V. Jimenez-Yuste

Acquired Haemophilia: Review and Meta‐Analysis Focused on Therapy and Prognostic Factors

Acquired haemophilia (AH) is a rare disease that occurs at a rate of approximately 1 person per million each year. Antifactor VIII is the most commonly recognized autoantibody directed against a clotting factor, and is associated with bleeding complications that can be life threatening. These bleeding episodes, however, can be controlled when the correct diagnosis is made quickly and appropriate therapy is applied. Although the aetiology of this disorder remains obscure, about 40–50% of cases are associated with other conditions, mainly the post-partum period, underlying malignancies, drug administration or autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. This article provides a succinct review of the clinical features, laboratory diagnosis, prognostic factors and therapeutic management of patients with AH.

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.

Joint protection in haemophilia

Summary.  Haemarthroses (intra‐articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on‐demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by‐passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non‐inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

Rituximab in the management of chronic immune thrombocytopenic purpura: an effective and safe therapeutic alternative in refractory patients

Rituximab induces B-cell depletion; therefore, it has been used in the treatment of immune thrombocytopenic purpura (ITP). The aim of this retrospective study was to evaluate the effectiveness of rituximab in the treatment of 89 patients with chronic ITP refractory to several treatments. All the patients had platelet counts <30 x 10(9)/l. They had received a median of five (2-13) previous treatments, and 47 had undergone splenectomy. Rituximab was administered i.v. at 375 mg/m(2) in four weekly doses in 77 patients, and 12 patients received 1-6 doses. Forty-nine patients (55.1%) reached platelet counts >50 x 10(9)/l; 41 (46%) achieved a complete response (CR; platelets >100 x 10(9)/l), and eight (9%) obtained a partial response (platelets 50-100 x 10(9)/l). Overall, 31 patients (35%) maintained response, including 15 patients in whom splenectomy failed, with a median follow-up of 9 months (2-42), 12 for more than 1 year. The unique predictor of a maintained response was to reach a CR. Heavily treated patients (more than three different previous treatments, including any corticosteroids) and those with longer ITP duration (>10 years from diagnosis) had a worse response. Non-splenectomized patients had a better early response rate than those splenectomized. Rituximab was well tolerated, with two fever episodes following infusion and two reports of skin rash. Rituximab induced clinical responses in multi-treated refractory ITP patients with little toxicity and should be considered as an early therapeutic option in this setting, even as an alternative to splenectomy in selected patients.

Prophylaxis in 10 patients with severe haemophilia A and inhibitor: different approaches for different clinical situations.

Summary.  The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Radiosynovectomy in hemophilia: quantification of its effectiveness through the assessment of 10 articular parameters

Summary.  Background: Radiosynovectomy (RS) can reduce the number of hemarthroses in chronic hemophilic synovitis. The purpose of this study was to quantitatively assess the effectiveness of RS in terms of the objective improvement of ten articular parameters. Methods: One‐hundred and fifty‐six radiosynovectomies were performed in 104 joints of 78 hemophiliacs diagnosed with chronic synovitis. The mean patient age was 18 years. The RS was carried out with either yttrium‐90 or rhenium‐186 (1–3 injections with a 6‐month interval between them). Results: RS resulted in significant improvement in nine of the 10 variables studied, namely in the number of episodes of hemarthrosis, articular pain, range of motion (ROM) in flexion. ROM in extension, muscle strength (MS) in flexion, MS in extension, the degree of synovitis detected on clinical examination, the size of the synovium as measured by means of imaging techniques (in millimeters), the clinical scale developed by the World Federation of Haemophilia (WFH), and the radiologic scale of the WFH. The tenth parameter, the WFH radiologic score, showed no improvement. The other nine parameters studied improved independently for each one of the intra‐articular injections of the radioisotope. Conclusions: Categorization of the variables with regard to the degree of improvement achieved showed that the number of episodes of hemarthrosis and the severity of pain were the variables associated with the greatest improvement, with a 70% decrease in the amount of bleeding and in the level of pain experienced by the patient. The reduction of articular bleeding after RS was 67.6% when RS‐1 was used, 62.1% with RS‐2 and 61.2% with RS‐3. Synovial hypertrophy as assessed clinically and by imaging techniques also showed a reduction of 30% and 39%, respectively. The WFH clinical scale revealed an improvement of around 19%. MS also improved in flexion and extension (7.9% and 8.2% improvement, respectively). ROM showed a slight but non‐significant improvement.

Complications of central venous catheters in patients with haemophilia and inhibitors

We report our clinical experience with central venous catheters (CVCs) in 15 patients with haemophilia who, in total, had 34 catheters inserted. Eighteen devices were Hickman, six were Port‐A‐Cath and 10 were nontunnelled catheters (one Quinton, seven antecubital, one jugular and one subclavian vein access). All patients had factor VIII/IX inhibitors at the time of insertion. The mean age at operation was 8.8 years (range 16 months–39 years). Eight of the 15 patients (26/34 implanted catheters, 76%) presented some kind of complication. Pericatheter bleeding during the postoperative period affected a total of seven CVCs (7/34, 20%) in six patients, which required substitutive treatment for several days. Infection was reported in 15 of the CVCs (15/34, 44%), and four of these (4/15, 26%) had more than one episode, with a mean of 1.4 infection episodes per catheter (21/15). The infection rate was 0.2 infections per 1000 patient days or 0.1 per 1000 catheter days. Despite the usefulness of CVCs in haemophilic patients, the high incidence of complications requires careful assessment of the type of device as well as continuous surveillance.

Haemophilia in Spain.

Summary.  . To determine the prevalence of haemophilia A and B and their complications in Spain, and to characterize the health care network providing support to haemophiliac patients. The study examines clinical and genetic characteristics, treatment options, and complications observed during the course of the disease. Cross‐sectional multi‐centre study. The study population were patients with HA and HB in active follow‐up at any Spanish hospital by December 2006. We studied 2400 haemophiliacs, 2081 (86.7%) HA and 319 (13.3%) HB patients. Illness was severe in 32.3% of patients, moderate in 16.4%, and mild in 51.3%. Genetic screening was carried out in 32.6% of the patients. Treatment administered in 2006 consisted of coagulation factor concentrates in 60% of patients. Until December 2006, 45.8% of severely ill patients were taking prophylaxis. The mean number of bleeding episodes in 2006 was four for patients not receiving primary prophylaxis and 1.3 for those taking primary prophylaxis. Thirty percent of patients had established haemophiliac arthropathy in at least one joint; 16.8% of patients were HIV‐infected and 34.8% HCV‐infected. Inhibitors were detected in 10% of severe HA patients and in 6.5% of severe HB patients. Immune tolerance induction therapy was started in 34 patients. This is the first comprehensive study on the epidemiology of haemophilia in Spain. It will enable us to draw comparisons with neighbouring countries, to assess the quality of care provided to haemophiliacs in Spain, and to provide evidence‐based guidance for the even provision and improvement of such care.

Psychometric field study of the new haemophilia quality of life questionnaire for adults: the 'Hemofilia-QoL'.

Summary.  Although there is a worldwide interest in the assessment of health‐related quality‐of‐life (HRQoL) in haemophilia patients, no non‐disease specific instruments (for adults) are readily available. In this paper, a haemophilia‐specific quality‐of‐life assessment measure for adults (the Hemofilia‐QoL questionnaire) has been developed and tested for psychometric properties in 121 adults with haemophilia living in Spain. The Hemofilia‐QoL questionnaire is a self‐report modular instrument that assesses nine relevant HRQoL domains for patients with haemophilia (e.g. physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, relationships and social activity). Psychometric examination involved the assessment of data quality, scaling assumptions, reliability (internal consistency and test–retest) and validity (concurrent; external clinical criterion and sensitivity). The Hemofilia‐QoL 36‐item version questionnaire had acceptable internal consistency and retest reliability values. The questionnaire shows excellent concurrent validity (with the SF‐36 Health Survey) and external clinical criterion validity (haemophilia clinical status) and sensitivity (health status changes) as well. The Hemofilia‐QoL is now available for adult assessment and is ready for use in clinical research in Spain.

Third Åland islands conference on von Willebrand disease, 26-28 September 2012: meeting report.

The first meeting of international specialists in the field of von Willebrand disease (VWD) was held in the Åland islands in 1998 where Erik von Willebrand had first observed a bleeding disorder in some members of a family from Föglö and a summary of the meeting was published in 1999. The second meeting was held in 2010 and a report of the meeting was published in 2012. Topics covered included progress in understanding of VWD over the last 50 years; multimers; classification of VWD; pharmacokinetics and laboratory assays; genetics; treating the paediatric patient; prophylaxis; geriatrics; gene therapy and treatment guidelines. This third meeting held over 3 days covered the structure and function of von Willebrand factor (VWF); type 1 VWD, the most common form of the disease; a lifespan of pharmacokinetics in VWD; detecting inhibitors in VWD patients; and special challenges in understanding and treating the female VWD patient.