Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

Castaman, Giancarlo; Federici, Augusto B.

doi:10.1055/s-0036-1579638

Cited by 17 publications

(6 citation statements)

References 33 publications

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“…Each sample grouping also represents potential heterogeneity. For example, most but not all type 2B patients present with loss of HMWM (‘typical’ presentation) . Thus, atypical 2B cases show elevated responsiveness in RIPA and genetic evidence of 2B VWD but may not show reduced VWF activity/Ag ratios, nor loss of HMWM.…”

Section: Discussionmentioning

confidence: 99%

Comparative assessment of von Willebrand factor multimers vs activity for von Willebrand disease using modern contemporary methodologies

et al. 2020

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Introduction Diagnosis of von Willebrand disease (VWD) is challenging due to heterogeneity of VWD and test limitations. Many von Willebrand factor (VWF) assays are utilized, including antigen (Ag), activity and multimer analysis. Activity assays include ristocetin cofactor using platelets (VWF:RCo) or other particles incorporating recombinant glycoprotein I (‘VWF:GPIbR’), or other GPI binding assays using gain‐of‐function mutations (‘VWF:GPIbM’), or collagen binding (VWF:CB). Aim To comparatively evaluate modern contemporary VWF activity assays vs VWF multimer analysis using modern contemporary methods. Materials and methods Several VWF activity assays (VWF:RCo, VWF:GPIbR, VWF:GPIbM, VWF:CB) assessed (typically as a ratio against VWF:Ag) against a new semi‐automated procedure for different types of VWD (1, 3, 2A, 2B, 2M), plus control material (n = 580). The evaluation also focussed on relative loss of high and very high molecular weight multimers (HMWM and VHMWM) by densitometric scanning. Results All evaluated VWF activity/Ag ratios showed high correlation to the presence/absence of HMWM and VHMWM, although VWF:CB/Ag and VWF:GPIbR/Ag ratios using an automated chemiluminescence method yielded highest correlation coefficients (r = .909 and .874, respectively, for HMWM). Use of the investigative procedure (VHMWM) identified fewer false positives for ‘loss’ in type 1 VWD. Conclusions This comparative investigation identified that new automated chemiluminescence VWF activity assays best identified relative loss or presence of HMWM and VHMWM according to activity to Ag ratios and an alternative investigative method for identifying VHMWM in multimer testing for a new commercial multimer method may lead to fewer false identifications of HMW loss in type 1 VWD.

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Section: Discussionmentioning

confidence: 99%

Comparative assessment of von Willebrand factor multimers vs activity for von Willebrand disease using modern contemporary methodologies

et al. 2020

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“…34 However, the ristocetin concentration to be used remains controversial. 48 Many authors suggest that 0.5 mg/mL should be used as the threshold. 49 In our case, the high number of patients with negative RIPA 0.5 mg/mL seen in p. R1308C mandates the evaluation of the threshold ristocetin concentration to avoid misdiagnosis.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation

Woods

Kempfer

Paiva

et al. 2016

Semin Thromb Hemost

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von Willebrand disease type 2B (VWD2B) expresses gain-of-function mutations that enhance binding of an individual's von Willebrand factor (VWF) to its platelet ligand, glycoprotein Ib (GPIb), and which are usually identified by increased ristocetin-induced platelet aggregation (RIPA). We describe here the phenotypic profile of 38 genotypically selected VWD2B-affected family members (AFMs) belonging to 19 unrelated families. Major bleeding was observed in 68.4% of AFMs (previous to their diagnosis and registered by lifetime interviews), with a total of 46 episodes (1.21/patient), and was found to be highly related to the individual bleeding score and presence of thrombocytopenia, but otherwise unrelated to other laboratory parameters. Excessive muco-cutaneous bleeding symptoms were often reported, the most frequent of which comprised menorrhagia, epistaxis, easy bruising, and bleeding after teeth extraction/in oral cavity. Eight unaffected family members were also studied. The prevalence of VWD2B within families was 0.826, and the penetrance of mutations was complete, making it mandatory to study entire family sets to complete diagnostic profiles. Seven heterozygous missense mutations were found, the most common being p.V1316M. In the p.R1308C group, 75% of the AFMs showed absence of RIPA at 0.5 mg/mL, 66.6% of whom had VWF:RCo < 10 IU/dL, and 50% of whom had VWF:CB < 10 IU/dL. In the p.S1310F group, none of the AFMs had VWF:RCo/VWF:Ag < 0.6 (RCo/Ag), but 100% had VWF:CB/VWF:Ag < 0.6/(CB/Ag). Patients with p.P1266L and p.R1304V were characterized as atypical VWD2B. Two de novo mutations were found in four AFMs belonging to two families. We also describe a novel mutation: p.Y1258C. Of our patients, 70.5% had O blood group. In conclusion, a normal RCo/Ag and a negative RIPA at 0.5 mg/mL do not necessarily rule out a diagnosis of VWD2B.

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“…[32][33][34] Although this classification may be helpful for guiding the clinical decision-making and therapeutic management, it is noteworthy that the clinical phenotype is also dependent upon additional factors such as age, acquired causes of bleeding (diet, trauma, liver, and renal function), primary hemostasis (i.e., platelet count and function, level and activity of VWF), activity of other coagulation factors, and global fibrinolytic potential. Additional informative second-line tests that can be implemented in routine clinical laboratories include the mixing test (for the differential diagnosis between congenital clotting factor deficiencies, the presence of inhibitors or anticoagulants), 35 VWF antigen and activity (e.g., ristocetin cofactor, collagen binding) assays (for diagnosing VWD) [7][8][9][10] and TT. This last test, also known as the thrombin clotting time is based on recalcification of citrated plasma and activation of fibrin formation by addition of an excess of thrombin in the sample.…”

Section: Second-and Third-line Coagulations Testsmentioning

confidence: 99%

Diagnostics of Inherited Bleeding Disorders of Secondary Hemostasis: An Easy Guide for Routine Clinical Laboratories

Lippi

Franchini

Favaloro

2016

Semin Thromb Hemost

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The investigation of inherited bleeding disorders of secondary hemostasis remains a challenge for most clinical laboratories, especially those that lack experience or specialized personnel. Bleeding can be essentially caused by a variety of acquired or congenital conditions, which impair either primary or secondary hemostasis. Since a universally agreed approach for the diagnostics of hemorrhagic disorders is still unavailable, this article aims to provide an easy guidance for routine clinical laboratories. This pragmatic approach to identifying and diagnosing inherited bleeding disorders of secondary hemostasis entails a multifaceted strategy, based on a collection of personal and family history, the results of first-line tests, which can then be followed by second- or third-line analyses to definitely establish the specific nature and the severity of the bleeding phenotype. Briefly, the presence of profound hemorrhages rather than mucocutaneous bleeding is suggestive of a disorder of secondary hemostasis. Although a positive family history is frequently reported in patients with congenital conditions, the lack of clinically meaningful symptoms in patient's relatives is not absolutely indicative of an acquired disorder. The next step encompasses the assessment of first-line coagulation tests (i.e., prothrombin time, activated partial thromboplastin time, and fibrinogen) if family history is not suggestive of a specific factor deficiency. The emergence of abnormal data of these assays and the variable combination of their results is then helpful to guide the performance of second-line tests, in particular specific factor assays, which will then provide a reasonable basis for a preliminary diagnosis. Third-line tests (namely, immunological assays of clotting factors and molecular biology) are then supportive for a final diagnosis and for identifying the nature of the factor deficiency (i.e., quantitative or functional).

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Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

Cited by 17 publications

References 33 publications

Comparative assessment of von Willebrand factor multimers vs activity for von Willebrand disease using modern contemporary methodologies

Comparative assessment of von Willebrand factor multimers vs activity for von Willebrand disease using modern contemporary methodologies

Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation

Diagnostics of Inherited Bleeding Disorders of Secondary Hemostasis: An Easy Guide for Routine Clinical Laboratories

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