Page 2267 - Hematology_ Basic Principles and Practice ( PDFDrive )

2014 Part XII Hemostasis and Thrombosis

generally lower, with 1 IU/kg increasing the FIX level by 0.8%. With inhibitors. Determining the factor level at trough every several days
the newer modified extended half-life FIX concentrates, recoveries ensures that the patient is achieving a hemostatic level of replacement.
appear to be variable, perhaps because of differences in their extra- An alternative method for maintaining hemostasis is by continu-
vascular distribution. Children exhibit lower recoveries of clotting ous clotting factor infusion. A lower dose of factor is required with
factor. FVIII concentrates have much shorter half-lives (approxi- this form of treatment, and the peaks and troughs of repeated bolus
mately 8–12 hours) than FIX concentrates (approximately 18–24 administration are avoided. In general, a FVIII infusion rate of 2 to
hours). There are large interindividual variations in clotting factor 3 U/kg/h is sufficient once the FVIII level is increased to 100% with
half-life because the half-life is affected by a number of variables. In a bolus infusion of 50 U/kg. There has been concern about inhibitor
the case of FVIII, it appears to be affected by the patient’s endogenous development with continuous infusion therapy, particularly in
VWF level, which in turn is related to the patient’s ABO blood group. patients with mild/moderate hemophilia A but there is no conclusive
Both FVIII and FIX half-lives are also affected by patient age; half- evidence that continuous infusion poses a risk for inhibitor
lives generally increase with age. development.
Recent cohort studies and a randomized open label study have The above recommendations are based on the use of conventional
challenged the assumption that the rate of inhibitor develop- half-life FVIII and FIX concentrates; different recommendations are
ment is similar with all plasma derived and recombinant FVIII needed for extended half-life FVIII and FIX and continuous infusion
concentrates. 20–22 The Sippet (Study on Inhibitors in Plasma-Product of these products is unlikely to be necessary to maintain hemostasis
Exposed Toddlers) study showed a 1.87-fold higher rate of inhibitor in patients undergoing surgery.
development with recombinant FVIII versus plasma derived FVIII
while the Rodin study showed a 1.6-fold higher rate of inhibitor
development with a second generation recombinant FVIII as com- Extended Half-life FVIII and FIX Concentrates
pared to a third generation recombinant FVIII. The findings of both
studies have been challenged because of methodologic study design A number of extended half-life or longer acting FVIII and FIX
issues and also on the basis of previous studies showing contrasting concentrates have been developed or (at the time of writing this
results. Over the next few years these studies may impact on the chapter) are undergoing prospective clinical studies (Table 135.8).
choice of FVIII chosen for newborn previously untreated patients Consequently, many such products are likely to be available in the
(PUP) with severe hemophilia A. next few years. These agents will alter the management of hemophilia,
Up until the present, the choice of recombinant FVIII concentrate particularly hemophilia B. Although all of the extended half-life
to use has been primarily influenced by cost. In the future, with newer or longer acting agents are recombinant proteins, the technology
extended half-life FVIII concentrates (see later section) the efficacy
and inhibitor incidence between newer products may be more vari-
able and thus may impact increasingly on choice of product.
The dose and duration of substitution therapy depend on the
severity of the bleed or the extent of the surgery. Table 135.7 shows TABLE Recommendations for Clotting Factor Replacement
the desired factor levels for various types of bleeding events and 135.7
surgeries. After the initial bolus of factor, repeat doses have tradition- Level Desired Hemophilia A Hemophilia B
ally been needed. For major bleeds, such as an ICH, or for major Site of Bleed (%) (rFVIII) (U/kg) (rFIX) (U/kg)
surgeries, such as joint replacement, 10 to 14 days of full factor
replacement may be required, but for less severe bleeds, such as an Oral mucosa >30 20 40
uncomplicated hemarthrosis, two or three treatments are usually Epistaxis >30 20 40
sufficient. For minor bleeds or minor surgeries (e.g., dental extrac- Joint or muscle >50 30 50
tion) only 1 to 3 days of factor is required. For patients who require GI >50 30 50
factor for a number of days, in addition to the initial dose of factor,
bolus infusions are generally required every 6 to 24 hours depend- GU >50 50 75
ing on the severity of the bleed or the surgery. Because of variable CNS >100 75 125
pharmacokinetics, factor levels should be monitored. This avoids Trauma or surgery >100 75 125
high factor levels, which might be prothrombotic and represent an
unnecessary expense, as well as low factor levels, which increase the CNS, Central nervous system; GI, gastrointestinal; GU, genitourinary; rFIX,
recombinant factor IX; rFVIII, recombinant factor VIII.
risk of bleeding. In addition, monitoring helps detect development of

TABLE Extended Half-Life FVIII and FIX Concentrates in Development
135.8
Product Technology Manufacturer T 1/2 (h) T 1/2 vs. Native FVIII/FIX
Extended Half-Life FIX
rFIXFc Fusion protein with Fc fragment of IgG1 Biogen Idec/Sobi 57–83 3-fold
rIX-FP Fusion protein with albumin CSL-Behring 89–96 >5-fold
N9-GP Site-specific glycopegylation with a 40-kDa PEG molecule Novo-Nordisk 96–110 >5-fold
Extended Half-Life FVIII
rFVIII-Fc B domain deleted FVIII fused to a monomeric Fc fragment of IgG Biogen Idec/Sobi 18.8–19 1.5–1.7-fold
BAY-94-9027 Site specific pegylation (60 kDa PEG) of a B domain–deleted FVIII Bayer 19 1.4-fold
BAX 855 Controlled pegylation (2–20 kDa branched chain PEG) of a Baxter (now Shire) NA 1.5-fold
full-length FVIII
N8-GP Single site specific glycopegylation (40 kDa PEG) of a B Novo Nordisk 19 1.6-fold
domain–truncated (21 AA) FVIII
AA, Amino acids; FIX, Factor IX; FVII, factor VIII; IgG, immunoglobulin G; NA, not available; PEG, polyethylene glycol; T 1/2, half-life.
Adapted from: Carcao M. Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia 20 (Suppl. 4):99, 2014.