Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low-dose immune tolerance induction.

The frequency of factor VIII inhibitor development was evaluated in a hundred severe haemophilia A patients < 18 years of age (mean 10.4 +/- 5.1 years); 25 were previously untreated patients (PUPs), with a mean age of 11.2 +/- 2.9 months. All were followed up for 3 years from December 1996. Immune tolerance (IT) was induced with low-dose factor VIII (FVIII); 25-50 IU kg(-1) every other day for the 10 haemophiliacs who developed persistent inhibitors. The incidence of inhibitors for PUPs was 3/25 (12%; 95% confidence interval [CI], 0. 7-24.7%) and were detected after 4, 15 and 20 exposure days (mean 13 +/- 8.2 days; 95% CI, 3.7-22.2%). Children with maximum inhibitor levels of > 40 Bethesda units (BU) per mL (n=4) received IT therapy as 25 U kg(-1) FVIII in the form of cryoprecipitate every other day for 1-4 months (mean 2.4 +/- 1.6 months; 95% CI, 0.8-3.9%), which was successful in all of them. FVIII (50 U kg(-1)) was given every other day for six patients with maximum inhibitor level > 40 BU mL(-1) for 3-9 months (mean 5.4 +/- 3.2 months; 95% CI, 2.9 -7.9%) with success in 4/6 (66.6%; 95% CI, 28.8-104.3%). Patients who showed a good IT response had an inhibitor level < or = 30 BU mL(-1), were < or = 9 years of age at inhibitor development with few exposure days to FVIII and had an early immune tolerance. In conclusion, inhibitor development in severe haemophilia A children exclusively treated with cryoprecipitate is low. Early low-dose IT induction for high responders may be achieved successfully if inhibitor level is < or = 50 BU mL(-1).     

Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response

Immune tolerance induction (ITI) is effective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n = 16), age >6 years (n = 16), previously failed ITI (n = 4), inhibitor peak >200 BU (n = 2) and inhibitor >10 BU when ITI was started (n = 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.     

Treatment of acquired haemophilia with factor eight inhibitor bypassing activity

Haemorrhagic manifestations in patients with acquired haemophilia can be fatal if not recognized and treated appropriately. A retrospective analysis of the efficacy of factor eight inhibitor bypassing activity (FEIBA) in patients with acquired haemophilia treated in three medical centres in the past 10 years was conducted. The median inhibitor titre at treatment was 128 Bethesda Units (BU) in patients with severe and 34 BU in patients with moderate bleeding; P = 0.001. The majority of patients received FEIBA at a dose of 75 u kg-1 every 8-12 h. The number of FEIBA doses administered was higher in patients with severe compared with moderate haemorrhage, 10 vs. 6 doses per bleeding episode; P = 0.001. Complete response (CR) was achieved in 76% of severe and 100% of moderate bleeding episodes with a total CR of 86%. When compared with patients with human inhibitor titre <50 BU, those with titre >51 BU at treatment had lower median porcine titre, 1 vs. 9.5 BU; P < 0.05, fewer doses of FEIBA, 6 vs. 8.5 doses; P < 0.05, and shorter time to CR, 29 vs. 42 h; P < 0.05. Patients exposed to factor VIII concentrates prior to FEIBA had significantly higher maximum recorded human inhibitor titre compared with patients without such exposure, 273 vs. 38 BU; P = 0.0001. Treatment with FEIBA was very well tolerated and with very few side effects. This study provides evidence that FEIBA is an effective agent in acquired haemophilia and suitable for all types of patients regardless of severity of haemorrhage, underlying disease or inhibitor titre.     

Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors

We report on 11 patients (nine unrelated and a brother pair) with severe haemophilia A and factor VIII (FVIII) inhibitor, in whom immune tolerance (IIT) was induced with recombinant FVIII (r-FVIII). Their age ranged from 11 months to 47 years. The number of exposure days (ED) at inhibitor detection varied from 11 to 130. Nine of the 11 patients were high responders [>10 Bethesda units (BU)] with peak inhibitor levels ranging from 10 to 566 BU. The other two were low responders with peak levels between 0.7 and 2 BU. Before inhibitor detection, the patients had been receiving products of various purities. The IIT regimens were very heterogeneous, and the treatment schedule varied from a short period with 50 IU kg^–1 every 2 days, followed by 100 IU kg^–1 every 2 days and then 220 IU kg^–1 daily. The outcome was considered successful when the inhibitor level fell to 0.6 BU or lower after IIT treatment. The outcome overall was successful in nine out of 11 patients (81.8%), with the nine successful cases comprising seven of the nine high responders (77.8%) and the two low responders. Definite failure of IIT was observed in one high responder after two different IIT regimens. A second high responder is still on IIT treatment. All patients in whom IIT was successful are currently receiving r-FVIII on demand or prophylactically at various dosages. Despite the variability of the patient characteristics and the IIT schedules, this study demonstrates that r-FVIII represents an effective alternative for the eradication of inhibitors through IIT.     

Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven.

Recombinant factor VIIa (rFVIIa) (NovoSeveng) is used to treat bleeding episodes in hemophilia A and B patients with inhibitor antibodies against factor VIII (FVIII) and factor IX. rFVIIIa has been studied in home treatment of mild-to-moderate joint, muscle, and mucocutaneous bleeds to assess safety and efficacy. Treatment with other factor concentrates was allowed according to treating physician's judgment. Blood samples were drawn before study start and after 6 and 12 months. It has thus been possible to follow the inhibitor titres during this period. Analyses of 53 patients (49 hemophilia A, four hemophilia B) showed inhibitor levels up to 1,208 BU/ml before study start. Based on the first analysis, hemophilia A patients were divided into high responders (> 5 BU/ml; 28 patients), low responders (> 1 and < 5 BU/ml; 15 patients) and very low responders (< or = 1 BU/ml; six patients). In high responders receiving rFVIIa as only treatment, FVIII inhibitor titre decreased to one-third of the initial level. For high responders receiving other factor treatments such as FVIII or prothrombin complex concentrates, inhibitor titre remained unchanged. Titres for low responders and very low responders remained unchanged independent of treatment. Thus, when rFVIIa is used as the only coagulation factor to treat hemophilia A/B high-responder inhibitor patients, inhibitor level declines significantly.     

Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two US centres

Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two US haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success – negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success – inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure – ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty‐eight subjects were included; 32 of 39 (82%) with high‐responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.     

Rituximab in the treatment of high responding inhibitors in severe haemophilia A

The development of antibodies to factor VIII (FVIII) in severely affected haemophilia A patients is a serious complication associated with increased morbidity and mortality. Bypassing agents are used to treat acute bleeding episodes; however, elimination of the inhibitors can only be achieved with immune tolerance therapy (ITT) in 60-80% of cases. High responding (HR) inhibitors are more likely to respond to ITT if the titre is decreased to <5 BU over time or in selected cases after the administration of immunosuppressive drugs, plasmapheresis or immunoabsorption, techniques difficult to apply in children. Anti-CD20 (rituximab), a monoclonal antibody, was given as an alternative treatment in two haemophilic children with HR inhibitors and impaired quality of life, due to recurrent haemarthrosis. Rituximab was given at the dose of 375 mg m(-2), once weekly for four consecutive weeks. Both patients showed a partial response to rituximab reducing the inhibitor titre to <5 BU, thus facilitating ITT initiation; however, only the older patient eradicated the inhibitor within 21 days after application of ITT. The second patient, despite depletion of B cells, did not respond to ITT. No long-term side effects have been observed in both patients for a follow-up period of 20 and 18 months respectively. In conclusion, rituximab appears to be an alternative effective therapy to rapidly reduce or eliminate the inhibitor in selected cases of severely affected haemophiliacs before further proceeding to ITT. However, the dose and appropriate schedule, as well as long-term side effects need further investigation.     

Canadian multi-institutional survey of immune tolerance therapy (ITT) – experience with the use of recombinant factor VIII for ITT

Immune tolerance therapy (ITT) is currently the most effective approach to eradicate inhibitors in patients with haemophilia A. Limited evidence suggests that the use of plasma-derived factor VIII (pdFVIII) for ITT may be associated with a greater success rate than recombinant factor VIII (rFVIII). Analysis of ITT cases in Canada offered the opportunity to examine the success rate of using rFVIII for ITT, as rFVIII has been used almost exclusively for Canadian haemophilia A patients since 1994. The results of 32 patients from five haemophilia treatment centres were collated. Three patients continue on ITT. Of the 29 patients who completed ITT, 25 (86.2%) used rFVIII exclusively, and four used pdFVIII exclusively or pdFVIII followed by rFVIII. The initial FVIII dosing frequency was once per day in 72.4% of patients at an average dose of 98 U kg(-1) (range 50-200). Eight patients (25%) received one or more adjuvant therapies. The median duration of ITT was 1.1 years (mean 1.5 years, range 9 days to 6 years). The overall success rate of the 29 patients who completed ITT was 79.3% (23/29), which is comparable with the results of immune tolerance registries. Our results suggest that the success rate of ITT using rFVIII is not inferior to the results with pdFVIII.     

Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors

Summary.  The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (≤50 IU kg⁻¹ twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0–517), 19.2 BU (range 3.6–515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (≤10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study.     

Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF

We report long-term results of treatment of myelodysplastic syndrome (MDS) with erythropoietin and granulocyte colony-stimulating factor (G-CSF). A total of 129 patients were followed up 45 months after last inclusion in the Nordic MDS Group studies. Erythroid response rate was 39% and median response duration 23 months (range, 3-116 months or more). Complete responders showed longer response duration than partial responders (29 versus 12 months, P = .006). The International Prognostic Scoring System (IPSS) groups Low/Intermediate-1 (Low/Int-1) had longer response duration than Int-2/High (25 versus 7 months, P = .002). The time until 25% developed acute myeloid leukemia (AML) was longer in the good and intermediate predictive groups for erythroid response compared with the poor predictive group (52 versus 13 months, P = .008). Only 1 of 20 long-term responders developed AML. We assessed the effect on long-term outcome by comparing treated patients with untreated patients selected from the IPSS database using multivariate Cox regression, adjusting for major prognostic variables. There was no difference in survival (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2; P = .55) or risk of AML evolution (OR, 1.3; 95% CI, 0.7-2.2; P = .40) between treated and untreated patients. Patients with high/intermediate probability of response and with IPSS Low/Int-1 show frequent and durable responses without adverse effects on outcome, while other patients should not be considered candidates for this treatment.     

Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.     

A review of immune tolerance induction with Haemate® P in haemophilia A

Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma‐derived, von Willebrand factor (VWF)‐containing FVIII concentrate Haemate^® P/Humate‐P^® in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate^® P/Humate‐P^® including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg⁻¹ every 2–3 days in patients with low‐responding (LR; n = 5) inhibitors to 300 IU kg⁻¹ day⁻¹ in patients with high‐responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age ≤7 years, pre‐ITI inhibitor titre <10 BU, historical inhibitor titre <200 BU, time between inhibitor detection and ITI start <2 years), and in 24 of 33 (73%) HR patients with poor prognostic factors. The time to complete success was 0.5–4 months in good‐prognosis patients and 0.5–42 months in poor‐prognosis patients. Few adverse events were observed during ITI, and no cases of inhibitor relapse were reported with follow‐up periods of up to 12 years. On the basis of this retrospective review of a diverse range of studies and case reports, we conclude that Haemate^® P/Humate‐P^® for ITI in patients with inhibitors is effective and produces high rates of ITI success.     

Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate

A solvent-detergent virus-inactivated plasma-derived FVIII concentrate (SD-pdFVIII) has been employed for treatment of Italian patients with haemophilia A for 15 years. This product is a non-monoclonally purified, high purity FVIII concentrate, containing large amounts of von Willebrand factor (VWF). A retrospective survey was carried out in Italy in order to evaluate the immunogenicity of SD-pdFVIII in previously untreated patients (PUPs) or in minimally treated patients (MTPs), i.e. previously exposed for up to 5 days only to other plasma-derived concentrates. The survey included 99 patients with ages ranging from 6 to 64 years (median=21.3) of whom 31 PUPs and 68 MTPs, the latter with a median of four exposure days (EDs; range 1-5) to other plasma products. Surveyed patients had been exposed to SD-pdFVIII for a median of 83 EDs (range 21-1580). Seven patients (three PUPs and four MTPs), all with severe haemophilia, had developed inhibitors [7.1%, 95%; confidence interval: 3-14%] after a median of 11 EDs (range 4-22). Of them, two were low responders (相似文献   

Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment.

OBJECTIVE--To determine whether chronic atrial fibrillation is associated with abnormalities in plasma fibrinogen, von Willebrand factor (vWF) (a marker of endothelial disturbance), or fibrin D- dimer (a measure of fibrin turnover); and if so, whether such levels are related to haemodynamic disturbance (enlarged left atrium, poor left ventricular function) or existing treatment with warfarin or aspirin. To investigate the effects of introducing warfarin in patients with atrial fibrillation on fibrinogen and D- dimer levels. DESIGN--Cross sectional population sample controlled study and longitudinal study of patients undergoing anticoagulation. SETTING--District general hospital. SUBJECTS--87 patients (44 men and 43 women of mean (SEM) age 63.0 (1.0)) with chronic atrial fibrillation. At the time of the study, 37 were taking no antithrombotic medication (group 1), 31 were taking warfarin (including two on warfarin and aspirin) (group 2) and 19 were taking aspirin alone (group 3). They were compared with 158 population controls from a random population sample (the second Glasgow monitoring trends and determinants in cardiovascular disease study). As part of clinical treatment warfarin was introduced in 20 patients with chronic atrial fibrillation (14 men and six women of mean (SEM) (range) age 63.9 (2.35 (32-74) years). RESULTS--Plasma fibrinogen remained significantly increased in patients of group 1 (no antithrombotic medication) compared with that of the population controls (median difference 1.23 g/l; 95% confidence interval (CI) 0.88 to 1.62, P < 0.0001). There was also a significant increase in plasma D-dimer levels (median difference 77 ng/ml; 95% CI 38 to 122, P < 0.01) and vWF (median difference 63 IU/dl; 95% CI 38 to 89, P < 0.0001). There was no significant difference in plasma fibrinogen (median difference 0.14 g/l; 95% CI -0.44 to 0.77, P = 0.65) or vWF (median difference 3.5 IU/dl; 95% CI - 41 to 41, P = not significant in patients of group 2 (warfarin treatment) compared with that of patients in group 1. Levels of D-dimer were significantly lower in group 2 (median difference 90 ng/ml, 95% CI 39 to 150, P < 0.0001) than in group 1. There were no significant differences in plasma fibrinogen (median difference 0.08 g/l; 95% CI - 0.52 to 0.77, P = 0.73), D-dimer (median difference - 34 ng/ml; 95% CI - 114 to 21.0, P = 0.25), or vWF (median difference 2%; 95% CI - 35 to 41, P = not significant) levels between patients of groups 1 and 3. There were no significant correlations between the coagulation indices and left atrial volume or ventricular function. There was a significant positive correlation between plasma fibrin D-dimer and vWF levels in patients of groups 1 and 3 (r = 0.52, P < 0.001). There was a significant reduction in median plasma fibrin D-dimer levels at 2 months after the introduction of warfarin (181 ng/ml v 80 ng/ml, P < 0.001), but no effect on plasma fibrinogen. CONCLUSIONS--Increased median plasma fibrinogen and vWF levels were found in patients with chronic atrial fibrillation. Plasma D-dimer levels were also increased in patients with chronic atrial fibrillation not receiving warfarin, suggesting increased intravascular thrombogenesis in such patients. Introduction of warfarin normalised circulating fibrin D- dimer levels, suggesting that warfarin treatment was effective in preventing excessive fibrin turnover, consistent with the antithrombotic effects of warfarin. These results suggest three possible thrombotic markers to assess patients with atrial fibrillation who are at high risk of thrombogenesis; D-dimer also merits assessment as a measure of reduction in thrombotic risk in patients receiving warfarin.     

Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death

Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 +/- 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.     

Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products

In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter. Of the 72 hemophilia A patients, 22 (32%) developed an inhibitor after 15 ED in median (range 4 to 195); 17 (77%) were high responders (>5 Bethesda Units [BU]), and the remaining 5 patients (23%) were low responders (>0.6 to 5 BU). The severely affected patients (n = 46) showed a significantly higher frequency of inhibitor formation (43%) than did the moderate ones (8%). Comparing the severely affected patients receiving pd products exclusively (n = 35) with those treated with recombinant concentrate (n = 11), 37% of the pd group developed a high-titer inhibitor (>5 BU, median 290 ED in noninhibitor patients) and 36% of the recombinant group (median 49 ED in the noninhibitor patients). However, the exposure status of the recombinant noninhibitor patients is rather low and therefore remains a high risk of developing further inhibitors in the future. The mutation type profile revealed no difference between the pd- and the recombinant-treated patients.     

Treatment options for bleeding episodes in patients undergoing immune tolerance therapy

Inhibitors to factor VIII develop in 4–20% of haemophilia A patients, with the percentage rising to 52% in certain subpopulations. The management of inhibitor patients is directed toward stopping acute haemorrhages, providing short-term haemostasis before and after surgery, and inducing immune tolerance to factor VIII (immune tolerance therapy or ITT). Several different protocols have been used for ITT, but they are all centred around ongoing exposure to high doses of factor VIII. High responders (those patients with a large increase in inhibitor level after exposure to factor VIII) are the prime candidates for ITT, but low responders may also benefit from this treatment. It is often necessary to treat bleeding episodes during ITT, because elimination of inhibitors may require many years of therapy. Treatment of haemorrhages in inhibitor patients is reviewed for both low and high responders during ITT and in the absence of ITT. The choice of clotting agent for inhibitor patients who have not yet responded to ITT depends on current and past inhibitor levels, the severity of the haemorrhage, the site of the haemorrhage or the setting in which it occurs (e.g. surgical), and the extent of inhibitor cross-reactivity with porcine factor VIII. Patients with high-titre inhibitors experiencing a critical haemorrhage are generally best managed with bypassing agents (AUTOPLEX® T or FEIBA® VH), porcine factor VIII or rFVIIa.     

Immune tolerance induction in haemophiliacs with inhibitor to FVIII: high- or low-dose programme

Summary. In 1993–94, 15 high responders were treated in our centre according to the Malmo protocol which was modified as follows: serial plasmapheresis was performed instead of extracorporeal adsorbtion to protein A for reducing inhibitor levels and, after the bolus dose to neutralize the inhibitor, factor VIII concentrate was administered by a continuous infusion. Thus, this regimen included continuous infusion of factor VIII(FVIII) for 1–4 weeks, iv cyclophosphamide for 2 days and orally for 8–10 days, and intravenous immunoglobulin (IVIG) from the fourth day for 5 days. All patients had been qualified for the treatment when the antibody level was < 15 BU mL⁻¹. Tolerance was induced in 10 patients (66.6% very good and good results). The treatment failed in five cases in which, due to a high inhibitor level, it was not possible to maintain a measurable factor VIII:C concentration throughout the whole period of infusion. We compared these results with results of our low-dose regimen: 25 IU FVIII kg⁻¹ b.w. twice a week (1985–89, 11 high responders). The modified Malmo Protocol is much shorter than the low-dose programme and this is a method of first choice in patients undergoing surgery in the near future.     

Risk Factors for Prognosis of Hepatocellular Carcinoma After Curative Resection In Patients with Low Hepatitis B Viral Load

BackgroundA retrospective cohort study was conducted to investigate the effect of hepatitis B surface antigen (HBsAg) level on prognosis in low viral load (< 2000 IU/mL) patients with hepatitis B-related hepatocellular carcinoma (HCC) after curative resection.Material and MethodsA total of 192 patients with low viral load who had received curative resection of pathologically confirmed HCC were analyzed to determine the factors affecting prognosis. The risk factors for survival, early and late recurrence (2 years as a cut-off) were studied.ResultsThe median follow-up time was 38.5 months. The overall survival rates at 1-, 3-, and 5-year after curative resection were 94.2%, 64.0%, and 45.2%, respectively. The cumulative recurrence rates at 1-, 3-, and 5-year after curative resection were 22.4%, 46.5%, and 67.0%, respectively. Patients with high serum HBsAg levels (> 250 IU/mL) had significantly lower survival rates than those with low HBsAg levels (HR: 1.517, 95% CI: 1.005-2.292, P = 0.047). Stratified analysis showed that patients with high HBsAg levels had a significantly higher late recurrence incidence than those with low HBsAg levels (HR: 2.155, 95% CI: 1.094-4.248, P = 0.026), but did not have a significantly higher risk of early recurrence postoperatively (HR: 1.320, 95% CI: 0.837-2.082, P = 0.233). Multivariate analysis revealed that HBsAg > 250 IU/mL was an independent risk factor associated with late recurrence (HR: 2.109, 95% CI: 1.068-4.165, P = 0.032).ConclusionsHBsAg > 250 IU/mL at the time of tumor resection was an independent risk factor for late recurrence in low viral load HCC patients.