Page 2283 - Hematology_ Basic Principles and Practice ( PDFDrive )

2030 Part XII Hemostasis and Thrombosis

are never as effective in inhibitor patients as is FVIII replacement in surgery, some experts advise an initial dose of rFVIIa of 120 µg/kg,
noninhibitor patients. Use of APCCs facilitates surgery in inhibitor followed by repeated 90 µg/kg doses every 2 to 3 hours. 117
patients and has been reported to be effective 108,109 and safe in large
populations. 109
APCC administration in a secondary prophylaxis regimen has also Parallel-Sequential Use of Activated Prothrombin
been deemed feasible, successful, and safe in reducing the frequency Complex Concentrates and Factor VIIa Concentrates
of bleeding events in severe hemophilia A patients with high-titer
FVIII inhibitors. In the randomized, prospective, crossover Pro- For active inhibitor-associated bleeding episodes that appear to be
FEIBA study, a statistically significant 62% reduction in all bleeding unresponsive to treatment with either the APCC or rFVIIa alone, the
events was observed during the prophylaxis phase of the study (85 administration of both products simultaneously or in an alternating
units/kg on 3 nonconsecutive days/week) compared with the regimen (within 12 hours) was reported to be successful. 119–121 This
on-demand period (85 units/kg every 6 to 12 hours). 110 combination is not recommended by the product manufacturers, and
Use of PCCs and APCCs is hampered by the lack of laboratory its clinical usefulness has not been set in a scientifically valid manner.
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tests to measure efficacy or to predict the potential for anamnesis In vitro sequential spiking experiments or ex vivo systematic infu-
(because of the presence of small amounts of FVIII) and the risk for sion studies using plasma specimens from inhibitor patients who have
precipitating thrombotic complications. The incidence of thrombosis received these two types of bypassing agents alone, simultaneously,
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is increased with regimens that exceed the recommended dosage and or in tandem have demonstrated enhanced hemostasis for the
in patients at risk for thrombotic events, such as older individuals combined approach. One study suggests that individualized bypass
with coronary artery disease. replacement therapy regimens can be designed for inhibitor patients
For acute bleeds, APCCs are administered at doses of 50 to 100 based on the ex vivo responses observed in thromboelastogram trac-
123
units/kg every 6 to 12 hours based on the clinical severity, with the ings. Even though the efficacy of parallel treatment with bypassing
maximum daily dose capped at 200 units/kg. This broader time agents may be good in inhibitor-related refractory bleeds, these regi-
frame allows for use at home for treatment of acute bleeds and for mens may increase the risk for thrombotic complications. A recent
prophylaxis. critical review of 49 inhibitor patients (9 acquired and 40 congenital),
rFVIIa was purified from plasma and first used to treat a patient who received both bypassing agents in combined or alternating
111
with hemophilia A with an inhibitor in 1983. Later, FVIIa pro- dosing regimens, reported 10 thromboembolic events, of which 1 was
duced by recombinant technology was found to be effective for fatal. 124
preventing and treating acute bleeding. A randomized dose-finding
trial determined that FVIIa effectively reversed 71% of joint and
112
muscle bleeds within two to three doses, given every 2 to 3 hours. Prophylaxis With Activated Prothrombin Complex
Another prospective study established that 90 µg/kg rFVIIa pro- Concentrate and Factor VIIa
moted adequate hemostasis during major surgical procedures, with
an efficacy rate of 83% to 100%. 113 Prophylaxis regimens using either APCC or rFVIIa to prevent acute
Randomized prospective studies have directly compared the effi- and chronic arthropathy in inhibitor patients can be classified as
cacy and safety of one dose of an APCC (factor eight inhibitor primary (children awaiting ITI) or secondary (patients in whom ITI
bypassing activity [FEIBA, Baxter], 85 to 90 IU/kg) with 1 to 2 doses failed). Though not formally compared, prophylaxis with bypassing
of FVIIa (NovoSeven [Novo Nordisk Health Care AG] 90 to 105 µg/ agents in inhibitor patients is not as efficacious as FVIII replacement
kg/dose) to treat acute joint bleeds. Although both products showed in patients without an inhibitor. However, an accumulation of case
around 80% efficacy after 12 hours, equivalence was not shown at reports and small clinical studies has suggested that prophylaxis with
the 6-hour primary outcome point, but this was probably because of bypassing agents is safe and feasible in the subset of inhibitor patients
114
study design and underpowered cohorts. When the primary with frequent bleeds, such as in target joints. The first prospective
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outcome was the percentage of patients who required additional controlled study of prophylaxis in inhibitor patients showed that
hemostatic replacement therapy 9 hours after initiation of treatment, a daily bolus dose of 270 µg/kg of FVIIa is superior to a 90 µg/kg
significantly lower percentages of the 270 µg/kg (8.3%) and 3 × dose (59% versus 45%) in reducing the bleeding frequency in com-
126
90 µg/kg (9.1%) FVIIa treatment dose cohorts required rescue thera- parison to the preprophylaxis period. An uncontrolled study
pies compared with the APCC treatment group (36.4%). 115 described equivalent efficacy and safety for FVIIa and APCC for
Use of FVIIa is associated with some drawbacks, such as the lack prophylaxis in patients with hemophilia A with inhibitors. Patients
of effective laboratory monitoring, very short half-life (≈2 to 3 hours, were placed on prophylaxis while awaiting initiation of ITI. In this
which necessitates frequent administration), potential for thrombotic context, the investigators favored the use of FVIIa to avoid potential
126
events (more frequently observed in noninhibitor patients), and anamnestic responses with APCC. A recent prospective controlled
expense. trial demonstrated that a prophylaxis APCC regimen at the dose of
For acute bleeding events in inhibitor patients, debate exists as to 85 IU/kg three times/week reduced bleeding events by 62% in
whether the more convenient dosing regimen of a single large bolus inhibitor patients, compared to the on-demand treatment regimen. 102
dose of FVIIa (270 µg/kg) is as safe and efficacious as the multiple-
dose regimen (90 µg/kg every 2 to 3 hours as recommended in the
package insert). The initial concern was related to the thrombogenic Fibrinolytic Inhibitors
potential of larger single doses, particularly in older individuals, since
the large single-dose regimen was studied predominantly in children. ε-Aminocaproic and tranexamic acid have long safety records and are
In reality, a recent analysis of the FVIIa dosages used in FVIII inhibi- commonly used in patients with hemophilia, including those with
116
tor patients in the United States (n = 20,469 doses, recommended inhibitors, as a sole treatment modality or as adjuncts to factor
dosages were the large ones, up to >270 µg/kg) revealed a very low replacement for mucosal bleeding, dental procedures, and some
116
incidence of thromboembolic complications (0.2%). Thus for orthopedic surgeries. 127
serious life- and limb-threatening hemorrhages, a single 270 µg/kg For children, ε-aminocaproic acid can be administered orally at
bolus dose is recommended, at least to start with. Treatment of acute doses of 50 to 100 mg/kg every 6 hours. If used before a surgical
bleeds with FVIIa concentrate should be initiated as soon as possible intervention, the first dose should be given 4 hours before the start
because efficacy is inversely related to time to treatment. of the procedure. In adults, a loading dose of 4 to 5 g can be given
Recently, a comparative study was conducted between Novoseven initially, followed by similar or lower doses every 6 to 12 hours until
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and an iranian biosimilar of rFVIIa in the range of 90–120 µg/kg/ bleeding is controlled (total suggested dose is 100 mg/kg/day).
body weight: no differences were noted in terms of efficacy score, Fibrinolytic inhibitors are useful adjuncts for the treatment or preven-
pain reduction, increased range of motion and side-effects. For tion of bleeds treated with DDAVP in patients with low-titer