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.
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).
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).
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.
•144 PUPs with Haemophilia A from seven countries in Central and Eastern Europe•Prophylaxis significantly protects against inhibitor development.•FVIII class does not influence incidence of inhibitor development.•Intensive peak treatment in first 50 EDs increases risk of inhibitor development.
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.
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.
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.
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.
Abstract
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.
The comprehensive management of patients with rare diseases, such as haemophilia and other bleeding disorders, must be organized with extreme care and systematically. The treatment of bleedings, ...their common consequences and complications as well as the enforcement of basic prevention measures can be very costly. However, the costs of subsequent consequences of an improper and inadequately organized treatment are much higher. Besides its negative medical impact on the patient himself, harm to the patients family and the society as a whole can be substantial and severe. Today, with proper treatment, the patient with haemophilia or other bleeding disorders can lead a completely normal and creative life. A potential cause of severe complications in patients with haemophilia and other bleeding disorders is the development of inhibitors against the missing coagulation factors, but today even this complication can be managed successfully. Therefore, the vital task of medical sta is to inform the patient and his family about the nature of his disease as well as about the treatment, its characteristics and overall complexity. Only a few doctors and medical professionals dispose of and can acquire enough knowledge for the proper management and support of patients with haemophilia and other bleeding disorders, comparable to the experience of the patient living with his 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.
Patients with haemophilia A (HA) or B (HB) can be given prophylactic or on-demand treatment administered by continuous infusion or bolus injections of factor VIII (FVIII) or IX (FIX). In this study ...we evaluated the efficacy and safety of low-dose continuous infusion of FVIII or FIX.
We studied all eligible patients with HA or HB treated with continuous infusion of factor concentrates over an 18-year period in a single Slovenian Haemophilia Comprehensive Care Centre. Treatment started with a bolus injection of FVIII or FIX, followed by continuous infusion at the initial rate of 2 IU/kg/h of FVIII in HA patients and 4.5 IU/kg/h of FIX in HB patients. The infusion rate was subsequently adjusted according to the indication for therapy.
A total of 66 continuous infusions (40 in major surgery, 10 in minor surgery and 16 with bleeding episode) in 46 HA patients and 16 (15 in severe and 1 in mild HA) in eight HB patients were included in the study. During the first week of treatment, the median continuous infusion rates in HA patients undergoing major surgery, minor surgery and a bleeding event were 2.18 (0.75-3.68), 1.48 (1.0-2.54) and 2.24 (1.33-3.93) IU/kg/h, respectively. The median FVIII activities were 0.69 (0.37-1.19), 0.47 (0.39-0.84) and 0.52 (0.36-1.06) IU/mL. After the first week of treatment, even lower doses of FVIII were needed. Red blood cell transfusions had to be administered to three patients (2 with severe and 1 with moderate HA) during the continuous infusion and inhibitors developed in five patients. In HB patients, the median continuous infusion rate was 1.85 (1.07-2.94) IU/kg/h and the median FIX activity was 0.62 (0.30-1.04) IU/mL. Red blood cell transfusions were not required, and thrombophlebitis and inhibitors did not appear.
Overall, low-dose continuous infusion was shown to be an effective and safe way of treating patients with HA. The protocol used also proved efficient and safe in all HB patients.
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.
To investigate renal function in a group of patients with a history of haemophilia and haematuria. We reviewed 32 medical records of the patients with haemophilia and gross haematuria identified ...through a computerized haemophilia registry, from January 1993 to December 2004. In all patients but three (two refused to participate and one died) clinical and laboratory tests were performed by the nephrologist. One patient had chronic renal failure because of diabetic nephropathy. In two patients reduced renal function was detected by creatinine clearance measurements, and one of them had Duchenne muscular dystrophy. In four patients minimal proteinuria was diagnosed by the biuret method. Mild reduction in renal function of unknown cause was found in only one of the 29 patients tested.
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.
The comprehensive management of patients with rare diseases, such as hemophilia and other bleeding disorders, must be organized with extreme care and systematically. Treatment of bleedings, their ...common consequences and complications as well as the enforcement of basic prevention maeasures can be very costly. However, the subsequent consequences of improper and inadequately organized treatment are much higher. Besides its negative medical impact on the patient himself, the harm for the patient's family and the society as a whole can be substantial and severe. Today, with proper treatment the patient with hemophilia or other bleeding disorders can lead a completely normal and creative way of life.
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