Periprocedural management of type 2N von Willebrand disease with efanesoctocog alfa.

Type 2 Normandy von Willebrand disease (type 2N VWD) is a rare qualitative defect in von Willebrand factor (VWF) that results in impaired factor VIII (FVIII) binding and consequently reduced FVIII levels. Current perioperative strategies require VWF concentrates to attain durable hemostatic FVIII levels. This case highlights the successful perioperative management of a 78-year-old female with type 2N VWD and coronary artery disease utilizing efanesoctocog alfa, a novel long-acting recombinant FVIII product approved for hemophilia A. By decoupling the FVIII-VWF interaction, efanesoctocog alfa achieves prolonged FVIII circulation independent of VWF. A single administration targeting 90% FVIII levels yielded sustained FVIII elevation without achieving supraphysiologic VWF levels, thus mitigating potential cardiovascular risks. This is the first report of efanesoctocog alfa use in type 2N VWD. Further clinical studies are necessary to corroborate its efficacy and safety for this indication.

Desmopressin response depends on the presence and type of genetic variants in patients with type 1 and type 2 von Willebrand disease.

Patients with type 1 and type 2 von Willebrand disease (VWD) can be treated with desmopressin. Although a previous study has shown that the location of the causative VWF gene variant is associated with desmopressin response in type 1 VWD, the association between variants in the VWF gene and desmopressin response is not yet fully understood. Our primary aim was to compare desmopressin response in type 1 VWD patients with and without a VWF gene variant. Secondly, we investigated whether desmopressin response depends on specific VWF gene variants in type 1 and type 2 VWD. We included 250 patients from the Willebrand in the Netherlands study: 72 type 1 without a VWF gene variant, 108 type 1 with a variant, 45 type 2A, 16 type 2M, and 9 type 2N patients. VWF gene was analyzed with ion semiconductor sequencing and Multiplex Ligation-dependent Probe Amplification. Complete response to desmopressin was observed in all type 1 VWD patients without a variant, 64.3% of type 1 patients with a variant, and 31.3% of type 2 patients (P < .001). Despite a large interindividual variability in desmopressin response, patients with the same variant had comparable desmopressin responses. For instance, in 6 type 1 patients with exon 4 to 5 deletion, mean VWF activity at 1 hour after desmopressin was 0.81 IU/mL, with a coefficient of variation of 22.9%. In conclusion, all type 1 VWD patients without a VWF gene variant respond to desmopressin. In type 1 and type 2 VWD patients with a VWF variant, desmopressin response highly depends on the VWF gene variants.

Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition.

INTRODUCTION: Type 2A von Willebrand disease (VWD) is common in type-2 group caused by qualitative deficiency of von Willebrand factor (VWF). Emicizumab is a bispecific antibody that mimics activated factor VIII (FVIIIa) cofactor function, and emicizumab prophylaxis substantially reduces bleeding in patients with haemophilia A. It is unknown whether emicizumab affects thrombus formation in type 2A VWD characterized by not only low FVIII levels but also the impaired platelet adhesion and aggregation. AIM: To examine the coagulant potential of emicizumab in type 2A VWD. PATIENTS/METHODS: Perfusion chamber experiments combined with immunostaining were performed using whole blood from 5 patients with type 2A VWD under high shear condition (2500 s-1 ). RESULTS: The addition of FVIII to type 2A VWD whole blood did not augment thrombus formation, whilst supplementation with VWF or FVIII/VWF enhanced. FVIII appeared to contribute to thrombus height rather than surface coverage. The addition of emicizumab enhanced thrombus formation in type 2A VWD compared with FVIII, but this potency was less than the presence of VWF. The effect on thrombus formation mediated by emicizumab appeared to be more rapid than that by FVIII for non-requirement of activation step of FVIII, whilst that by FVIII showed more impact on thrombus formation at the late phase. CONCLUSION: Emicizumab-induced enhancing effects of thrombus formation, independent on VWF, may be useful as an alternative therapy for type 2A VWD patients. These results supported a critical role for the FVIII-VWF complex facilitating thrombus formation under high shear.

Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent VWF single nucleotide polymorphisms to inhibit mutant VWF. The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.

Recombinant Von Willebrand factor concentrate in 2A Von Willebrand disease: comparison to plasma-derived Von Willebrand factor concentrate therapy.

: Type 2A sub-type of Von Willebrand disease (VWD) is characterized by the loss of high molecular weight multimers. Several plasma-derived Von Willebrand factor concentrates (PD-VWFC) are available for treatment and recently a recombinant VWF concentrate (rVWFC) has been approved for use in VWD for adults in the United States. We describe a patient with Type 2A VWD who had persistent refractory epistaxis despite treatment with PD-VWFC. We describe differences in VWF multimeric composition and Factor VIII (FVIII) levels after plasma-derived and rVWF concentrates. Despite similar VWF levels, VWF multimeric composition after PD-VWFC remained abnormal while it corrected with rVWFC. Post-PD-VWFC, high levels of FVIII were seen, which were not observed after rVWFC. Recombinant VWFC may offer some advantages over PD-VWFC. This finding needs to be confirmed in larger studies.

How I treat type 2B von Willebrand disease.

Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder caused by changes in von Willebrand factor (VWF) that enhance binding of VWF to GPIb on platelets. Although this disorder is seemingly well defined because of this single molecular defect, in reality type 2B VWD is a clinically heterogeneous disorder that can be difficult to identify and manage. Diagnostic criteria include a history of mucocutaneous bleeding, laboratory studies showing enhanced VWF binding of platelets and/or a 2B VWD genetic variant, and a family history consistent with autosomal dominant inheritance. Thrombocytopenia, although not always present, is common and can be exacerbated by physiologic stressors such as pregnancy. The mainstay of therapy for type 2B VWD is VWF replacement therapy. Adjunct therapies useful in other types of VWD, such as antifibrinolytics, are also used in type 2B VWD. 1-Desamino-8-d-arginine vasopressin (DDAVP) is controversial because of exacerbation of thrombocytopenia, but is, in practice, sometimes used for minor bleeding. Here we review the available evidence and provide 3 clinical cases to illustrate the intricacies of diagnosing type 2B VWD to describe the response to DDAVP and to review complexities and management during pregnancy.

Enfermedad de von Willebrand tipo 2A y parto. A propósito de un caso / Von Willebrand disease type 2A and labor. A case report

La enfermedad de von Willebrand es la coagulopatía congénita más frecuente en la población general, ligada al cromosoma 12, que ocasiona una alteración cuantitativa o funcional del factor von Willebrand. En el embarazo fisiológico se incrementan los niveles plasmáticos de diferentes factores de coagulación, fundamentalmente en el tercer trimestre, y retornan a niveles basales pregestacionales en el puerperio, lo que aumenta el riesgo de hemorragia posparto. Se describe el caso de una mujer embarazada con antecedentes hereditarios y personales de enfermedad de von Willebrand tipo 2A. La atención especializada con un equipo multidisciplinario y la planificación del momento del parto ayudaron a evitar complicaciones

Von Willebrand disease is the most frequent congenital coagulopathy in the general population. In physiological pregnancy, plasma levels of different coagulation factors are increased, mainly in the third trimester, and return to baseline pregestacional leves in the postpartum period, increasing the risk of postpartum hemorrhage. It narrates a case of a pregnant woman with a hereditary and personal history of von Willebrand disease type 2A. The specialized care with a multidisciplinary team and planning the moment of labor managed to avoid complications

Advances in the diagnosis and treatment of Von Willebrand disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.

Management of Type 2B von Willebrand Disease during Pregnancy.

Type 2B von Willebrand disease is a rare bleeding condition resulting in thrombocytopenia and a reduction in large VWF multimers. It usually has an autosomal dominant pattern of inheritance. We report the management of a patient with type 2B von Willebrand disease, whose diagnosis was confirmed by demonstration of a R1306W mutation, through her first pregnancy. The patient's von Willebrand factor (VWF) antigen and VWF ristocetin cofactor levels rose throughout pregnancy, with an associated drop in the platelet count. The patient was successfully managed through labour to a surgical delivery with VWF concentrate, platelet transfusions and tranexamic acid. The patient delivered a male baby who was found to have inherited type 2B von Willebrand disease and had a significant cephalhaematoma at delivery. The baby was managed with VWF concentrate and platelet transfusions and made a full recovery. There is a lack of evidence to guide the best management of pregnant patients with type 2B von Willebrand disease. We adopted a pragmatic management plan, in keeping with other published case reports. To the best of our knowledge, this is the first case report in which the child was found to have inherited type 2B von Willebrand disease and encountered bleeding problems, making this case unique amongst the published literature.

Use of a thrombopoietin receptor agonist in von Willebrand disease type 2B (p.V1316M) with severe thrombocytopenia and intracranial hemorrhage.

We present here a 63-year old woman with a long history of immune thrombocytopenia. She was hospitalized for a traumatic intracranial hemorrhage with thrombocytopenia. Following inefficient treatment of four platelet transfusions, immunoglobulins, and corticosteroids, we initiated treatment with a thrombopoietin (TPO) receptor agonist (eltrombopag 25 mg/d) with a good efficacy. Her mother and sister also had chronic thrombocytopenia. Clinical history, hemostasis results, and gene analysis revealed von Willebrand disease (VWD) type 2B with the mutation (c.3946G>A; p.V1316M), which combines a von Willebrand factor defect with severe thrombocytopenia, as well as a thrombocytopathy. The efficacy of TPO receptor agonists appears to counterbalance, at least to some extent, the thrombocytopathy associated with this mutation. As such, the use of TPO receptor agonists could represent an alternative therapeutic approach in cases of VWD type 2B with severe thrombocytopenia.

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.

How I treat type 2 variant forms of von Willebrand disease.

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.

Life-threatening bleeding in a patient with mild hemophilia A and heterozygosity for von Willebrand disease Type 2N.

Hemophilia A and von Willebrand disease (VWD) are distinct bleeding disorders with a spectrum of clinical phenotypes. They are characterized by mutations in either factor VIII (F8) or von Willebrand factor (VWF) genes, respectively. The pattern of inheritance and appropriate laboratory evaluation differentiates these diseases, and treatment strategies for both are different. Here, we report a male patient with hemophilia A and VWD Type 2 Normandy (N) mutations who presented with life-threatening bleeding. We document his medical history, clinical course, management, and diagnostic work up.

An update on type 2B von Willebrand disease.

Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients' abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.

Similarity in joint and mucous bleeding syndromes in type 2N von Willebrand disease and severe hemophilia A coexisting with type 1 von Willebrand disease in two Chinese pedigrees.

In this study, we investigated the molecular basis of two unrelated Chinese patients with hemostatic disorders. The proband of the first family had severe hemophilia A (HA) coexisting with type 1 von Willebrand disease (VWD) and the proband of the second family had type 2N VWD. Both probands had similar phenotypes, which included joint and mucosal bleeding, very low factor VIII (FVIII) activity (FVIII:C), and moderate reductions in VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:Rco), as well as a normal multimeric pattern. One FVIII mutation and three VWF mutations were identified: FVIII p.R446* and VWF heterozygous p.E216K mutations were detected in proband 1 and compound heterozygosity of VWF mutations (p.R816W and c.1911delC) in proband 2. Transient expression studies in HEK293T cells proved that R816W mutation abolished the binding of FVIII to VWF and slightly impaired protein synthesis and secretion; 1911delC mutation mainly impaired VWF protein synthesis and secretion. These results provided insight into the possible pathogenic mechanism of type 2N VWD in Chinese patients carrying these mutations.