Annarita Tagliaferri

Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study

This case–control study investigated the interactions between genetic and environmental factors and inhibitor development in 108 children with haemophilia A exclusively treated with recombinant factor VIII (FVIII). Sixty patients with inhibitors were compared with 48 inhibitor‐free controls. Family history of inhibitors and null mutations in the FVIII gene were more prevalent in cases than in controls (20% vs. 2%, P = 0·001 and 83% vs. 64%, P = 0·04, respectively). On the other hand, there was no difference between cases and controls for such putative risk factors of inhibitor development as amniocentesis/villocentesis, premature/caesarean birth, breast‐feeding, treatment during infections/vaccinations, surgical procedures and central nervous system bleeding. A trend was found for an increased risk of inhibitor development in children first treated at a young age (<11 months); however, this was not confirmed after adjusting for genetic factors. The implementation of prophylaxis was evaluated as a putative risk factor in a subgroup of 25 cases: seven who started prophylaxis prior to inhibitor development and 18 potentially eligible for prophylaxis because they were inhibitor‐free up to the age of 35 months (i.e. the upper limit of the age range at prophylaxis onset in cases and the median age at prophylaxis onset in controls). Patients who started prophylaxis had a lower inhibitor risk than those treated on demand (adjusted odds ratio 0·2, 95% confidence interval 0·06–0·9). The protective effect on inhibitor development shown by prophylaxis may represent an additional advantage prompting its use in haemophilic children.

Effects of secondary prophylaxis started in adolescent and adult haemophiliacs

Summary.  While primary prophylaxis is a well‐established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on‐demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease‐related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on‐demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well‐being in this cohort of adolescent/adult haemophiliacs.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: A critical systematic review

Inhibitor development represents currently the most serious and challenging complication of clotting factor replacement therapy. A number of studies have analyzed the impact of the type of factor VIII (FVIII) replacement therapy (plasma-derived versus recombinant concentrates) on inhibitor development in hemophilia A patients with conflicting results. In order to shed light on this controversial issue, we performed a systematic review and meta-analysis on the published prospective studies evaluating the incidence rate of inhibitors in previously untreated patients (PUPs) with severe hemophilia A. Data from a total of 800 patients enrolled in 25 prospective studies published between 1990 and 2007 were included in this review. The quality of the studies was evaluated using two different systems: the Newcastle-Ottawa Scale (NOS) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE). Overall, the inhibitor incidence rate did not differ significantly between recipients of plasma-derived and recombinant FVIII concentrates (weighted means: 21%; 95% CI, 14-30 versus 27%; 95% CI, 21-33). Similarly, high titer inhibitors did not differ significantly between patients treated with plasma-derived (weighted means: 14%; 95% CI, 8-25) or recombinant FVIII concentrates (weighted means: 16%; 95% CI, 13-20). Thus, the main conclusion of this systematic review performed using selective criteria is that the type of FVIII product (i.e., plasma-derived versus recombinant FVIII concentrates) does not seem to influence the inhibitor rate in PUPs with severe hemophilia A.

Development and definition of a simplified scanning procedure and scoring method for Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US)

The aim of this study was to develop a simplified ultrasound scanning procedure and scoring method, named Haemophilia Early Arthropathy Detection with UltraSound [HEAD-US], to evaluate joints of patients with haemophilic arthropathy. After an initial consensus-based process involving a multidisciplinary panel of experts, three comprehensive and evidence-based US scanning procedures to image the elbow, knee and ankle were established with the aim to increase sensitivity in detection of early signs of joint involvement while keeping the technique easy and quick to perform. Each procedure included systematic evaluation of synovial recesses and selection of a single osteochondral surface for damage analysis. Based on expert consensus, a simplified scoring system based on an additive scale was created to define the joint status and, in perspective, to offer a tool to evaluate disease progression and monitor the result of treatment in follow-up studies.

Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia a: a 2013 update.

Nowadays, patients with hemophilia A receive a high standard of care; therefore, the most challenging complication of factor VIII (FVIII) replacement therapy has become the development of FVIII inhibitors, which render the concentrate infusion ineffective and expose patients to an increased risk of morbidity and mortality. Among environmental risk factors influencing inhibitor development, the type of FVIII products has always drawn the attention of investigators. Conflicting results are reported in the literature concerning rates of inhibitor development after either plasma-derived or recombinant FVIII concentrates. To help elucidate this controversial issue, we have performed a systematic review and meta-analysis of prospective studies evaluating the incidence of inhibitors in previously untreated patients with severe hemophilia A receiving plasma-derived or recombinant FVIII products. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS), the STrenghtening the Reporting of OBservational studies in Epidemiology and an ad hoc quality score. Overall, 28 prospective studies, including 1,421 patients with hemophilia A, fulfilled our selection criteria and were included in the systematic review. No statistically significant differences were observed in the inhibitor incidence between plasma-derived and recombinant FVIII concentrates considering all (weighted means: 23%, 95% CI: 15-33% vs. 29%, 95% CI: 26-32%) and high titer (16%, 95% CI: 10-26% vs. 18%, 95% CI: 15-21%) inhibitors. Similarly, no significant differences were found in the inhibitor incidence among the different classes of recombinant products. In conclusion, the results of our meta-analysis show that the different types of FVIII products are not associated with different risks of inhibitor development.

Prophylaxis in people with haemophilia

A four-decade clinical experience and recent evidence from randomised controlled studies definitively recognised primary prophylaxis, i.e. the regular infusion of factor concentrates started after the first haemarthrosis and/or before the age of two years, as the first-choice treatment in children with severe haemophilia. The available data clearly show that preventing bleeding since an early age enables to avoid or reduce the clinical impact of muscle-skeletal impairment from haemophilic arthropathy and the related consequences in psycho-social development and quality of life of these patients. In this respect, the aim of secondary prophylaxis, defined as regular long-term treatment started after the age of two years or after two or more joint bleeds, is to avoid (or delay) the progression of arthropathy. The clinical benefits of secondary prophylaxis have been less extensively studied, especially in adolescents and adults; also in the latter better outcomes and quality of life for earlier treatment have been reported. This review summarises evidence from literature and current clinical strategies for prophylactic treatment in patients with severe haemophilia, also focusing on challenges and open issues (optimal regimen and implementation, duration of treatment, long-term adherence and outcomes, cost-benefit ratios) in this setting.

Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies

Summary.  Inhibitor development, because of its impact on patients’ morbidity and quality of life, is presently the most serious complication of haemophilia A treatment. The identification of several genetic and non‐genetic risk factors may be used for the stratification of inhibitor risk and the definition of prevention strategies, particularly for patients with a high‐risk genetic profile. The most extensively studied genetic factor is the type of F8 mutation, i.e. large deletions, nonsense mutations and inversions, which are associated with a higher risk of inhibitor development. This is the basis for the increased risk in patients with inhibitor family history; however, concordance family studies showed that factors other than F8 mutations are involved. An emerging role is investigated for polymorphisms of immune‐regulatory genes that may increase (IL‐10 and TNF‐α) or reduce (CTLA‐4) inhibitor risk and whose heterogeneous ethnic distribution may correlate to the higher inhibitor risk in non‐caucasian patients. A role for FVIII haplotypes, particularly in black haemophiliacs, has been recently proposed. Recent studies report an increased inhibitor risk for initial intensive treatments (surgery or severe bleeds requiring high‐dose and/or prolonged treatment, presence of danger signals), whereas regular prophylaxis (absence of danger signals) exerts a protective effect. A clinical score including the type of F8 mutation, family history of inhibitors and intensive treatment has been recently validated for predicting inhibitor risk. Because of the lack of useful data regarding the role of different types of FVIII concentrates, the stratification of risk in patients starting replacement treatment together with the careful evaluation of indications, doses and duration of treatment at first exposures and further efforts for overcoming barriers to early implementation of prophylaxis are encouraged, particularly for patients with a predictable high inhibitor risk.

Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges.

Recurrent joint bleeding leading to progressive musculoskeletal damage (hemophilic arthropathy), in spite of on-demand replacement with deficient factor concentrates, is the clinical hallmark of severe hemophilia A and B (i.e., the congenital deficiencies of coagulation factors VIII and IX with circulating levels <1 IU/dL). Fifty years of clinical experience, which began in Northern Europe and then initiated in other European countries and in North America, up to the recent randomized clinical trials, have provided definitive evidence that preventing bleeding from an early age through long-term regular prophylactic concentrate infusions limits the adverse clinical consequences of arthropathy and its complications in the quality of life of hemophilic children. Primary prophylaxis started after the first joint bleed and/or before the age of 2 is now the evidence-based, first-choice treatment in severe hemophilia. Interestingly, recent data also suggest a role for early prophylaxis in preventing inhibitor development, the most serious complication of hemophilia therapy. Secondary prophylaxis is aimed to avoid (or delay) the progression of arthropathy. The earlier the treatment is started, the better the outcomes in joint status and quality of life. Although prophylaxis has radically transformed the natural history of severe hemophilia, relevant barriers to its implementation and diffusion remain. Beyond the obvious economic constraints and problems with venous access and long-term adherence, uncertainties regarding the optimal prophylaxis regimen require further evaluation in prospective studies to optimize approaches based on definite outcome measures and cost-effectiveness/cost-utility analyses. Scientific evidence, current clinical strategies, and open issues of prophylaxis in children with hemophilia will be addressed in this review.

Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII

There have been recent reports of unexpected poor efficacy of a B‐domain‐deleted recombinant factor VIII (BDD‐rFVIII) in haemophiliacs, and inhibitor development in previously treated patients (PTPs) switched to BDD‐rFVIII. The results of a 6‐month prospective study of 25 PTPs and of a retrospective survey of 94 PTPs, all switched to BDD‐rFVIII, were used to evaluate efficacy and inhibitor development. The prospective study showed that 89% of 362 bleeds were controlled by one to two infusions, reproducing the efficacy profiles of other recombinant products (rFVIIIs). One patient, previously treated with plasma‐derived FVIII only, developed a high titre inhibitor (30 BU) after 5 days of exposure. The retrospective survey, carried out in the total Italian PTP population switched to BDD‐rFVIII, involved 19 PTPs at higher inhibitor risk due to previous exposure of ≤ 50 days and 75 PTPs at lower inhibitor risk due to previous exposure of >50 days. One patient developed an inhibitor: he was a high‐risk, severe PTP previously exposed to another rFVIII for 3 days only. Among the entire low‐risk population of severe Italian PTPs switched to BDD‐rFVIII (25 in the prospective study, 49 in the retrospective cohort) only one developed an inhibitor (1·3%). These data indirectly support the views that BDD‐rFVIII is equivalent to other rFVIIIs in term of efficacy and inhibitor development.