An orthopaedic assessment of the joint status of seven severe haemophiliacs (mean age 12.5 y - range 8.9-15.5) on prophylactic treatment (PT) by magnetic resonance imaging (MRI) and physical examination was carried out. Median duration of PT of these patients was 84 months (range 32-107). A locally designed MRI joint score considering seven parameters (1 - joint effusion, 2 - synovial membrane thickening, 3 - haemosiderin deposits, 4 - joint cartilage injury, 5 - subchondral bone erosion, 6 - subchondral bone cysts, 7 - osteonecrosis) was used (maximum score = 13 points). MRI scans were performed in 17 joints (nine ankles, seven knees and one elbow): mean MRI scores for the affected joints was 5.1. A poor consistency between physical examination and MRI findings or the real extent of joint damage was found (Cohen kappa index 0.320). MRI is a precise non-invasive tool for the assessment of early joint cartilage and synovium pathological changes still undetectable by physical examination or conventional X-rays in the haemophilic setting.

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.

BackgroundThe diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis.Patients/methodsSubjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest.ResultsOf the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed.ConclusionsOur study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects.

Factor VIII (FVIII) activation by thrombin leads to proteolytic cleavage and loss of B-domain and formation of a heterotrimeric structure constituted by A2 domain linked by weak ionic interactions to A1 and A3-C1-C2 subunit. Dissociation of the A2 domain results in the formation of the heterodimeric inactive FVIII molecule. About 5% of haemophilia A patients show a normal concentration of FVIII antigen (FVIII:Ag) levels (at least 30% of normal) but markedly reduced FVIII activity (FVIII:C) suggesting dysfunctional FVIII protein; this type of haemophilia is known as cross-reacting material positive (CRM+) [1]. A subset of these patients with a mild phenotype exhibit a discrepancy between FVIII:C results elicited in one-stage and two-stage assays [2-4] and 11 mutations in the A1, A2, A3 and C domains have been identified so far as responsible for that in vitro phenomenon [5]. Arg 531 His is one of the best-characterized mutations, its molecular basis consisting of an increase in the dissociation rate of the A2 subunit from the activated FVIII (FVIIIa) heterotrimer which leads to increased rate of inactivation and discrepancies in the plasma FVIII concentrations elicited with different assays and assay conditions [3,6]; Arg 1966 Gln is, however, the most frequently found (10% of mild haemophiliacs overall and 38% of discrepant patients) and has similar pathogenetic consequences [5].

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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.

observed in the cases mutated for INV22 inversion. This discrepancy could be attributed to the low number of patients who have so far proven positive for intron 1 inversion. Among our 9 patients who were positive for this inversion, two developed inhibitors with the titres of 8.96BU and 6.72BU. These two patients received pdFVIII only for the treatment of severe bleeding episodes. In China, the majority of HA patients receive little replacement therapies as result of the financial constraints and shortage of the plasma. Most patients were exposed to limited amount and restricted types of intermediate-purity FVIII other than high-purity FVIII or rFVIII. The overall prevalence of inhibitors in Chinese HA patients was 3.9% and the prevalence of severe haemophiliacs was 4.3% [5], much lower than that reported in the Western countries. The limited types of treatment regimens and limited exposure days may contribute to low inhibitor rate in Chinese HA patients. In this study, the frequency of the inhibitor developed in the patients with INV1 is 22.22%, much higher than the inhibitor rate in the Chinese population as a whole and agrees well with that found among INV22 carriers (21.5-34.5%; [4]). Based on less therapyrelated risk factors of inhibitor development in China, it seems that the genetic factors may contribute more to the inhibitor development. As estimating the risk of developing inhibitors has relevant implications for the clinical management strategy, these preliminary data need further support in a much larger series of patients.In summary, it seems that the frequency of the intron 1 inversion is lower and the risk of inhibitor development higher than that reported in most previous studies. Nevertheless, this mutation remains the second most frequent molecular cause of HA after the intron 22 inversion. As it is easy and fast to analyse, we recommend this test as the second step in a mutation-screening programme after exclusion of the intron 22 inversion and before screening of the entire gene. DisclosuresThe authors stated that they had no interests which might be perceived as posing a conflict or bias. References1 Keeney S, Mitchell M, Goodeve A. The molecular analysis of haemophilia A: a guideline from the UK haemophilia centre doctors organization haemophilia genetics laboratory network. Haemophilia 2005; 11: 387-97. 2 Brinke A, Tagliavacca L, Naylor J et al. Two chimeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia. Hum Mol Genet 1996; 5: 1945-51. 3 Schroder J, El-Maarri O, Schwaab R et al. Factor VIII intron-1 inversion: frequency and inhibitor prevalence.The results of the first epidemiological study carried out in Spain in 51 haemophilia treatment centres throughout the country (85% of them) were published in 2009 [1]. On the basis of this study, we aimed to achieve knowledge of the real current situation of primary (PP) and secondary prophylactic (SP) treatments provided to hae...

Recombinant factor VIIa (rfVIIa) has been widely used for the treatment and prevention of bleeding episodes in haemophiliacs with high-titre inhibitors. High single doses are the treatment of choice for joint and muscle bleeds in those patients. There are only a few reports on the value of rfVIIa in cirrhotic patients with haemostatic impairment but this drug can consistently correct the prothrombin time in these individuals. We report a case of a good response to a single high dose of rfVIIa in a patient with advanced liver disease who suffered from severe refractory postoperative haematuria.