFpp and multimeric pattern, suggesting a VWD2M phenotype. The DDAVP challenge test, compared to controls (VWD2M patients with mutations in VWF‐A1 domain), showed lower increase of FVIII:C and VWF:Ag than in heterozygous, but very similar to homozygous control. Two mutations were found in heterozygous and trans presentation: p.Pro1648fs*45 and a novel missense mutation, p.Arg1426Cys. The mother was p.Arg1426Cys heterozygous carrier, with few clinical symptoms. The father was asymptomatic, with no mutations. The p.Pro1648fs*45 was considered an apparent de novo mutation; proband's AS‐PCR revealed mosaicism in the paternal allele. According to the predicted models, p.Arg1426Cys would not be affecting the binding of GPIbα to A1 domain, whereas p.Pro1648fs*45 seems to modify the folding of A2 domain, and in this way, it would affect the binding to GPIbα and type VI collagen. We believe that the combination of these two heterozygous mutations, in a child with O blood group, could result in a defective phenotype enhancer.

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“…Under normal conditions, VWF circulates in the plasma in a spherical conformation [24]. Upon vascular damage, VWF is released by ECs and binds via its A1 domain (to collagen type I, III, IV and VI) and A3 domain (to type I and III) which is present in the perivascular connective tissue of the damaged vessel wall [20,21,[25][26][27]. The binding of VWF to collagen will induce a conformational change that results in a stretched conformation thereby exposing the A1 domain [28].…”

Section: Von Willebrand Factor (Vwf)mentioning

confidence: 99%

VWF, Platelets and the Antiphospholipid Syndrome

Huang

Ninivaggi

Chayouâ

et al. 2021

IJMS

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The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Laboratory criteria for the classification of APS include the detection of lupus anticoagulant (LAC), anti-cardiolipin (aCL) antibodies and anti-β2glycoprotein I (aβ2GPI) antibodies. Clinical criteria for the classification of thrombotic APS include venous and arterial thrombosis, along with microvascular thrombosis. Several aPLs, including LAC, aβ2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have been associated with arterial thrombosis. The Von Willebrand Factor (VWF) plays an important role in arterial thrombosis by mediating platelet adhesion and aggregation. Studies have shown that aPLs antibodies present in APS patients are able to increase the risk of arterial thrombosis by upregulating the plasma levels of active VWF and by promoting platelet activation. Inflammatory reactions induced by APS may also provide a suitable condition for arterial thrombosis, mostly ischemic stroke and myocardial infarction. The presence of other cardiovascular risk factors can enhance the effect of aPLs and increase the risk for thrombosis even more. These factors should therefore be taken into account when investigating APS-related arterial thrombosis. Nevertheless, the exact mechanism by which aPLs can cause thrombosis remains to be elucidated.

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VWF collagen (types III and VI)‐binding defects in a cohort of type 2M VWD patients – a strategy for improvement of a challenging diagnosis

Cited by 6 publications

References 10 publications

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Combined effects of two mutations in von Willebrand disease 2M phenotype

VWF, Platelets and the Antiphospholipid Syndrome

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