Abstract
Introduction. Whereas von Willebrand disease is the most common constitutional bleeding disorder, acquired von Willebrand syndrome (AVWS) is rare with an estimated prevalence between 0.04 to 0.5%(1). AVWS has been related in various pathophysiological conditions including cardiovascular diseases such as aortic stenosis, autoimmune and lymphoproliferative disorders. To our knowledge, the prevalence of AVWS in lymphoproliferative disorders has never been investigated.
Methods. We conducted an observational monocentric prospective study in Caen university hospital to evaluate the incidence of AVWS in B cell chronic lymphoproliferative disorders (B-CLPD) and characterize its phenotype. Inclusion criteria were the presence of a BCLPD in patients with no personal or family history of bleeding. Every enrolled patients was tested for Biological parameters were measured including closure time, von Willebrand Antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and factor VIII procoagulant activity (FVIII:C). The bleeding phenotype was evaluated using Tossetto bleeding score(2). AVWS was suspected when patients presented a decrease of VWF:Ag and VWF:RCo and/or a VWF:RCo/VWF:Ag below 0.7.
Results. A total of 147 patients were included with the following diagnosis: fifty five patients (37%) with chronic lymphocytic leukemia, 48 patients (33%) with monoclonal gammopathies of undetermined significance (MGUS), 22 patients (15 %) with non hodgkin B cell lymphoma, 9 patients (6 %) with multiple myeloma, 4 patients (3 %) with Waldenstrom macroglobulinemia and 9 patients with other B-CLPD. Closure times, with epinephrine and ADP, were prolonged for six patients (6/147, 4.1%) with median levels of VWF:Ag, VWF:RCo, FVIII:C and VWF:RCo/VWF:Ag ratio at 29.5 IU/dL [9-284], 11.4 IU/dL [1-140] , 42.5 [6-204] and 0.3 [0.04-0.84], respectively. Five of these 6 patients had MGUS and 1 patient presented a follicular lymphoma. Serum protein electrophoresis revealed a monoclonal component in 5 patients with a median concentration at 8.45 g/L [4.4-9.1]. Four out of these 6 patients presented mucocutaneous bleedings including menorragia, ecchymoses, epistaxis, gingival bleedings, post-operative bleedings and gastro intestinal bleedings. The median bleeding score of these six patients was 4.5 [-1 – 12]. In four patients, the biological phenotype was a type 2 von Willebrand disease, with decreased VWF:RCo/VWF:Ag ratio (<0.7), loss of high and intermediate molecular weight multimers and a decrease of von Willebrand binding to collagen (VWF:CB) (VWF:CB/VWF:Ag<0.6). Anti-von Willebrand factor inhibitor screening was negative for the six patients. Four of these 6 patients presented an accelerated clearance of VWF with increased von willebrand factor propeptide/VWF:Ag ratios.
Different proposed cutoffs with their prospective sensitivity, specificity, and likelihood ratios (LR).
| Cutoff > | Sensitivity % | 95% CI | Specificity % | 95% CI | LR + | LR - |
|---|---|---|---|---|---|---|
| 503.50 | 100.00 | 66.37% to 100.0% | 0.30 | 0.007557% to 1.652% | 1.00 | 0.00 |
| 2514.00 | 88.89 | 51.75% to 99.72% | 75.22 | 70.24% to 79.76% | 3.59 | 0.15 |
| 5020.00 | 77.78 | 39.99% to 97.19% | 85.67 | 81.46% to 89.24% | 5.43 | 0.26 |
| Cutoff > | Sensitivity % | 95% CI | Specificity % | 95% CI | LR + | LR - |
|---|---|---|---|---|---|---|
| 503.50 | 100.00 | 66.37% to 100.0% | 0.30 | 0.007557% to 1.652% | 1.00 | 0.00 |
| 2514.00 | 88.89 | 51.75% to 99.72% | 75.22 | 70.24% to 79.76% | 3.59 | 0.15 |
| 5020.00 | 77.78 | 39.99% to 97.19% | 85.67 | 81.46% to 89.24% | 5.43 | 0.26 |
Conclusion: In this original prospective study, we observed AVWS for 4.1% of patients with B-CLPD. Monoclonal gammopathies of undetermined significance (MGUS) were associated with AVWS in 5 of 6 patients with AVWS. For patients with type 2 phenotypes, an increased clearance of VWF was the main mechanism of AVWS. The annual follow-up of these patients will give informations regarding the time of appearance and clinical informations for AVWS.
Tiede A et al. Blood 2011.
Tosetto A et al. Blood Rev 2007.
No relevant conflicts of interest to declare.
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