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

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.

scholarly journals Severe haemophilia a in a preterm girl with turner syndrome - a case report from the prenatal period to early infancy (part I)

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Agnieszka Berendt ◽  
Monika Wójtowicz-Marzec ◽  
Barbara Wysokińska ◽  
Anna Kwaśniewska
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Turner Syndrome ◽  
X Chromosome ◽  
Diagnostic Procedures ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Preterm Children ◽  
Initial Symptoms ◽  
The Central Nervous System

Abstract Background Bleedings are more frequent in the population of preterm children than among those born at term, much less in older children. The reasons for such bleedings in preterms include plasma factor deficiencies, immaturity of small vessels in the germinal matrix region, prenatal hypoxia or sepsis. They affect the brain tissue, the gastrointestinal tract and the respiratory system, or are manifested by prolonged bleedings from injection sites. Haemophilia is a rare cause of haemorrhages in the neonatal period, and in the female population it is even seen as an extremely rare disorder. Its aetiology in girls is diverse: inheriting defective genes from their parents, skewed X inactivation or a single X chromosome. Case presentation The article presents a case of a preterm girl born in the 28th week of pregnancy, who was diagnosed with severe haemophilia A stemming from the absence of the X chromosome. The girl’s father is healthy, but her mother’s brother suffers from haemophilia. On the second day of the child’s life, a prolonged bleeding from the injection site was observed. A coagulation profile revealed prolonged APTT which pointed to haemophilia A diagnosis. Moreover, a marked clinical dysmorphy, female sex and a negative family history on the father’s side led the treating team to extend the diagnostic procedures to encompass karyotype evaluation. The girl was diagnosed with Turner syndrome. No bleeding to the central nervous system was observed during her hospital stay. Conclusions Preterm children belong to the risk group of bleeding into the central nervous system or haemorrhages in the course of sepsis. Rare causes of such bleedings should also be borne in mind, including haemophilia. The initial symptoms of haemophilia in preterm children occur in the first days of their lives, which is connected with a number of invasive procedures required in that period. Genetic conditions may coexist with one another. Arriving at one diagnosis does not mean one should abandon further diagnostic procedures in cases where additional atypical symptoms are present which do not match the clinical image of a primary disease.

POINT-MUTATION OF FACTOR VIII CODING SEQUENCES IN HAEMOPHILIA A

1987 ◽  
Author(s):  
R J Matthews ◽  
I R Peake ◽  
A L Bloom
Keyword(s):  
Factor Viii ◽  
Point Mutation ◽  
Cdna Probe ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Coding Region ◽  
Cdna Fragment ◽  
Coding Sequences ◽  
Restriction Sites

In order to study the molecular basis of haemophilia A, DNA from 26 haemophilia A patients (8 severe with inhibitors, 13 severe noninhibitors and 5 mild/moderate) was screened by the Southern blotting method with FVIII cDNA probe A (a i.7kb Kpnl cDNA fragment that spans exons 1 to 12) probe B (a 4.7kb EcoRI cDNA fragment that contains exons 14 to 25 and part of exon 26) probe C (a 1.8kb EcoRI cDNA fragment that contains the remainder of exon 26 and probe D (an Apal/EcoRI 783bp cDNA fragment that includes all of exons 22 to 25 and parts of exons 21 and 26). All cDNA probes were kindly provided by Genetics Institutes Inc.No large structural alterations of the FVIII gene were detected in any of the patients. However altered TaqI restriction sites within the coding regions of 3 patients were observed. DNA from patient 1 with severe haemophilia (VIIIAg < 0.1 u/dl, inhibitor negative) when probed with probe C showed a substitution of the normal 2.6kb TaqI and 4.5kb EcoRI fragments with novel 12kb TaqI and 11.5kb EcoRI fragments respectively. In addition he showed the normal 4kb Bglll fragment with probe C. A point mutation or small deletion (50bp is suspected to be present within exon 26.Patient 2 had severe haemophilia and a FVIII inhibitor of 12 units (Bethesda). DNA from patient 2 when probed with probe B revealed a novel 5.0kb TaqI fragment instead of the normal 2.2kb and 2.8kb fragments.The location of the altered Taq I restriction site within the coding region of exon 18 was confirmed with intragenomic probe pi 14.12 that includes exons 17and 18 (kindly provided by Genentech Inc.) A family study with this mutation specific fragment showed the patients sister and mother to be carriers.DNA from Patient 3 (severe haemophilia, factor VIII inhibitor 33 units) when probed independently with probes B and D revealed the absence of the normal 2.4kb and 1.4kb TaqI fragments and the generation of a novel 3.8kb TaqI fragment suggesting an alteration of the TaqI site within the coding region of exon 23.The detection of altered TaqI restriction sites in 3of our patients is further evidence that 'CG' dinucleotide sequences might be relative hot-spots for mutation when occurring within coding sequences of genes.

Successful liver transplantation in a patient with severe haemophilia A and a high-titre factor VIII inhibitor

Haemophilia ◽  
2004 ◽  
Vol 10 (6) ◽  
pp. 735-737 ◽  
Author(s):  
A. A. Ashrani ◽  
M. T. Reding ◽  
A. Shet ◽  
J. Osip ◽  
A. Humar ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Factor Viii ◽  
High Titre ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Viii Inhibitor

Homoeopathic Management of a Case of Severe Haemophilia Type A with Inhibitor Positive: Case Report

2020 ◽  
Vol 33 (04) ◽  
pp. 302-308
Author(s):  
Hiral Shah ◽  
Tapas Kumar Kundu ◽  
Afroz Farooque Shaikh
Keyword(s):  
Case Report ◽  
Factor Viii ◽  
Replacement Therapy ◽  
Psychological Status ◽  
Clotting Factor ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Clotting Factors ◽  
Bleeding Episodes

AbstractHaemophilia is an X-linked inherited immunogenetic bleeding disorder resulting from deficiency of clotting Factor VIII (haemophilia A) or Factor IX (haemophilia B). Haemophilia patients suffer from complication of developing autoantibodies/inhibitor against clotting factors used for the treatment; most commonly patients are treated with Factor VIII replacement therapy. In modern medicine, haemophiliacs with inhibitor positive status are treated with bypassing agents such as Factor VIII inhibitor bypassing agent and immune tolerance induction therapy (ITI) because such patients do not respond to traditional factor replacement therapy during an event of active bleeding. Treatment with ITI is very expensive and it requires medical expertise. Moreover, high cost of such treatment is one part of the problem, while its availability is another problem especially in developing countries. The inhibitor status among haemophilia patients is identified by conducting a blood test which measures the Bethesda units (BU) levels in the blood. In this case report, the homoeopathic management of a patient with haemophilia A severe type (Factor VIII <1%), inhibitor positive (4 BU/mL), is presented. The patient underwent treatment for a span of 4 years. After closely assessing the patient's condition and applying the principles of homeopathy medicine selection, his frequent bleeding episodes were treated with homoeopathic medicines such as Hamamelis Virginica Q, Phosphorus, Arnica montana, Rhus toxicodendron, Calendula officinalis, and Pulsatilla nigricans. Intercurrent medicine—Tuberculinum bovinum—was given when the most indicated medicine failed to relieve the symptoms of the case and was given during non-bleeding phase. The medicines not only helped in reducing haemophilia-related bleeding episodes but also improved complaints of pain, relieved skin complaints, and showed improvement in overall psychological status of patient. It can be concluded that homeopathy medicines were able to successfully reduce the frequency of bleeding and intensity of pain in this patient. Owing to reduced bleeding, he required relatively a smaller number of factor replacement treatment compared with earlier when he was not taking homeopathy. Homoeopathy proved to be effective in managing severe haemophilia patient as a supportive therapy and was able to contribute toward reduced inhibitor levels in severe haemophilia patient.

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

1997 ◽  
Vol 77 (02) ◽  
pp. 234-237 ◽  
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.

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

2015 ◽  
Vol 114 (10) ◽  
pp. 676-684 ◽  
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).

Comparison of Anti-Human and Anti-Porcine Factor VIII Inhibitor Levels in 63 Patients with Severe Haemophilia A

Vox Sanguinis ◽  
1993 ◽  
Vol 64 (4) ◽  
pp. 210-214 ◽  
Author(s):  
M. Fiks-Sigaud ◽  
L. Bendelac ◽  
A. Parquet ◽  
F. Verroust ◽  
M.F. Torchet ◽  
...  
Keyword(s):  
Factor Viii ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Viii Inhibitor
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