Page 2268 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 135 Hemophilia A and B 2015

used to extend the half-life differs among products. The two main intranasal administration, the usual dose is 150 µg (1 nasal puff) for
methods involve fusion technology and pegylation. Both technologies patients weighing less than 50 kg and 300 µg (1 nasal puff into each
work by interfering with the natural clearance of factor concentrates nostril) for patients weighing 50 kg or more. The maximum effect
by cells of the mononuclear phagocyte system and by sinusoidal of DDAVP is achieved within 30 minutes when given intravenously
endothelial cells. and within 60 minutes when given intranasally. In general the safest
Fusion technology involves linking the cDNA sequences approach to avoid hyponatremia is to restrict fluids in patients
of clotting factors to the cDNAs of proteins (the Fc portion of receiving DDAVP and to administer only isotonic solutions such as
immunoglobulin or albumin) that have long half-lives primar- normal saline.
ily because they bind to the neonatal Fc receptor in endothelial Because DDAVP stimulates VWF release from endothelial cells,
endosomes. This protects them and whatever is attached to them it may increase platelet adhesiveness. In patients with hemophilia
from degradation within endothelial cells, and then recycles the with risk factors for coronary or cerebral artery thrombosis, this may
proteins back into the plasma. There are currently two extended result in angina, myocardial infarction, or stroke. Consequently,
half-life fusion FIX concentrates: in one, recombinant FIX is bound DDAVP should be used with caution in elderly men with hemophilia.
to recombinant Fc and in the other, recombinant FIX is bound Because DDAVP also stimulates the release of tissue plasminogen
to recombinant albumin. There is also one Fc fusion FVIII. For activator, it may exacerbate bleeding. Consequently, DDAVP is often
pegylation, polyethylene glycol molecules of different sizes are bound administered in conjunction with antifibrinolytic agents.
to either recombinant FVIII or FIX. There is one pegylated FIX
and at least three pegylated or glycopegylated FVIII concentrates in
development. Antifibrinolytic Agents
These newer concentrates have significantly prolonged half-lives.
The half-life of FIX is extended three- to fivefold, while that of FVIII Antifibrinolytic agents are useful in the management of bleeding from
is extended by about 1.5-fold likely reflecting the dominant role of mucosal sites where there is high fibrinolytic potential (e.g., the
VWF in FVIII clearance. oropharynx, nose, GI tract, and uterine-vaginal lining). In hemo-
These products, particularly the newer FIX concentrates, offer the philia, antifibrinolytic agents (e.g., tranexamic acid or epsilon ami-
possibility for fewer infusions and the achievement of higher trough nocaproic acid) are generally used in the context of oral bleeding or
levels. The extent to which these products will transform hemo- dental surgery. Oral tranexamic acid (25 mg/kg every 6 to 8 hours)
philia management including such things as prophylaxis regimens, should be started 24 hours before the scheduled procedure whereas
proportion of patients on prophylaxis, adherence to prophylaxis, intravenous tranexamic acid (10 mg/kg every 8 hours) can be given
long-term joint outcomes, and patient quality of life remains to be immediately before the procedure. Tranexamic acid is available in
determined. 500-mg tablets, which can be crushed and dissolved in liquids for
administration to young children. The usual dosage of epsilon ami-
Adjunctive Treatments nocaproic acid is 75 mg/kg every 6 hours. In general, antifibrinolytic
agents should be administered for 3 to 10 days after a bleeding
episode or an invasive procedure. Longer durations of therapy are
Desmopressin required for tonsillectomy–adenoidectomy because bleeding often
occurs about 7 days after the procedure when the eschar detaches.
In the mid-1970s, Mannucci and colleagues showed that DDAVP The major contraindication to the use of antifibrinolytic agents is
(1-deamino-8 D-arginine vasopressin, desmopressin, Ferring Pharma- hematuria.
ceuticals, Langley, UK), a synthetic analogue of the natural antidi-
uretic hormone vasopressin, raises circulating levels of VWF and
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FVIII:C. DDAVP causes the release of endogenous VWF and Fibrin Sealants
endogenous FVIII from the Weibel-Palade bodies in endothelial cells
into the blood. DDAVP also increases platelet adhesiveness and Experience with fibrin sealants in patients with hemophilia is increas-
shortens the bleeding time independent of its effect on raising ing. Fibrin sealants function both as local hemostatic agents and as
FVIII:C and VWF levels. Because DDAVP is not a blood-derived promoters of wound healing. They are particularly useful for dental
product or a factor concentrate, it is free of both infectious complica- procedures. Fibrin sealants have been used successfully to reduce
tions and potential inhibitor development. Furthermore, it is much bleeding with dental procedures, circumcision, and after excision of
less costly than factor concentrates and has few, generally mild and hemophilic pseudotumors.
transient adverse events (flushing, headache, mild tachycardia, and
hypotension). DDAVP has antidiuretic activity and thus carries a risk
of hyponatremia and seizures, particularly if given to very young Adjunctive and Alternative Management Strategies
children or to those with excessive fluid intake. Because of concern for Joint Bleeds
about hyponatremia, many clinicians do not give DDAVP to children
younger than 3 years of age, and administer DDAVP only once daily In the management of joint bleeds, appropriate hemostatic support
unless patients are hospitalized and serum sodium levels and fluid is critical, but other important measures include appropriate joint
intake are monitored. The effectiveness of DDAVP decreases with rest, analgesia, and graduated physiotherapy. The application of rest,
repeated administration (tachyphylaxis) because of exhaustion of ice (for 20 minutes every 3–4 hours), compression, and elevation
VWF/FVIII stores. Therefore, DDAVP should not be given for more (RICE protocol) during the first 24 hours after a joint bleed can
than 3 consecutive days. provide substantial benefits. The role of joint aspiration in the
Most patients with mild hemophilia respond to DDAVP with a management of joint bleeds remains controversial, but the procedure
doubling or tripling of their FVIII:C levels to 30% or greater. In is advocated by some groups for management of persistent pain in
patients with moderate hemophilia, DDAVP rarely increases FVIII:C large-volume hemarthrosis or for exclusion of septic arthritis. Orthot-
levels into a hemostatically effective range. All individuals with mild ics and physical therapy are of vital importance in the management
hemophilia A should be assessed for DDAVP responsiveness to of acute joint bleeds and in dealing with long-term joint damage in
determine whether they will benefit from this synthetic product. This patients with hemophilia. Ankle guards and arch supports are useful
involves determining FVIII and VWF levels before and 30 minutes for patients with ankle arthropathy to improve gait and weight-
to 1 hour after DDAVP administration. bearing capacity. Shoe lifts can equalize the length of the lower
DDAVP can be administered intravenously, subcutaneously, extremities when there is a leg length discrepancy. Muscle strength
or intranasally. The usual dose for intravenous administration is training enhances the mechanics of joint movement and provides
0.3 µg/kg given in 50 mL of normal saline over 30 minutes. For protection and stabilization of the joint.