Page 1999 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 117 Transfusion Therapy for Coagulation Factor Deficiencies 1773

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of centers and avoided in 11%. Complications such as infections 1-Deamino 8-D Arginine Vasopressin Trial
and thrombosis limit the life of a device and add to the morbidity of
the patient. From a metaanalysis of 48 studies, the incidence of 1. Collect citrated plasma from the patient immediately before
infection was 0.66 per 1000 catheter-days. A multivariate analysis of DDAVP infusion for testing with the postinfusion blood specimen.
these data showed that the presence of an inhibitor was associated 2. Administer DDAVP IV (0.3 µg/1 kg) in 25–50 mL normal saline.
with an increased risk of infection; additionally, they demonstrated 3. Wait approximately 30 minutes after the infusion, carefully
that the risk of infection with a fully implantable device was one-third observing the patient for possible adverse side effects
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that of an external device. In one prospective study of catheter- (increased blood pressure, facial flushing, signs or symptoms of
related deep venous thrombosis (DVT) in boys with hemophilia, hyponatremia).
69% of children had a DVT when screened and 81% at the 2-year 4. Collect post-DDAVP infusion specimen in sodium citrate at 60,
120, and 240 minutes.
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rescreening. One study of 38 hemophilia patients confirmed that 5. Compare the pre- and post-DDAVP factor VIII and vWF:Ag
AVF is feasible, with complications in 34% of the patients; this group levels to confirm a therapeutic response, threefold increase from
suggests that in patients with inhibitors, AVF should be considered baseline (for mild or moderate hemophilia, response is defined as
the first line for venous access because they frequently require long- twofold increase in factor VIII: C levels or an absolute level above
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term, daily administration of factor. In deciding on which approach 0.31 U/mL at 1 hour). 71
to IV access for a patient, practitioners should address the risks and
benefits of each type of device on an individual basis. Use of central
catheters is attended by the risks of catheter-induced septic and
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thrombotic complications. With longer acting products becoming
available and the potential for more convenient modes of administra- spray Stimate (CSL Behring) is available in a metered-dose pump that
tion (subcutaneous), the need for semi-permanent vascular access delivers 0.1 mL (150 µg) per activation (spray). The dose is one
devices will decrease over time. activation for patients weighing less than 50 kg and two activations
in separate nostrils for those weighing more than 50 kg. In general,
TREATMENT OF HEMOPHILIA only three consecutive doses of DDAVP should be used unless oth-
erwise advised by an experienced hemophilia treater. Because DDAVP
Products Available for Treatment of is a vasopressin analog, there is a risk of fluid retention with its use.
Changes in fluid balance can result in hyponatremia and seizures,
Factor VIII Deficiency especially when DDAVP is used in individuals on nonfluid-restricted
or salt-restricted diets (e.g., elderly or very young patients or surgical
Products available for the treatment of bleeding episodes or prophy- patients undergoing fluid replacement with solutions with concentra-
laxis against bleeding in patients with mild or moderate hemophilia tions <0.9% sodium). For this reason, DDAVP is not recommended
A include DDAVP (1-deamino 8-D arginine vasopressin), a vasoac- for children younger than 2 years of age. Caution is advised with the
tive peptide that stimulates release of stored factor VIII, and infusible use of DDAVP in patients at risk for arterial thrombosis because there
products containing exogenous factor VIII protein. These may be have been reports of myocardial infarction and cerebral thrombosis
blood components, concentrates purified from blood plasma, or with its use. 72
concentrates containing recombinant factor VIII protein.
Factor VIII Concentrates
DDAVP
In developed countries, the current standard of care for the treatment
The preferred product for treatment of patients with mild or moder- and prevention of bleeding episodes in patients with severe hemo-
ate hemophilia A is the synthetic octapeptide DDAVP, a vasopressin philia A and in patients with mild or moderate disease who do not
analog. DDAVP causes a release of factor VIII (and von Willebrand respond to DDAVP is the infusion of recombinant human factor
factor [vWF]) from endothelial cells, raising plasma factor VIII by VIII. Recovery of recombinant factor VIII ranges from 1.5%to 2.5%/
approximately threefold (range, 2–12-fold) in patients with hemo- IU/kg so that dosing assumes a rise in plasma factor VIII activity of
philia in whom the disease is caused by decreased production or 2% for every 1 IU/kg infused. Available concentrates are optimized
secretion of a functional protein or a protein that has decreased to enhance viral clearance during purification and undergo one or
activity. To be effective, DDAVP relies on a partial quantitative more viral inactivation steps during manufacture. Plasma-derived
deficiency of factor VIII; thus, patients with severe hemophilia will factor VIII concentrates, treated with multiple purification and viral
not benefit from its use if the causative mutation results in no syn- inactivation steps, are also available and have an excellent recent
thesis, secretion, or a nonfunctional protein. In a retrospective study record of safety.
assessing response to a DDAVP challenge in mild or moderate
hemophilia, 57% of patients with mild hemophilia had a positive
response, and several who failed the initial challenge had a response Intermediate- and High-Purity
after a mean of 6 years, increasing the response rate to 71% in the Plasma-Derived Concentrates
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mild group. The response to DDAVP in an individual patient is
typically reproducible, and an effective response must be documented Intermediate-purity plasma-derived concentrates are prepared from
before its routine use or as prophylaxis for bleeding in surgical pro- cryoprecipitated plasma or fresh-frozen plasma (FFP), from which
cedures (see box on 1-Deamino 8-D Arginine Vasopressin Trial). IV factor VIII is further purified using precipitation, gel permeation, ion
and intranasal preparations are available. The IV product has been exchange, or affinity chromatography, often in combination. Specific
used in a subcutaneous route of administration. The intranasal factor VIII coagulant activity in these products ranges from 2 to more
preparation more easily allows a patient to administer the compound than 100 IU/mg of protein, and many of the methods used also
on an as-needed basis in a home therapy regimen. The phenomenon copurify significant amounts of vWF, making them useful for the
of tachyphylaxis, the decreased effectiveness of repeated doses of the treatment of some patients with von Willebrand disease (vWD; see
same compound, occurs after several, typically three, consecutive later discussion on treatment of vWD). More highly purified plasma-
doses. derived concentrates are produced using heparin ligand or immuno-
Injectable DDAVP (Sanofi Aventis) is available in 4 µg/mL. The affinity purification methods and have specific activities ranging from
recommended dose is 0.3 µg/kg, mixed in 30 mL normal saline (for 140 to greater than 3000 IU/mg. To stabilize the factor VIII molecule,
children <10 kg, 10 mL normal saline), infused IV slowly over 30 the majority of these products are formulated by adding human
minutes. This dose can be repeated after 12–24 hours. DDAVP nasal albumin before lyophilization.