Hepatitis-free interval after clotting factor therapy in first infused haemophiliacs

Post-infusion hepatitis is known to occur very frequently in haemophiliacs after treatment with unheated commercial clotting factor concentrates, obtained from large plasma donation pool. On the contrary, single-donor cryoprecipitate is likely to carry a lower risk of transmitting hepatitis. To evaluate this hypothesis, we retrospectively reviewed the medical records of 25 first infused haemophiliacs (from 1981 to 1984) treated with unheated commercial clotting factor concentrates (n = 19) or cryoprecipitate (n = 6). The hepatitis-free interval after the beginning of therapy was expressed as exposure days. The end point of each patient, i.e. the hepatitis occurrence, was defined as an increase of amino-transferases (ALT and AST) and/or the seroconversion of HBV-markers, which were checked every three months. The life-table method and log-rank test showed that cryoprecipitates had a significantly longer hepatitis-free interval (p = 0.0131, log-rank test) and a lower risk of transmitting hepatitis (p = 0.01-0.05, life-table method) than the commercial concentrates. However, the safety of cryoprecipitate therapy was shown to cover only a few exposure days, and so the real advantage of this product depends on the bleeding frequency of the patient concerned. We believe that these methods and our findings may be useful to assess and compare the safety of the new "heat-treated" clotting factor concentrates.     

Intra-articular injections of hyaluronic acid induce positive clinical effects in knees of patients affected by haemophilic arthropathy

IntroductionHaemophilic arthropathy is the most common clinical manifestation of haemophilia, secondary to recurrent haemarthrosis and chronic synovitis, and the knee represents the main target joint. Modern bleeding prevention has significatively limited the incidence of severe arthropathy, and primary approach is usually conservative. Viscosupplementation is felt as one of the most efficient treatments for the early stages of knee haemophilic arthropathy, based on short-term follow-up studies. The aim of this prospective case series study is to assess the clinical effectiveness of intra-articular administration of hyaluronic acid in the knee, evaluating long-term results, and focusing on the necessity of further treatments after viscosupplementation.MethodsTwenty-seven haemophilic patients with knee arthropathy underwent at least two cycles of injections of hyaluronians between 2003 and 2009. They were evaluated with VAS, SF-36, WFH, Pettersson score, and WOMAC, with a seven-year follow-up.ResultsAll patients showed improvement in pain relief and functional recovery without any complications. Considering the severity of arthropathy in haemophilic patients, only a limited number of subjects (five) underwent total knee arthroplasty for persistent pain or functional limitation.ConclusionsViscosupplementation is a safe and effective therapeutic strategy in knee haemophilic arthropathy, with no complications, persisting good clinical results, and determining in most cases a delay of surgery.     

Brain activation and connectivity in anorexia nervosa and body dysmorphic disorder when viewing bodies: relationships to clinical symptoms and perception of appearance

Brain Imaging and Behavior - Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted perception of appearance, yet no studies have directly compared the neurobiology...     

Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma‐derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood‐borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non‐inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence‐based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.     

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX,in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double‐blind, non‐inferiority, cross‐over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL ^?1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4–18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8–59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg^?1 or nonacog alfa. The lower limit of the one‐sided 95% confidence interval for the ratio of AUC_0‐t and AUC_0‐∞ (IB1001/nonacog alfa) was 0.90, establishing non‐inferiority. Terminal phase half‐lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non‐inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.     

Product type and the risk of inhibitor development in nonsevere haemophilia A patients: a case‒control study

Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case‒control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case‒control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2–40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0·96, 95% confidence interval (CI) 0·36–2·52) or for specific types of FVIII concentrates.     

Identification of 18 High Risk F8 Mutations for Inhibitor Development in 2,700 Non-Severe Hemophilia A Patients

Tijdschrift voor Kindergeneeskunde -     

Clinical pharmacokinetics of factor VIII in patients with classic haemophilia

Studies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis. Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed. To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined 'therapeutic window' of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualization). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.     

Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey.

BACKGROUND: Antibodies to glycoprotein (GP) IIb-IIIa and/or HLA may render platelet transfusions ineffective to stop bleeding or to cover surgery in patients with Glanzmann's thrombasthenia (GT). Anecdotal reports suggest recombinant factor (rF)VIIa might be a therapeutic alternative in these situations. OBJECTIVES: An international survey was conducted to evaluate further the efficacy and safety of rFVIIa in GT patients. PATIENTS: We analyzed the use of rFVIIa during 34 surgical/invasive procedures and 108 bleeding episodes in 59 GT patients including 29 with current or previous antiplatelet antibodies, and 23 with a history of refractoriness to platelet transfusion. RESULTS: rFVIIa was effective in 29 of the 31 evaluable procedures, and in 77 of the 103 evaluable bleeding episodes of which eight had a recurrence. A significantly higher success rate was observed in severe bleeding episodes when an arbitrarily defined 'optimal regimen' derived from the Canadian pilot study results (> or = 80 micro g kg(-1) rFVIIa/injection, dosing interval < or = 2.5 h, three or more doses before failure declaration) was used compared with other regimens (77%; 24/31 vs. 48%, 19/40; chi(2), P = 0.010). Patients given maintenance doses had significantly fewer recurrences within 48 h of bleed cessation compared with those not given any (Fisher's exact test, P = 0.022). One thromboembolic event and one blood clot in the ureter occurring in surgical patients following prolonged continuous infusion of high-dose rFVIIa and antifibrinolytic drug use have been previously reported. CONCLUSION: rFVIIa seems a potential alternative to platelet transfusion in GT patients, particularly in those with antiplatelet antibodies and/or platelet refractoriness.