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Inhibitor development


approximately 11–12 hours with a wide range; t1/2


is shorter in infants and children.4 Determination of a t1/2


traditionally requires multiple blood samples over many hours and is logistically very difficult in small children and tedious for adults. Half-life determination is usually reserved for assessing the success of immune tolerance (see below).


Clinically, the appearance of an inhibitor may be suspected when a patient fails to stop bleeding after treatment. The majority of inhibitors, however, are first detected by routine laboratory screening, which is carried out frequently and routinely in all small children with severe haemophilia A, in those with mild/moderate haemophilia after treatment with factor VIII and in all patients annually.


Many inhibitors are low level, often transient (lasting only a few months) and may go undiagnosed, unless relatively frequent blood samples are collected and assessed by the Bethesda technique. Some inhibitors are persistent over long periods of time and severely compromise effective therapy, especially with the 10–20% which are high responders and may persist, if untreated, for the rest of the patient’s life.


Severe haemophilia A


Patients with severe haemophilia with low titre inhibitors (<5 Bu/ml) often clinically respond to larger than normal and more frequent does of factor VIII. After an infusion it is important to measure the level of factor VIII, as there is no way of accurately predicting this and the clinical efficacy to stop bleeding correlates with the post-infusion factor VIII concentration. In low-responding patients, it may be possible to continue treatment for many days with factor VIII, as the inhibitor will not rise significantly, but in high responders it will rapidly increase after five days to levels which may be as high as several thousand units. At these levels, the factor VIII is immediately neutralised and therapy is ineffective.


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For patients with a high-level inhibitor, that is, >5 Bu/ml, treatment with factor VIII concentrate is likely to be ineffective and concentrates that ‘bypass’ the blocking effect of the inhibitor should be used. Currently there are two ‘bypassing’ therapies: recombinant VIIa concentrate (rVIIa) and an activated prothrombin complex concentrate (aPCC), which contains clotting factors II,


www.hospitalpharmacyeurope.com Adapted from Reference 2.


“An inhibitor is observed in about a quarter of small children with severe haemophilia A”


VII, IX and X, some of which are activated (FEIBA – Factor Eight Inhibitor Bypassing Activity). FEIBA also contains traces of factor VIII, which may be sufficient to stimulate anamnesis in a high responder and this may be undesirable in a patient waiting to start immune tolerance (see below). There is no specific laboratory test readily available to monitor the efficacy of these two agents, although the possibility that global blood coagulation assays may be clinically useful is being assessed in current research projects.


For treatment of a bleed, rVIIa can be given in a dose of 90ug/kg two hourly,


with between one and three doses usually being necessary. Doses of rVIIa often have to be given relatively frequently because its half-life is only 2.6 hours. Alternatively, rVIIa infused as a single dose of 270 ug/kg is equally effective.5


FEIBA at a dose


usually of 50-75u/kg 8 hourly is recommended until bleeding stops (max daily dose 200u/kg/day). These two concentrates are of similar efficacy although some patients and some types of bleed may respond more readily to one therapy than the other.6


Apart from each


patient’s prior experience, there is no way to predict which therapy will give better haemostasis on a particular occasion. If a patient does not respond quickly to one of these concentrates, the other should be offered. In some instances, these two agents have been used sequentially (see Surgery below). If severe bleeding is not controlled by either of these agents singly, their concomitant use has been reported, although it is likely that such a combination will be associated with a


Table 1: Risk factors for inhibitor development Risk factor


Effect


Host-related factors Mutation in factor VIII


Severe haemophilia A


High risk – large deletions and stop codons Medium risk – intron 1 and 22 inversions


Low risk – small deletions / insertions and missense mutations Mild/moderate haemophilia A


Usually low risk but few specific mutations higher risk Severe haemophilia B


Increased risk with major gene deletions Ethnicity


Family history Age


Increased risk 2–3-fold in Hispanic and African origin compared to Caucasians Increased with first degree relative with inhibitor Severe haemophilia A


HIV status


Treatment-related factors Previous treatment


Greatest risk below the age of five years Increasing risk over 60 years Mild haemophilia A Increases with age Lower risk in HIV-positive individuals


Severe haemophilia A


Highest risk during first 10–15 days of exposure to concentrate Lowest risk after 150 days of exposure Severe haemophilia B


Intensity of exposure


Highest risk during initial exposure Severe haemophilia A


Higher risk if treatment > five consecutive days Mild haemophilia Increases if treatment > five consecutive days


Prophylaxis Type of concentrate Surgery Severe haemophilia A Early prophylaxis associated with reduced risk (retrospective study)


No evidence for different risks for plasma-derived compared with recombinant concentrates


Severe haemophilia A Risk increased if surgery combined with intensive first exposure > 4 days Mild moderate haemophilia A


Risk increases with intensive exposure at surgery especially with a high risk mutation


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