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2174 Part XII: Hemostasis and Thrombosis Chapter 126: von Willebrand Disease 2175

Management of AVWS is generally aimed at treating the underly- influence of other factors in the magnitude of DDAVP effect. For
339
ing disorder. VWF levels and bleeding symptoms often improve with patients requiring repeated infusions of DDAVP, the FVIII activity and
successful treatment of hypothyroidism or an associated malignancy. VWF responses may not be of the same magnitude as after the first
Refractory patients have been treated with glucocorticoids, plasma infusion. Although this decay in response has considerable individual
exchange, intravenous gamma globulin, rituximab, DDAVP, and VWF- variability, after one infusion of DDAVP per day for 4 days it was found
containing FVIII concentrates. 317,329 that the responses on days 2 to 4 were reduced approximately 30 percent
compared to day 1. 336–338,340
Therefore, in patients for whom DDAVP is potentially the treat-
THERAPY, COURSE, AND PROGNOSIS ment of choice, a test dose should be given at the planned therapeutic
The mainstays of therapy for VWD are DDAVP, which induces secre- dose and route in advance of the first required course of treatment with
tion of both VWF and FVIII (reviewed in Ref. 330), and replacement measurements of before and after VWF and FVIII:C levels to ensure
therapy with VWF-containing plasma concentrates. The choice of treat- an adequate therapeutic response. Sampling additional time points
ment in any given patient depends upon the type and severity of VWD, after DDAVP infusion should be considered as some type 1 and type 2
the clinical setting, and the type of hemostatic challenge that must be VWD patients have a significantly shortened VWF half-life and it may
met. Type 1 patients are most often treated with DDAVP alone, types be more appropriate to treat with VWF replacement therapy in clini-
2A and 2B with a combination of DDAVP and a VWF-containing FVIII cal scenarios requiring more durable therapy to maintain hemostasis.
product, and type 2N and type 3 patients with VWF-containing con- For patients with type 1 VWD who are undergoing surgical procedures,
centrates. A previous history of trauma or surgery and the success DDAVP can be administered 1 hour before surgery and approximately
150
of previous treatment are important parameters to include in assessing every 12 hours thereafter for up to two to four doses before loss of clin-
the risk of bleeding. Prophylaxis is used in anticipation of hemostatic ically significant response. Patients should be monitored for response
challenges, such as dental extractions, and is efficacious in preventing of FVIII and ristocetin cofactor activity and side effects, particularly
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331
recurrent bleeding in severe VWD patients. Although in general there hyponatremia (and then should be water restricted), when DDAVP is
is a correlation between normal hemostasis and correction of VWF and administered at frequent intervals. VWF-containing FVIII concentrates
FVIII activity, this does not occur in all cases. should be available for infusion as backup.
Approximately 20 to 25 percent of patients with VWD do not
respond adequately to DDAVP. Type 2 VWD patients are less likely to
DESMOPRESSIN have a response than type 1 patients, 341,335 and virtually no patients with
DDAVP is an analogue of antidiuretic hormone that acts through type type 3 VWD respond. The response to DDAVP of patients with type
2 vasopressin receptors to induce secretion of FVIII and VWF, likely via 2A VWD is variable. Although most patients respond only transiently,
cyclic adenosine monophosphate–mediated secretion from the Weibel- some patients exhibit complete hemostatic correction after DDAVP
Palade bodies in endothelial cells. When DDAVP is administered to infusion. 342,343 It has been hypothesized that the differences in DDAVP
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healthy subjects, it causes sustained increases of FVIII and ristocetin efficacy among type 2A patients may correspond to the type of muta-
cofactor activity for approximately 4 hours. Patients with type 1 VWD tion, with better responses predicted in patients with group 2 mutations.
332
treated with DDAVP release unusually high-molecular-weight VWF A prospective study of the biologic response to DDAVP in well-charac-
multimers into the circulation for 1 to 3 hours after the infusion. 332,333 terized VWD patients included type 2A VWD patients with both group
Therapy with DDAVP often increases the FVIII activity, VWF:Ag, and 1 and group 2 defects. Although patients with group 2 mutations had
ristocetin cofactor activity to two to five times the basal level. greater improvements in VWF:RCo and shortening of bleeding times
DDAVP has become a mainstay for the treatment of mild hemo- than patients with group 1 defects, neither groups could be classified as
philia and VWD because it is relatively inexpensive, widely avail- responders. 341
334
able, and avoids the risks of plasma-derived products. Approximately Common side effects of DDAVP administration are mild cutane-
80 percent of type 1 VWD patients have excellent responses to DDAVP, ous vasodilation resulting in a feeling of heat, facial flushing, tachycar-
although this figure may be substantially lower depending on the cri- dia, tingling, and headaches. The potential for dilutional hyponatremia,
teria for diagnosis and response. It is regularly used in the setting of especially in elderly and very young patients and with repeat dosing,
335
mild to moderate bleeding and for prophylaxis of patients undergoing requires appropriate attention to fluid restriction, as it may result in
surgical procedures. DDAVP is administered at a dose of 0.3mcg/kg seizures. There have been isolated reports of acute arterial thrombo-
continuous intravenous infusion over 30 minutes. DDAVP is also avail- sis associated with administration of DDAVP, but the risk appears to
able for subcutaneous injection (at the same 0.3mcg/kg dose) and in be very low when judged against the total number of patients treated.
intranasal form (at a fixed dose of 300mcg for adults and 150mcg for DDAVP is contraindicated in patients with unstable coronary artery
children), which appears to be similar in efficacy to intravenous admin- disease because of increased risk of thrombotic events, such as myocar-
istration, 336,337 although the response may be more variable. dial infarction. Patients receiving DDAVP at closely spaced intervals
344
The response to DDAVP in any given individual with VWD is gen- of less than 24 to 48 hours can develop tachyphylaxis. 340
erally reproducible and predicts response to future doses as long as the Many experts consider DDAVP to be contraindicated in the treat-
follow doses are at least 2 to 4 days later. In one study, 22 type 1 VWD ment of type 2B VWD, as the high-molecular-weight VWF released
patients showed a departure of less than 20 percent from the mean FVIII from storage sites has an increased affinity for binding to GPIb and
peak level calculated from two separate infusions. In addition, the con- might be expected to induce spontaneous platelet aggregation and wors-
229
sistency of response in one patient reliably predicted the future response ening thrombocytopenia. However, there are reports of DDAVP used
of that patient and other affected family members. In a study of 77 successfully in type 2B VWD patients, with an associated shortening
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type 1 VWD patients, DDAVP response was associated both with VWF of bleeding times and variable thrombocytopenia. 345,346 Although type
mutation and baseline multimeric pattern, although subtle abnormali- 2N patients can exhibit increased FVIII:C levels after DDAVP, in some
ties in VWF multimers did not preclude a patient response to DDAVP. cases the FVIII:C levels rapidly decline, likely a result of the absence of
Interestingly, patients with the same VWF mutation did not necessar- stabilizing normal VWF, attenuating clinical efficacy. Type 2M patients
ily exhibit the same degree of responsiveness to DDAVP, implying the generally do not have a satisfactory response to DDAVP. 341,347

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