Clinical Review

Von Willebrand Disease: Approach to Diagnosis and Management



DDAVP, a synthetic derivative of vasopressin, promotes release of stored VWF from endothelial cells. Most individuals with type 1 VWD and some with type 2A VWD respond to treatment with DDAVP: a therapeutic trial to confirm adequate DDAVP response should be performed prior to its clinical use. Assessment of VWF:Ag, VWF:RCo, and FVIII levels should be performed before and at several time points after the DDAVP administration up to and including 4 hours. Peak VWF levels are achieved 30 and 90 minutes after intravenous and intranasal delivery, respectively. An increase in VWF:Ag/VWF:RCo and FVIII levels to at least 30 IU/dL is adequate for most dental procedures, minor surgery, or the treatment of epistaxis or menorrhagia. DDAVP may be adequate to treat major bleeds or for major surgery when VWF levels increase well above 50 IU/dL. Decisions surrounding the use of DDAVP versus a VWF/FVIII concentrate will depend on the expected DDAVP response, the type of surgery, and the anticipated duration of therapy required to achieve hemostasis. If treatment is required for more than 3 days, concerns regarding tachyphylaxis and side effects may limit its use. Significantly decreased VWF:Ag/VWF:RCo or FVIII at the 4-hour time point of a DDAVP trial may indicate type 1C or type 2N VWD, which are associated with increased clearance of endogenous VWF or FVIII, respectively. Despite the transient response in these patients, DDAVP remains a therapeutic option and its use should be assessed on a case-by-case basis.47

The parenteral dose of DDAVP is 0.3 μg/kg infused in 30 to 50 mL of normal saline over approximately 30 minutes every 12 to 24 hours. The dose of the highly concentrated intranasal preparation is 150 μg for children under 50 kg and 300 μg for larger children and adults (1 spray per naris). It is important to note that the products used to treat VWD (eg, Stimate) deliver 150 μg per spray, a much higher concentration than that used to treat enuresis. Repeated DDAVP dosing is associated with the development of tachyphylaxis: with subsequent dosing, the magnitude of the VWF and FVIII increments can fall to approximately 70% of that obtained with the initial dose.48 DDAVP is safe and generally well tolerated. Side effects include facial flushing, headache, tachycardia, light-headedness, and mild hypotension. The most serious side effects, severe hyponatremia and seizures,49 can be avoided by fluid restriction for 24 hours after DDAVP administration. Serum sodium levels should be monitored with repeated doses. DDAVP is generally avoided in those younger than 2 years of age because of a higher risk of hyponatremia. Patients who are intolerant of DDAVP or have a poor VWF response need to be treated with a VWF/FVIII concentrate.

VWF/FVIII Concentrate

VWF/FVIII concentrates are required for patients who do not have an adequate response to DDAVP, who have side effects from or contraindications to DDAVP, or who require a long duration of treatment, rendering the use of DDAVP impractical. Purified, viral-inactivated, plasma-derived VWF/FVIII concentrates are the products most frequently used (eg, Humate-P, Wilate, Alphanate SD/HT). The quantity of VWF:RCo activity relative to FVIII:C varies by product; Humate-P contains 2.4 VWF:RCo units for each unit of FVIII:C; Wilate contains a 1:1 ratio; and Alphanate contains a 0.5:1 ratio. Both Humate-P and Wilate are reported to contain a full spectrum of VWF multimers, including HMW multimers, and closely resemble normal plasma, but Alphanate SD/HT lacks HMW mutimers.11,50 Thus, the available VWF/FVIII vary in terms of VWF:RCo to FVIII concentrate, HMW multimer composition, reported VWF:RCo, and FVIII half-lives and even approved indications. They should not be considered interchangeable, and further information should be sought from the respective product inserts.

Dosing recommendations are provided either in VWF:RCo (North America) or FVIII:C units (Europe) and are weight-based (Table 4); repeat infusions can be given every 8 to 24 hours depending on the type of surgery/injury and the product used.

For surgeries, the goal is to maintain VWF:RCo and FVIII:C greater than 100 IU/dL at peak and greater than 50 IU/dL at trough until hemostasis is achieved during the acute bleed or at the time of surgical intervention. The duration of factor replacement is 5 to 10 days for major surgeries and 1 to 4 days for minor surgeries. With VWF/FVIII concentrates, the FVIII:C response is higher and more sustained than predicted from the dose because of the stabilizing effect of exogenous VWF on endogenous FVIII.51 VWF:RCo and FVIII:C levels should be measured in patients receiving repeat infusions to ensure appropriate hemostatic levels and to avoid supratherapeutic levels because thromboembolic events have been associated with high FVIII levels. Thromboembolic events are rare, and most cases have been described in surgical patients with other risk factors.52 Adverse reactions to VWF/FVIII concentrates are rare but include allergic and anaphylactic symptoms.53 A rare complication is the development of alloantibodies to VWF, which occurs in 5% to 10% of type 3 patients and manifests as a loss of hemostatic response to infused concentrates or anaphylactic reactions.22


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