Different bleeding risk in type 2A and 2M von Willebrand disease: a 2‐year prospective study in 107 patients

Castaman, Giancarlo; Federici, Augusto B.; Tosetto, Alberto; Marca, Silvia La; Stufano, Francesca; Mannucci, Pier Mannuccio; Rodeghiero, Francesco

doi:10.1111/j.1538-7836.2012.04661.x

Cited by 122 publications

(135 citation statements)

References 45 publications

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“…Heterogeneity in both symptoms and laboratory findings has been demonstrated for other VWF variants. 33 The classification of p.R1315C is presently unclear; Ribba and colleagues reported on a series of patients with this variant who all lacked high-molecular-weight multimers and would thus be considered type 2A, but not all of the subjects in our study had multimer defects. 28 The presence of other modifying factors apart from either VWF levels or VWF genetics cannot be excluded and highlights the importance of individual consideration with regard to diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 71%

Crucial role for the VWF A1 domain in binding to type IV collagen

Flood¹,

Schlauderaff²,

Haberichter³

et al. 2015

Blood

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• Collagen 4 binds to the VWF A1 domain, and this binding is reduced or abrogated by select VWF A1 domain sequence variations.• Platelet binding to collagen 4 under flow conditions is dependent on the presence of VWF.Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.

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Section: Discussionmentioning

confidence: 71%

Crucial role for the VWF A1 domain in binding to type IV collagen

Flood¹,

Schlauderaff²,

Haberichter³

et al. 2015

Blood

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“…42 In a prospective cohort of 46 patients with type 2A and 61 with type 2M VWD, patients having a BS .9 had an almost sixfold higher risk of spontaneous bleeding during follow-up than those with a normal BS. 39 Finally, in a recent large prospective investigation performed in 796 patients with all types of VWD, a BS .10 at enrollment was the strongest predictor of bleeding with a 5.5-fold increased risk during 1-year follow-up. 43 These observations suggest that patients with a significant previous bleeding history may be at higher bleeding risk.…”

Section: Type 2 Vwd: a Heterogeneous Disease Subgroupmentioning

confidence: 95%

“…38 Prospective studies have demonstrated that the bleeding risk in type 2A patients is much higher than that observed in type 2M patients, with gastrointestinal hemorrhage being a very common symptom. 39 Mucocutaneous bleeding (epistaxis, ecchymosis, menorrhagia, and gastrointestinal bleeding) are the most prevalent manifestations in types 2A, 2B, and 2M variants. Type 2N VWD patients usually present with symptoms suggestive of mild-to-moderate hemophilia A, mainly related to trauma or surgery.…”

Section: Type 2 Vwd: a Heterogeneous Disease Subgroupmentioning

confidence: 99%

“…There are several reports of bleeding from gastrointestinal angiodysplasia occurring mainly in type 2A and type 2B, both characterized by the lack of HMW VWF multimers in plasma. 39,[59][60][61][62][63][64] A few patients with type 2, especially with types 2A and 2B, may benefit from prophylaxis to manage this type of bleeding, as in the presented case. However, replacement therapy significantly reduces but does not completely abolish transfusion requirement.…”

Section: Treatment Of Type 2 Vwd: a Case-based Approachmentioning

confidence: 99%

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How I treat type 2 variant forms of von Willebrand disease

Tosetto

Castaman²

2015

Blood

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Type 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, 4 different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment of the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared with patients with actual quantitative deficiency (type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-factor VIII concentrates represents the safe mainstay of treatment of all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal antihemorrhagic prophylaxis in the individual patient.

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“…In type 2M, high-molecular-weight multimers have normal structure, which differentiates the disorder from type 2A VWD. This type is associated with a milder bleeding phenotype than the other VWD [13]. Some dysfunctional variants of 2M type have abnormal binding to collagen, particularly collagen types I, III, and VI, and therefore have abnormal VWF collagen binding activity (VWF:CB).…”

Section: Vwd Classification and Geneticsmentioning

confidence: 99%