Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease

Abstract

We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

“…Because VWF:Ag and FVIII:C levels are associated with bleeding phenotype in VWD, 14,16 it may be expected that VWFpp also associates with bleeding phenotype in VWD patients, either indirectly through its association with VWF:Ag or by binding to mature VWF in the circulation. 30 Interestingly, we found that the presence of VWFpp in patients with VWF:Ag levels ,5 IU/dL correlates with a milder bleeding phenotype.…”

“…13,14 The inclusion criteria for the WiN study were hemorrhagic diathesis or a family history of VWD and historically low VWF levels #30 U/dL (VWF:Ag and/or VWF ristocetin cofactor [VWF:RCo]) and/or FVIII:C levels #40 U/dL. Patients were excluded if they were known to have other hemostatic disorders resulting in hemorrhagic diathesis.…”

“…14,15 To calculate a bleeding score (BS), as previously described by Tosetto, 16 we used information on the number and severity of clinically relevant bleeding of 12 specific bleeding symptoms. The Tosetto BS assigns a high score when desmopressin or replacement therapy is needed to control bleeding; however, when this replacement therapy was used prophylactically before a surgical intervention, dental extraction, or delivery to prevent bleeding, this bleeding symptom was not scored as a bleeding that required replacement therapy because that would overestimate the score.…”

“…The Tosetto BS assigns a high score when desmopressin or replacement therapy is needed to control bleeding; however, when this replacement therapy was used prophylactically before a surgical intervention, dental extraction, or delivery to prevent bleeding, this bleeding symptom was not scored as a bleeding that required replacement therapy because that would overestimate the score. 14,17 However, if bleeding did occur despite prophylactic treatment, this bleeding was scored according to the Tosetto BS.…”

“…At the time of the study, no international standard was yet available for VWFpp, and therefore the plasma pool was arbitrarily set at 100 U/dL. Details on the blood-sampling procedure and laboratory measurements at inclusion in the WiN study have been described in more detail by de Wee et al 14 …”