scholarly journals The Use of Chromogenic Factor VIII Assay Changes Treatment Approach in a Portion of Mild Hemophilia A Patients with Factor VIII Assay Discrepancy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 906-906
Author(s):  
Muntadhar Al Moosawi ◽  
Karen L. Dallas ◽  
Steven Wong ◽  
Shannon Jackson
Keyword(s):  
Factor Viii ◽  
Gene Mutation ◽  
Roc Curve ◽  
Hemophilia A ◽  
Treatment Approach ◽  
Gene Mutations ◽  
P Value ◽  
Moderate Severity ◽  
Mutation Database ◽  
Study Population

Introduction Hemophilia A is an X-linked inherited bleeding disorder characterized by a deficiency of coagulation factor VIII (FVIII). FVIII assays used for diagnosis and classification of hemophilia are the widely used one-stage assay (OSA) and the chromogenic assay (CSA), a more costly and less commonly used test. The CSA has the advantages of improved precision and insensitivity to pre-activation effects of FVIII that can lead to erroneous results. In approximately one-third of mild hemophilia A cases, reliance on OSA can lead to overestimation of factor level in comparison to CSA, and this 'discrepancy' phenomenon is closely associated with the FVIII molecular abnormality. In mild or moderate hemophilia A, assay discrepancy can lead to misclassification or inappropriate treatment. The objectives of this retrospective study were to determine the proportion of patients with OSA/CSA discrepancies defined by OSA to CSA ratio of >1.5 or <0.5, to identify previously reported and new F8 gene mutations and to classify the impact of assay discrepancy on clinical treatment approach. Also, the study aimed to re-evaluate published discrepant OSA/CSA ratios to identify a ratio with the highest sensitivity to indicate that a change of treatment approach or intensity may be required. Methods We reviewed the charts of adult (>18 years old) patients with mild or moderate hemophilia A followed at the Adult British Columbia Hemophilia clinic with concomitant OSA and CSA results between January 2013 and March 2019. Data collected included patient age, disease severity classification, baseline OSA FVIII:C, and F8 gene mutation. Bleeding phenotype and impact of discrepancy on treatment approach was evaluated and determined independently by two individuals and was correlated with concomitant OSA and CSA. Gene mutation data was collected to determine whether OSA/CSA discrepancy has been previously reported in the international hemophilia A mutation database (www.factorviii-db.org). Descriptive data was reported as medians and ranges. Statistical analyses using Spearman's correlation, logistic regression and receiver operating characteristics (ROC) curve were performed using IBM SPSS v. 22.0. Results 98 patients were included in the study with median age of 53 years (18-88). 75 patients were classified by OSA at baseline as mild and 23 patients as moderate severity. Median FVIII:C by OSA was 15% (6%-40%) in the mild group and 3% (1%-5%) in the moderate severity group. Median FVIII:C using CSA was 13% (2%-66%) in the mild group and 4% (1%-7%) in the moderate group. Based on ratio alone, OSA/CSA discrepancy was detected in 51 (52%) patients out of which 3 (3%) were reverse discrepancies (CSA higher than OSA). Treatment approach was changed as a result of CSA introduction in 14 (27%) patients with OSA/CSA discrepancy (14% of the entire study population). OSA had overall good correlation with CSA (r = 0.84) and as expected, there was no correlation between age and OSA to CSA ratio (r = 0.03). In the patients with OSA/CSA discrepancies, neither age nor OSA/CSA predicted a change of treatment approach (OR 1.02 for age; 95% CI 0.99-1.06; p value 0.213 and OR 1.48 for OSA/CSA; 95% CI 0.96-2.28; p value 0.08). The OSA to CSA ratio of 1.8 to 3.5 demonstrated the highest area under the ROC curve and sensitivity for identification of requirement for treatment change in patients with OSA/CSA discrepancy (AUC 0.75; sensitivity 71%, negative predictive value 75%). Six F8 gene mutations with OSA/CSA discrepancies previously not reported in the database were identified. Conclusions OSA/CSA discrepancies were detected in 52% of the patients with mild or moderate hemophilia A and resulted in change of treatment approach in 27% of discrepant patients. Use of an adjusted OSA/CSA ratio between 1.8 to 3.5 was more likely to detect cases with a requirement for change of treatment approach and use of this ratio to indicate discrepancy may be more clinically meaningful. Six gene mutations associated with OSA/CSA discrepancies previously not described in the international hemophilia A mutation database were identified in the study population, highlighting the need for genotyping discrepant cases. Disclosures No relevant conflicts of interest to declare.

WAG-F8m1Ycb rats harboring a factor VIII gene mutation provide a new animal model for hemophilia A

2010 ◽  
Vol 8 (11) ◽  
pp. 2472-2477 ◽  
Author(s):  
C. J. BOOTH ◽  
M. B. BROOKS ◽  
S. ROCKWELL ◽  
J. W. MURPHY ◽  
H. M. RINDER ◽  
...  
Keyword(s):  
Animal Model ◽  
Factor Viii ◽  
Gene Mutation ◽  
Hemophilia A ◽  
Factor Viii Gene

Factor VIII gene mutations and RFLP analysis in hemophilia A

Stem Cells ◽  
1993 ◽  
Vol 11 (S1) ◽  
pp. 72-76 ◽  
Author(s):  
A. Křepelová ◽  
R. Brdicka ◽  
Z. Vorlová
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Gene Mutations ◽  
Rflp Analysis ◽  
Factor Viii Gene

scholarly journals F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

Blood ◽  
2012 ◽  
Vol 119 (12) ◽  
pp. 2922-2934 ◽  
Author(s):  
Samantha C. Gouw ◽  
H. Marijke van den Berg ◽  
Johannes Oldenburg ◽  
Jan Astermark ◽  
Philip G. de Groot ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gene Mutation ◽  
Hemophilia A ◽  
High Titer ◽  
Meta Analysis ◽  
Gene Mutations ◽  
Secondary Outcome ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Inhibitor Development

Abstract This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

Bleeding Symptoms in Carriers of Hemophilia A — Association to the Factor VIII Gene Mutation?

2004 ◽  
pp. 228-231 ◽  
Author(s):  
W. Miesbach ◽  
Th. Vigh ◽  
I. Stier-Brück ◽  
J. Oldenburg ◽  
I. Scharrer
Keyword(s):  
Factor Viii ◽  
Gene Mutation ◽  
Hemophilia A ◽  
Factor Viii Gene

The Clinical Impact of Mild Hemophilia A, Report of a Cohort Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3210-3210 ◽  
Author(s):  
Mary-Frances Scully ◽  
David MacGregor ◽  
Meghan Walsh ◽  
Brendan Barrett ◽  
Marc Kawaja ◽  
...  
Keyword(s):  
Factor Viii ◽  
Range Of Motion ◽  
General Health ◽  
Hemophilia A ◽  
P Value ◽  
Base Line ◽  
Role Emotional ◽  
Left Ankle ◽  
Sf 36 ◽  
Significant Difference

Abstract Due to a founder affect certain regions of the Canadian province of Newfoundland and Labrador have a very high prevalence of mild Hemophilia A. To accurately plan for future health related needs of these patients, a base-line cross-sectional study of a large cohort segregating a known founder mutation (Val2016Ala) was undertaken. Characteristics of Study Participants Characteristic Affected Males Control Males P-Values (Affected vs Control) Carrier Females Control Females P-Value (Carrier vs Control) Values are expressed as number, mean*, median(interquartile range)†, or percentage Overall N 61(5–76yrs) 44(4–81yrs) 0.883 88(8–88yrs) 65(16–78yrs) 0.935 Factor VIII* 0.15(0.05) 1.29(0.37) <0.001 0.78(0.31) 1.34(0.41) <0.001 Hepatitis Bc Antibodies 15.8%(9/57) 0%(0/28) 0.012 0%(0/75) 0%(0/58) - Hepatitis C Positive 19.7%(12/61) 0%(0/33) 0.001 0%(0/88) 0%(0/65) - HIV Positive 1.6%(1/61) 0%(0/33) 0.420 0%(0/88) 0%(0/65) - Diabetes 24.4%(11/45) 6.1%(2/33) 0.031 - - - BMI†(Adults Only) 30.0(27.0–33.0) 27.0(26.0–30.0) 0.028 29.0(20–57) 28.0(19–46) .446 Statistically Significant Difference SF-36 & Colorado PE-05 Mean Scores for Affected and Unaffected Males Affected Males Affected Males Affected Males Unaffected Siblings Unaffected Siblings Unaffected Siblings t-test Difference vs References Dimension n Mean SD n Mean SD P-Value P<0.05)* Affected Males(age 23–76 years) Unaffected Siblings(age 20–81 years) SF-36 Scores General Health Scale 44 58.1 28.7 32 71.4 21.4 0.024* Role Emotional 44 89.2 19.9 33 98.0 5.5 0.007* Colorado PE-05 Musculoskeletal Scores Axial Deformity 47 0.9 1.4 33 0.2 0.8 0.008* Range of Motion 47 4.2 2.0 33 2.9 1.8 0.005* Gait 47 2.4 3.5 33 0.4 1.4 0.002* Left Ankle 47 3.3 5.0 33 1.0 2.9 0.015* Right Ankle 47 3.2 4.6 33 0.7 1.3 0.002* There was a positive association between the SF-36 General Health Scale scores and the following values of the Colorado PE-05 Scores. Gait (R -.45, p<.001), Range of Motion (R-.08, P=.508), Axial Deformity (R -.35, P<.001), Right Ankle (R -.42, p<.001), and Left Ankle (R-.49, p<.001). The association between the SF-36 Role Emotional Scales for affected males and the values of the Colorado PE-05 was also positive. Gait (R -.52, P<.001), Range of Motion (R - .30, P = .01), Axial Deformity (R -.54, P<.001), Right Ankle (R -.06, P<.001) and Left Ankle (R-.52, p<.001). No patients studied have acquired an inhibitor to Factor VIII. Obese males (BMI >30) had significantly greater impairment in their Range of Motion than non-obese males (4.59 vs (3.34), p<0.05) independent of whether or not they had hemophilia. These results are consistent with our clinical experience that mild Hemophilia A causes episodic bleeding, lack of recognition and delayed treatment leads to significant morbidity. The association with diabetes was unexpected. Future interventions will now focus on prevention and early treatment of ankle bleeds and will include strategies to reduce the risk of obesity.

scholarly journals Mutations of factor VIII cleavage sites in hemophilia A

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 1022-1028 ◽  
Author(s):  
J Gitschier ◽  
S Kogan ◽  
B Levinson ◽  
EG Tuddenham
Keyword(s):  
Amino Acid ◽  
Factor Viii ◽  
Cleavage Site ◽  
Hemophilia A ◽  
Activated Protein C ◽  
Gene Mutations ◽  
Coagulation Factor ◽  
Cleavage Sites ◽  
Severe Hemophilia ◽  
Thrombin Activation

Abstract Hemophilia A is caused by a defect in coagulation factor VIII, a protein that undergoes extensive proteolysis during its activation and inactivation. To determine whether some cases of hemophilia are caused by mutations in important cleavage sites, we screened patient DNA samples for mutations in these sites by a two-step process. Regions of interest were amplified from genomic DNA by repeated rounds of primer- directed DNA synthesis. The amplified DNAs were then screened for mutations by discriminant hybridization using oligonucleotide probes. Two cleavage site mutations were found in a survey of 215 patients. A nonsense mutation in the activated protein C cleavage site at amino acid 336 was discovered in a patient with severe hemophilia. In another severely affected patient, a mis-sense mutation results in a substitution of cysteine for arginine in the thrombin activation site at amino acid 1689. This defect is associated with no detectable factor VIII activity, but with normal levels of factor VIII antigen. The severe hemophilia in this patient was sporadic; analysis of the mother suggested that the mutation originated in her gametes or during her embryogenesis. The results demonstrate that this approach can be used to identify factor VIII gene mutations in regions of the molecule known to be important for function.

Factor VIII gene mutations profile in 148 Chinese hemophilia A subjects

2010 ◽  
Vol 85 (3) ◽  
pp. 264-272 ◽  
Author(s):  
Feng Xue ◽  
Lei Zhang ◽  
Tao Sui ◽  
Jing Ge ◽  
Dongsheng Gu ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Gene Mutations ◽  
Factor Viii Gene

scholarly journals Large Cohort of Symptomatic Female Carriers of Hemophilia in an Extended Native American Family

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4700-4700
Author(s):  
Becki Berkowitz ◽  
Amber Federizo ◽  
Garrett E. Bergman ◽  
Paula J. Ulsh
Keyword(s):  
Soft Tissue ◽  
Factor Viii ◽  
Board Of Directors ◽  
Gene Mutation ◽  
Hemophilia A ◽  
Clotting Factor ◽  
Factor Level ◽  
Advisory Committees ◽  
Low Levels ◽  
Female Carriers

Abstract Hemophilia A is an X-linked recessive genetic bleeding disorder resulting in a lack of clotting factor VIII. Although this disorder primarily affects males, a female who inherits one affected X chromosome from a parent becomes a carrier of hemophilia. While it is widely believed that carriers are asymptomatic, some of these women have mild hemophilia, defined by ISTH as a circulating factor VIII level > 0.5 to 0.40 IU/ml or 5 - 40 % of normal. (White et al Thromb Haemost 2001) Data demonstrates hemophilia A carriers have the same risk for bleeding as a male with mild hemophilia A at the corresponding factor level. Carriers report significantly more bleeding events than non-carriers from small wounds and after invasive procedures, and their bleeding tendency is inversely correlated to their factor level. (Plug et al Blood 2006) Carriers have been shown to demonstrate decreased joint range of motion, soft tissue and osteochondral changes on MRI, consistent with subclinical joint bleeds leading to structural abnormalities in their joints. (Gilbert et al Haemophilia 2014). Additionally, carriers have been shown to report higher scores on pictorial blood assessment charts, a semi-quantitative measure of menstrual blood loss. (Kadir et al Haemophilia 1999) We report here a unique patient population from our Owyhee Indian Health Hemophilia Treatment Center Outreach Clinic on the Duck Valley Indian Reservation in Owyhee, NV. On this reservation, a German Immigrant with hemophilia A married 2 women of the Shoshone Indian Tribe, and they had 14 children (8 females and 6 males). The family tree reveals after four generations there are currently 162 descendants with the same hemophilia A gene mutation, which has been identified. Factor VIII levels in the female family members range from 7% to 50%. The male hemophilia A patients are treated on demand with plasma-derived factor VIII products, currently Koate-DVI, for traumatic events, and prophylactically for medical or dental procedures, or surgery. Approximately 20-25% of the female carriers in this population have been treated with plasma-derived FVIII concentrates, currently Koate-DVI, for childbirth and surgeries. Additionally, all female carriers from teenage years to age 30 are treated with desmopressin acetate nasal spray (Stimate) for menorrhagia and are treated with oral aminocaproic acid (Amicar) for nose bleeds and soft tissue bleeds. Carriers of hemophilia A with factor VIII levels in the range observed in this family, particularly when symptomatic, should receive the diagnosis of "mild hemophilia". Their propensity for developing subclinical as well as clinical bleeding needs to be recognized to assure the receive treatment appropriate to their symptomatology. The low levels of FVIII observed in this family are likely due to extreme lyonization associated with their particular gene mutation. Familial low levels of FVIII can also be seen in some forms of type 2 von Willebrand Disease secondary to poor FVIII binding and a shortened half-life. However, since VWD is inherited in an autosomal recessive pattern, males would not selectively have the severity observed here. Optimal diagnostic and therapeutic strategies as well as many other aspects concerning mild hemophilia remain to be clarified. Additional studies to define these findings are underway. Disclosures Berkowitz: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Speakers Bureau; Baxter: Speakers Bureau. Federizo:Emergent: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Bergman:Kedrion Biopharma: Employment. Ulsh:Kedrion Biopharma: Employment.

scholarly journals Impact of Interleukin-6 and Interleukin-10 Gene Polymorphisms on Inhibitor Development in Patients with Moderate and Severe Hemophilia a

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5026-5026
Author(s):  
Hoda Hassab ◽  
Marwa Hanafi ◽  
Ahmed Abdelmaksoud ◽  
Shimaa ElSayed
Keyword(s):  
Factor Viii ◽  
Interleukin 6 ◽  
Hemophilia A ◽  
Gene Promoter ◽  
Human Leukocyte ◽  
Interleukin 10 ◽  
Promoter Polymorphism ◽  
P Value ◽  
Severe Hemophilia ◽  
Gene Promoter Polymorphism

Abstract Background: An important complication of administration of factor VIII concentrates to treat or prevent bleeding,is the development of autoantibodies that block the activity of the relevant factor (inhibitors). These inhibitory antibodies occur in approximately 25 % of patients with severe hemophilia A. Inhibitors are much less common in patients with mild or moderate disease. Recently, significant progress has been made in our understanding of the mechanisms that lead to inhibitor formation. Polymorphisms of the immune response genes have been suggested to be contributing determinants of the inhibitor risk. Previous immunogenetic studies have shown the implication of human leukocyte antigen (HLA) alleles and some of the cytokine polymorphisms in inhibitors formation such as IL-6 and IL-10. Aim: This study aimed to investigate the associations between interleukin-6 gene promoter polymorphism at position (−174 G/C), interleukin-10 gene promoter polymorphism at position (-1082G/A) and susceptibility of patients with hemophilia A to develop factor VIII inhibitors. Methods and subjects: After medical ethical committee approval, the present study was conducted on 50moderate and severehemophilia A males aged ≤ 18 years who are attending hematology outpatient clinic of Alexandria University Children's Hospital at El-Shatby. The 50 children were undergoing a)Detailed history taking, with special emphasis on: Age of the patient at the time of diagnosis, clotting activity of factor VIII, Age at first exposure to factor VIII, Type and dose of administered factor VIII concentrate. Exposure days (EDs), Age at first surgical intervention, Detection of factor VIII inhibitors b)Laboratory investigations: Identification of genetic variant IL-6 (rs1800795) , IL-10 ( rs1800896 ) using real time PCR. Results: Thirtyone (72.1%) patients had severe hemophilia and 19 (27.9%) had moderate Hemophilia. Eight (16%) of the studied patients were inhibitor positive. As regard interleukin-6 gene promoter polymorphism at position (−174 G/C), the frequency of G allele was greater than C allele in patients who developed inhibitors (χ2= 0.63) with P value = 1.000. regarding interleukin-10 gene promoter polymorphism at position (-1082G/A), the frequency of G allele was greater than A allele in patients who developed inhibitors (χ20.75) with P value = 0.891.There was no statistically significantdifference as regards interleukin-6 polymorphism at position (−174 G/C), interleukin-10 polymorphism at position (-1082G/A) between inhibitor positive and inhibitor negative patients. Conclusion: There was no relation between interleukin-6 polymorphism at position (−174 G/C) , interleukin-10 polymorphism at position (-1082G/A)and the development of factor VIII inhibitors in patients with hemophilia A despite of the high frequency of G allele among inhibitors corresponding to the previous studies done . Further studies are recommended with larger cohort and other SNPs. Disclosures Hassab: Global Blood Therapeutics: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document