Retrospective analysis of 1,226 Chinese patients with haemophilia in a single medical centre

Haemophilia A (HA) and B (HB) are X-linked congenital disorders caused by deficiencies of Factor VIII and FIX. Being the world’s most populous country, China potentially has a large population of haemophilia patients. During the last decade, no studies have been published regarding the clinical information of haemophilia in China. A retrospective study was conducted in patients with HA and HB referred to Tianjin Haemophilia Centre between 2002 and 2012. We identified 1,226 males with haemophilia (1,019 HA and 207 HB). The results revealed that activate partial thromboplastin time was negatively correlated plasma factor level of person with haemophilia. Our data did not offer sufficient evidence of any relationship existed between disease severity and risk or site of haemorrhage. There was a trend toward a higher inhibitor incidence induced by plasma-derived factor VIII products, than by recombinant FVIII (rFVIII) alone. It seemed that second generation of rFVIII more likely developed inhibitor, and first generation of rFVIII was nevertheless more closely connected to high-titer inhibitor. We found that delay in diagnosis and blood-borne infections were significantly reduced, while the joint deformity rate did not decrease despite the wide variety of products to choose from in this decade. The development of inhibitor still remains a major challenge in replacement therapy in haemophilia.     

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin‐free recombinant factor VIII product (ADVATE®)

Summary. Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin‐free recombinant full‐length FVIII product (ADVATE^®). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell‐produced to a baby hamster kidney cell‐produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.     

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.     

Allergic reaction in a cohort of haemophilia A patients using plasma‐derived factor VIII (FVIII) concentrate is rare and not necessarily triggered by FVIII

In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma‐derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti‐FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti‐pdFVIII IgE and IgG4, but no anti‐recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high‐responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti‐pdFVIII and anti‐rFVIII IgG4 were detected, no anti‐FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti‐FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti‐FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII.     

Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma-derived factor VIII concentrates

The development of inhibitors to factor VIII or IX is the most serious complication of haemophilia therapy. While early surveys revealed inhibitor prevalences of 3.6-25%, recent studies, especially those using recombinant DNA-derived products, have prompted speculation as to whether ultrapurified products may cause a higher incidence of inhibitors. Although studies of ultrapure rFVIII in previously treated patients have not shown an increased inhibitor risk, in previously untreated patients (PUPs) with severe haemophilia A (factor VIII < 2%), cumulative incidences of approximately 30% have been reported. The majority of these inhibitors are low responders; many have disappeared spontaneously despite continued treatment with the study product (i.e. transient inhibitors), and were most probably detected as a consequence of frequent inhibitor testing. The mutation causing haemophilia has recently been shown to be a significant risk factor for developing an inhibitor; mutations leading to the absence of endogenous factor VIII protein (for example, large multidomain deletions, nonsense mutations, isochromosomal intron 22 inversions) are associated with the highest risk of inhibitor development. Furthermore, recent prospective studies of plasma-derived products reveal inhibitor incidences (i.e. 21-52%) that are comparable to those obtained with recombinant products. When comparing the incidences of high-responder inhibitors (> 10 BU) among recent prospectively studied severe haemophilia A cohorts (i.e. 11-41%), differences between plasma-derived and recombinant products cannot be discerned. New studies of either recombinant or plasma-derived products should consider all known parameters influencing inhibitor formation, thereby facilitating meaningful comparisons of inhibitor risk.     

A prospective clinical trial of implantable central venous access in children with haemophilia

To assess the risks associated with the use of central venous ports in children with haemophilia, 15 HIV-negative patients were prospectively evaluated. Port insertion was required for immune tolerance in two inhibitor patients and continuous prophylaxis in 13 patients with severe factor VIII deficiency, for whom surgery was covered with recombinant factor VIII (rFVIII), then given daily at home until day 6. One inhibitor patient (titre 7 BU/ml) received high-dose rFVIII by continuous infusion until day 3, followed by an immune tolerance treatment scheme; the other (titre 12 BU/ml) was given recombinant activated factor VII by continuous infusion until day 7. After training on the use of the port, all patients continued their infusion programme at home. All ports remained in place for a median period of 413 d (range 125–509). The median number of entries into the port was 184 (range 53–567). Port-site haematoma and infection occurred in one patient on day 7 when an inhibitor became detectable (titre 12 BU/ml). An infectious complication occurred in another patient after 310 d. The port infection rate was 0.42 per 1000 patient-days (0.33 per 1000 entries into the port). This protocol for port placement with short hospitalization appears feasible and safe.     

Epidemiology of inhibitor formation with recombinant factor VIII replacement therapy

This article reviews the epidemiology of inhibitor formation in patients receiving recombinant factor VIII (rFVIII) replacement therapy for haemophilia A. Data from pivotal trial programmes, post-marketing surveillance studies, and pharmacovigilance studies for all available rFVIII products were reviewed. To date, no comparative studies have been performed, and in the non-comparative studies, there were differences in the patient population enrolled and study design (including the number of patient exposure days). In the absence of comparative clinical trials, it is not possible to make comparisons between inhibitor data for the various rFVIII products. This review of the epidemiological data shows that across the pivotal trial programmes for rFVIII products, the observed incidence of inhibitors was in the range of 15-32% in previously untreated patients (PUPs) and 0.9-2.9% in previously treated patients (PTPs). High-titre inhibitors (peak >5 BU) were detected in 10-16% of PUPs and 0-2.3% of PTPs. Several initiatives proposed to help standardize collection and interpretation of inhibitor data for patients receiving rFVIII treatment are described. Such standardization would help to clarify the epidemiology of inhibitor formation across FVIII treatments.     

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate®): a prospective pharmacovigilance study

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.     

Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development

Summary.  The development of inhibitors in previously untreated patients (PUPs) with haemophilia A is correlated with a variety of endogenous and exogenous risk factors. It is still controversial whether recombinant factor VIII (rFVIII) products pose a higher risk for inhibitor development than plasma-derived (pd) FVIII concentrates, particularly with intact von Willebrand factor (VWF). A systematic review on the epidemiology of inhibitors in haemophilia A investigated the influence of different FVIII products on inhibitor formation. Patients treated with a single pd product had a lower cumulative incidence (0–12.4%) than those treated with a single recombinant concentrate (36.0–38.7%) independent of disease severity, study size, or inhibitor testing frequency. However, this analysis does not take into account the heterogeneity of the study populations. A study investigating the effects of different variables on inhibitor development in PUPs was started 13 years ago by the Paediatric Committee of the German, Austrian and Swiss Society on Thrombosis and Haemostasis Research. This prospectively conducted study revealed a slight difference ( P  = 0.08) in terms of type of concentrate. In the group of severe haemophiliacs treated with pdFVIII concentrate ( n  = 57), 12 patients developed an inhibitor (21%), whereas 17 of 47 patients receiving rFVIII (36%) were affected by this complication. This observation was substantiated by retrospective Italian and French analyses. These results, as well as hypothetical considerations, indicate that there is a body of evidence that FVIII products with VWF may be less immunogenic in PUPs. However, in order to provide more evidence a well-designed randomized study is needed.     

The uptake of recombinant Factor VIII in the Netherlands

In comparison with other biotechnology substitutions, the adoption of recombinant Factor VIII (rFVIII) has been relatively slow. We sent a postal questionnaire to all Dutch haemophilia patients and haemophilia-treating physicians, to determine which factors predict whether a patient uses plasma-derived FVIII (pdFVIII) or rFVIII and to investigate patients' and doctors' opinions on both products. Fifty-six per cent of patients received rFVIII. This percentage varied widely between centres. Only one doctor would choose to use pdFVIII if he suffered from haemophilia A himself, and 74% would choose to use rFVIII. Younger patients, those not infected with the human immunodeficiency virus or hepatitis C, and those who did not have family members who used pdFVIII switched more often from pdFVIII to rFVIII. Patients who rated themselves as innovative, who had family members who used rFVIII, and those who were treated in a large haemophilia treatment centre were also more likely to have switched. For physicians and patients alike, the respondents generally did not see large differences between rFVIII and pdFVIII, except for the risk of infections and the knowledge of long-term effects (both larger for pdFVIII). Although haemophilia patients represent one of the most empowered patient groups, physicians appear to have been influential in choosing between pdFVIII and rFVIII.     

Continuous infusion of recombinant factor VIII formulated with sucrose in surgery: Non‐interventional,observational study in patients with severe haemophilia A

In haemophilia A, continuous infusion (CI) of FVIII perioperatively provides a more constant FVIII level than conventional bolus injections, avoiding low trough levels that could increase bleeding risk. Due to the low number of surgical cases in clinical trials, especially in haemophilia, more information on the clinical practice of CI from observational studies is helpful. We aimed to evaluate the effectiveness and safety of CI with recombinant factor VIII formulated with sucrose (rFVIII‐FS) in a typical surgery practice setting. This was a non‐interventional study in 12 centres. Patients with severe haemophilia A who received rFVIII‐FS by CI during and after surgery were included in this study if they had more than 150 exposure days (EDs) to any FVIII product and had no history of inhibitors before CI. Patients were observed during the entire course of CI, with monitoring up to 3 months thereafter. Twenty‐five patients with 28 surgeries were included in the analysis. Median age was 51.7 (range 10–75). Most (75%; 21/25) patients underwent orthopaedic surgeries. The median dose of rFVIII‐FS consumed during CI was 376 IU kg^?1 (range 157.9–3605.6 IU kg^?1) with a greater median dose for orthopaedic surgeries (424.0 IU kg^?1) compared to non‐orthopaedic surgeries (278.5 IU kg^?1). 95% of all FVIII measurements (214/224) were on target. Efficacy and tolerability were rated as good/excellent in 89.3% (25/28) of surgeries. No inhibitors were observed during or after surgery. This study demonstrates the effectiveness of CI with rFVIII‐FS during surgery in patients with severe haemophilia A in a clinical practice setting.     

Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy

Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE®) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2–5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9–5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU^?1 kg^?1 (± 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean ? 37.2 cells mm–3 yr^?1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.     

Safety and efficacy of a sucrose-formulated recombinant factor VIII product for the treatment of previously treated patients with haemophilia A in China

The use of plasma-derived products has contributed to a high rate of blood-borne infections among haemophilia patients in China. Recombinant factor VIII (rFVIII) products that are manufactured without human or bovine albumin and include dedicated viral inactivation steps, hold a significant safety advantage over plasma products. However, there is little information published on the use of rFVIII products in non-caucasian populations. This is the first reported evaluation of the efficacy and safety of a rFVIII product in Chinese haemophiliacs. An open-label, non-randomized, prospective, multicentre trial enroled previously treated Chinese patients with haemophilia A. All treatments were administered using a sucrose-formulated rFVIII-FS (Kogenate((R))). Forty-nine patients received totals of 291 infusions (mean, 5.94/patient) and 742 140 IU rFVIII-FS (mean, 2550.3 IU/infusion). Of the 60 acute bleeding episodes that were treated, 90% were successfully managed with only one (81.7%) infusion or two (8.3%) infusions. Physicians reported haemostasis control for acute bleeds to be 'Excellent' or 'Improved' with rFVIII-FS therapy. No FVIII inhibitors were detected in any patient. Only one treatment-related adverse event was reported, which was mild dizziness that resolved spontaneously. rFVIII-FS was efficacious, safe and well tolerated in the treatment of previously treated patients with haemophilia A in China.     

Antibody formation and specificity in Bethesda‐negative brother pairs with haemophilia A

Antibodies directed towards non‐neutralizing epitopes on the factor VIII protein (FVIII) may be detected in patients with haemophilia A. We evaluated the prevalence of non‐neutralizing antibodies, in 201 inhibitor‐negative brother pairs with severe haemophilia A, enrolled in the Malmö International Brother Study and the Haemophilia Inhibitor Genetics Study. To evaluate binding specificity of the antibodies, ELISA plates were coated with two recombinant full‐length (FL) FVIII‐products and one recombinant B‐domain‐deleted (BDD) product. Seventy‐nine patients (39.3%) had a history of positive inhibitor titre measured by Bethesda assay, and FVIII antibodies were detected in 20 of them (25.3%). Additional 23 samples from subjects without a history of FVIII inhibitors were ELISA‐positive corresponding to a frequency of non‐neutralizing antibodies of 18.9%. The antibody response towards the different FVIII products was heterogenous, and was raised not only towards the non‐functional B‐domain but also towards both FL‐rFVIII and BDD‐rFVIII. In patients considered successfully treated with immune tolerance induction, 25.4% had remaining FVIII antibodies. The number of families with an antibody response in all siblings was increased when the total antibody response was taken into account, further supporting the concept of a genetic predisposition of the immune response. Further studies and careful monitoring over time are required to appreciate the immune response on the risk of inhibitor development or recurrence in the future.     

Real‐life evidence in evaluating effectiveness of treatment in Haemophilia A with a recombinant FVIII concentrate: A non‐interventional study in emerging countries

Some progress has been made regarding availability of recombinant factor VIII concentrates and prophylaxis for haemophilia A in emerging countries, where plasma‐derived concentrates were used in the vast majority. Clinical studies to document their introduction and effectiveness are so far not widely available in literature. This non‐interventional study evaluates the real‐life effectiveness and safety of prophylactic and on‐demand treatment with recombinant factor VIII formulated with sucrose (rFVIII‐FS) for bleed control and preservation of joints in emerging countries from Eastern Europe, North Africa and Middle East area. One hundred and eighty‐six patients from 11 countries were enrolled, mean ± SD age 12.8 ± 12.7 years. At enrolment, majority (79.6%) had severe haemophilia A (<2% IU mL^?1), 47.8% had a target joint, 15% had an inhibitor history and one patient was on immune tolerance induction. During the 24‐month observation period, 58.1% of the patients were prescribed prophylaxis at every visit, 31.7% were on an on‐demand regimen. Patients with severe haemophilia A on prophylaxis (n = 82) had a mean annual rate of treated bleeds of 2.8 ± 4.4, whereas it was 19.1 ± 32.0 for the on‐demand group (n = 31), and a mean total Gilbert Score of 9.9 ± 10.3 at baseline and 4.1 ± 6.7 at study end; vs. 15.2 ± 17.3 and 13.7 ± 17.1 for on‐demand respectively. The majority of the bleeds (91.1%) were treated with one or two infusions. Four patients without inhibitor history had a first positive inhibitor test during the study. This study demonstrates the effective use of rFVIII‐FS in emerging countries and adds to the established safety profile of rFVIII‐FS.     

Treatment patterns, health-related quality of life and adherence to prophylaxis among haemophilia A patients in the United States

Summary. Prophylaxis and adherence to prophylaxis are increasingly recognized as important factors for the health‐related quality of life (HRQOL) of haemophilia patients. This study aims to assess treatment practices over time, HRQOL and adherence among severe haemophilia A patients in the US. Severe haemophilia A patients or their caregivers participated in a 2009 cross‐sectional survey. HRQOL was measured using either PEDS‐QL or SF‐12; adherence was measured using the VERITAS‐Pro. Student t‐tests evaluated differences between children vs. adults and self‐infusion status. A total of 117 respondents participated in the survey, capturing data for 64 adults (mean age = 37.9 years) and 53 children (mean age = 10.5 years). Although 96% of paediatric patients were currently receiving prophylaxis, only 32 (50%) adults reported receiving prophylaxis at some point in their life. Adults who have always been on prophylaxis reported better physical functioning and physical HRQOL (both P < 0.05) than adults who had not. The paediatric group reported better adherence compared to the adult group on the total scale (38 vs. 45.8, P < 0.05). Children <12 years had higher adherence than adolescents 12–18 years old (35.5 vs. 40.8; P < 0.05). Paediatric patients infused by family members showed better adherence than paediatric self‐infusers (P < 0.05). This study showed different treatment patterns between paediatric and adult patients and how the patterns impacted HRQOL. It also provided the first standardized evaluation of adherence using the VERITAS‐Pro in a US national sample. This study enhances understanding of treatment practices and adherence for the US haemophilia population and may offer insight into where adherence can be improved.     

Successful induction of immune tolerance by continuous infusion of recombinant factor VIII in a haemophilia A patient with high-inhibitor titres

The successful and persistent abolition of the inhibitor is of significant clinical benefit, as it allows for the restoration of the usual treatment with clotting factor concentrate. We describe a successful induction of immune tolerance by continuous infusion of recombinant factor VIII (rFVIII) in a 5-year-old boy with severe haemophilia A and high-responding inhibitor. He had previously been subjected to immune tolerance induction (ITI) with rFVIII at 100 units (U) kg(-1) three times weekly. One year after the beginning of therapy tolerance was not achieved and a high titer of inhibitor was detected (15 Bethesda Units). The patient had a sudden onset of severe neck pain. The diagnosis of spinal epidural haematoma was revealed by magnetic resonance imaging, and emergency laminectomy with evacuation of the haematoma was required. The patient received sequential therapy for surgery first as bolus rFVIII injection of 500 U kg(-1) in order to overwhelm the inhibitor and then as continuous infusion at 6 to 12 U kg(-1) hour(-1) to avoid bleeding episodes in the postoperative period. After the 3 weeks of continuous infusion, the inhibitor became undetectable. Thereafter, prophylactic treatment with rFVIII was started three times weekly, and the inhibitor has remained undetectable for 6 months. The, present case suggests that continuous infusion of rFVIII may be an effective therapy to induce immune tolerance.     

Prophylaxis therapy in haemophilia A: current situation in Spain

Summary. The Spanish Epidemiological Study in Haemophilia carried out in 2006 enrolled 2400 patients [2081–86.7% with haemophilia A (HA) and 319–13.3% with haemophilia B]; 465 of them (19.4%) were on prophylaxis. These rates were higher in patients with severe haemophilia (45.4%) and severe paediatric cases (72.5%). On the basis of information recorded in this study, we analysed the current situation of prophylaxis therapy administered to patients with HA in Spain, as well as their orthopaedic status. Prophylaxis was used in 399 (19.2%) patients with HA; such prophylaxis was primary (PP) in 20.3% and secondary (SP) in 75.9% of cases. Among severe HA patients, 313 (45.9%) were on prophylaxis (22.3% on PP and 74.7% on SP). Taking into account the patients’ age, 34.7% of severe HA adults were on prophylaxis (6% PP and 92.1% SP), whereas 71.5% of severe HA paediatric patients (40.5% PP and 55.4% SP) received this kind of treatment. Established haemophilic arthropathy (EHA) was detected in 142 from 313 severe HA patients (45.3%) on prophylaxis, but only in 2.9% of patients under PP vs. 59% of patients receiving SP. There was no EHA in adult severe HA patient on PP, whereas 70.4% on SP had joint damage (P < 0.00001). Among paediatric severe HA patients, EHA was detected in 3.3% under PP and 37.8% under SP (P < 0.00001). In conclusion, our data suggest that an early initiation of prophylaxis avoids EHA in the long‐term in patients with severe HA. We should emphasize the early onset of prophylaxis regimens.