THE DIAGNOSIS and MANAGEMENT OF FACTOR VIII and IX INHIBITORS: A GUIDELINE FROM THE UK HAEMOPHILIA CENTRE DOCTORS' ORGANIZATION (UKHCDO)
2000; Wiley; Volume: 111; Issue: 1 Linguagem: Inglês
10.1111/j.1365-2141.2000.02327.x
ISSN1365-2141
AutoresC. R. M. Hay, Trevor Baglin, P. Collins, F. G. H. Hill, David Keeling,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoThe expected incidence of inhibitors in severe haemophilia A and B approaches 33% and 3% respectively (Katz, 1996). The occurrence of this complication has significant clinical implications, as the response to treatment becomes uncertain, morbidity is increased and life expectancy reduced. Direct medical costs are much higher for inhibitor patients (Goudemand, 1998), as are direct non-medical costs to the patient, their family and to society as a whole. This must be fully recognized by commissioners or purchasers of haemophilia services. Since the previous guideline on the detection and management of factor VIII inhibitors was published, significant diagnostic and therapeutic advances have taken place (Hay et al, 1996a). The UK Haemophilia Centre Doctors' Organization (UKHCDO) has therefore revised, updated and substantially rewritten the earlier guideline. In doing so, we have tried to define best current practice internationally, as reflected by the literature. We have avoided recommending one haemostatic product over another where no direct comparative trials have been conducted. Where marked national differences in clinical practice exist, in immune tolerance induction for example, we recommend the strategy for which the highest level of evidence exists. This evidence-based approach highlights the need for future clinical trials in areas where current treatment strategies are based on uncontrolled observations and where there is a dichotomy of clinical opinion. The guidelines were drafted by the UKHCDO Inhibitor Working Party and circulated to the Executive Committee of the UKHCDO for consultation and editorial commentary. These include several members who practice only paediatric haematology and two members who are primarily general haematologists. Members of the working party make an annual declaration of interest to UKHCDO. Relevant scientific papers were identified from Medline using the index terms h(a)emophilia, factor VIII and IX, inhibitors, antibodies, alloantibodies, autoantibodies and management [Agency of Health Care Policy and Research (AHCPR), 1992]. Recommendations were based on reports with the highest levels of evidence available (see Appendix). Inhibitors develop in patients with severe haemophilia A after a median of 9–12 treatment days (Ehrenforth et al, 1992; Addiego et al, 1993; Lusher et al, 1993). Outbreaks of inhibitors among frequently treated adults normally considered to be at low risk of inhibitor development have also been reported in relation to changes in factor VIII concentrate manufacture (Peerlinck et al, 1993; Rosendaal et al, 1993; Rosendaal (1997). Therefore, patients should be screened more frequently during the early phase of treatment and following any change to a new and un-established type of factor VIII concentrate. Patients with factor IX deficiency should be monitored in the same way. In vitro laboratory tests for the detection and quantification of factor VIII antibodies will detect those neutralizing inhibitor antibodies that interfere with the function of factor VIII or IX. Factor VIII recovery and plasma half-life studies are required for the detection of inhibitor antibodies that reduce factor VIII survival and for the detection of very low-level inhibitors. Children on regular prophylaxis and lacking free antibody are an example of this. Patients should be screened for inhibitors after every 5th exposure day or every 3 months until the 20th exposure day, every 6–12 months thereafter and prior to any surgical procedure. Patients should also be screened for inhibitors if the frequency of bleeding increases or if the clinical or laboratory response to replacement therapy is poor (grade B recommendation based on level III evidence). If the clinical response or factor VIII increment are poor, an estimate of factor VIII recovery and/or half-life should be conducted, particularly if the inhibitor assay is negative (grade B recommendation based on level III evidence). Screening for inhibitors is normally conducted using an activated partial thromboplastin time (APTT)-based or Bethesda method, but children on regular prophylaxis should be screened using factor VIII/IX recovery or half-life measurements (commonly peak and trough factor VIII/IX measurements in the first instance) (grade C recommendation based on level IV evidence). Factor VIII inactivation by inhibitors is time and temperature dependent (Lossing et al, 1977) and so the APTT of the patient:pooled-plasma mixture should be measured immediately after mixing and after incubation. The most widely used APTT screening method for factor VIII inhibitors compares the APTT of a patient:pooled-plasma mixture immediately after mixing and after 2 h incubation (Ewing & Kasper, 1982). Each laboratory must standardize this test independently and determine what they consider an abnormal result. It is recommended that an APTT-based method should be used to screen patients for factor VIII inhibitors (level 1b recommendation based on grade A evidence). The Bethesda assay has been recommended as the standard method for measuring the factor VIII inhibitor titre (Kasper et al, 1975). The original Bethesda method may give false-positive results owing to loss of factor VIII activity caused by a pH shift and reduced protein concentration unrelated to the presence of an inhibitor. The Nijmegen modification of the assay avoids this pH shift (Verbruggen et al, 1995). False-positive results are eliminated by this modification, which has now been recommended by the International Society of Thrombosis and Haemostasis Factor VIII/IX Scientific Sub-committee (Giles et al, 1998). The Bethesda assay can be modified to measure the degree to which an inhibitor inactivates porcine factor VIII using porcine factor VIII concentrate as substrate (Hyate:C, Ipsen, UK). This is diluted in haemophilic plasma to a concentration of 100 IU/dl and measured in a standard factor VIII assay using the usual reagents and standards. Factor IX inhibitory activity may be quantified using the Bethesda method, but omitting the two-hour incubation (Ewing & Kasper, 1982). There are no published data on the role of the Nijmegen modification for the quantification of factor IX inhibitors. Factor VIII inhibitors should be quantified using the Nijmegen modification of the Bethesda assay (grade A recommendation based on level Ib evidence). Factor VIII inhibitor titre should initially be quantified to both human and porcine factor VIII and, subsequently, if treatment with porcine factor VIII is contemplated (grade B recommendation based on level III evidence.) Factor IX inhibitors should be quantified using the Bethesda assay without an incubation period (grade B recommendation based on level III evidence). The diagnosis is established by the demonstration of an isolated, time-dependent, prolongation of the APTT. Specific tests for the lupus anticoagulant should be negative. A marked reduction in factor VIII is commonly accompanied by more modest in vitro reductions in factor IX, XI and XII activity, which may create the false impression that the inhibitor is non-specific. This is a laboratory artefact caused by depletion of factor VIII in the substrate plasma, which may be 'diluted out' so that assays of increasing dilutions of the patient's plasma give progressively increasing factor IX, XI and XII levels while having no effect on the uniformly low factor VIII level. The inhibitor titre should be determined using both human and porcine factor VIII because factor VIII auto-antibodies usually exhibit little inhibitor activity against porcine factor VIII (Kasper, 1991; Fiks-Sigaud et al, 1993; Morrison et al, 1993). The Bethesda assay may underestimate inhibitor potency in acquired haemophilia because the second-order reaction kinetics result in the persistence of low levels of factor VIII, even after prolonged incubation. It has been suggested that, for consistency, in this situation, one should report the inhibitor titre calculated from the lowest dilution that results in approximately 50% residual factor VIII after the 2 h incubation (Kasper, 1991). The diagnosis of acquired haemophilia should be based upon the clinical presentation, an isolated prolongation of the APTT that corrects initially with normal plasma, but which prolongs on incubation, a marked reduction in factor VIII concentration (usually < 0·01 IU/ml) and an inhibitor measurable using the Bethesda Assay. Specific tests for the lupus anticoagulant should also be negative. It is also recommended that the inhibitor in acquired haemophilia should be quantified using both human and porcine factor VIII, calculated from the lowest dilution that results in approximately 50% residual factor VIII (grade B recommendation based on level III evidence). For pharmacokinetic studies in adult patients, samples are taken at several time-points up to 2 h after infusion to establish the peak factor VIII value. Recovery is calculated from the peak plasma factor VIII concentration using a formula that requires an estimation of plasma volume and which is unsuitable for paediatric use (Kjellman, 1984; Kasper, 1991; Morfini et al, 1991). In routine clinical practice, a single measurement taken 30–60 min after infusion is usually used. Factor recovery percentage should be calculated with reference to the recovery constant (k) for that product, as this constant may vary from one product to another. k is commonly taken as 2·0 for factor VIII and 1·0 for factor IX, but different values apply to some factor VIII concentrates and to recombinant IX (Benefix, Genetics Institute, USA). Normal recovery values range from 75% to 100% (Kjellman, 1984). Recovery and half-life are commonly lower in children. A factor VIII recovery as low as 66% and a half-life as low as 6 h may be observed in small haemophilic children lacking inhibitors. There are minor differences when recovery is calculated using one- or two-stage assays and recovery may be 20–30% higher when the chromogenic assay method is used (Lee et al, 1996). Pharmacokinetic studies of B-domain-deleted recombinant factor VIII (BDDrFVIII, Refacto, Wyeth, USA) should be conducted using either the chromogenic method or a one-stage method that uses a specific standard or a thromboplastin optimized for this product. The standard one-stage factor VIII assay may underestimate BDDrFVIII recovery by 30–50%. Factor VIII recovery should be based upon the difference in factor VIII concentration between a sample taken pre- and 30–60 min after infusion (grade C recommendation based on level IV evidence). B-domainless factor VIII should be measured using either a chromogenic assay or a one-stage assay using a specific, standard (grade B recommendation based upon level IIb evidence). Factor VIII recovery in children should be calculated using a simple formula that requires no estimate of plasma volume (grade B recommendation based upon level III evidence). Factor VIII activity-time curves fit a biphasic two-compartment model. The initial decline in factor VIII is the distribution (disappearance) half-time and is complete within 4 h. The second slope of decay is the elimination half-life. The half-disappearance time is the time from infusion until the factor VIII concentration has fallen to 50% of the peak post-infusion level. Short half-life studies are influenced more by the distribution half-life than by the elimination half-life and so it is recommended that half-life studies are continued for at least 24–48 h after infusion. Model-dependent or model-independent analysis may be used to analyse the data, but will not give the same results (Lee et al, 1990; Morfini et al, 1991). Different computer programmes used to analyse the same data set may also give different estimates of pharmacokinetic parameters. Although a non-compartmental model is less subject to this variability, it may give different results from a two-compartment model (Pascual & Montoro, 1997). In most half-life studies, 50 U/kg of factor VIII or 75 IU/kg of factor IX are infused after a washout period of at least 72 h or when the baseline factor level is reached (typically < 0·01 u/dl). Samples should be taken regularly for 48 h or until the factor activity has fallen to baseline levels. In the absence of a pharmacokinetic computer model, the elimination half-time should be calculated by linear least-squares regression analysis (Kjellman, 1984; Kasper, 1991). At least four sample-points are required to establish a log-linear phase (Kasper, 1991). Half-life studies should be conducted after a wash-out period or when the factor VIII or IX level has reached baseline. A sample should be taken at 1 h, 4 h and at several points thereafter until the factor VIII activity has fallen to baseline (grade B recommendation based on level III evidence). The two aspects of inhibitor management, inhibitor abolition through immune tolerance induction and the haemostatic management of bleeding episodes and surgery, will be reviewed separately. Immune tolerance induction (ITI) requires study on an international collaborative basis if we are to learn how this approach may be optimized and applied in the most cost-efficient way. ITI must be viewed as a long-term investment and the period of intensive treatment compared with the cost of life-long treatment in the presence of a persistent high inhibitor titre. Treatment of acute bleeding must be active and initiated early, as this aggressive approach should reduce patient morbidity or mortality and also reduce overall direct medical costs. It is important that commissioners and treaters enter into partnership so that the clinical effectiveness, cost benefit and cost-effectiveness of immune tolerance and other treatment approaches are studied and analysed prospectively by national and international studies. The management of such patients should be supervised by a Haemophilia Comprehensive Care Centre, as defined in the NHS Executive Health Service Guidelines (HSG) 30 (1993). Factor VIII inhibitors may be abolished in more than 80% of selected patients with severe haemophilia A ITI (Nilsson et al, 1988; Mariani et al, 1994; Kreuz et al, 1995; Mauser-Bunschoten et al, 1995; Brackmann, 1996; DiMichele et al, 1999,2001). Successful ITI leads to normalization of the factor VIII half-life, a marked improvement in the patient's quality of life and a considerable reduction in the future cost of treatment. Current knowledge of ITI for factor VIII and IX inhibitors is derived from uncontrolled series of patients treated using various factor VIII dose regimens and the results of three retrospective surveys of ITI. These surveys include the International Immune Tolerance Registry (IITR, Mariani et al, 1994), the North American Immune Tolerance Registry (NAITR, DiMichele et al, 1999, 2001) and the German Immune Tolerance Registry (GITR, Lenk, 1999). There are no controlled comparisons of the regimens currently used for ITI and no agreement on the optimal regimen to be used. The most important predictor of successful ITI is the inhibitor titre at the start of ITI, which affects both the likelihood of success and the time taken to achieve tolerance. An inhibitor titre of < 10 Bethesda units (BU)/ml at the time of initiation of ITI significantly correlated with successful outcome in both the NAITR and the IITR (P = 0·004 and 0·001 respectively) (Mariani et al, 1994; DiMichele et al, 1999,2001; Lenk, 1999). The success rate and time to success for patients starting ITI with an inhibitor titre of < 10 BU/ml was 85% and 11 months compared with 43% and 15 months for patients with inhibitors of > 10 BU. Most other studies show a similar relationship between the starting inhibitor titre, the outcome and the time taken to achieve tolerance (Kreuz et al, 1995; Mauser-Bunschoten et al, 1995). A low peak historical inhibitor titre prior to ITI has been said to predict successful ITI, but this variable was far less strongly related to outcome than the inhibitor titre at the start of ITI in the IITR or NAITR (Mariani et al, 1994; DiMichele et al, 1999). Very high starting inhibitor titres of > 500 BU/ml are associated with resistance and a poor response to ITI (level IIb, Mariani et al, 1994; Kreuz et al, 1995; Mauser-Bunschoten et al, 1995; DiMichele et al, 1999). Although it is widely believed that ITI should start as soon as possible after the inhibitor is detected, there is no firm scientific basis for this approach. A short interval between inhibitor detection and the initiation of ITI predicted a successful outcome in some studies (Mariani et al, 1994; Kreuz et al, 1995), but not others (Mauser-Bunschoten et al, 1995; DiMichele et al, 1999, 2001). The chance of achieving successful ITI should be enhanced by deliberately deferring the initiation of ITI until the inhibitor titre has declined below 10 BU/ml and preferably below 5 BU/ml, as the success of ITI relates significantly to the starting inhibitor, but not to the peak historical inhibitor titre. Series in which ITI was deferred either deliberately or by circumstance until the inhibitor titre was < 10 BU/ml have been notably successful (Mauser-Bunschoten et al, 1995; Smith et al, 1999; Rocino et al 2000). These authors report similar success-rates of 88–100%, despite using widely varying factor VIII dose rates. The influence of the dose of factor VIII used is disputed. The IITR suggested that larger doses are significantly more effective, particularly in patients with inhibitor titres of > 10 BU/ml (Mariani et al, 1994). In contrast, neither the NAITR nor the GITR were able to demonstrate such a dose relationship (DiMichele et al, 1999, 2001; Lenk, 1999). Furthermore, the low-dose regime has been reported to achieve a success rate of 88% amongst a cohort in whom the inhibitor titre had declined to < 10 BU/ml before the initiation of ITI (Kreutz et al, 1995; Mauser-Bunschoten et al, 1995; Brackmann, 1996; Lenk, 1999). Tolerance may be induced more easily in younger patients whose inhibitors are not long established (Mariani et al, 1994; Kreuz et al, 1995; Mauser-Bunschoten et al, 1995), although this is disputed by DiMichele et al (1999,2001). There are no convincing data to suggest that any particular type or brand of factor VIII concentrate is more or less effective for ITI. Although Kreuz has suggested that patients may be more readily tolerized using intermediate-purity factor VIII concentrate, this data is inconclusive and is based on uncontrolled observations in six patients (Kreuz et al, 1996). Others have demonstrated similar success using high-purity or recombinant factor VIII concentrates (Smith et al, 1999; Rocino et al 2000). Many low-level inhibitors will disappear spontaneously without ITI, although troublesome inhibitors may also present with a low titre. It would be reasonable therefore for inhibitors presenting with a titre of 2 BU/ml or less to be monitored weekly for evidence of an increase in titre and to defer initiation of ITI. Tolerance is achieved by the regular administration of factor VIII or IX over a period of a few months to two or more years. Widely differing doses of factor VIII have been used, varying from 50 IU/kg three times a week to 300 IU/kg/d. Intermediate doses of 50 or 100 IU/kg/d are also widely used with success. The regimens in common use are summarized in Table I. Regimens that combine intensive factor VIII/IX replacement with concomitant immunosuppression have also been described and are outlined in the table (Nilsson et al, 1988). The best described of these is the Malmo regimen, in which high-dose factor VIII or IX replacement is combined with cyclophosphamide, high-dose immunoglobulin and protein A immuno-adsorption (Nilsson et al, 1988; Berntorp & Nilsson, 1996). This regimen is not in wide use as immuno-adsorption is difficult in small children and clinicians are also reluctant to use cyclophosphamide in this group. The optimum approach to immune-tolerance induction has not been agreed. Although high-dose regimens may achieve tolerance more rapidly, it is not clear whether their overall success rate is superior to that obtained using a low-dose regimen. Low-dose regimens may be administered more readily than high-dose regimens without the use of central lines and may also be more acceptable for the patient and parents. Intensive factor VIII or IX replacement therapy for ITI may require central venous access and the immediate availability of bypass therapy such as FEIBA or Autoplex (Baxter) or recombinant VIIa (rVIIa, Novoseven, Novo Nordisk, Denmark). Interruption of ITI and intercurrent infection should be avoided during the course of ITI, as they may adversely influence both success and the time taken to achieve tolerance (Kreuz et al, 1995; Brackmann, 1996; Lenk, 1999). During immune tolerance therapy, the inhibitor should be quantified at regular intervals until free inhibitor is no longer detectable using the Bethesda assay. Factor VIII recovery should be estimated at intervals until normal (≥ 66%). When recovery is normal, the factor VIII half-life should be determined at intervals until it is also normal (≥ 6 h). Tolerance is generally taken as restoration of normal factor VIII recovery and half-life. In North America, ITI is discontinued and factor VIII prophylaxis started as soon as tolerance has been demonstrated (DiMichele et al, 1999). In Europe, it is more usual to continue ITI for several months after tolerance is established and then to tail the factor VIII dose down over 3 months before starting normal prophylaxis (Mariani et al, 1994; Kreuz et al, 1995; Brackmann, 1996; Lenk, 1999). This tailing-off procedure is not of proven value, given that the rate of relapse is very low regardless of whether the patient's factor VIII dose is tailed off or stopped abruptly. There are few published reports of immune-tolerance induction in haemophilia B as factor IX inhibitors are rare. All the regimens previously described have been used for haemophilia B with some success using doses of factor IX similar to the doses of factor VIII used for ITI of factor VIII inhibitors (Nilsson et al, 1988; DiMichele et al, 1999). Considerations peculiar to ITI in haemophilia B include the risk of treatment-related thrombosis, transfusion reactions, the nephrotic syndrome and a comparatively poor overall response rate to ITI. Immune tolerance should be attempted using high purity factor IX concentrates or recombinant factor IX to avoid the thrombogenicity associated with high doses of prothrombin complex concentrates (PCCs). Some patients with a history of allergic reactions have received ITI with factor IX, but most continued to require premedication with anti-histamines and steroids (Warrier, 1998;Warrier et al, 1998). An association between allergic reactions to factor IX and nephrotic syndrome has also been reported in patients treated with large doses of factor IX for ITI. The nephrotic syndrome arose after a median of 9 months ITI (range 8–36 months) (Ewenstein et al, 1997; Warrier, 1998; Warrier et al, 1998). These patients did not respond to steroids, but some improved following a dose reduction or discontinuation of ITI (Warrier, 1998; Warrier et al, 1998). The relative risks and benefits of ITI should be carefully considered in patients with factor IX inhibitors and a history of reactions in view of the relatively low success rate reported and the high risk of the nephrotic syndrome. Immune tolerance induction is recommended for patients with congenital haemophilia A or B and a confirmed factor VIII or IX inhibitor and should be considered as early as possible after the presence of an inhibitor has been confirmed (grade B recommendation, level of evidence IIB). ITI should be conducted under the supervision of a Haemophilia Comprehensive Care Centre as defined by NHS Management Executive Health Service Guidelines (HSG) 30 (1993) (grade C recommendation based on level IV evidence). Immune tolerance induction is demanding for both patients and parents, and documented informed consent should be obtained from the parents or guardian before starting (grade C recommendation based on level IV evidence). The haemophilia centre conducting the ITI should have immediate availability of factor VIII/IX bypass therapy (Feiba, Autoplex or recombinant factor VIIa) and facilities for the placement of central venous catheters for IV access (grade B recommendation based on level IIb evidence). It is recommended that, prior to the initiation of ITI, bleeding should be managed on demand with bypass therapy, preferably using recombinant factor VIIa (Novoseven) to avoid an anamnestic rise in inhibitor titre. ITI should be deferred until the inhibitor titre has fallen below 10 BU/ml (and preferably below 5 BU/ml). It is recommended that all patients undergoing ITI be entered into comparative clinical trials of ITI for which they are eligible, or that data from their ITI procedure be included in one of the international registries of ITI (grade B recommendation based on level III evidence). Current UKHCDO policy is that immune tolerance in children under the age of 16 years should be conducted using recombinant factor VIII or IX, where available, in accordance with the Health Service Circulars (HSC)1998/033 (1998),HSC1999/006 (1999) and current UKHCDO therapeutic Guidelines (UKHCDO, 1997) (grade B recommendation based on level 1B evidence). Interruption of ITI should be avoided (grade C recommendation based on level IV evidence). During immune tolerance, the inhibitor titre should be estimated monthly until free inhibitor is no longer detectable. Recovery should then be determined monthly until normal and then half-life determined every 3 months until tolerance is confirmed. Tolerance is defined as the restoration of normal factor VIII recovery and half-life (grade C recommendation based on level IV evidence). Once tolerance has been achieved it is recommended that factor VIII or IX prophylaxis start immediately, without further ITI or tailing-off of the factor VIII/IX dose (grade B recommendation based on level III evidence). A number of haemostatic agents are available for the treatment of bleeding in patients with congenital haemophilia A and inhibitors. Patients with low-titre inhibitors of < 2 BU/ml will respond well to increased doses of human factor VIII. It is common clinical experience that inhibitors of up to 5 BU/ml may be overcome by large doses of human factor VIII, although other products may be more effective. When the inhibitor titre is in excess of 5 BU/ml, human factor VIII is probably ineffective. Porcine FVIII may not cross-react with the patient's antibody to human FVIII. A retrospective survey of 154 patients found a median inhibitor cross-reactivity to porcine FVIII of 15%. Twenty-seven per cent of these patients had no reactivity at all to this product in the Bethesda assay (Hay et al, 1996b). Efficacy has been reported in up to 90% of bleeds (Gatti & Mannucci, 1984; Kernoff et al, 1984; Brettler et al, 1989). Anamnesis may follow the use of porcine FVIII less frequently than human FVIII, occurring after 25–35% of infusions (Gatti & Manucci, 1984; Kernoff et al, 1984; Brettler et al, 1989). Specific anti-porcine FVIII inhibitors may also arise following treatment, preventing regular replacement therapy in about a third of patients who have a brisk specific anamnestic response. A post-infusion fall in platelet count is common after treatment, but is usually transient and clinically insignificant (Kernoff et al, 1984; Brettler et al, 1989; Hay et al, 1996b). Intensive replacement therapy may sometimes be associated with a progressive fall in platelet count. This has been attributed to agglutination by porcine von Willebrand factor (Altieri et al, 1986). It has been suggested that platelet activation with this product may provide an additional mechanism for haemostasis, accounting for the clinical observation that patients with very high inhibitors may still respond to porcine factor VIII in the absence of a measurable factor VIII increment (Chang et al, 1998). Transfusion reactions follow 3–5% of infusions, but are usually minor or moderate in degree and follow the administration of large doses (Kernoff et al, 1984; Brettler et al, 1989; Hay et al, 1996b). Occasional patients have reactions with every infusion and may not be treated regularly with this product (Hay et al, 1996b). The risk of reactions and the effect on platelet count are reduced by the administration of porcine factor VIII by continuous infusion, a mode of administration that should also have pharmacokinetic advantages (Bona et al, 1993; unpublished observations). Although porcine FVIII is not virally attenuated, most porcine viruses are not zoonotic and have not been shown to transmit viral infection to man. Prothrombin complex concentrates contain varying amounts of the vitamin K-dependent factors II, VII, IX and X. It is not clear how they promote haemostasis, but it is presumed to be as a result of small amounts of activated factors VIIa, IXa and Xa. PCCs are effective in approximately 50% of haemarthroses (Lusher et al, 1980). aPCCs [factor VIII inhibitor by-passing activity (FEIBA) and Autoplex] have undergone a deliberate controlled activation during manufacture and so contain higher levels of activated factors. FEIBA was found to be more effective than PCCs in a controlled comparison, with response rates of 64% and 52% respectively (Sjamsoedin et al, 1981). In a further randomized, controlled trial, Autoplex was found to be no better than a PCC (Lusher et al, 1983). Response rates with FEIBA have been reported to be as high as 80–90% (Hilgartner & Knatterud, 1983; Negrier et al, 1997). Negrier et al (1997) reported that FEIBA had controlled bleeding effectively after 95% of surgical procedures. Success rates of 75% (three out of four) and 95% (13 out of 14) hav
Referência(s)