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Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)

2012; Wiley; Volume: 160; Issue: 2 Linguagem: Inglês

10.1111/bjh.12091

1365-2141

Peter W. Collins, Elizabeth Chalmers, Daniel P. Hart, Ri Liesner, Savita Rangarajan, Kate Talks, Mike Williams, C. R. M. Hay,

Hemostasis and retained surgical items

This document updates UK Haemophilia Centre Doctors Organization (UKHCDO) guidelines on the management of factor VIII/IX (FVIII/IX) inhibitors in congenital haemophilia (Hay et al, 2000, 2006). Acquired haemophilia is excluded and will be covered separately. Most data apply to FVIII inhibitors and the recommendations for FIX inhibitors are sometimes extrapolated from this. Low titre inhibitors are defined as 4 ED) compared to first exposure without surgery OR 4 (95% confidence interval, 2–8·4) Mild moderate haemophilia A: Risk increased by intensive exposure at the time of surgery especially associated with high-risk mutation Eckhardt et al (2009), Eckhardt et al (2011), Mauser-Bunschoten et al (2012) FVIII/FIX mutation analysis should be undertaken in all patients with haemophilia A and B, especially newly diagnosed patients (Grade 2C). Previously untreated and minimally treated patients with severe haemophilia A who have received an intensive FVIII exposure [≥5 exposure days (EDs)] should be closely monitored for inhibitor formation (Grade 1B). Some consideration may be given to starting early prophylaxis (Grade 2C). All patients who require replacement therapy with concentrate, including previously untreated patients, should be treated with recombinant FVIII/IX (Grade 1C). Inhibitor testing should be performed if a patient has a poor clinical response to concentrate or lower FVIII/IX levels than expected after concentrate infusion. Early detection of an inhibitor is crucial to minimize anamnesis and, if the inhibitor does not rise above 10 BU/ml, allow immune toleration induction (ITI) to be started without delay. Early detection will also limit exposure to sub-optimal treatment. Inhibitor testing is required before elective invasive procedures, when the clinical or laboratory response to concentrate is sub-optimal, before and after a switch of concentrate and 2–3 weeks after intensive treatment (≥5 EDs) or surgery in mild or moderately affected patients. An inhibitor screen should be performed in patients with severe haemophilia at least every third ED or every 3 months if concentrate exposure has occurred (whichever is sooner) until 20 EDs have been achieved. Thereafter, inhibitor testing should be undertaken every 3–6 months until 150 EDs. Most boys with severe haemophilia are established on prophylaxis by the 20th ED and the pragmatic approach is to measure trough levels at least every 3–6 months: if FVIII/IX is measurable further testing is not necessary but if 7 h. In patients with mild or moderate haemophilia A the sensitivity of an inhibitor test may be improved by heating the plasma at 58°C for 90 min to inactive residual FVIII (Kitchen et al, 2009 and Miller et al, 2012). FVIII/IX inhibitors should be quantified with a Bethesda assay (Kasper et al, 1975) with Nijmegen modification for FVIII (Verbruggen et al, 1995). When recombinant B-domain-deleted porcine FVIII concentrate becomes available, appropriate quantification of cross-reactive inhibitors will also be required. An ELISA method may be useful if a lupus anticoagulant is present or for inhibitors which increase clearance rather than inhibiting activity (Sahud et al, 2007). However, an ELISA test may also detect non-inhibitory antibodies. FVIII in vivo recovery (IVR) is calculated by subtracting the pre-infusion from the post-infusion level; it should be reported as the increase in iu/dl divided by the infused dose in iu/kg. Inaccuracies in measuring IVR (Björkman et al, 2007) will be exacerbated by the presence of an inhibitor. In haemophilia A, samples taken 1-h post-infusion underestimate the IVR in most patients lacking an inhibitor (Björkman et al, 2010). The optimal sampling time in the presence of a low titre inhibitor is unknown but it should be standardized so that serial results can be compared. By consensus, we recommend that the post-infusion sample be taken at 15 min. IVR is of limited use for monitoring the strength of an inhibitor but is important for guiding replacement therapy when treating bleeding episodes. The most sensitive way to detect and quantify an inhibitor is to measure the clearance of FVIII/IX. An expert consensus has suggested that a FVIII inhibitor be considered to be present in very young children when the elimination half-life was <6 h. However, the only available published study in children aged 1–6 years, who had no detectable or past history of an inhibitor, (n = 54) reported a median (95% confidence interval) FVIII half-life of 9·4 (7·4–13·1) h (Blanchette et al, 2008) and methodological considerations related to the reduced blood sampling schedule suggest that this half-life may be an underestimate (Björkman et al, 2010). When these data were re-analysed using a population pharmacokinetic method the shortest half-life was about 7 h, even in children aged 1 year (Björkman et al, 2012). In addition, the normal half-life for an individual who has an inhibitor is very unlikely to be known because this will not have been measured prior to inhibitor development. In view of these emerging data we suggest that a FVIII inhibitor should be considered to be present if the half-life is <7 h. There are no consensus criteria for recognition of a FIX inhibitor because normal FIX half-life is uncertain; reports vary widely with values for plasma-derived (pd) FIX ranging from 29 to 43 h and for recombinant FIX (rFIX) from 18 to 24 h (Björkman, 2011). The half-life of rFIX in infants and young children is unknown (Shapiro et al, 2005). For pharmacokinetic studies, 50 iu/kg of FVIII or 75 iu/kg of FIX are infused after a 3-d washout period. The International Society on Thrombosis and Haemostasis FVIII/FIX Scientific and Standardization Committee (ISTH SSC) recommendations state that samples should be taken; pre-dose, and at 10–15 min, 30 min, 1, 3, 6, 9, 24, 28, 32 and 48 h post-infusion for FVIII and an additional sample taken 72 h post-infusion for FIX (Lee et al, 2001). This is very difficult to achieve in young children and times of 1, 3, 6–8, 24 and 48 h are suggested for FVIII in these patients, although this results in an apparently shorter half-life compared to full sampling in non-inhibitor patients (Björkman et al, 2010).This may, therefore, suggest the presence of an inhibitor when none exists. The effect of reduced sampling time points is virtually eliminated by the use of population pharmacokinetic models (Björkman et al, 2012) but no population model is available for patients with low titre inhibitors at present. International Society on Thrombosis and Haemostasis FVIII/FIX Scientific and Standardization Committee guidelines recommend that a series of simple linear regression models can reduce calculations involved in half-life estimation but they emphasize that rigorous statistical analysis is required in order to assign the correct regression function (Lee et al, 2001). A number of computer programs can be used to estimate FVIII half-life but none have been validated for the measurement of half-life in the presence of an inhibitor. The calculation of an accurate half-life in the presence of a low titre inhibitor is a highly specialized procedure, beyond the ability of most centres. If half-life needs to be measured, the sampling schedule and methodology for calculation (Win-Non-Lin software; Pharsight, St Louis, MO, USA) used in the International ITI (I-ITI) study should be used so that patient outcomes can be compared to the results of that study (Hay & DiMichele, 2012). It should be recognized, however, that this sampling schedule (pre, 0·25–0·5, 1, 2, 4, 6, 24 and 48 h) may underestimate the half-life (Björkman et al, 2010). A definition of an inhibitor based on half-life is the hardest and most sensitive measure but is difficult to apply in most routine clinical circumstances. In view of this, and because of the challenge of measuring FVIII half-life in patients with low titre inhibitors in routine practice, we will use a pragmatic and clinically relevant surrogate measure of normal FVIII pharmacokinetics in this guideline, as a FVIII level ≥1 iu/dl at 48 h in an individual receiving standard prophylaxis (20–50 iu/kg on alternate days). An inhibitor test should be performed in severely affected patients with haemophilia A or B at least every third ED or every 3 months until the 20th ED (Grade 2C). After the 20th ED an inhibitor test should be done every 3–6 months up to 150 EDs. For haemophilia A, inhibitor testing should continue 1–2 times a year indefinitely (Grade 1C). For haemophilia B, testing after 150 EDs is only required if clinically indicated. An inhibitor test should be performed in all patients with haemophilia A before any change in concentrate and at least twice in the first 6 months after the change or if there is any change in bleeding pattern or response to FVIII (Grade 2C). An inhibitor test should be performed in mild and moderate haemophilia A yearly (if they have been exposed to FVIII) or after intensive exposure (≥5 EDs) or after surgery (Grade 1C). Patients with mild/moderate haemophilia A and a mutation with high inhibitor prevalence and/or family history of inhibitors should undergo inhibitor testing after all exposures (Grade 1C). Patients with haemophilia B should be tested after an allergic reaction to replacement therapy before any further FIX exposure occurs (Grade 1B). Tests to detect the presence or titre of an inhibitor should be done after a washout that ensures that the baseline factor level has been reached (Grade 1B). With currently available methodology it is difficult to accurately monitor FVIII half-life in patients with low titre inhibitors in routine clinical practice. If required, half-life should be measured by the methods described in the International Immune Tolerance study (Grade 2C). The current consensus definition for a FVIII inhibitor is an elimination half-life of <6 h, but this is likely to be an underestimate (Grade 2B) and the definition suggested in this guideline is <7 h (Grade 2B). We suggest that a pragmatic and clinically relevant surrogate measure of normal pharmacokinetics is a FVIII level ≥1 iu/dl at 48 h in an individual receiving standard prophylaxis (20–50 iu/kg on alternate days) (Grade 2C). There is no criterion for recognition of a FIX inhibitor other than the presence of a positive Bethesda assay (Grade 2C). IVR is a relatively inaccurate method to assess the strength of an inhibitor but is useful for guiding replacement therapy (Grade 2B). Inhibitor treatment involves the control and prevention of bleeds and strategies to eradicate the inhibitor. Immune tolerance induction (ITI) must be viewed as a long-term investment and the high initial cost compared with the cost of life-long treatment in the presence of a persistent inhibitor. Patients with a FVIII inhibitor, measured on more than one occasion, that interferes with prophylaxis or treatment of bleeds at standard doses of FVIII should undergo ITI to eliminate the inhibitor and restore normal clinical responsiveness to FVIII. Factors that potentially affect the outcome of ITI are listed in Table 2. Good risk patients are defined as having an inhibitor titre <10 BU/ml and an historic peak titre 250 BU/ml The best indicator of success or failure of ITI on multivariate analysis of the International ITI study No evidence of difference in first line ITI between plasma-derived (pd) and recombinant FVIII Uncontrolled reports of responses to pdFVIII after failure of first-line ITI Kreuz et al (1996), Gringeri et al (2007), Kurth et al (2011) Kroner (1999), Brackmann et al (1996) Mauser-Bunschoten et al (1995) Kreuz et al (1995), DiMichele (2003) It is important to avoid interruption to ITI and to follow a protocol closely because the first attempt at ITI carries a considerably greater chance of achieving long-term tolerance than rescue therapy (Lenk, 1999). ITI regimens should be reviewed by a haemophilia clinician every month, and more formally reviewed every 3 months by a clinician with expertise in ITI. Previous reports have suggested that most patients achieve tolerance within 6–12 months and a minority may take 1–3 years or more (Kreuz et al, 1995; Brackmann et al, 1996). The International ITI Study, however, found that, in good risk patients, the median time on ITI in the low-dose arm was 16·4 months and in the high-dose arm 14·2 months (Hay & DiMichele, 2012). Patients who are super-high responders (inhibitor titre rises to >500 BU/ml after starting ITI) usually have a poor outcome (DiMichele & Kroner, 2002; Hay & DiMichele, 2012). ITI can be abandoned in such patients after 6–9 months and second-line therapy considered (see section 6.1.7) unless there is evidence of a significant ongoing decline in inhibitor titre (at least a 20% fall in inhibitor titre in each 6 month period). Uncontrolled data have suggested that tolerance may be more readily achieved using low-purity pdFVIII than with recombinant FVIII (rFVIII) (Kreuz et al, 1996; Gringeri et al, 2007; Kurth et al, 2011). This remains controversial and there are a number of studies showing that the reported success-rates for ITI do not appear to be influenced by the product-type (Mauser-Bunschoten et al, 1995; Brackmann et al, 1996; Batlle et al, 1999; Rocino & de Biasi, 1999; Smith et al, 1999). A randomized comparison of the efficacy of high-dose pdFVIII or rFVIII for ITI in poor-risk patients is in progress (Gringeri, 2007). First-line ITI should be conducted using rFVIII concentrate, unless as part of a clinical trial, and is usually performed with the product used by the patient at the time of inhibitor development. Starting titre is the most powerful predictor of ITI success (Mariani et al, 1994; DiMichele & Kroner, 2002) and regimens that delay treatment until the inhibitor has fallen below 10 BU/ml show very high success-rates (Mauser-Bunschoten et al, 1995; Rocino & de Biasi, 1999; Smith et al, 1999). It took a median of 5 months from diagnosis for titres to fall to <10 BU/ml in the I-ITI study (Hay & DiMichele, 2012). Rate of response to ITI did not decline until ITI had been delayed for 5 years from the time of diagnosis in the North American ITI registry (NAITR) (DiMichele & Kroner, 2002). Inhibitors that fail to fall to <10 BU/ml over 12–24 months often respond less well to ITI. Bleeds should be treated with activated recombinant FVII (rFVIIa) during this time to avoid an anamnestic response. Immune toleration induction should therefore be delayed until the inhibitor titre has fallen below 10 BU/ml. If the inhibitor is 200 BU/ml, starting titre >10 BU/ml) are best tolerized using a high-dose regimen (100–200 iu/kg/d FVIII) (Mariani et al, 1994; DiMichele & Kroner, 2002). These registries and the I-ITI study suggest that high dose and low-dose (50 iu/kg three times weekly) regimens are equally effective in inducing tolerance in good risk patients (Mariani et al, 1994; Mauser-Bunschoten et al, 1995; DiMichele & Kroner, 2002; Hay & DiMichele, 2012). By implication, therefore, 200 and 100 iu/kg/d can be assumed to be equally efficacious for inducing tolerance in good risk patients (Hay & DiMichele, 2012) but the relative effect of these high dose regimens on bleeding is unknown. Low-dose ITI (50 iu/kg three times a week or on alternate days) takes longer to achieve a negative Bethesda titre (DiMichele & Kroner, 2002; Hay & DiMichele, 2012) and is associated with significantly more intercurrent bleeding before the Bethesda titre becomes negative, a period during which 85% of intercurrent bleeding on ITI takes place (Hay & DiMichele, 2012). Low-titre inhibitors (historic peak titre 5 BU/ml requiring ITI should be started with high-dose to minimize inter-current bleeding. However, in good risk patients, dose reduction in stages can reduce costs as long as there is no subsequent increase in break-through bleeds that require by-passing therapy. This strategy would not be expected to increase the time taken to achieve tolerance (Hay & DiMichele, 2012). Although not tested in a controlled trial, a similar regimen has been reported to be successful in a small series of patients (Smith et al, 1999). There is limited evidence to guide recommendations for the conduct of ITI and the following is a pragmatic, practical consensus method. It recognizes the fact that the accurate measurement of FVIII half-life in patients with low-titre inhibitors is difficult for most haemophilia centres, that the normal FVIII half-life of an individual patient is unknown and that a FVIII half-life of 6 h is likely to be too short to be a suitable criterion for tolerance. The definition used for restoration of normal pharmacokinetics is, therefore, a post-washout half-life of >7 h or a measureable FVIII trough level at 48 h in an individual receiving standard prophylaxis (20–50 iu/kg). The regimen supports the consideration of dose reduction, whilst aiming to minimize joint bleeds and preserving long-term joint status, by tailoring to a 24- or 48-h- trough level ≥1 iu/dl, once these have become measurable (Collins