Evaluation of liposomal dose in recombinant factor VIII reconstituted with pegylated liposomes for the treatment of patients with severe haemophilia A

SummaryPatients with haemophilia A treated prophylactically require frequent factor VIII (FVIII) infusions for bleed protection. Recombinant sucrose-formulated FVIII (rFVIII-FS) with pegylated liposomes (PEGLip-rFVIII-FS) was previously shown to extend the bleed-free period after prophylactic infusion versus rFVIII-FS using two doses of FVIII with a fixed amount of liposomal diluent. This randomised, subject-blinded, four-way crossover study evaluated the efficacy and safety of PEGLip-rFVIII-FS using various quantities of pegylated liposomes with a fixed FVIII dose. Adults with severe haemophilia A were randomised to one of four treatment arms. Each arm had four treatment segments, with each segment consisting of a prophylactic infusion followed by on-demand infusions. The prophylactic infusions used a fixed dose of 35 IU/kg rFVIII-FS, but varied in the amount of pegylated liposomes used for reconstitution (4.2, 12.6, or 22.1 mg/kg of body weight or water as a control). On-demand infusions all used 35 IU/kg rFVIII-FS. After treatment of spontaneous bleeds and a wash-out, subjects crossed to another treatment segment (i.e. another PEGLip-rFVIII-FS dose or control).Sixteen subjects enrolled in and completed the study. Mean number of bleed-free days after prophylactic infusion increased from 7.8 days for control rFVIII-FS to 8.7, 10.8, and 10.9 days for PEGLip-rFVIII-FS reconstituted in 4.2, 12.6, and 22.1 mg/kg of pegylated liposomes, respectively. The difference in bleed-free days approached but did not achieve statistical significance in this small study population. No drug-related adverse events or inhibitors were reported. This study helps establish the optimal concentration of liposomes in PEGLip-rFVIII-FS to prolong the post-infusion bleed-free period.

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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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Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings

Thrombosis and Haemostasis ◽

10.1160/th14-09-0760 ◽

2015 ◽

Vol 114 (10) ◽

pp. 676-684 ◽

Cited By ~ 6

Author(s):

Laszlo Nemes ◽

Victor Jimenez-Yuste ◽

Luminita Rusen ◽

Ana Cid ◽

Robert Charnigo ◽

...

Keyword(s):

Factor Viii ◽

Clinical Manifestations ◽

Surveillance Study ◽

Haemophilia A ◽

Severe Haemophilia ◽

Inhibitor Development ◽

On Demand ◽

Fviii Inhibitor ◽

Increased Risk ◽

Clinically Significant

SummaryThis prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1–139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5 % of bleeding episodes resolved after one infusion. LETE incidence was 0.06 % and 0.19 % in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

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Comparison of the efficacy and safety of 12‐month low‐dose factor VIII tertiary prophylaxis vs on‐demand treatment in severe haemophilia A children

Haemophilia ◽

10.1111/hae.13770 ◽

2019 ◽

Cited By ~ 3

Author(s):

Novie A. Chozie ◽

Fitri Primacakti ◽

Djajadiman Gatot ◽

Rahajuningsih D. Setiabudhy ◽

Angela B. M. Tulaar ◽

...

Keyword(s):

Factor Viii ◽

Low Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Efficacy And Safety ◽

On Demand ◽

Dose Factor

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Secondary prophylaxis in an adult patient with severe haemophilia A

Hämostaseologie ◽

10.5482/hamo-12-07-0013 ◽

2013 ◽

Vol 33 (03) ◽

pp. 241-244 ◽

Cited By ~ 1

Author(s):

C. Schubert ◽

S. Schlenkrich

Keyword(s):

Factor Viii ◽

Prospective Studies ◽

Primary Prophylaxis ◽

Secondary Prophylaxis ◽

Haemophilia A ◽

Severe Haemophilia ◽

Bleeding Rate ◽

On Demand ◽

Optimal Dosing ◽

Joint Protection

SummaryPrimary prophylaxis has been proven as the gold standard for preserving joint function in severe haemophilia. Secondary prophylaxis in children has also been shown to have a more beneficial effect on joint protection as on-demand treatment. The outcome of delayed secondary prophylaxis started in adulthood is rarely studied. The case of a man (age: 47 years) with severe haemophilia A demonstrates the successful switch from on-demand therapy to prophylaxis with sub-sequent reduction of annual bleeding rate and number of days of work lost. The small increase of factor VIII consumption (16%) and the decrease of bleeding rate are compared with data from two recently published prospective studies.An optimal dosing schedule needs to be discussed and larger and longer prospective studies targeting the benefits of secondary prophylaxis with factor VIII started in adulthood are necessary.

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Intranasal DDAVP induced increases in plasma von Willebrand factor alter the pharmacokinetics of high-purity factor VIII concentrates in severe haemophilia A patients

Haemophilia ◽

10.1046/j.1365-2516.1999.00282.x ◽

1999 ◽

Vol 5 (2) ◽

pp. 88 ◽

Cited By ~ 2

Author(s):

STEVEN R. DEITCHER

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

High Purity ◽

Haemophilia A ◽

Severe Haemophilia ◽

Factor Viii Concentrates ◽

Von Willebrand ◽

Willebrand Factor

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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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HLA Genotype of Patients with Severe Haemophilia A due to Intron 22 Inversion with and without Inhibitors of Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655945 ◽

1997 ◽

Vol 77 (02) ◽

pp. 238-242 ◽

Cited By ~ 129

Author(s):

J Oldenburg ◽

J K Picard ◽

R Schwaab ◽

H H Brackmann ◽

E G D Tuddenham ◽

...

Keyword(s):

Factor Viii ◽

Major Gene ◽

Statistical Significance ◽

Strong Association ◽

Molecular Genetic ◽

Single Mutation ◽

Severe Haemophilia ◽

Extended Haplotype ◽

Intron 22 Inversion ◽

Hla Genotype

SummaryMolecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterised mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

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Severe haemophilia A in a preterm girl with Turner syndrome: case report – a diagnostic and therapeutic challenge for a paediatrician (Part 2)

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01103-7 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Berendt Agnieszka ◽

Wójtowicz-Marzec Monika ◽

Wysokińska Barbara ◽

Kwaśniewska Anna

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Family History ◽

Factor Viii ◽

Turner Syndrome ◽

Factor Viii Inhibitor ◽

Haemophilia A ◽

Severe Haemophilia ◽

Prolonged Bleeding ◽

Increased Risk

Abstract Background Haemophilia A is an X-linked genetic condition which manifests itself mainly in male children in the first 2 years of life, during gross motor skill development. This disorder is rare in females. The clinical manifestation of severe haemophilia in preterm infants poses a great challenge to the therapeutic team. As extreme prematurity is linked to an increased risk of central nervous system or gastrointestinal bleeding, a well-informed and balanced treatment from the first days of life is crucial to prevent long-term damage. Haemophilia is most commonly caused by inheriting defective genes, and can also be linked to skewed X inactivation and Turner syndrome. The coincidental occurrence of haemophilia A and Turner syndrome is extremely rare, with only isolated cases described to date. Hence, a multidisciplinary approach is needed. Case presentation The authors report on a preterm girl (gestational age 28 weeks) diagnosed with haemophilia and Turner syndrome. The first manifestation of haemophilia was prolonged bleeding from injection sites on the second day of life. Indeterminate aPTT and factor VIII level < 1% confirmed the diagnosis of haemophilia A. Dysmorphic features which did not match the typical clinical picture of haemophilia, the female sex, and a negative paternal family history led to the diagnosis of Turner syndrome. While in hospital, the girl received multiple doses of recombinant factor VIII in response to prolonged bleedings from the injection sites and from a nodule on the girl’s head, and before and after retinal laser photocoagulation. No central nervous system or abdominal cavity bleeding was observed. The substitutive therapy was complicated by the development of factor VIII inhibitor (anti-factor VIII (FVIII) antibodies). Treatment was continued with recombinant factor VIIa. This article aims at demonstrating the complexity of the diagnostics and treatment of a preterm child with two genetic disorders. Conclusions Haemophilia should always be considered in the differential diagnosis of prolonged bleeding, even in patients with a negative family history. In the case of coinciding atypical phenotypic features, further diagnostics for another genetic disease are recommended. Infant care should follow current care standards, while considering certain individual features.

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