Inhibitor development in haemophilia according to concentrate

SummaryInhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study’s objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22–30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2–16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10–0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00–0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.

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Inhibitor development in non-severe haemophilia across Europe

Thrombosis and Haemostasis ◽

10.1160/th14-12-1044 ◽

2015 ◽

Vol 114 (10) ◽

pp. 670-675 ◽

Cited By ~ 9

Author(s):

Alfonso Iorio ◽

Riitta Lassila ◽

Flora Peyvandi ◽

Gabriele Calizzani ◽

Alex Gatt ◽

...

Keyword(s):

Potential Role ◽

Incidence Rates ◽

Clotting Factor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Inhibitor Development ◽

Haemophilia B ◽

Previously Treated Patients ◽

Previously Treated ◽

Factor Concentrate

SummaryEvidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95 % confidence intervals (95 % CI) were calculated according to diagnosis and concentrate used. Between 1–10–2008 and 31–12–2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95 % CI 0.30–0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20-80); with 72 % occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001–0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII.

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P107 Prevalence of haemarthrosis and clinical impact on the musculoskeletal system in people with haemophilia in the United Kingdom: evaluation of UKHCDO and haemtrack patient reported data

Rheumatology ◽

10.1093/rheumatology/keaa111.105 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Richard A Wilkins ◽

Heidi J Siddle ◽

Graham Chapman ◽

Anthony J Redmond ◽

Hau Xiang ◽

...

Keyword(s):

United Kingdom ◽

Ankle Joint ◽

Health Research ◽

Clotting Factor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Research Support ◽

Haemophilia B ◽

The United Kingdom ◽

Joint Health

Abstract Background Haemarthrosis whereby bleeding occurs within a joint is a significant feature of haemophilia. Despite the availability of prophylaxis clotting factor concentrates in the United Kingdom haemarthrosis is associated with worsening joint health and haemarthropathy in people with severe haemophilia. The ankle joint has been identified as the most affected joint followed by the knee and elbow. Whilst annual joint bleed rates (AJBR) are commonly reported in haemophilia research, bleed rates in individual affected joints and joint health status in paediatric and adult patients is yet to be established. Methods In 2018, paediatric (<18 years) and adult (≥18 years) patients with severe non-inhibitor haemophilia A and B registered with the United Kingdom Haemophilia Centres Doctors Organisation (UKHCDO) National haemophilia Database (NHD) were evaluated for haemarthrosis prevalence and associated joint health. Fully itemised Haemophilia Joint Health Scores (HJHS) were obtained from NHD records in combination with AJBR from Haemtrack (HT) compliant patients. Haemarthrosis prevalence and AJBR were reported as a total and for individual joints (ankles, knees and elbows). Results During 2018, 2233 individuals were identified; 273 reported ≥75% simultaneous HT compliance and electronic fully itemised HJHS data. The median (range) age of children is 10 (6-14) years and adults 40 (25-51) years. The joint bleed prevalence of haemophilia A and B in children is 33% and 47% respectively, and in adults 42% and 60% respectively. In children with haemophilia A (n = 80) the knee (data) was the most common site of bleeding. In haemophilia A adults (n = 157) the ankle and elbow were equally affected. In haemophilia B children (n = 17) and adults (n = 19) the elbow was the most prevalent site. Total HJHS scores in children with haemophilia A and B were 0.00 (1.00 SD) and 0.40 (0.90 SD) respectively. Total HJHS scores in adults with haemophilia A and B were 21.20 (16.80 SD) and 15.40 (15.10 SD) respectively. Mean HJHS scores itemised by joint were higher in adults compared with children. In children with haemophilia A and haemophilia B, mean (3.80) and median (4.00) scores for the ankle joint were higher than for the knee (2.90 and 1.00) and elbow joint (3.30 and 1.00). Conclusion Whilst there are limitations to this self-select subset of individuals with severe haemophilia, the prevalence of haemarthrosis is evenly distributed in all adult joints with a trend towards the knee in paediatrics. Despite prophylaxis 30% of children and 60% adults still reported bleeding over a 12-month period. Irrespective of the prevalence of joint bleeds in children with haemophilia the HJHS does not appear to be clinically sensitive enough to detect changes in joint health. Adults deemed adherent with prophylaxis and haemtrack still demonstrate worsening HJHS scores despite a low AJBR. Disclosures R.A. Wilkins Grants/research support; Funded by the National Institute for Health Research. H.J. Siddle Grants/research support; Funded by the National Institute for Health Research. G. Chapman None. A.J. Redmond None. H. Xiang None. M. Scott None. M. Richards None. L. Horn None. B. Palmer None. D. Stephensen None.

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Neue Daten aus dem Deutschen Hämophilieregister

Hämostaseologie ◽

10.1055/s-0037-1619799 ◽

2013 ◽

Vol 33 (S 01) ◽

pp. S15-S21 ◽

Cited By ~ 3

Author(s):

B. Haschberger ◽

M. Heiden ◽

R. Seitz ◽

W. Schramm ◽

J. Hesse

Keyword(s):

Informed Consent ◽

Coagulation Factor ◽

Clotting Factor ◽

Haemophilia A ◽

Online Data ◽

Aggregated Data ◽

Haemophilia B ◽

Number Of Patients ◽

Coagulation Factor Deficiency ◽

Von Willebrand

SummaryThe German Haemophilia Registry records online data from patients with haemophilia A, haemophilia B, von Willebrand`s disease and other coagulation factor deficiency disorders since 2009. Patient´s pseudonymised data will only be enrolled in the German Haemophilia Registry if the patient signs an informed consent. Without the informed consent, only aggregated data according to §21 German Transfusion Law are reported. These data include the number of persons with congenital haemostasis disorders classified to type of disease and severity as well as patients’ age, and the consumption of clotting factor according to each group. Results: The highest number of patients with haemophilia was reported in 2010: 3375 patients with haemophilia A and 614 with haemophilia B respectively; the highest number of patients with von Willebrand`s disease was 1473, reported in 2011. Conclusion: In comparison to data from registries in Austria and Switzerland it can be assumed that most of the patients with severe haemophilia are registered in the German Haemophilia Registry whereas patients with moderate and mild forms are still missing.

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Inhibitor treatment by rituximabin congenital haemophilia A

Hämostaseologie ◽

10.1055/s-0037-1617028 ◽

2009 ◽

Vol 29 (02) ◽

pp. 151-154 ◽

Cited By ~ 13

Author(s):

Escuriola Ettingshausen ◽

R. Linde ◽

G. Kropshofer ◽

L.-B. Zimmerhackl ◽

W. Kreuz ◽

...

Keyword(s):

B Cell ◽

Immune Tolerance ◽

High Titre ◽

Clotting Factor ◽

Severe Bleeding ◽

High Morbidity ◽

Haemophilia A ◽

Concomitant Treatment ◽

Bleeding Tendency ◽

Severe Haemophilia

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

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Management of Haemophilia in Sweden

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647991 ◽

1976 ◽

Vol 35 (03) ◽

pp. 510-521 ◽

Cited By ~ 13

Author(s):

Inga Marie Nilsson

Keyword(s):

Factor Viii ◽

Total Population ◽

Age Groups ◽

Factor Ix ◽

Haemophilia A ◽

Severe Haemophilia ◽

Haemophilia B ◽

Human Fraction ◽

Mild Haemophilia

SummaryThe incidence of living haemophiliacs in Sweden (total population 8.1 millions) is about 1:15,000 males and about 1:30,000 of the entire population. The number of haemophiliacs born in Sweden in 5-year periods between 1931-1975 (June) has remained almost unchanged. The total number of haemophilia families in Sweden is 284 (77% haemophilia A, 23% haemophilia B) with altogether 557 (436 with A and 121 with B) living haemophiliacs. Of the haemophilia A patients 40 % have severe, 18 % moderate, and 42 % mild, haemophilia. The distribution of the haemophilia B patients is about the same. Inhibitors have been demonstrated in 8% of the patients with severe haemophilia A and in 10% of those with severe haemophilia B.There are 2 main Haemophilia Centres (Stockholm, Malmo) to which haemophiliacs from the whole of Sweden are admitted for diagnosis, follow-up and treatment for severe bleedings, joint defects and surgery. Minor bleedings are treated at local hospitals in cooperation with the Haemophilia Centres. The concentrates available for treatment in haemophilia A are human fraction 1-0 (AHF-Kabi), cryoprecipitate, Antihaemophilic Factor (Hyland 4) and Kryobulin (Immuno, Wien). AHF-Kabi is the most commonly used preparation. The concentrates available for treatment in haemophilia B are Preconativ (Kabi) and Prothromplex (Immuno). Sufficient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 million units of factor IX are given per year. Treatment is free of charge.Only 5 patients receive domiciliary treatment, but since 1958 we in Sweden have practised prophylactic treatment of boys (4–18 years old) with severe haemophilia A. At about 5-10 days interval they receive AHF in amounts sufficient to raise the AHF level to 40–50%. This regimen has reduced severe haemophilia to moderate. The joint score is identical with that found in moderate haemophilia in the same age groups. For treatment of patients with haemophilia A and haemophilia B complicated by inhibitors we have used a large dose of antigen (factor VIII or factor IX) combined with cyclophosphamide. In most cases this treatment produced satisfactory haemostasis for 5 to 30 days and prevented the secondary antibody rise.

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Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study

BMJ Open ◽

10.1136/bmjopen-2018-022719 ◽

2019 ◽

Vol 9 (4) ◽

pp. e022719 ◽

Cited By ~ 2

Author(s):

Lisette M Schütte ◽

Marjon H Cnossen ◽

Reinier M van Hest ◽

Mariette H E Driessens ◽

Karin Fijnvandraat ◽

...

Keyword(s):

Factor Viii ◽

Combination Treatment ◽

Bleeding Risk ◽

Clotting Factor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Registration Number ◽

Concentrate Treatment ◽

Factor Viii Concentrates ◽

Von Willebrand

IntroductionHaemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption.Methods and analysisIn the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment.Ethics and disseminationThe DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences.Trial registration numberNTR5383; Pre-results.

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Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry‐based study

Haemophilia ◽

10.1111/hae.14100 ◽

2020 ◽

Vol 26 (5) ◽

pp. 809-816

Author(s):

Carla J. Jonker ◽

Katrien Oude Rengerink ◽

Arno W. Hoes ◽

Peter G. M. Mol ◽

H. Marijke Berg

Keyword(s):

Clinical Study ◽

Haemophilia A ◽

Severe Haemophilia ◽

Inhibitor Development

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Dental management of patients with haemophilia in the era of recombinant treatments: increased efficacy and decreased clinical risk

BMJ Case Reports ◽

10.1136/bcr-2018-227974 ◽

2019 ◽

Vol 12 (4) ◽

pp. e227974

Author(s):

Antonio Liras ◽

Luis Romeu

Keyword(s):

Factor Viii ◽

Conventional Treatment ◽

Coagulation Factors ◽

Clotting Factor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Optimal Result ◽

Dental Management ◽

Efficient Access

Haemophilia is a hereditary X-linked recessive disorder caused by a deficiency of either clotting factor VIII (haemophilia A) or IX (haemophilia B). Conventional treatment is currently based on the use of either plasma derived or recombinant coagulation factors. This paper reports on the case of a patient with severe haemophilia who presented with mesial decay and interproximal tartar build-up, for which extraction and scaling to remove tartar deposits were indicated. Following extraction, the usual haemostasis techniques were applied, and postoperative prophylactic antihaemophilic treatment was indicated for 2 or 3 days. The patient presented with moderate bleeding for a few minutes immediately after the procedure. Administration of factor VIII before surgery as well as the patient’s favourable pharmacokinetic response allowed for an optimal result. This treatment has afforded patients with haemophilia a better quality of life, and safe and efficient access to invasive surgical procedures.

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Carrier Detection In Haemophilia A By Measurement Of Factor VIII Clotting Antigen (VIIICAg) And Factor VIII Related Antigen (VIIIRAg

10.1055/s-0038-1652532 ◽

1981 ◽

Author(s):

I R Peake ◽

R G Newcombe ◽

B L Davies ◽

R A Furlong ◽

C A Ludlam ◽

...

Keyword(s):

Factor Viii ◽

Laboratory Data ◽

Carrier Detection ◽

Clotting Factor ◽

Haemophilia A ◽

Immunoradiometric Assay ◽

Plasma Samples ◽

Severe Haemophilia ◽

Likelihood Ratios ◽

Unequal Variance

In order to assess the value of measurement of VIIICAg in the detection of carriers of haemophilia A, plasma samples were obtained on three separate occasions from each of 23 obligate carriers of mild and severe haemophilia, and 26 normal females. At each visit each sample was divided into three and each aliquot was then assayed for VIIICAg (immunoradiometric assay), clotting factor VIII (VIIIC) (two stage assay) and VIIIRAg (Laurell immu noelectrophoresis). After calculating median values at each visit, and for the three visits, a comparison of the ratios VIIIC/VIIIRAg and VIIICAg/VIIIRAg was made. Likelihood ratios (of being a carrier) were calculated using an unequal variance predictive method for both ratios. These showed that laboratory data calculated on the median of the three-visit medians had greater discriminatory power than a single-visit median value. Using the median of three visits both VII IC/VIIIRAg and VIIICAg/VIIIRAg gave the same proportional misclassification of carriers as normals (4 of 23- 17%). However the ratios VII ICAg/VIIIRAg were more discriminatory due to the greater reproducibility between visits of VIIICAg results than those of VIIIC. There was no statistically significait difference between VII ICAg/VIIIRAg (or VII IC/VIIIRAg) ratios obtained from carriers of mild or severe haemophilia. The ratio VII ICAg/VIIIRAg was therefore shown to be the method of choice for carrier detection except theoretically in the rare CRM+ families.

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Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO)

Hämostaseologie ◽

10.1055/s-0039-3399493 ◽

2019 ◽

Vol 40 (01) ◽

pp. 119-127

Author(s):

Rebecca Mahn ◽

Kristina Schilling ◽

Robert Klamroth ◽

Karim Kentouche ◽

Volker Aumann ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Moderate Increase ◽

Haemophilia A ◽

Severe Haemophilia ◽

Prophylactic Regimen ◽

Bleeding Rate ◽

Haemophilia B ◽

Hämorrhagische Diathese ◽

The Past

Abstract Introduction In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. Methods Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. Results We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. Conclusions Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

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