FVIII inhibitor risk correlated with F8 gene variants in 296 unrelated male Chinese patients with haemophilia A

Haemophilia ◽  
2020 ◽  
Author(s):  
Hongfei Kang ◽  
Jingjing Li ◽  
Shengmei Chen ◽  
Bai Li ◽  
Yin Feng ◽  
...  
Keyword(s):  
Chinese Patients ◽  
Haemophilia A ◽  
Gene Variants ◽  
Fviii Inhibitor ◽  
Unrelated Male

scholarly journals Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhongzhong Chen ◽  
Xiaoling Lin ◽  
Yunping Lei ◽  
Haitao Chen ◽  
Richard H. Finnell ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Han Chinese ◽  
Genome Wide Association ◽  
Chinese Patients ◽  
Genome Wide Association Studies ◽  
Gene Variants ◽  
Genome Wide ◽  
Chinese Cohort

Abstract Background Hypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). There is little known at present about any possible hypospadias risk associations in Han Chinese populations. Methods To systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 197 moderate-severe hypospadias cases and 933 unaffected controls. Suggestive loci (p < 1 × 10− 4) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory and protein-protein interactions (PPIs) were then conducted for the functional analyses of candidate variants. Results We identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe hypospadias [SP1/SP7, rs11170516, Pcombine = 3.5 × 10− 9, odds ratio (OR) = 1.96 (1.59–2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait locus (cis-eQTL). Protein SP1 could affect the risk of hypospadias via PPIs. Conclusions We performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression and subsequent PPIs. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

Combining gene variants with clinical characteristics improves outcome prediction in Chinese patients with myelodysplastic syndromes

2019 ◽  
Vol 61 (4) ◽  
pp. 919-926
Author(s):  
Yan Yu ◽  
Tongtong Zhang ◽  
Xiebing Bao ◽  
Qinrong Wang ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Clinical Characteristics ◽  
Outcome Prediction ◽  
Chinese Patients ◽  
Gene Variants

Mutational spectrum ofF8gene and prothrombotic gene variants in haemophilia A patients from Southern Italy

Haemophilia ◽  
2008 ◽  
Vol 14 (4) ◽  
pp. 796-803 ◽  
Author(s):  
V. SANNA ◽  
F. ZARRILLI ◽  
P. NARDIELLO ◽  
V. D'ARGENIO ◽  
A. ROCINO ◽  
...  
Keyword(s):  
Southern Italy ◽  
Haemophilia A ◽  
Gene Variants ◽  
Mutational Spectrum

Neutralisation of factor VIII inhibitors by anti-idiotypes isolated from phage-displayed libraries

2016 ◽  
Vol 116 (07) ◽  
pp. 32-41 ◽  
Author(s):  
Anja Schmidt ◽  
Kerstin Brettschneider ◽  
Jörg Kahle ◽  
Aleksander Orlowski ◽  
Karin Becker-Peters ◽  
...  
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
Coagulation Factor ◽  
Cross Reactivity ◽  
Hybridoma Cells ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Fviii Inhibitor ◽  
Antiidiotypic Antibody

SummaryFollowing replacement therapy with coagulation factor VIII (FVIII), up to 30 % of haemophilia A patients develop FVIII-specific inhibitory antibodies (FVIII inhibitors). Immune tolerance induction (ITI) is not always successful, resulting in a need for alternative treatments for FVIII inhibitor-positive patients. As tolerance induction in the course of ITI appears to involve the formation of anti-idiotypes specific for anti-FVIII antibodies, such anti-idiotypes might be used to restore haemostasis in haemophilia A patients with FVIII inhibitors. We isolated antiidiotypic antibody fragments (scFvs) binding to murine FVIII inhibitors 2-76 and 2-77 from phage-displayed libraries. FVIII inhibitor/anti-idiotype interactions were very specific as no cross-reactivity with other FVIII inhibitors or isotype controls was observed. ScFvs blocked binding of FVIII inhibitors to FVIII and neutralised their cognate inhibitors in vitro and a monoclonal mouse model. In addition, scFv JkH5 specific for FVIII inhibitor 2-76 stained 2-76-producing hybridoma cells. JkH5 residues R52 and Y226, located in complementary determining regions, were identified as crucial for the JkH5/2-76 interaction using JkH5 alanine mutants. SPR spectroscopy revealed that JkH5 interacts with FVIII inhibitor 2-76 with nanomolar affinity. Thus, FVIII inhibitorspecific, high-affinity anti-idiotypes can be isolated from phagedisplayed libraries and neutralise their respective inhibitors. Furthermore, we show that anti-idiotypic scFvs might be utilised to specifically target inhibitor-specific B cells. Hence, a pool of anti-idiotypes could enable the reestablishment of haemostasis in the presence of FVIII inhibitors in patients or even allow the depletion of inhibitors by targeting inhibitor-specific B cell populations.

HUMAN AND PORCINE FVIII INHIBITOR RESPONSE FOLLOWING INFUSION OF HUMAN FVIII CONCENTRATE - MEASUREMENT USING AN AGAROSE GEL SYSTEM

1987 ◽  
Author(s):  
D J Perry ◽  
F G H Hill
Keyword(s):  
High Responder ◽  
Agarose Gel ◽  
Haemophilia A ◽  
Single Treatment ◽  
Fviii Inhibitor ◽  
Antibody Titres ◽  
Appropriate Therapy ◽  
Gel Technique ◽  
Mild Haemophilia ◽  
Coagulation Inhibition

Conventional methods for determining inhibitor levels in haemophiliacs are time consuming and labour intensive. The agarose gel technique of Jorquera et al. (1) has been modified and standardized to measure human and porcine inhibitors to VIII:C.26 samples from 12 haemophiliacs with inhibitors were analysed and in all cases antibody to human and porcine VIII:C was detected.Six haemophiliac patients with 'high responder-type' inhibitors were studied using stored plasma and the rise in antibody titres to both human and porcine VIII:C was determined sequentially during treatment with human FVIII concentrate.One patient (J. C.) had received a single treatment with porcine concentrate (Hyate:C) with no rise in porcine VIII:C.In 5 of 6 patients both porcine and human inhibitor titres rose but the porcine levels were less than the human. However, in the remaining high responder patient (I. I.) with previously mild haemophilia and no exposure to porcine FVIII, the rise in porcine antibody titre greatly exceeded that of human. This patient has continued to be treated with human FVIII concentrate during which time the human inhibitor titres have fallen more than the porcine.This method is simple to perform and has the advantage that both human and porcine inhibitor titres can be easily and quickly assessed so that the most appropriate therapy can be given.1. Jorquera JI, Carmona E, Aznar JA, Peiro A and Sanchez-Cuenca JM. (1985) A Standardized Method for Measuring Anti-FVIII:C Inhibitors in Haemophilia A by Coagulation Inhibition in Agarose Gel. Thromb. Haemostas. 54(2): 377-380.

Paraneoplastic acquired haemophilia A in extensive-stage small cell lung cancer (ES-SCLC) in the era of immunotherapy

2021 ◽  
Vol 14 (1) ◽  
pp. e236973
Author(s):  
Mehrnoosh Pauls ◽  
Natalia Rydz ◽  
Nancy A Nixon ◽  
Doreen Ezeife
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
High Dose ◽  
Haemophilia A ◽  
Small Cell Lung ◽  
Fviii Inhibitor ◽  
Acquired Haemophilia ◽  
Extensive Stage

Small cell lung cancer (SCLC) is a deadly and rapidly progressive disease that can present with various paraneoplastic syndromes on initial workup. Acquired factor VIII (FVIII) deficiency, also known as acquired haemophilia A (AHA), has been identified as a rare paraneoplastic syndrome in SCLC. Here, we present a 61-year-old woman with a massive gastrointestinal bleed and prolonged activated partial thromboplastin time (PTT) in the emergency department. She was diagnosed with rare paraneoplastic AHA secondary to extensive-stage SCLC (ES-SCLC). She was treated with high-dose steroids and factor bypassing agents, which led to the resolution of bleeding and undetectable FVIII inhibitor levels. She was subsequently treated for ES-SCLC with carboplatin, etoposide and atezolizumab. This case report highlights a rare clinical presentation of paraneoplastic AHA that necessitates prompt recognition in patients with SCLC with ongoing bleeding and elevated PTT.

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

Blood ◽  
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 &lt;1%) at the age of 13 months. Her father suffered from severe haemophilia A (FVIII:C &lt;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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