Immune Tolerance Induction (ITI) with a pdFVIII/VWF Concentrate (octanate) in 100 Patients in the Observational ITI (ObsITI) Study.

Background Immune tolerance induction (ITI) with repeated factor VIII (FVIII) administration is the only strategy proven to eradicate inhibitors. The observational ITI study is evaluating ITI with a range of FVIII products. Methods This subgroup analysis reports prospective interim data for patients treated with a plasma-derived, von Willebrand factor-stabilized FVIII concentrate (pdFVIII/VWF, octanate). Complete success (CS) of ITI required achievement of three criteria: inhibitor titer < 0.6 BU/mL; FVIII recovery ≥ 66%; FVIII half-life ≥6 hours. Partial success (PS) required achievement of two criteria and partial response (PR) one. ITI success was defined as CS or PS. Data were analyzed for patients who achieved CS, had 36 months' observation, or failed ITI. Results One-hundred prospectively enrolled patients were included in the analysis; 91 had poor prognosis factors for ITI success. The mean (standard deviation) daily ITI dose was 116.4 (61.1) IU FVIII/kg in 14 low responders (< 5 BU/mL) and 173.7 (112.0) IU FVIII/kg in 86 high responders (≥ 5 BU/mL). Inhibitor titers < 0.6 BU/mL were achieved in 71% of patients in a median of 4.01 months, accompanied by a 93% reduction in bleeding rate. ITI success was achieved by 70% of patients and 56 of 72 (78%) primary (first-line) ITI patients. PR was achieved by 5 patients; ITI failed in 25 patients. PS and CS were achieved in a median of 5.55 and 11.25 months, respectively. Conclusions ITI with pdFVIII/VWF led to rapid eradication of FVIII inhibitors, normalization of FVIII pharmacokinetics in the majority of patients, and a significant reduction in bleeding rates.

Incidence of inhibitor development in PUPs with severe Haemophilia A in the CEE region between 2005 and 2015.

INTRODUCTION: This study analyses real-world data on 144 previously untreated patients (PUPs) with severe Haemophilia A, from seven countries in Central and Eastern Europe (CEE: Bulgaria, Croatia, Czech Republic, Hungary, Latvia, Serbia, and Slovenia), over a period of 11 years. It analyses the risk factors associated with development of inhibitors to factor VIII concentrates. METHODS: Cox proportional hazard models were used to estimate the hazard risk of factors possibly influencing the development of inhibitors. Patients were followed for up to 100 exposure days (EDs). RESULTS: Cumulative inhibitor incidence at the time of 100 EDs was 18.7%, slightly lower than the 25-35% incidence reported in most studies. Of PUPs who developed inhibitors, a majority (56%) developed them within the first 20 EDs and 88% by the 50th ED. FVIII class (recombinant or plasma-derived) did not influence the inhibitors' incidence rate (p = 0.64). We found a significant protective effect of prophylaxis compared to on-demand treatment (p = 0.003). PUPs who had an intensive peak treatment during the first 50 EDs were at significantly higher risk for inhibitor development (HR (95% CI) 5.3 (2.3-12.5), p < 0.001). CONCLUSION: Inhibitors are and will continue to be the most significant complication of haemophilia treatment with factor concentrates. This is particularly true for haemophilia A. In our cohort, we were able to show that the treatment regimen used during first 50EDs influenced significantly the inhibitor risk, but the class of the factor concentrate did not play an important role. Real world data will remain one of the important resources for improving our knowledge of haemophilia.

von Willebrand factor alloantibodies in type 3 von Willebrand disease.

: The development of neutralizing antibodies is a rare complication of von Willebrand disease treatment. In major surgical procedures for severe forms of the disease, the recognition of ineffective therapy and alternative treatment protocols are lifesaving. We report the case of a 6-year-old girl with type 3 von Willebrand disease in whom inhibitors were sought due to ineffective haemostasis together with lower than expected von Willebrand factor (VWF) recoveries after a surgical procedure. Replacement therapy first with recombinant factor VIIa and then with high doses of recombinant factor VIII in continuous infusion successfully stopped the bleeding. A high level of anti-VWF antibodies was determined by the immunological method. A frameshift mutation associated with premature termination codon (c.2435delC, p.Pro812ArgfsTer31) was determined in our patient. Although the reports on association of this mutation with inhibitor risk are inconsistent, it represents an evidence-based diagnostic and management practice in recognition of high-risk VWF genotype.

Specific and global coagulation tests in patients with mild haemophilia A with a double mutation (Glu113Asp, Arg593Cys).

BACKGROUND: Heterogeneous bleeding phenotypes are observed in haemophilia A patients with the same mutation in the F8 gene. Specific mutations in the A2 domain of factor VIII are associated with mild haemophilia and a higher risk of inhibitor development. Double mutations in mild haemophilia A are rarely reported. In this study, we investigated the in vitro function of factor VIII, performing different specific and global coagulation assays, observed clinical characteristics and assessed the possible predictive diagnostic value of the differences. MATERIALS AND METHODS: The clinical features of haemophiliacs with a mild phenotype were reviewed. Blood samples were obtained and analysed for mutations and coagulation assays: activated partial thromboplastin time, one-stage and chromogenic factor VIII activity, factor VIII antigen and rotational thromboelastometry. RESULTS: We report on a cohort of 22 patients with double Glu113Asp, Arg593Cys mutations. All our patients have a quantitative defect of factor VIII and preserved similar functional activity. Factor VIII activities measured by the one-stage or chromogenic method were not discrepant, although the chromogenic assay resulted in 20% lower factor VIII activities. Waveform analysis showed a lower maximum value of the second derivative curve (Max2) of APTT with curve shape alternation, while thromboelastometry (INTEM) showed low sensitivity in comparison to results in a normal population. DISCUSSION: In genotyping, the coexistence of a second mutation should never be excluded, especially in cases of discordant clinical presentation. Waveform analysis correlates better with factor VIII activity than thromboelastometry and the Max2 parameter could provide additional information in managing haemophilia patients. The utility of specific factor activity and global haemostatic assays in general practice still needs to be investigated.

De novo mutation in DMD gene in a patient with combined hemophilia A and Duchenne muscular dystrophy.

We report an unusual case of a patient with two combined X-linked diseases, severe hemophilia A (HA) and Duchenne muscular dystrophy (DMD), of which only HA was hereditary. There was no family history of muscular dystrophy. Genetic analysis revealed that HA was caused by the hereditary coagulation factor VIII (F8) intron 22 inversion (distal/type I inversion), whereas DMD was caused by a de novo deletion in the dystrophin gene. This is the first report of a patient with two severe X-linked diseases, of which only HA was hereditary. Despite the fact that the probability of acquiring two X-linked abnormalities, one hereditary and one de novo, is extremely low, the emergence of such cases indicates that genetic testing for distinct X-linked diseases could be of importance in patients with hereditary hemophilia.

Individualized long-term enzyme therapy for Gaucher disease type 1 in Slovenia.

BACKGROUND: Gaucher disease type 1 (GD1) was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed. We describe the management of eight GD1 patients in Slovenia who were diagnosed between the ages of 2 and 15 years. METHODS: Patients were individually assessed to establish initial enzyme doses and monitored frequently to determine the effects of long-term enzyme dose regimens. Outcomes up to 10 years after long-term treatment are described by changes in the Zimran severity score index, chitotriosidase and acid phosphatase levels, and after 2001, bone parameters (DEXA bone mineral density scores and the MRI bone marrow burden score). RESULTS: Following the initiation of enzyme therapy with individualized dose regimens (range 25-56 U/kg/14 days) and followed by a gradual reduction of doses (range 12-35 U/kg/14 days) during long-term maintenance, disease status improved in all patients as measured by the Zimran severity score index (from a mean of 11.25 [median 11.5] before therapy to a mean of 4.12 [median 3.5] at last report). Anemia and leucopenia resolved in all patients, chitotriosidase and acid phosphatase levels decreased in all patients (and by over 75% in six patients) within 1 year of treatment. Bone marrow burden scores improved in all monitored patients and DXA scores improved in six of seven monitored patients. CONCLUSIONS: We conclude that enzyme therapy with relatively low, individualized dose regimens is well-tolerated and effective in children and young adults with GD1 disease, who are regularly monitored for changes in disease status.

Radiosynoviorthesis for treatment of hemophilic hemarthrosis--Slovenian experience.

UNLABELLED: Radiosynoviorthesis is a well-accepted method for the treatment of recurrent hemarthrosis in hemophilic patients. OBJECTIVES: The aims of our study were to evaluate the effectiveness of radiosynoviorthesis in patients suffering from hemophilic hemarthrosis, to determine the effect of treatment on antihemophilic factor consumption, and to assess the patient's satisfaction with radiosynoviorthesis. METHODS: Between 2001 and 2003, 26 radiosynoviortheses were done in 21 hemophilic patients; in 4 patients the treatment was repeated, and in 1 patient two joints were treated. 90Y colloid was used for the knee joint, and 186Re colloid was used for ankle, shoulder, and elbow radiosynoviorthesis. RESULTS: The bleeding frequency decreased by at least 50% in 53% of patients in the year after radiosynoviorthesis, as compared to the year prior to the therapy. Considering only those patients who had at least 12 bleedings into the treated joints in the year preceding the therapy, the bleeding frequency decreased by at least 50% in 62% of these patients. In this group, the consumption of the antihemophilic factor was notably reduced (on average, by 25,800 I.U./year). All patients reported that the treated joint was much better or better than before the radiosynoviorthesis. CONCLUSION: Radiosynoviorthesis is an effective method for the treatment of hemophilic hemarthrosis, particularly in patients with frequent intra-articular bleedings. The antihemophilic factor consumption was markedly reduced only in patients with frequent joint bleeding. Radiosynoviorthesis is well accepted by patients suffering from hemophilic hemarthrosis.