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DOI: 10.1160/TH10-11-0697
Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance
Publikationsverlauf
Received:
04. November 2010
Accepted after minor revision:
24. Januar 2010
Publikationsdatum:
28. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201104/lookinside/thumbnails/10-1160-th10-11-0697-1.jpg)
Summary
Accelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16–9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01–9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role.
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References
- 1 Castaman G, Tosetto A, Rodeghiero F. von Willebrand disease. In: Practical Hemostasis and Thrombosis. (2nd edition) Blackwell; 2009. pp. 73-87.
- 2 Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood 2009; 114: 1158-1165.
- 3 Tosetto A, Rodeghiero F, Castaman G. et al. A quantitative analysys of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4: 766-773.
- 4 Federici AB, Mannucci PM, Castaman G. et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113: 526-534.
- 5 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007; 109: 112-121.
- 6 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109: 145-154.
- 7 Rodeghiero F, Castaman G, Tosetto A. Optimizing treatment of von Willebrand disease by using phenotypic and molecular data. Hematology Am Soc Hematol Educ Program 2009; 113-123.
- 8 Silwer J. von Willebrand‘s disease in Sweden. Acta Paediatr. Scand Suppl 1973; 238: 1-159.
- 9 Federici AB. Clinical diagnosis of von Willebrand disease. Haemophilia 2004; 10 (Suppl. 04) 169-176.
- 10 Lak M, Peyvandi F, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Wille-brand disease. Br J Haematol 2000; 111: 1236-1239.
- 11 Castaman G, Tosetto A, Rodeghiero F. Reduced von Willebrand factor survival in von Willebrand disease: pathophysiologic and clinical relevance. J Thomb Haemost 2009; 7 (Suppl. 01) 71-74.
- 12 Brown SA, Eldridge A, Collins PW. et al. Increased clearance of von Willebrand factor antigen post-DDAVP in Type 1 von Willebrand disease: is it a potential pathogenic process?. J Thromb Haemost 2003; 1: 1714-1717.
- 13 Millar CM, Riddell AF, Brown SA. et al. Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations. Thromb Haemost 2008; 99: 916-924.
- 14 Haberichter SL, Balistreri M, Christopherson P. et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108: 3344-3351.
- 15 Castaman G, Lethagen S, Federici AB. et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111: 3531-3539.
- 16 Castaman G, Giacomelli SH, Jacobi P. et al. Homozygous type 2 N R854W von Willebrand factor is poorly secreted and causes a severe von Willebrand disease phenotype. J Thromb Haemost 2010; 8: 2011-2016.
- 17 von Willebrand EA. Hereditar pseudohemophili. Finska Lakaresallskaptes Hand-lingar 1926; 672: 7-112.
- 18 Schneppenheim R, Federici AB, Budde U. et al. Von Willebrand disease type 2 M “Vicenza” in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families. Thromb Haemost 2000; 83: 136-140.
- 19 Mannucci PM, Lombardi R, Castaman G. et al. von Willebrand disease “Vicenza” with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 1988; 71: 65-70.
- 20 Casonato A, Pontara E, Sartorello F. et al. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99: 180-184.
- 21 Castaman G, Missiaglia E, Federici AB. et al. An additional unique candidate mutation (G2470A; M740I) in the original families with von Willebrand disease type 2 M Vicenza and the G3864A (R1205H) mutation. Thromb Haemost 2000; 84: 350-351.
- 22 Jacobi PM, Gill JC, Friedman KD. et al. Intersection of Mechanisms of Type 2A Von Willebrand Disease through Defects in Von Willebrand Factor Multimerization, Secretion, ADAMTS-13 Susceptibility, and Regulated Storage. ASH Annual Meeting Abstracts. Blood 2008; 112: 588.
- 23 Lester WA, Guilliat AM, Surdhar GK. et al. Inherited and de novo von Willebrand disease Vicenza in UK families with the R1205H mutation: diagnostic pitfalls and new insights. Br J Haematol 2006; 135: 91-96.
- 24 Castaman G, Eikenboom JCJ, Missiaglia E. et al. Autosomal dominant type 1 von Willebrand disease due to G3639T mutation (C1130F) in exon 26 of von Wille-brand factor gene: description of five Italian families and evidence for a founder effect. Br J Haematol 2000; 108: 876-879.
- 25 Budde U, Schneppenheim R, Eikenboom J. et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost 2008; 6: 762-771.
- 26 Haberichter SL, Castaman G, Budde U. et al. Identification of type 1 von Wille-brand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111: 4979-4985.
- 27 Rodeghiero F, Castaman G, Tosetto A. et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multi-center study. J Thromb Haemost 2005; 3: 2619-2626.
- 28 Castaman G, Rodeghiero F, Mannucci PM. The elusive pathogenesis of von Wille-brand disease Vicenza. Blood 2002; 99: 4243-4244.
- 29 Schooten CJ, Tjernberg P, Westein E. et al. Cysteine-mutations in von Willebrand factor associated with increased clearance. J Thromb Haemost 2005; 3: 2228-2237.
- 30 Kadir RA, Lee CA, Sabin CA. et al. Pregnancy in women with von Willebrand‘s disease or factor XI deficiency. Br J Obstet Gynaecol 1998; 105: 314-321.
- 31 Castaman G, Federici AB, Bernardi M. et al. Factor VIII and von Willebrand factor changes after desmopressin and during pregnancy in type 2M von Willebrand disease Vicenza: a prospective study comparing patients with single (R1205H) and double (R1205H-M740I) defect. J Thromb Haemost 2006; 4: 357-360.
- 32 Castaman G, Eikenboom JCJ, Contri A. et al. Pregnancy in women with type 1 von Willebrand disease caused by heterozygosity for von Willebrand factor mutation C1130F. Thromb Haemost 2000; 84: 351-352.
- 33 Castaman G, Tosetto A, Rodeghiero F. Pregnancy and delivery in women with von Willebrand disease and different von Willebrand factor mutations. Haematologica 2009; 95: 963-969.
- 34 Mannucci PM, Bettega D, Cattaneo M. Consistency of responses to repeated DDAVP infusions in patients with von Willebrand disease and haemophilia A. Br J Haematol 1992; 82: 87-93.