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Current Management of von Willebrand’s Disease

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Summary

von Willebrand’s disease (vWD) is the most frequent inherited bleeding disorder and is the result of a deficiency and/or abnormality of von Willebrand factor (vWF). As a consequence, the level of factor VIII, the presence of which reflects the ability of vWF to stabilise it, is usually low. Bleeding time, which reflects the ability of vWF to promote platelet adhesion to subendothelium, is therefore prolonged. However, from a therapeutic point of view, it appears that the correction of factor VIII and bleeding time is sufficient to prevent or treat bleeding in these patients.

There are 2 main therapeutic tools to improve or normalise these major determinants of the bleeding tendency in this disorder. The majority of patients, identified by a test infusion, can be successfully treated by giving desmopressin (DDAVP), a synthetic analogue of vasopressin. Desmopressin is able to induce the increase of autologous vWF released from endothelial cells, leading to the correction of factor VIII levels and of bleeding time. In the remaining cases, blood products, namely factor VIII/vWF concentrates, are required to accomplish haemostasis. All these concentrates are able to correct factor VIII levels, whereas their effect on bleeding time may not be consistent. The modern virucidal techniques virtually abolish the risk of transmission of blood-borne viruses (e.g. hepatitis viruses and HIV) and make these products safer than blood-bank cryo-precipitate.

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References

  1. Ruggeri ZM, Ware J. Von Willebrand factor. FASEB J 1993; 7: 308–16

    PubMed  CAS  Google Scholar 

  2. Mancuso DJ, Tuley EA, Westfield LA, et al. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253–69

    Article  PubMed  CAS  Google Scholar 

  3. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6: 217–46

    Article  PubMed  CAS  Google Scholar 

  4. Zimmerman TS, Ratnoff OD, Powell AE. Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Willebrand disease. J Clin Invest 1971; 50: 244–54

    Article  PubMed  CAS  Google Scholar 

  5. Marder VJ, Mannucci PM, Firkin BG, et al. Standard nomenclature for factor VIII and von Willebrand factor: a recommendation by the International Committee on Thrombosis and Haemostasis. Thromb Haemostas 1985; 54: 871–2

    CAS  Google Scholar 

  6. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454–9

    PubMed  CAS  Google Scholar 

  7. Werner EJ, Broxson EH, Tucker EL, et al. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123: 893–8

    Article  PubMed  CAS  Google Scholar 

  8. Miller CH, Graham JB, Goldin LR, et al. Genetics of classic von Willebrand’s disease: I. Phenotypic variation within families. Blood 1979; 54: 117–36

    PubMed  CAS  Google Scholar 

  9. Silwer J. von Willebrand’s disease in Sweden. Acta Paediatr Scand 1973; 238 Suppl.: 1–159

    CAS  Google Scholar 

  10. Conti M, Mari D, Conti E, et al. Pregnancy in women with different types of von Willebrand disease. Obstet Gynecol 1986; 68: 282–5

    PubMed  CAS  Google Scholar 

  11. Abildgaard CF, Suzuki Z, Harrison J, et al. Serial studies in von Willebrand’s disease: variability versus ‘variant’. Blood 1980; 56: 712–6

    PubMed  CAS  Google Scholar 

  12. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691–5

    PubMed  CAS  Google Scholar 

  13. Rodeghiero F, Castaman G, Tosetto A. von Willebrand factor antigen is less sensitive than ristocetin cofactor for the diagnosis of type I von Willebrand disease — results based on an epidemiological investigation. Thromb Haemostas 1990; 64: 349–52

    CAS  Google Scholar 

  14. Mazurier C. von Willebrand disease masquerading as hemophilia A. Thromb Haemostas 1992; 67: 391–6

    CAS  Google Scholar 

  15. Ruggeri ZM, Pared FI, Mannucci PM, et al. Heightened interaction between platelets and factor Vlll/von Willebrand factor in a new subtype of von Willebrand’s disease. N Engl J Med 1980; 302: 1047–51

    Article  PubMed  CAS  Google Scholar 

  16. Holmberg L, Nilsson IM, Borge L, et al. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II von Willebrand’s disease. N Engl J Med 1983; 309: 816–21

    Article  PubMed  CAS  Google Scholar 

  17. Weiss HJ, Meyer D, Rabinowitz R, et al. Pseudo-von Willebrand’s disease. An intrinsic platelet defect with aggregation by unmodified human factor Vlll/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med 1982; 306: 326–33

    Article  PubMed  CAS  Google Scholar 

  18. Miller JL, Castella A. Platelet-type von Willebrand’s disease: characterization of a new type of bleeding disorder. Blood 1982; 60: 790–4

    PubMed  CAS  Google Scholar 

  19. Miller JL, Kupinski JM, Castella A, et al. von Willebrand factor binds to platelets and induces aggregation in platelet-type but not type IIb von Willebrand disease. J Clin Invest 1983; 72: 1532–42

    Article  PubMed  CAS  Google Scholar 

  20. Takahashi H, Nagama R, Hattori A, et al. Platelet aggregation induced by DDAVP in platelet-type von Willebrand’s disease. N Engl J Med 1984; 310: 722–3

    PubMed  CAS  Google Scholar 

  21. Mannucci PM, Bloom AL, Larrieu MJ, et al. Atherosclerosis and von Willebrand factor: I. Prevalence of severe von Willebrand’s disease in western Europe and Israel. Br J Haematol 1984; 57: 163–9

    PubMed  CAS  Google Scholar 

  22. Sadler EJ. A revised classification of von Willebrand disease. Thromb Haemostas 1994; 71: 520–5

    CAS  Google Scholar 

  23. Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895–904

    PubMed  CAS  Google Scholar 

  24. Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand factor gene and pseudogene. Thromb Haemostas 1993; 69: 185–91

    CAS  Google Scholar 

  25. Peake IR, Bowen D, Bignell P, et al. Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene. Blood 1990; 76: 555–61

    PubMed  CAS  Google Scholar 

  26. Ploos van Amstel HK, Reitsma PH. Tetranucleotide repeat polymorphism in the vWF gene. Nucleic Acids Res 1990; 18: 4597

    Article  Google Scholar 

  27. Mercier Gaucher Mazurier Characterisation of 98 alleles in 105 unrelated individuals in the F8VWF gene. Nucleic Acids Res 1991; 19: 4800

    Google Scholar 

  28. Ginsburg D, Sadler JE. Von Willebrand disease: a database of point mutations, insertions, and deletions. Thromb Haemostas 1993; 69: 177–84

    CAS  Google Scholar 

  29. Lyons SE, Bruck ME, Bowie EJW, et al. Impaired cellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424–30

    PubMed  CAS  Google Scholar 

  30. Eikenboom JCJ, Reitsma PH, Peerlinck KMJ, et al. Recessive inheritance of von Willebrand’s disease type I. Lancet 1993; 341: 982–6

    Article  PubMed  CAS  Google Scholar 

  31. Mannucci PM, Cattaneo M. Alloantibodies in congenital von Willebrand’s disease. Res Clin Lab 1991; 21: 119–25

    Article  CAS  Google Scholar 

  32. Mannucci PM, Lattuada A, Castaman G, et al. Heterogeneous phenotypes of platelet and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand disease. Blood 1989; 74: 2433–6

    PubMed  CAS  Google Scholar 

  33. Eikenboom JCJ, Reitsma PH, Castaman G, et al. Dominant type 1 von Willebrand disease associated with mutated cysteine residues in the D3 domain of von Willebrand factor [abstract no. 1032]. Thromb Haemost 73; 1995: 1170

    Google Scholar 

  34. Castaman G, Eikenboom JCJ, Reitsma PH, et al. Genetic characterisation of type 3 and type 1 von Willebrand disease (vWD) patients in the Veneto region: founder effect and relationship with desmopressin responsiveness [abstract no. 1035]. Thromb Haemost 73; 1995: 1170

    Google Scholar 

  35. Rodeghiero F, Castaman G, Meyer D, et al. Replacement therapy with virus-inactivated plasma concentrates in von Willebrand disease. Vox Sang 1992; 62: 193–9

    Article  PubMed  CAS  Google Scholar 

  36. Rodeghiero F, Castaman G, Mannucci PM. Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease. Blood Rev 1991; 5: 155–61

    Article  PubMed  CAS  Google Scholar 

  37. Hashemi S, Palmer DS, Aye MT, et al. Platelet-activating factor secreted by DDAVP-treated monocytes mediates von Willebrand factor release from endothelial cells. J Cell Physiol 1993; 154: 496–505

    Article  PubMed  CAS  Google Scholar 

  38. Rodeghiero F, Castaman G, Di Bona E, et al. Hyper-responsiveness to DDAVP for patients with type I von Willebrand’s disease and normal intra-platelet von Willebrand factor. Eur J Haematol 1988; 40: 163–7

    Article  PubMed  CAS  Google Scholar 

  39. Mazurier Gaucher Jorieux S, et al. Biological effect of desmopressin in eight patients with type 2N (‘Normandy’) von Willebrand disease. Br J Haematol 1994; 88: 849–54

    Article  Google Scholar 

  40. Castaman G, Lattuada A, Mannucci PM, et al. Factor VIII: Cincreases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. Br J Haematol 1995; 89: 147–51

    Article  PubMed  CAS  Google Scholar 

  41. Mannucci PM, Lombardi R, Bader R, et al. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66: 796–802

    PubMed  CAS  Google Scholar 

  42. Gralnick HR, Williams SB, McKeown LP, et al. DDAVP in type IIa von Willebrand’s disease. Blood 1986; 67: 465–8

    PubMed  CAS  Google Scholar 

  43. Fowler WE, Berkowitz LR, Roberts HR. DDAVP for type II von Willebrand’s disease. Blood 1989; 74: 1859–60

    PubMed  CAS  Google Scholar 

  44. Connaghan DG, Gralnick HR. Beneficial response to desmopressin in type IIvon Willebrand’s disease [abstract]. Blood 1990; 76: 417

    Google Scholar 

  45. Casonato A, Fabris F, Girolami A. Platelet aggregation and pseudothrombocytopenia induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in type II von Willebrand’s disease. Eur J Haematol 1990; 45: 36–42

    Article  PubMed  CAS  Google Scholar 

  46. Mannucci PM, Ruggeri ZM, Pareti FI, et al. DDAVP in haemophilia. Lancet 1977; 2: 1171–2

    Article  PubMed  CAS  Google Scholar 

  47. Rodeghiero F, Castaman G, Di Bona E, et al. Consistency of responses to repeated DDAVP infusions in patients with von Willebrand’s disease and hemophilia A. Blood 1989; 74: 1997–2000

    PubMed  CAS  Google Scholar 

  48. Mannucci PM, Bettega D, Cattaneo M. The development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992; 82: 87–93

    Article  PubMed  CAS  Google Scholar 

  49. Rose EH, Aledort LM. Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 1991; 114: 563–8

    PubMed  CAS  Google Scholar 

  50. Kohler M, Mariani G. Intravenous and subcutaneous desmopressin: clinical results. In: Mariani G, Mannucci PM, Cattaneo M, editors. Desmopressin in bleeding disorders. New York: Plenum, 1993: 309–16

    Google Scholar 

  51. Smith TJ, Gill JC, Ambroso DR, et al. Hyponatremia and seizures in young children given DDAVP. Am J Hematol 1989; 31: 199–202

    Article  PubMed  CAS  Google Scholar 

  52. Weinstein RE, Bona RD, Altman AJ, et al. Severe hyponatremia after repeated intravenous administration of desmopressin. Am J Hematol 1989; 32: 258–61

    Article  PubMed  CAS  Google Scholar 

  53. Castaman G, Rodeghiero F, Lattuada A, et al. Desmopressininduced thrombocytopenia in type I platelet discordant von Willebrand disease. Am J Hematol 1993; 43: 5–9

    Article  PubMed  CAS  Google Scholar 

  54. Ludlam CA, Peake IR, Allen N, et al. Factor VIII and fibrinolytic response to deamino-8-D-arginine vasopressin in normal subjects and dissociate response in some patients with haemophilia and von Willebrand’s disease. Br J Haematol 1980; 45: 499–511

    Article  PubMed  CAS  Google Scholar 

  55. Castaman G, Ruggeri M, Di Bona E, et al. Management of spontaneous bleeding and prevention of bleeding after dental extractions and other surgical procedures in mild hemophilia A and von Willebrand’s disease: ten years of experience at the Vicenza Hemophilia and Thrombosis Center. In: Mariani G, Mannucci PM, Cattaneo M, editors. Desmopressin in bleeding disorders. New York: Plenum, 1993: 267–75

    Chapter  Google Scholar 

  56. Berry EW, Berry PR. DDAVP — clinical use and therapeutic limitations in patients with congenital bleeding disorders: the Auckland experience. In: Mariani G, Mannucci PM, Cattaneo M, editors. Desmopressin in bleeding disorders. New York: Plenum, 1993: 249–59

    Chapter  Google Scholar 

  57. Lethagen S, Ragnarson-Tenvall G. Self-treatment with desmopressin intranasal spray in patients with bleeding disorders. Effect on bleeding symptoms and socioeconomic factors. Ann Hematol 1993; 66: 257–60

    Article  PubMed  CAS  Google Scholar 

  58. Lethagen S, Harris AS, Sjorin E, et al. Intranasal and intravenous administration of desmopressin: effect on f VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemostas 1987; 58: 1033–6

    CAS  Google Scholar 

  59. Castaman G, Mannucci PM, Rodeghiero F. Subcutaneous concentrated desmopressin (Emosint) for the in-hospital and home-treatment of patients with von Willebrand disease (vWD) and mild or moderate hemophilia A (HA): preliminary results of a multicenter Italian study [abstract no. 1040]. Thromb Haemost 1995; 73: 1172

    Google Scholar 

  60. Bennet EA, Dormandy K. Pool’s cryoprecipitate and exhausted plasma in the treatment of von Willebrand’s disease and F XI deficiency. Lancet 1966; 2: 731–2

    Article  Google Scholar 

  61. Perkins HA. Correction of the hemostatic defects in von Willebrand’s disease. Blood 1967; 30: 375–80

    PubMed  CAS  Google Scholar 

  62. Mannucci PM, Moia M, Rebulla P, et al. Correction of the bleeding time in treated patients with severe von Willebrand disease is not solely dependent on the normal multimeric structure of plasma von Willebrand factor. Am J Hematol 1987; 25: 55–65

    Article  PubMed  CAS  Google Scholar 

  63. Mannucci PM, Lattuada A, Ruggeri ZM. Proteolysis of von Willebrand factor in therapeutic plasma concentrates. Blood 1994; 83: 3018–27

    Google Scholar 

  64. Burnouf-Radosevich M, Burnouf T. Chromatographic preparation of a therapeutic highly purified von Willebrand factor concentrate from human cryoprecipitate. Vox Sang 1992; 62: 1–11

    Article  PubMed  CAS  Google Scholar 

  65. Morfini M, Mannucci PM, Tenconi PM, et al. Pharmacokinetics of monoclonally-purified and recombinant factor VIII in patients with severe von Willebrand disease. Thromb Haemostas 1993; 70: 270–2

    CAS  Google Scholar 

  66. Nilsson IM, Blomback M, Jorpes E, et al. Von Willebrand’s disease and its correction with human plasma fraction I-O. Acta Med Scand 1957; 159: 180–8

    Google Scholar 

  67. Cornu P, Larrieu MJ, Caen J, et al. Transfusion studies in von Willebrand’s disease: Effect on bleeding time and factor VIII. Br J Haematol 1963; 9: 189–202

    Article  PubMed  CAS  Google Scholar 

  68. Mannucci PM, Tenconi PM, Castaman G, et al. Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial. Blood 1992; 79: 3130–7

    PubMed  CAS  Google Scholar 

  69. Meriane F, Zerhouni L, Djeha N, et al. Biological effects of a S/D-treated, very high purity, von Willebrand factor concentrate in five patients with severe von Willebrand disease. Blood Coag Fibrinol 1993; 4: 1023–9

    CAS  Google Scholar 

  70. Cattaneo M, Moia M, Delia Valle P, et al. DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor. Blood 1989; 74: 1972–6

    PubMed  CAS  Google Scholar 

  71. Castillo R, Monteagudo J, Escolar G, et al. Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients. Blood 1991; 77: 1901–5

    PubMed  CAS  Google Scholar 

  72. Mannucci PM, Ruggeri ZM, Ciavarella N, et al. Precipitating antibodies to factor VIII/von Willebrand factor in von Willebrand’s disease: effects on replacement therapy. Blood 1981; 57: 25–31

    PubMed  CAS  Google Scholar 

  73. Mannucci PM, Tamaro G, Nerchi G, et al. Life-threatening reaction to factor VIII concentrate in a patient with severe von Willebrand disease and alloantibodies to von Willebrand factor. Eur J Haematol 1987; 39: 467–70

    Article  PubMed  CAS  Google Scholar 

  74. Bloom AL, Peake IR, Furlong RA, et al. High potency factor VIII concentrate: more effective than cryoprecipitate in a patient with von Willebrand’s disease and inhibitor. Thromb Res 1979; 16: 847–52

    Article  PubMed  CAS  Google Scholar 

  75. Jakway JL. Acquired von Willebrand’s disease. Hematol Oncol Clin North Am 1992; 6: 1409–19

    PubMed  CAS  Google Scholar 

  76. Mannucci PM, Lombardi R, Bader R, et al. Studies of the pathophysiology of acquired von Willebrand’s disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood 1984; 64: 614–21

    PubMed  CAS  Google Scholar 

  77. Castaman G, Rodeghiero F, Di Bona E, et al. Clinical effectiveness of desmopressin in a case of acquired von Willebrand’s syndrome associated with benign monoclonal gammopathy. Blut 1989; 58: 211–4

    Article  PubMed  CAS  Google Scholar 

  78. Macik BG, Gabriel DA, White GC, et al. The use of high-dose intravenous gamma-globulin in acquired von Willebrand syndrome. Arch Pathol Lab Med 1988; 112: 143–6

    PubMed  CAS  Google Scholar 

  79. Delannoy A, Saillez AC. High-dose intravenous gammaglobulin for acquired von Willebrand’s disease. Br J Haematol 1988; 70: 387

    Article  PubMed  CAS  Google Scholar 

  80. Delmer A, Horellou MH, Brechot JM. Acquired von Willebrand disease: correction of hemostatic defect by high-dose intravenous immunoglobulins. Am J Hematol 1992, 40: 151–2

    Article  PubMed  CAS  Google Scholar 

  81. Castaman G, Tosetto A, Rodeghiero F. Effectiveness of highdose intravenous immunoglobulin in a case of acquired von Willebrand syndrome with chronic melena not responsive to desmopressin and factor VIII concentrate. Am J Hematol 1992; 41: 132–6

    Article  PubMed  CAS  Google Scholar 

  82. Uehlinger J, Rose E, Aledort LM, et al. Successful treatment of an acquired von Willebrand factor antibody by extracorporeal immunoadsorption. N Engl J Med 1989; 320: 254–5

    Article  PubMed  CAS  Google Scholar 

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Castaman, G., Rodeghiero, F. Current Management of von Willebrand’s Disease. Drugs 50, 602–614 (1995). https://doi.org/10.2165/00003495-199550040-00003

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