Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS‐IPS, an international and collaborative cross‐sectional study

Abstract

Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM‐1VWD bleeding questionnaire in patients enrolled in the 3WINTERS‐IPS and MCMDM‐1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five‐fold over‐represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

“…[7][8][9][10] The majority of these studies involved small groups of patients, and the authors have either focused on clinical symptoms and biochemical phenotype or on the patients' genotype. 6,7 The 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study) is an investigator-initiated, multicenter, European/Iranian observational study that aims to comprehensively evaluate the clinical symptoms of VWD3 patients, 11 their phenotypic laboratory findings, and the VWF variants, as well as the safety and efficacy of replacement therapy for the treatment and prevention of bleeding manifestations (registered at www.clinicaltrials.gov as #NCT02460458).…”

ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease

“…Patients with type 3 VWD may experience joint bleeds similar to those seen in hemophilia. 21 Heavy menstrual bleeding is of particular concern in women because of its monthly occurrence, affecting their quality of life as well as their overall health. 22,23 Many women experience iron deficiency and anemia resulting from the presence of unrecognized or inadequately treated heavy menstrual bleeding.…”

Diverse activities of von Willebrand factor in traumatic brain injury and associated coagulopathy

“…Individuals with VWF deficiency (von Willebrand disease 49 ) not only develop spontaneous mucocutaneous bleeding (in rare cases, intracranial hemorrhage), but also suffer much severe hemorrhage upon injury. [50][51][52] The level of plasma VWF is approximately 10 μg/ mL at baseline, 53 but it can increase more than 100% during acute TBI, and is widely used as a marker for endothelial injury. We recently demonstrated in mouse models of lateral fluid percussion injury that TBI induces a rapid but transient increase in plasma VWF, reaching its peak 3 hours after injury.…”

“…As an acute phase reactant, VWF is a key part of the hemostatic defense system for preventing blood loss upon vascular injury. Individuals with VWF deficiency (von Willebrand disease 49 ) not only develop spontaneous mucocutaneous bleeding (in rare cases, intracranial hemorrhage), but also suffer much severe hemorrhage upon injury 50‐52 . The level of plasma VWF is approximately 10 μg/mL at baseline, 53 but it can increase more than 100% during acute TBI, and is widely used as a marker for endothelial injury 54‐56 .…”