Page 2320 - Hematology_ Basic Principles and Practice ( PDFDrive )

2062 Part XII Hemostasis and Thrombosis

DDAVP, which promotes release of stored VWF and raises levels Dosing recommendations are provided either in VWF : RCo
3–10-fold. Peak effects are achieved 30 and 90 minutes after intra- (North America) or FVIII : C (Europe) units and are weight-based;
venous and intranasal delivery, respectively. The usual parenteral repeat infusions can be given every 8 to 24 hours, depending on the
dose is 0.3 µg/kg infused intravenously in approximately 50 mL of clinical situation. The goal is to maintain VWF : RCo and FVIII : C
normal saline over approximately 30 minutes. The dose of the highly at more than 100 IU/dL at peak and at more than 50 IU/dL at
concentrated intranasal preparation is 150 µg for children under trough until hemostasis is achieved. With VWF/FVIII concentrates,
50 kg and 300 µg for larger children and adults. It is important the FVIII : C response is higher and more sustained than predicted
to note that highly concentrated products (e.g., Stimate) deliver from the dose because of the stabilizing effect of exogenous VWF on
150 µg per spray, a much higher concentration than that used to treat endogenous FVIII. Details regarding dosing can be found in the
enuresis. product inserts. VWF : RCo and FVIII : C levels should be measured
After VWD diagnosis, a DDAVP challenge is advisable to assess in patients receiving repeat infusions, not only to ensure adequate
VWF response. VWF and FVIII levels should be determined before hemostasis but also to monitor for supraphysiological levels of FVIII
and at several points after DDAVP administration (e.g., at baseline because thromboembolic events have been associated with high FVIII
and at 1 and 4 hours). A threefold increase in VWF and FVIII levels levels. The overall incidence of thrombotic events is very low, and
to at least 0.30 IU/mL (30%) is usually considered adequate for situ- most cases occurred in surgical patients with other risk factors.
ations such as dental procedures, minor surgery, or the treatment of Therefore mechanical and anticoagulant thromboprophylaxis should
epistaxis or menorrhagia. be considered on a case-by-case basis. Adverse reactions to VWF/
DDAVP is safe and generally well tolerated. Common side effects FVIII concentrates are rare but include allergic and anaphylactic
include facial flushing and headache. Tachycardia, lightheadedness, symptoms, such as urticaria, chest tightness, rash, pruritus, and
and mild hypotension can occur. The most serious side effects are edema.
severe hyponatremia and seizures. Reduction of fluid intake for 24 VWF : FVIII concentrates are effective in over 97% of events. In
hours after DDAVP administration is an important precaution to the rare event that infusion of a VWF/FVIII concentrate is ineffective
prevent water intoxication. Serum sodium levels should be monitored at stopping bleeding, transfusion of platelet concentrates may be
in patients receiving repeated doses of DDAVP. In addition, DDAVP beneficial, presumably because they facilitate the delivery of small
should be used with caution in those younger than 2 years of age amounts of platelet VWF to the site of vascular injury.
because of a higher risk for hyponatremia. There are case reports of A new recombinant VWF (rvWF) concentrate, which is admin-
DDAVP precipitating coronary artery vasospasm and acute myocar- istered with recombinant FVIII in a 1.3 RCo : FVIII ratio, has
dial infarction. Therefore DDAVP should be used with caution in recently been studied in a prospective phase 1 randomized clinical
patients with a history of coronary artery disease or in the older adult. trial. The trial demonstrated safety, tolerability, and a pharmacoki-
In persons who are intolerant to DDAVP or have a poor VWF netic profile comparable to that with plasma-derived VWF concen-
response, clotting factor concentrate is required. trates. Larger clinical studies are needed and are ongoing, but rvWF
An important limitation in the use of DDAVP is the development represents an important advance in the treatment options for VWD.
of tachyphylaxis with repeated administration. When given repeat-
edly at intervals of less than 24 hours, the magnitude of the VWF
and FVIII increments can fall to approximately 70% of those obtained Prophylaxis
with the initial dose. For practical purposes, a single dose of DDAVP
before dental extractions or minor procedures is usually sufficient. Short-term prophylaxis with a combination of an antifibrinolytic,
Although repeated doses can be given at 12 or 24 hours, the potential DDAVP, and/or VWF/FVIII concentrates, in anticipation of a
for tachyphylaxis must be considered. Additionally, in situations defined bleeding challenge, such as surgery, is the standard of care in
where repeat dosing is considered, more prolonged fluid restriction the treatment of VWD. The role of long-term continuous prophy-
is required. laxis, defined as primary if initiated before long-term sequelae have
Although most type 1 VWD patients respond adequately to developed (e.g., joint damage) or secondary if initiated after the
DDAVP, type 3 VWD patients typically do not respond to this drug, development of chronic changes, is less established in VWD than it
and the response in type 2 VWD patients is variable. Type 2A patients is in severe hemophilia. Individuals with severe cases of VWD, in
often exhibit an adequate response and may benefit from a DDAVP particular type 3 VWD and certain patients with severe type 1 or
trial. Type 2M patients typically do not respond well to DDAVP. type 2 VWD, may experience recurrent joint bleeds, as well as severe
DDAVP is generally contraindicated in type 2B VWD because of the and frequently recurrent nasal/oral, GI, or menstrual bleeding. The
transient thrombocytopenia that accompanies the release of mutant resultant anemia, hospitalizations, and absences from school or work
VWF. In type 2N VWD, DDAVP produces a two-fold to ninefold may have a significant impact on quality of life. Although there is
increase in FVIII, but the increase persists for approximately 3 hours. limited evidence, several cohort and case studies suggest that both
Therefore DDAVP should be reserved for situations in which a primary and secondary long-term prophylaxis improve quality of life,
transient rise in FVIII is sufficient. alleviate anemia, reduce hospitalizations, and prevent chronic joint
disease. Complications are unusual aside from rare cases of VWF
inhibitor formation (approximately 3%). Controversy exists about
von Willebrand Factor/Factor VIII Concentrates the specific indications, schedules, and dosing of prophylactic regi-
mens. This is the subject of an ongoing international trial, known as
VWF/FVIII concentrates are required for patients who do not have the VWD International Prophylaxis trial, which began recruitment
an adequate response, experience side effects, or have contraindica- of patients in 2007.
tions to DDAVP. Because of tachyphylaxis and the risk of hypona-
tremia with DDAVP, patients with severe bleeding or those requiring
major or repeated surgery often need VWF replacement therapy. Pediatric Issues
Purified, viral-inactivated, plasma-derived VWF/FVIII is the product
most frequently used (e.g., Humate-P, Wilate). The quantity of ris- Prenatal diagnosis for pregnancies at increased risk (generally only for
tocetin cofactor activity (VWF : RCo) relative to FVIII : C varies by type 3 VWD) is possible by analysis of DNA extracted from fetal
product; Humate-P contains 2.4 VWF : RCo units for each 1 FVIII : C cells obtained by chorionic villus sampling at 11–13 weeks of gesta-
unit, whereas Wilate contains a 1 : 1 ratio. Both products contain a tion or amniocentesis at 15–18 weeks of gestation. The disease-
full spectrum of VWF multimers, including HMW multimers, and causing allele(s) of an affected family member must be identified
closely resemble normal plasma. Highly purified FVIII concentrates before prenatal testing. Preimplantation genetic diagnosis may be
(monoclonal antibody purified and recombinant) should not be used available for families in which the disease-causing mutation(s) have
to treat VWD because they lack VWF. been identified.