Acquired von Willebrand syndrome in patients with monoclonal gammopathy of undetermined significance investigated using a mechanistic approach

BACKGROUND: Acquired von Willebrand syndrome (AVWS) has been reported to occur in association with monoclonal gammopathy, usually of undetermined significance (MGUS). It may present as a type 1 or type 2 von Willebrand factor (VWF) defect depending on the patient’s representation of large VWF multimers. MATERIALS AND METHODS: The mathematical model by Galvanin et al., already employed for studying inherited von Willebrand disease (VWD), was used to explore the pathogenic mechanisms behind MGUS-associated AVWS. RESULTS: The patients studied showed significantly reduced VWF levels and function; an increased VWF propeptide to VWF antigen ratio; and all VWF multimers present but in reduced quantities, with the low-molecular-weight VWF forms being significantly more represented than those of higher molecular weight. Our mathematical model revealed a significantly increased VWF elimination rate constant, with values similar to those of type Vicenza VWD. An even more increased VWF proteolysis rate constant was observed, with values one order of magnitude higher than in type 2A VWD but, in contrast, no loss of large multimers. The model predicted the same elimination rate for high- and low-molecular-weight VWF multimers, but proteolysis of the high-molecular-weight forms also contributes to the pool of low-molecular-weight oligomers, which explains why they were relatively over-represented. DISCUSSION: In MGUS-associated AVWS the increase of both clearance and proteolysis contributes to the circulating levels and multimer pattern of VWF, with a phenotype that appears to be a combination of type Vicenza and type 2A VWD. Hence, the mechanisms behind the onset of AVWS seem to differ from those of inherited VWD

Identifying type Vicenza von Willebrand disease

Increased clearance of von Willebrand factor (VWF) is one of the main features of type Vicenza von Willebrand disease (VWD), a variant with plasma and platelet VWF level discrepancies and unusually large VWF multimers. Diagnosing type Vicenza VWD may not be easy, due to its heterogeneous phenotype. Here we describe the criteria we adopted to identify type Vicenza in a large group of VWD patients. Emphasizing the contribution of platelet VWF by comparison with plasma values, a first step involved selecting the candidate Vicenza patients on the basis of low or very low plasma VWF and a normal platelet VWF content. After excluding type 2A and 2B VWD patients, who may have normal platelet VWF, 18 candidates were found to meet our selection criteria. Genetic analysis revealed that 15 patients (from 5 unrelated families) were type Vicenza VWD and that all carried both G2220A and G3614A type Vicenza mutations barring one, who only had the G3614A mutation. All patients had a reduced VWF survival, and all but the patient with the G3614A mutation alone had ultralarge VWF multimers. Thus, low-plasma VWF associated with a normal platelet VWF content may be a first useful indicator for identifying type Vicenza VWD patients

Abnormally large von Willebrand factor multimers in Henoch-Sch\uf6nlein purpura.

Abstract Allergic vasculitis phenomena seem to be involved in Henoch-Sch\uf6nlein purpura (HSP). Elevated plasma levels of von Willebrand factor (vWf) are a well recognized feature of vasculitis and have been taken as an indication of in vivo endothelial cell damage. Plasma factor VIII:C and vWf levels and vWf multimeric pattern were studied in 8 patients with HSP, during active disease and twice during the remission (3 and 9 months later). Plasma vWf multimeric composition was evaluated using low resolution gels which better resolve large vWf multimers. During active disease plasma factor VIII:C, vWf:Ag, and vWf:RCoF were normal in 5% of patients and increased in three, but in each patient, platelets appeared to aggregate at doses of ristocetin lower than in normals. Furthermore, all patients demonstrated the presence of abnormally large vWf multimers usually found only in platelets and endothelial cells. Three and 9 months later, during remission, in spite of the normalization of factor VIII:C and vWf levels, the abnormal multimers were still detectable, as well as hyper-responsiveness to ristocetin. These findings confirm that damage and/or perturbation of endothelial cells is associated with HSP. Moreover, the persistence of abnormality in the vWf multimeric pattern, when the disease is inactive, suggests that the mechanisms involved operate through the entire clinical course

Eltrombopag for the treatment of inherited thrombocytopenias: A phase II clinical trial

Patients with inherited thrombocytopenias often require platelet transfusions to raise their platelet count before surgery or other invasive procedures; moreover, subjects with clinically significant spontaneous bleeding may benefit from an enduring improvement of thrombocytopenia. The hypothesis that thrombopoietin-mimetics can increase platelet count in inherited thrombocytopenias is appealing, but evidence is scarce. We conducted a prospective, phase II clinical trial to investigate the efficacy of the oral thrombopoietin-mimetic eltrombopag in different forms of inherited thrombocytopenia. We enrolled 24 patients affected by MYH9-related disease, ANKRD26-related thrombocytopenia, X-linked thrombocytopenia/ Wiskott-Aldrich syndrome, monoallelic Bernard-Soulier syndrome, or ITGB3-related thrombocytopenia. The average pre-treatment platelet count was 40.4 x109/L. Patients received a 3- to 6-week course of eltrombopag in a dose-escalated manner. Of 23 patients evaluable for response, 11 (47.8%) achieved a major response (platelet count >100 x109/L), ten (43.5%) had a minor response (platelet count at least twice the baseline value), and two patients (8.7%) did not respond. The average increase of platelet count compared to baseline was 64.5 x109/L (P<0.001). Four patients with clinically significant spontaneous bleeding entered a program of long-term eltrombopag administration (16 additional weeks): all of them obtained remission of mucosal hemorrhages, with the remission persisting throughout the treatment period. Treatment was globally well tolerated: five patients reported mild adverse events and one patient a moderate adverse event. In conclusion, eltrombopag was safe and effective in increasing platelet count and reducing bleeding symptoms in different forms of inherited thrombocytopenia. Despite these encouraging results, caution is recommended when using thrombopoietin-mimetics in inherited thrombocytopenias predisposing to leukemia