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Inhibitor development


significant increased risk of thrombosis – this being the principal, although uncommon, side effect of both these agents when used individually. Thrombosis is more common in those with co-morbidities, especially those with an existing precondition to thrombosis, for example, atherosclerosis. There is evidence that the haemostatic efficacy of rVIIa may be enhanced if tranexamic acid is given simultaneously. Tranexamic, according to the manufacturer’s instructions, is contraindicated with FEIBA because of the risk of precipitating DIC or thrombosis, although their concomitant use has recently been reported without an adverse outcome.


Mild haemophilia A


For patients with mild haemophilia A and an inhibitor, desmopressin may raise the level of factor VIII transiently to a level sufficient to give haemostasis particularly following minor trauma or surgery. It is important to monitor the factor VIII level after a test dose to ensure that a sufficient level is achieved. The fibrinolytic inhibitor, tranexamic acid, which impedes lysis of the haemostatic plug, is often given concomitantly. For a patient with mild haemophilia A, who either has a factor VIII gene mutation increasing the risk of an inhibitor, or who has previously had an inhibitor, the use of desmopressin is particularly valuable because exposure of such a patient to concentrate may stimulate an inhibitor that cross-reacts with the patient’s endogenous factor VIII and reduces its level to <1%. Such patients may bleed spontaneously and severely into soft tissues. With a severe bleed or major surgery when a persistent high factor VIII level is necessary, concentrate therapy may be unavoidable. In this situation, it is important to monitor the patient’s factor VIII level daily during treatment and two weeks after the end of concentrate therapy, also to detect whether an inhibitor has developed.


Surgery


For any patient with an inhibitor, surgery is considerably more hazardous than in an individual without an inhibitor, as no clotting factor concentrate can be guaranteed to produce haemostasis, and some procedures pose a particularly high risk of haemorrhage, for example, orthopaedic surgery. The potential benefits of surgery, therefore, have to be very carefully weighed against the risks of uncontrollable bleeding. Surgery should


be supervised by clinicians with experience in this field – it’s not for the inexperienced or faint hearted. For a patient with a low-level, low-responding inhibitor, larger than normal and more frequent doses of factor VIII concentrate (with frequent monitoring of levels) may give an adequate concentration to allow surgery to be safely accomplished. For those with mild haemophilia and an inhibitor, use of DDAVP may be appropriate if it can be demonstrated that the patient has a sufficient durable response (see above). For those with a high-level (>5 BU/ml) or high-responding inhibitor, haemostasis will need to be secured with either rVIIa or FEIBA. FEIBA is usually given either 75u/kg 8 hourly or 100u/kg 12 hourly.7 rVIIa is infused at a preoperative dose of 120u/kg, then two hourly 90ug/kg for


to preserve joint function it is essential to try to prevent such haemorrhage. This has been attempted with regular infusions of FEIBA and rVIIa. As the half-life of rVIIa is short, daily infusions have been used and small studies report a decreased incidence of bleeds. In one study with a dose of 90ug or 270ug/kg/day rFVIIa, there was a reduction from 14 bleeds in three months prior to regular infusions to eight and four bleeds, respectively, with daily infusions over the same time period.10,11


This was not a randomised


study and an unexpected observation was that, after prophylaxis ended, the rate of joint bleeds continued at the same rate as during prophylaxis. FEIBA has been used at a variety of doses and time intervals but in one study, at a dose of 50–100 u/ kg on alternate days, there was a reported reduction of 83% in bleeds.12


“As the presence of an inhibitor severely compromises the ability to both prevent and treat bleeds, it is highly desirable to consider methods by which an inhibitor can be eradicated”


2–3 days, thereafter the dose is maintained at 90ug/kg and the frequency of infusions decreased.8


Some operations


have been covered initially with rVIIa and then the patients have been switched to FEIBA after several days.9


Infusions of


these agents should be continue until there is wound healing and it may need to be extended, in a targeted manner, to cover physiotherapy, for example, after orthopaedic surgery.


Prophylactic therapy


To prevent recurrent joint bleeds, which inevitably lead to severe disabling arthropathy, it is now recommended that factor VIII should be given regularly to prevent bleeding. In the absence of an inhibitor, the half-life of factor VIII is approximately 12 hours and infusions have to be given every second day to prevent bleeding by keeping the level of the clotting factor above 1–2%. In the presence of even a very low-level inhibitor, the half-life of factor VIII/IX is dramatically reduced and, therefore, to maintain haemostasis, infusions would need to be given several times per day. Patients with severe haemophilia and an inhibitor, like those without an inhibitor and not receiving prophylaxis, will experience spontaneous joint bleeds and


evidence to suggest that it is appropriate to consider the possibility of preventing haemorrhage with either of these bypassing agents. When embarking on such therapy, it is important to monitor its efficacy; if one agent is not demonstrably effective, it is prudent to try the other. It is readily evident that these agents are not as effective in preventing bleeds as regular factor VIII/IX infusions in non-inhibitor patients.


Eradication of inhibitors As the presence of an inhibitor severely compromises the ability to both prevent and treat bleeds, it is highly desirable to consider methods by which an inhibitor can be eradicated, so that factor VIII/IX therapy becomes haemostatic. What emerged from the pioneering work in Bonn and Malmo in the 1970s is that daily infusions of large doses of factor VIII/IX continued over 6–36 months will, in many patients, lead to the inhibitor disappearing in a process known as immune tolerance induction (ITI). There have been a number of studies of different regimens and these have led to the identification of the patient factors that are associated with a good outcome and also studies which have demonstrated the most appropriate infusion frequency and


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Thus there is


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