Acquired von Willebrand Syndrome with a Type 2B Phenotype: Diagnostic and Therapeutic Dilemmas

Abstract

In this report, we provide evidence of an acquired von Willebrand syndrome (AVWS) with a type 2B phenotype rather than the expected type 1 or 2A. The patient was referred prior to surgical removal of a fibrous mass within the maxillary sinus. His first bleeding 7 years earlier following a retinal tear had been complicated by monocular blindness. Several mucocutanous bleedings followed. Hematological investigations revealed von Willebrand factor (VWF):Ag 91 IU/ml, factor VIII 86 IU/ml, VWF:RCo 34 IU/ml and profound thrombocytopenia with platelet clumping. VWF multimer analysis showed a loss of high-molecular-weight multimers and his plasma aggregated normal platelets under low ristocetin concentration, consistent with type 2B von Willebrand disease (VWD). Sequencing of VWF exon 28 and of the platelet GP1BA gene to investigate the possibility of platelet-type VWD failed to reveal mutations. Serum protein electrophoresis showed a monoclonal IgG protein and led to the diagnosis of monoclonal gammopathy of unknown significance (MGUS), raising suspicion of an AVWS. Over 2 years, he experienced severe gingival bleedings and traumatic intracerebral hemorrhage. Following debridement of the sinus mass, the patient required 20 units of packed red blood cells, despite high-dose Humate-P, continuous Amicar and twice-daily platelet transfusions. Bleeding finally ceased following infusion of activated factor VIIa. A history of prior uncomplicated vasectomy and tendon laceration, no family history of bleeding, the inability to identify a causative mutation in either exon 28 VWF or platelet GP1BA and the MGUS led to diagnosis of AVWS with a type 2B phenotype. This case highlights the difficulties in assigning a diagnosis and the management of bleeding in a patient with an atypical presentation of AVWS.

Frequency of Platelet type versus Type 2B von Willebrand Disease

“…It is worth noting that a cousin of one of the Australian cases was clinically misdiagnosed at an earlier date as ITP. The one US case had atypical presentation and further investigations during the study led to the diagnosis of an acquired VWD with atypical type 2B phenotype (28).…”

“…The six Argentinean cases were subjected to comprehensive phenotypic analysis including VWF multimers, RIPA and RIPA mixing studies, all of which was consistent with 2B VWD, yet three cases did not show an identifiable GP1BA or VWF-A1-domain mutation (28). In Brazil, RIPA was performed in 14/18 cases, showing an enhanced response in 12, yet genetic analysis identified 2B VWD mutations in only three cases.…”

“…The one US case was interesting since despite a typical 2B VWD presentation, both VWF and GP1IBA were mutation negative. Further analysis ultimately resulted in a diagnosis of an acquired VWD (28).…”

2B or not 2B? A prothrombotic tendency masquerading as a bleeding disorder

“…AVWS has also been associated with numerous medical disorders including cancer, lymphoproliferative and myeloproliferative disorders, immunologic diseases, and other cardiovascular diseases . AVWS mimicking 2B VWD is extremely rare; the few published case reports having all been associated with monoclonal gammopathy of undetermined significance …”

Asymptomatic Severe Acquired von Willebrand’s Syndrome in Association With a Glioblastoma Multiforme: A Case Report

“…von Willebrand's Disease (vWD) is the most common inherited bleeding disorder affecting both males and females in equal frequency, presenting mostly in childhood [3]. Occurring in an autosomal dominant fashion, the pathology is characterized by the functional, structural and quantitative alterations of the von Willebrand factor (vWF) leading to a propensity of catastrophic bleeding.…”