Desmopressin

Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of vasopressin, initially used for the treatment of diabetes insipidus. Desmopressin was designed to have prolonged duration without hemodynamic effects. In the mid-1970s it was first reported that desmopressin at high dosage stimulated the release of endogenous FVIII, VWF and tissue plasminogen activator (t-PA). The effect is immediate, with on average 2-6-fold increases in plasma concentrations of FVIII, VWF and t-PA. Optimal hemostatic effect is achieved with a dosage of 0.3 µg/kg given intravenously. A higher dose will not improve the response [1]. Subcutaneous or intranasal spray administrations are both effective and suitable for home treatment. The response to subcutaneous or intranasal administration is of comparable magnitude, but somewhat slower in onset than that of intravenous administration.

Dose and modes of administration

  • 0.3 µg/kg i.v. or s.c.

  • 300 µg i.n. (spray) (150 µg if BW<30/50 kg)

Intravenously (i.v.): slow injection of DDAVP (diluted in saline to 10 mL) during 15 minutes or infusion (diluted in 50 – 100 mL saline) during 30 minutes diluted in 50-100 mL saline. Peak FVIII/VWF levels are observed at 60 minutes.

Subcutaneously (s.c.): Peak FVIII/VWF levels are reached after about 120 minutes.

Octostim® solution (15 µg/mL) is the most suitable for s.c. administration, due to its high concentration. Often a single 15 µg dose s.c. will suffice in adults.

Intranasal (i.n.) spray: Peak FVIII/VWF levels are reached at 120 minutes.

One spray to each nostril will provide the normal adult dose of 300 µg. For patients with a body weight <30 kg, a dose of 150 µg is recommended (one spray in one nostril). In small children (body weight less than about 15 kg) the spray should not be used.

Contraindications

Hyponatremia, cystic fibrosis, poorly controlled hypertension, acute coronary syndrome, tendency for severe migraines/headache and severe renal disease. Smokers are at risk for thrombosis in association with DDAVP administration, and DDAVP is at least a relative contraindication. In children weighing below 15 kg body weight and in pregnancy, DDAVP is not recommended and should be used carefully.

Dosage intervals

Twelve to 24 hours is the ordinary dose interval. The risk of severe hyponatremia must be noted if repeated doses are given. The patient should be put on fluid restriction if repeated doses are given, the limitations of fluid intake is 1.5 liter per day of administration. Tachyphylaxis may develop after repeated dosing.

Treatment with desmopressin related to the nature of the bleeding episode

Major bleeds

Response criteria:

DDAVP can be used for treatment of bleeds in patients in whom the administration leads to normal or at least >50 IU/dl VWF:RCo and FVIII:C levels. The levels should increase at least 2-3 fold and remain at least above 50 IU/dL 4 hours post DDAVP (consensus opinion).  In connection with life threatening and other severe bleeds, a VWF/FVIII concentrate should be administered as the first line treatment. If the response to DDAVP is suboptimal or the duration is short, a VWF/FVIII concentrate should be administered.

Minor bleeds

Response criteria:

VWF:RCo and FVIII:C should reach a level of at least 30 IU/dL within 2 hours after DDAVP and last for over 4 hours.

Type of invasive procedure

All procedures – VWF and FVIII activities should reach normal levels within the first 2 hours and stay elevated ≥ 30 IU/dL for at least 12 hours post DDAVP.

If treatment ≥ 3 days is required, tachyphylaxis and antidiuretic effects may lower the efficacy. Sodium and factor levels should be monitored, and managed accordingly, with low VWF levels replacement therapy should be commenced.

Treatment varies with the procedure and more options at different procedures are given in appendix 2.

Desmopressin may still be useful in some instances of mild bleeding for type 2 VWD, mainly some 2M variants with confirmed responses in the DDAVP trial.

Limitations with desmopressin

  • Consider the subtype of VWD, duration of treatment and age of the patient.

  • Half-life is short in type 1C VWD, consider against treating with desmopressin in the absence of a desmopressin test (4 h).

  • Patients with classical type 2B VWD should not be given DDAVP due to subsequent platelet aggregation and thrombocytopenia. Patients with VWD type 3 are non-responders to DDAVP. Patients with type 1C VWD do not benefit from DDAVP in the setting of surgery

  • Half-life of FVIII:C may be short in 2N.

  • DDAVP should preferably not be given to small children (<15 kg body weight, elective testing 4 years), and adult patients with cardiovascular disease or comorbidities (e.g., history of angina pectoris, myocardial infarction, stroke, peripheral arterial occlusive disease, arrhythmias, and epilepsy).

  • If DDAVP is administered to young children, fluid administration must be restricted, and electrolytes monitored closely. Upon repeated dosing to patients of any age, fluid administration should be restricted.

  • Duration of treatment should normally not exceed 3 days. Treatment may be prolonged if factor levels and sodium are monitored, but tachyphylaxis has been reported after several doses of treatment with DDAVP.

  • Precaution in pregnancy due to possible side effects for both the pregnant women and the fetus/child.

Adverse effects with desmopressin

The adverse effects of DDAVP include tiredness, headache, nausea, decreased appetite, temporary lowering of blood pressure with secondary tachycardia, facial flushing, fluid retention, hyponatremia and seizures, which will limit its use.