Desmopressin in Mild Hemophilia A: Indications, Limitations, Efficacy, and Safety

ABSTRACT

Replacement therapy with blood products has long been the only available therapeutic option for patients with bleeding disorders. Plasma-derived cryoprecipitate and factor (F) VIII concentrates, which have been used for hemophilia A patients, involve the risk of transmitting blood-borne diseases. Both plasma-derived and recombinant FVIII concentrates are expensive, and there is a global shortage. The synthetic vasopressin analogue desmopressin acetate (1-deamino-[8-D-arginine]-vasopressin, DDAVP) increases plasma concentrations of coagulation FVIII and von Willebrand factor (vWF) two fold to six fold through endogenous release. The drug is an attractive therapeutic alternative because it carries no risk of transmission of infectious diseases. Desmopressin is today a widely used hemostatic agent not only in patients with mild hemophilia A or von Willebrand disease (vWD) but also in those with congenital or acquired platelet dysfunction. There is a long clinical experience with the drug because it has been used for prevention of bleedings in connection with invasive procedures and for treatment of bleedings since the mid-1970s. Not all hemophilia A patients can be treated. The clinical usefulness depends on the postdesmopressin plasma concentration of FVIII, which in turn depends on the patient's basal FVIII level. Therefore, a test dose is recommended in candidate patients. In general, only the mildest hemophilia A patients respond sufficiently. Optimal hemostatic effect is achieved with a dosage of 0.3 μg/kg given intravenously. An intranasal desmopressin spray is suitable for the home treatment.

KEYWORD

Hemophilia A - von Willebrand disease - desmopressin - DDAVP - bleeding - factor VIII

REFERENCES

• 1 Cash J D, Gader A MA, Da Costa J. The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, AT III and OT in man.  Br J Haematol . 1974;  27 363-364
• 2 Mannucci P M, Åberg M, Nilsson I M, Robertsson B. Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs.  Br J Haematol . 1975;  30 81-93
• 3 Mannucci P M, Ruggeri Z M, Pareti F I, Capitanio A. 1-deamino-8-D-arginine vasopressin: a new pharmacological approach to the management of hemophilia and von Willebrand disease.  Lancet . 1977;  1 869-872
• 4 Warrier I, Lusher J M. DDAVP-a useful alternative to blood components in moderate hemophilia A and von Willebrand's disease.  J Pediatr . 1983;  102 228
• 5 Mariani G, Ciavarella N, Mazzucconi M G. et al . Evaluation of the effectiveness of DDAVP in surgery and bleeding episodes in hemophilia and von Willebrand disease. A study of 43 patients.  Clin Lab Haematol . 1984;  6 229-238
• 6 de la Fuente B, Kasper C K, Rickles F R, Hoyer L W. Response of patients with mild and moderate hemophilia A and von Willebrand disease to treatment with desmopressin.  Ann Intern Med . 1985;  103 6-14
• 7 Mannucci P M, Canciani M T, Rota L, Donovan B S. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects, and patients with hemophilia A and von Willebrand disease.  Br J Haematol . 1981;  47 283-293
• 8 Nilsson I M, Lethagen S. Current status of DDAVP formulations and their use. In: Lusher JM, Kessler CM, eds. Hemophilia and von Willebrand Disease in the 1990s Amsterdam: Elsevier Science Publishers B.V. 1991: 443-453
• 9 Mannucci P M, Vicente V, Alberca I. et al . Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses.  Thromb Haemost . 1987;  58 1037-1039
• 10 Ghirardini A, Mariani G, Iacopino G. et al . Concentrated DDAVP: further improvement in the management of mild factor VIII deficiencies.  Thromb Haemost . 1987;  58 896-898
• 11 Rose E H, Aledort L M. Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease.  Ann Intern Med . 1991;  114 563-568
• 12 Lethagen S, Harris A S, Sjörin E, Nilsson I M. Intranasal and intravenous administration of desmopressin: effect on f VIII/ VWF, pharmacokinetics and reproducibility.  Thromb Haemost . 1987;  58 1033-1036
• 13 Lethagen S, Egervall K, Berntorp E, Bengtsson B. The administration of desmopressin by nasal spray. A dose determining study in patients with mild haemophilia A and von Willebrand's disease.  Haemophilia . 1995;  1 97-102
• 14 Lethagen S, Ragnarson-Tenvall G. Self-treatment with desmopressin intranasal spray in patients with bleeding disorders. Effect on bleeding symptoms and socio-economic factors.  Ann Hematol . 1993;  66 257-260
• 15 Nilsson I M, Lethagen S. Current status of DDAVP formulations and their use. In: Lusher JM, Kessler CM, eds. Hemophilia and von Willebrand Disease in the 1990s Amsterdam: Elsevier Science Publishers B.V. 1991: 443-453
• 16 Mudad R, Kane W H. DDAVP in acquired hemophilia A: case report and review of the literature.  Am J Hematol . 1993;  43 295-299
• 17 Nilsson I M, Felding P, Timberg L, Jonsson S, Harris A S. Clinical experience with DDAVP. In: Ciavarella NL, Ruggeri Z, Zimmerman TS, eds. Factor VIII/von Willebrand Factor. Biological and Clinical Advances Proceedings of Bari Int Conference. Milano: Wichtig Editore 1986: 63-80
• 18 Lowe G, Pettigrew A, Middleton S, Forbes C D, Prentice C RM. DDAVP in hemophilia.  Lancet . 1977;  2 614-615
• 19 Theiss W, Schmidt G. DDAVP and von Willebrand disease: repeated administration and the behaviour of the bleeding time.  Thromb Res . 1978;  13 1119-1123
• 20 Mannucci P M, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP).  Br J Haematol . 1992;  82 87-93
• 21 Mannucci P M. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders.  Blood . 1988;  72 1449-1455
• 22 Koskimies O, Pylkkänen J, Vilska J. Water intoxication in infants caused by the urine concentration test with vasopressin analogue (DDAVP).  Acta Paediatr Scand . 1984;  73 131-132
• 23 Sheperd L L, Hutchinson R J, Worden E K, Koopman C F, Coran A. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis.  J Pediatr . 1989;  114 470-472
• 24 Weinstein R E, Bona R D, Altman A J. et al . Severe hyponatremia after repeated intravenous administration of desmopressin.  Am J Hematol . 1989;  32 258-261
• 25 Smith T J, Gill J C, Ambruso D R, Hathaway W E. Hyponatremia and seizures in young children given DDAVP.  Am J Hematol . 1989;  31 199-202
• 26 Salvatoni A, Maghnie M, Lorini R, Marni E. Hyponatremia and seizures during desmopressin acetate treatment in hypothyroidism.  J Pediatr . 1990;  116 835-836
• 27 Binch L JC, Jacobsen M B. Hyponatremi ved behandling av von Willebrands sykdom.  Tidsskr Nor Laegeforen . 1992;  112 3670-3671
• 28 Beach P S, Beach R E, Smith L R. Hyponatremic seizures in a child treated with desmopressin to control enuresis. A rationale approach to fluid intake.  Clin Pediatr (Phila) . 1992;  31 566-569
• 29 Yaouyanc G, Jonville A P, Yaouyanc-Lapalle H. et al . Seizure with hyponatremia in a child prescribed desmopressin for nocturnal enuresis.  J Toxicol Clin Toxicol . 1992;  30 637-641
• 30 Humphries K E, Siragy H. Significant hyponatremia following DDAVP administration in a healthy adult.  Am J Hematol . 1993;  44 12-15
• 31 Lethagen S, Frick K, Sterner G. Antidiuretic effect of desmopressin given in hemostatic dosage to healthy volunteers.  Am J Hematol . 1998;  57 153-159
• 32 O'Brien J R, Green P J, Salmon G. et al . Desmopressin and myocardial infarction (Letter).  Lancet . 1989;  664
• 33 van Dantzig M J, Duren D R, ten Cate W J. Desmopressin and myocardial infarction (Letter).  Lancet . 1989;  664
• 34 Bond L, Bevan D U. Myocardial infarction in a patient with hemophilia treated with DDAVP (Letter).  N Engl J Med . 1988;  318 121
• 35 Mannucci P M, Lusher J M. Desmopressin and thrombosis.  Lancet . 1989;  ii 675-676
• 36 Mannucci P M, Carlsson S, Harris A S. Desmopressin, surgery and thrombosis.  Thromb Haemost . 1994;  71 154-155