Inhibitorentwicklung nach früher hoher Exposition und Hirnblutung

SummarySevere haemophilia A was diagnosed postpartum in a newborn. The mother was known as a conductor (intron 22 inversion) and an uncle had a persistently high titer inhibitor after failed ITI.Due to a cephalhaematoma, a high-dose pdFVIII substitution was given within the first days after birth. At the age of six month a severe cerebral haemorrhage occurred, making a high-dose pdFVIII substitution and neurosurgical intervention necessary. Several days later a porth-a-cath-system was implanted. The development of a high titer inhibitor occured six days later, an ITI was started according to the Bonn Protocol. Initially rFVIIa was given in addition to the pdFVIII substitution. Seven days after the beginning of treatment the inhibitor was no longer detectable. At monthly intervals the FVIII dosage was reduced until the dosage complied with a prophylaxis in severe haemophilia A.The duration of the ITI was nine months. A total of 30 mg rFVIIa and 276 000 IU pdFVIII were used; costs in total: 280 173.60 Euro.

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French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615358 ◽

1998 ◽

Vol 80 (11) ◽

pp. 779-783 ◽

Cited By ~ 60

Author(s):

Y. Laurian ◽

E. P. Satre ◽

A. Borel Derlon ◽

H. Chambost ◽

P. Moreau ◽

...

Keyword(s):

Factor Viii ◽

Immune Tolerance ◽

Hemophilia A ◽

High Titer ◽

Recombinant Factor Viii ◽

High Dose ◽

Severe Hemophilia ◽

Inhibitor Development ◽

Intron 22 Inversion ◽

Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

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High Titer Inhibitors in Severe Haemophilia A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648832 ◽

1994 ◽

Vol 72 (01) ◽

pp. 162-164 ◽

Cited By ~ 26

Author(s):

E Briët ◽

F R Rosendaal ◽

W Kreuz ◽

V Rasi ◽

K Peerlinck ◽

...

Keyword(s):

High Titer ◽

Haemophilia A ◽

Severe Haemophilia

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Another Variant Pattern of Intron 22 Inversion in the Factor VIII Gene Seen in a Severe Haemophilia A Patient

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657738 ◽

1997 ◽

Vol 78 (04) ◽

pp. 1303-1303 ◽

Cited By ~ 2

Author(s):

Mohammed S Enayat ◽

Bimal D M Theophilus ◽

Michael D Williams ◽

Jonathan T Wilde ◽

Frank G H Hill

Keyword(s):

Factor Viii ◽

Haemophilia A ◽

Severe Haemophilia ◽

Factor Viii Gene ◽

Intron 22 Inversion ◽

Variant Pattern

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Sports participation and physical activity in adult Dutch and Swedish patients with severe haemophilia: A comparison between intermediate‐ and high‐dose prophylaxis

Haemophilia ◽

10.1111/hae.13683 ◽

2019 ◽

Vol 25 (2) ◽

pp. 244-251 ◽

Cited By ~ 2

Author(s):

Olav Versloot ◽

Erik Berntorp ◽

Pia Petrini ◽

Rolf Ljung ◽

Jan Astermark ◽

...

Keyword(s):

Physical Activity ◽

Sports Participation ◽

High Dose ◽

Haemophilia A ◽

Severe Haemophilia

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Case Report on a Female Patient with Congenital Haemophilia a and An Acquired Type-2 Inhibitor to FVIII

Blood ◽

10.1182/blood.v112.11.4525.4525 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4525-4525

Author(s):

Karin Kurnik ◽

Christoph Bidlingmaier

Keyword(s):

Half Life ◽

Female Child ◽

Haemophilia A ◽

Severe Haemophilia ◽

Hormonal Change ◽

Fviii Inhibitor ◽

Intron 22 Inversion ◽

Depth Analysis ◽

Recombinant Fviii

Abstract Only rare cases of female haemophilia have been reported. Moreover, no case of congenital haemophilia A associated with an acquired type-2 inhibitor to FVIII in a female child has been described in literature yet. We report the case of a 15-year old girl, diagnosed with severe haemophilia A (FVIII:C <1%) at the age of 13 months. Her father suffered from severe haemophilia A (FVIII:C <1%) due to an intron 22 inversion. In the girl both an intron 22 inversion and a non-random X-inactivation were found. At 3 years the girl received prophylactic treatment, and recombinant FVIII (3 × 40 IU/kg/week) from 6 years of age. Bleeding episodes were rare. Aged 13 she developed two large spontaneous haematomas. In-depth analysis confirmed decreased FVIII-recovery, –half-life and an inhibitor titre of 7.6 BU following type-2 kinetics (haemophilic autoantibodies). All of the few reported children with an aquired FVIII inhibitor presented with other autoimmune diseases or had used penicillin. Our patient showed none of this, but interestingly experienced menarche 4 weeks after inhibitor detection. This lets us speculate that the ethiology of the inhibitor formation in our patient at the time of hormonal change might be similar to that in pregnant or postpartum women. Taking into account the recommendations of Ma et al. (2006) regarding inhibitor development during pregnancy in healthy women, we initiated a modified ITI with 75 IU/kg rFVIII concentrate (4,000 IU per infusion) every other day without additional immunosuppressive therapy. After 6 weeks of ITI, inhibitor titres declined and became negative after 8 months, resulting in a normal FVIII half-life till now.

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Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A

Thrombosis and Haemostasis ◽

10.1160/th11-09-0642 ◽

2012 ◽

Vol 107 (06) ◽

pp. 1072-1082 ◽

Cited By ~ 19

Author(s):

Guenter Auerswald ◽

Alexis Thompson ◽

Michael Recht ◽

Deborah Brown ◽

Raina Liesner ◽

...

Keyword(s):

Family History ◽

Adverse Events ◽

Prospective Trial ◽

High Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Serious Adverse Events ◽

Inhibitor Development ◽

Treatment Regimens ◽

History Of

SummaryWe report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate®). Ondemand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Nonserious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95 [1.29–19.06]), non-Caucasian ethnicity (4.18, [1.18–14.82]), and intensive treatment at high dose (4.5 [1.05–19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.

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Severe haemophilia A in a neonate presenting as haemopneumothorax after tracheo-oesophageal fistula-oesophageal atresia repair

BMJ Case Reports ◽

10.1136/bcr-2018-225526 ◽

2018 ◽

pp. bcr-2018-225526

Author(s):

Zita Hung ◽

Mohammed Bahari ◽

Mark J Belletrutti ◽

Chloe Joynt

Keyword(s):

Factor Viii ◽

Oesophageal Atresia ◽

Male Infant ◽

Fresh Frozen Plasma ◽

Haemophilia A ◽

Severe Haemophilia ◽

Intron 22 Inversion ◽

Viii Level ◽

Fresh Frozen ◽

Frozen Plasma

A male infant with oesophageal atresia and distal tracheo-oesophageal fistula (TEF type C) underwent right thoracotomy and transpleural repair of TEF on day 4 of life. He did not have a family history of coagulation disorders. A preoperative finding of prolonged partial thromboplastin time (PTT)>200 s was overlooked, and he went to surgery. There were no concerns with haemostasis prior to and even during the operation. The prolonged PTT was treated with one 10 mL/kg dose of fresh frozen plasma in the immediate postoperative period. On the fourth postoperative day, the infant developed a right haemopneumothorax, requiring fresh frozen plasma and packed cell transfusions. He was subsequently diagnosed with severe haemophilia A due to intron 22 inversion in the factor VIII gene, with factor VIII level <0.01 IU/mL.

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Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

Thrombosis and Haemostasis ◽

10.1160/th17-01-0059 ◽

2017 ◽

Vol 117 (12) ◽

pp. 2274-2282 ◽

Cited By ~ 5

Author(s):

Maria Elisa Mancuso ◽

Kathelijn Fischer ◽

Elena Santagostino ◽

Johannes Oldenburg ◽

Helen Platokouki ◽

...

Keyword(s):

Risk Factors ◽

Immune Tolerance ◽

Laboratory Data ◽

Tolerance Induction ◽

High Titre ◽

High Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Immune Tolerance Induction ◽

Potential Risk Factors

AbstractIn children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

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HLA Class II Profile: A Weak Determinant of Factor VIII Inhibitor Development in Severe Haemophilia A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655944 ◽

1997 ◽

Vol 77 (02) ◽

pp. 234-237 ◽

Cited By ~ 123

Author(s):

C R M Hay ◽

W Oilier ◽

L Pepper ◽

A Cumming ◽

S Keeney ◽

...

Keyword(s):

Factor Viii ◽

Statistical Significance ◽

Class Ii ◽

Hla Class Ii ◽

Factor Viii Inhibitor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Factor Viii Gene ◽

Intron 22 Inversion ◽

Viii Inhibitor

SummaryThe risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (>10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion.HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies from 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA- DRB*1501, DQB 1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7,1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB 1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB 1*01, DQB 1 *0501, DQA 1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

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