Type 2M and Type 2A von Willebrand Disease: Similar but Different.

Analogous to the differentiation between hemophilia A and B, respectively, reflecting deficiency in factor VIII (FVIII) and FIX, and increasing being recognized as reflecting clinically different disorders, types 2A and 2M von Willebrand disease (VWD) can also be shown to express both similarities and differences in their prevalence, genetic defects, laboratory test results, clinical features, and treatment responses. In this narrative review, we explore these two "subtypes" of type 2 VWD, identifying parallels and dissimilarities in various aspects of their presentation to clinicians and to scientists/laboratories. This differential will become increasingly important as we strive to provide personalized approaches to future management of patients with VWD, particularly in the emerging landscape of recombinant von Willebrand factor.

von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor.

The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests.

An evaluation of the DDAVP infusion test with PFA-100 and vWF activity assays to distinguish vWD types in children.

von Willebrand disease (vWD) is classified into partial (type 1), qualitative (type 2), and total deficiency (type 3).The aims of the study were to evaluate prospectively the potency of the DDAVP infusion test together with von Willebrand factor (vWF) ristocetin cofactor (vWF:RCo), vWF antigen (vWF:Ag), factor VIII coagulant activity (FVIII:C), and platelet function analyzer (PFA)-100 to distinguish vWD types. Genetic analysis and multimeric analysis of vWF was not applied. We classified the 112 patients and 47 healthy children phenotypically according to the laboratory test results and bleeding severity score. PFA-100 closure times (CT), FVIII:C, vWF:RCo, vWF:Ag, ristocetin-induced platelet aggregation (RIPA), and the response of FVIII:C and vWF parameters to desmopressin (DDAVP) were used to define types 1, 2, and 3 vWD. Type 1 vWD is mild in 34 cases (vWF:RCo % 40-55), moderate in 29 (vWF:RCo %27-40), severe type 1 vWD or nonclassical type 2 vWD in 12 cases (vWF:RCo % 4-16), and type 2 vWD in 23 cases (vWF:RCo %4-38).The response to DDAVP of vWF parameters is normal in all patients with mild/moderate type 1 vWD, 6 patients with severe type 1 vWD or nonclassical type 2 vWD and 11 patients with type 2 vWD. In conclusion, this study showed that measurement of vWF:RCo, vWF:Ag, FVIII:C, and PFA-100 parameters can differentiate vWD types but not severe type 1 vWD or nonclassical type 2 vWD. In the differentiation of severe type 1 vWD and nonclassical type 2 vWD, DDAVP response may be used.