HEMOPHILIA B IN CANINES IS DUE TO A POST-TRANSCRIPTIONAL DEFECT

1987 ◽  
Author(s):  
K A High ◽  
J P Evans ◽  
J L Ware ◽  
D W Stafford ◽  
H R Roberts
Keyword(s):  
Severe Disease ◽  
Northern Blotting ◽  
Factor Ix ◽  
Hemophilia B ◽  
Cdna Libraries ◽  
Transcriptional Level ◽  
Activity Levels ◽  
Large Deletions ◽  
Guanidinium Thiocyanate ◽  
Normal Carrier

Factor IX is a vitamin K dependent plasma proteinsynthesized in the liver; a deficiency of Factor IX results in hemophilia B. An animal model for hemophilia B exists in dogs; affected animals have severe disease, with activity levels of less than 1%. The purpose of the current study is to determine the molecular basis of canine hemophilia. In previous work, we had shown that the Factor IX gene in hemophilic dogs appeared to be at least partly intact; thus, genomic DNA from normal, carrier and hemophilic dogs, when probed with sequences from the 4th, 7th, and 8th exons of the human gene, gave identical patterns on Southern blot. We have now completed the mapping of the hemophilic gene, using probes from the first, second, third and sixth exons, and have shown it to beentirely intact, that is, free of any large deletions or rearrangements, as determined by Southern blotting. In addition, using the guanidinium thiocyanate technique, we h^ve prepared total RNA from normal and -hemophilic dog livers add analyzed these samples by Northern blotting. The results show that the hemophilic dog synthesizes a Factor IX transcript of approximately 3 kilobases, that is, of the same size asthe normal dog. In addition, baaed on signal intensity, the transcript appears to be produced in roughlyequivalent amounts in the normal and hemophilic dogs.We conclude that the defect responsible for canine hemophilia B interferes with the production of the normal Factor IX protein at a post-transcriptional level. Moreover, since the hemophilic dogs produce Factor IX mRNA it should be possible to elucidate the gene defect in the hemophilic animals by preparing normal and hemophilic canine liver cDNA libraries and isolating and characterizing the respective Factor IX cDNAs.

scholarly journals Gene Therapy For Hemophilia B Using CB 2679d-GT: A Novel Factor IX Variant With Higher Potency Than Factor IX Padua

Blood ◽  
2021 ◽  
Author(s):  
Nisha Nair ◽  
Dries De Wolf ◽  
Phuong Anh Nguyen ◽  
Quang Hong Pham ◽  
Ermira Samara ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bleeding Time ◽  
Factor Ix ◽  
Hemophilia B ◽  
Activity Levels ◽  
Liver Inflammation ◽  
Dosing Regimen ◽  
Total Blood ◽  
Blood Loss Volume ◽  
Dose Limiting Toxicity

Sustained expression of therapeutic factor IX (FIX) levels has been achieved after adeno-associated viral (AAV) vector-based gene therapy in patients with hemophilia B. Nevertheless, patients are still at risk of vector dose-limiting toxicity, particularly liver inflammation justifying the need for more efficient vectors and a lower dosing regimen. A novel increased potency FIX (designated as CB 2679d-GT), containing three amino acid substitutions (R318Y, R338E, T343R), significantly outperformed the R338L-Padua variant after gene therapy. CB 2679d-GT demonstrated a statistically significant ~3-fold improvement in clotting activity when compared to R338L-Padua after AAV-based gene therapy in hemophilic mice. Moreover, CB 2679d-GT gene therapy showed a significantly reduced bleeding time (~5 to 8-fold) and total blood loss volume (~4-fold) compared with mice treated with the R338L-Padua, thus achieving a more rapid and robust hemostatic correction. FIX expression was sustained for at least 20 weeks with both CB 2679d-GT and R338L-Padua while immunogenicity was not significantly increased. This is a novel gene therapy study demonstrating the superiority of CB 2679d-GT highlighting its potential to obtain higher FIX activity levels and superior hemostatic efficacy following AAV directed gene therapy in hemophilia B patients than what is currently achievable with the R338L-Padua variant.

Molecular Epidemiology of Factor IX Germline Mutations in Mexican Hispanics: Pattern of Mutation and Potential Founder Effects

1995 ◽  
Vol 74 (06) ◽  
pp. 1416-1422 ◽  
Author(s):  
Erik C Thorland ◽  
Brian G Weinshenker ◽  
Jing-zhong Liu ◽  
Rhett P Ketterling ◽  
Erica L Vielhaber ◽  
...  
Keyword(s):  
Severe Disease ◽  
Germline Mutations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Founder Effects ◽  
Founder Mutations ◽  
Mexican Families ◽  
Recurrent Mutations ◽  
Previous Hypothesis ◽  
Haplotype Data

SummaryGermline mutations in patients with hemophilia B generally have arisen within the past 150 years. Evidence suggests that these germline mutations generally result from endogenous processes. However, a unique pattern would be expected if a population were exposed to a physiologically important germline mutagen since mutagens generally produce characteristic patterns, or “fingerprints”, of mutation. To determine the pattern of mutation in Mexican Hispanics, the regions of likely functional significance in the factor IX gene were screened by di-deoxy fingerprinting (ddF) in 31 families with hemophilia B. Mutations were found in 30 of these families. Haplotype analysis was performed on individuals with identical mutations to help distinguish independent, recurrent mutations from founder effects. Analysis of these 30 mutations, along with 7 mutations reported previously in Mexican Hispanic families, reveals a pattern of independent mutation that is similar to the pattern of mutation observed in 127 U. S. Caucasian families (p = 0.89). These results may reflect either an underlying pattern of germline mutation due to endogenous processes or the presence of an ubiquitous mutagen. Further analyses of the recurrent mutations revealed that two mutations, T296M and R248Q, accounted for 19% of the mutations found in the Mexicans. Haplotype data suggest that the multiple occurrences of T296M and R248Q are associated with founder effects and that screening for these mutations may allow rapid mutation detection and carrier diagnosis in a significant minority of Mexican families with hemophilia B. These two mutations also are associated with founder effects in the U. S. Caucasian population. However, the haplotypes are different in these two populations, indicating independent origins. The occurrence of identical founder mutations in distinct populations provides evidence for the previous hypothesis that the number of different mutations giving rise to mild or borderline mild/moderate hemophilia B is small compared to deleterious mutations causing more severe disease.

Pharmacokinetics of Idelvion (rIX-FP) in a Patient with Renal Failure

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4957-4957
Author(s):  
Adam S. Kotowski ◽  
Shilpa Jain ◽  
Steven John Ambrusko ◽  
Linda Belling ◽  
Karen Kovach
Keyword(s):  
Renal Failure ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Half Life ◽  
Factor Ix ◽  
Hemophilia B ◽  
Activity Levels ◽  
Recombinant Factor Ix ◽  
Stage Renal Disease ◽  
End Stage

Abstract Life expectancy for people with hemophilia has improved and is now approaching that of the general population. This growing population will likely experience age-related co-morbidities such as cardiovascular diseases, diabetes, and chronic kidney disease. Distribution of endogenous and exogenous (plasma or recombinant) factor IX between the intravascular and extravascular spaces have not been fully elucidated. In vivo recovery and elimination half-life have been suggested to be inadequate descriptors of effective pharmacokinetics (PK) of FIX, but that differences in distribution might be clinically important (Bjorkman Haemophilia 2013). Pharmacokinetics (PK) of the long acting recombinant Factor IX albumin fusion protein (rIX-FP) with albumin demonstrated improved PK in a pivotal trial. However, no data exists in patients with end stage renal failure requiring dialysis. We present PK data for a single patient on dialysis who has received a single dose of rIX-FP, Case: 71 y/o male with moderate hemophilia B with factor IX activity levels ranging between 2-4%. He averaged 2 bleeds per year until 2013, when his creatinine increased to 1.93-2.3 (GFR approx. 30mL/min). He averaged 2-4 joint or soft tissue bleeds since 2013. His GFR dropped to 7-10 mL/min in 2015. He tested negative for HCV, HIV, and multiple myeloma. A kidney biopsy and angiogram was not performed. He had nephrotic range proteinuria. His renal ultrasound was unremarkable. Hypertensive nephrosclerosis was the working diagnosis. The patient had a central line placed and AV fistula created in April 2016, which was complicated by bleeding despite factor replacement with Benefix (Pfizer). He began hemodialysis in May 2016 using a tunneled central catheter while awaiting maturation. The patient wanted to switch to peritoneal dialysis (PD). For the PD catheter placement we recommended Idelvion for factor replacement and conducted a pharmacokinetic study. A dose of 100 IU/kg (10,879 units) was administered. Factor IX levels were drawn at 1 hour (h), 24 (h), 72 (h), 168 (h), 216 (h), and 336 (h), with factor IX activity levels of 91%, 59%, 34%, 18%, 16%, and 11% respectively. Dialysis occurred 2 (h), 4 days, 1 week, and 11 days during the 2 week PK study. Samples were analyzed with a one stage assay using a silica activator (PTT A Diagnostica Stago) on a Stago Evolution Conclusion: rIX-FP's demonstrated improved pharmacokinetic parameters in half-life, clearance and AUC in a recent study. To our knowledge, no data exist in patients with end-stage renal disease. We have presented data in a dialysis patient and show comparable PK parameters to that shown in the aforementioned study. Our patient's half-life (t1/2) was 165.2 (h) and AUC was 7663.5. It appears that dialysis and end-stage renal disease does not alter PK of rIX-FP. Further studies are needed in more hemophilia B patients with end-stage renal disease to confirm our findings. Disclosures Jain: Biogen: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria.

scholarly journals Bleeding Risk Reduction in Relation to Predicted Factor IX Levels in Hemophilia B Patients Receiving Idelvion (rIX-FP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1411-1411
Author(s):  
John Roberts ◽  
Cecilia Fosser ◽  
Michael Tortorici ◽  
Alex Veldman ◽  
Iris C. Jacobs ◽  
...  
Keyword(s):  
Risk Reduction ◽  
Bleeding Risk ◽  
Factor Ix ◽  
Hemophilia B ◽  
Phase Iii ◽  
Activity Levels ◽  
Bleeding Events ◽  
On Demand ◽  
Bleeding Episodes ◽  
Trough Levels

Abstract Factor IX (FIX) replacement is an effective therapy for hemophilia B patients. The current clinical rationale for maintaining higher trough levels of FIX is to transition patients from a severe hemophilia phenotype (eg. FIX <1% of normal) to a moderate (FIX of 1-5%) or mild disease state (FIX >5%), thereby reducing the total number of bleeding events. Although there is a tentative linkage between trough FIX levels and bleeding tendency which guides hemophilia B management, a thorough quantitative analysis was undertaken for rIX-FP (Idelvion) to robustly define the FIX exposure versus clinical outcome relationship. Pooled adult hemophilia B data from the rIX-FP Phase III development program was utilized for the analysis. A Cox proportional hazards model was employed to relate time-to-bleed event data and various individual measures of exposure (FIX activity) and dosing regimen, while testing the influence of covariates (e.g. baseline FIX). FIX activity levels were simulated using a validated rIX-FP population pharmacokinetic (PK) model. The analysis included all recorded bleeding episodes in subjects receiving either prophylaxis and/or on-demand regimens. Dose amounts and intervals included 50 IU/kg (every 1 week) and 75 IU/kg (every 2 weeks, or every 10 days). A total of 478 bleeding episodes (267 spontaneous bleeds, 190 traumatic bleeds, 21 other bleeds) from 57 adult patients were included in the primary analysis. The highest proportion of bleeds occurred during the on-demand portion of the clinical studies. Patients maintaining cumulative FIX activity trough levels above 5% and 10% were predicted to have significant reductions in bleeding risk of 83% and 81%, respectively, per 1 year above these levels, compared to patients not maintaining these FIX activity trough levels. Cumulatively, maintaining FIX levels above 2% was not statistically significant for risk reduction. Furthermore, a time-direct evaluation relating daily FIX trough activity to daily bleeding risk found that >2%, >5% and >10% FIX activity thresholds were significant predictors of bleeding events with 69% (95% CI, 53 to 80) 77% (95% CI, 67 to 84) and 78% (95% CI, 69 to 85) risk reductions, respectively. Although >2% was significant, the wider confidence intervals suggest a more reliable risk reduction at the >5% and >10% levels. This in-depth exposure-response analysis of rIX-FP determined a strong relationship between FIX activity levels and hemophilia B bleeding risk reduction. Trough FIX activity above 5% (either cumulatively or on any given day) was identified as a statistically significant and overall sufficient pharmacological threshold for reduction of bleeding risk in adult hemophilia B patients receiving rIX-FP. Trough FIX activity > 10% was also a predictor of significant risk reduction, and the magnitude of risk reduction was similar to that of achieving levels > 5%. These results are aligned with existing World Hemophilia Foundation (WFH) hemophilia severity definitions where patients with a range of observed FIX activity 5-40% are categorized as a single mild hemophilia phenotype. Post-approval clinical exposure versus response relationships may also be affected by an individual's level of physical activity which was not assessed in the current analysis. Overall, this analysis demonstrates the quantitative clinical rationale for optimization of adult rIX-FP dose regimens through targeting and maintaining FIX activity trough levels above 5% to 10%. Disclosures Roberts: CSL Behring: Employment. Fosser:CSL Behring: Consultancy; Cytel: Employment. Tortorici:CSL Behring: Employment. Veldman:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Sidhu:CSL Behring: Employment.

Genetic disorders of coagulation

2010 ◽  
pp. 4518-4531
Author(s):  
Eleanor S. Pollak ◽  
Katherine A. High
Keyword(s):  
Genetic Disorders ◽  
Severe Disease ◽  
Factor Ix ◽  
Careful Study ◽  
Activity Levels ◽  
Factor X ◽  
Coagulation Proteins ◽  
Hereditary Disorders ◽  
Severity Of The Disease ◽  
Enzymatic Complex

Much of what is understood about specific coagulation proteins has emerged from the careful study of hereditary disorders of blood coagulation. Haemophilia is a familial X-linked disorder due to deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), components of the intrinsic enzymatic complex that activates factor X. The severity of the disease correlates with predicted concentrations of activated factor protein, and those with activity levels below 1% are defined as having severe disease....

Factor VIII and Factor IX Mutation Analysis in 600 U.S. Hemophilia Patients: Correlation of Mutation Type with History of Inhibitor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1017-1017
Author(s):  
Connie H. Miller ◽  
Craig Hooper ◽  
Thomas C. Abshire ◽  
Paula L. Bockenstedt ◽  
Doreen B. Brettler ◽  
...  
Keyword(s):  
Splice Site ◽  
Hemophilia A ◽  
Severe Disease ◽  
Pcr Primers ◽  
Factor Ix ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Large Deletions ◽  
Intron 1 ◽  
History Of

Abstract More than 600 U.S. hemophilia patients have been genotyped as part of the pilot study for a prospective surveillance system for factor inhibitors conducted at 12 U.S. Hemophilia Treatment Centers. 80% of enrolled subjects had hemophilia A, 58% with severe disease, 24% moderate, and 18% mild. Age ranged from &lt;1 to 84 years. 83% were white, 8% black, and 4% Hispanic. In hemophilia A patients, all exons, all intron-exon junction regions, and the 3′ untranslated region of the factor VIII (F8) gene were resequenced in both directions by automated sequencer. The VariantSEQr™ protocol was used for resequencing on a 3730 DNA Analyzer from Applied Biosystems. The PCR primers and M13 sequencing primers are described at http://www.ncbi.nlm.nih.gov/sites/entrez?db=probe with a few modifications to the PCR primers to enhance throughput and reproducibility. Data were analyzed with SeqScape®. Inversions of intron 22 and intron 1 in the F8 gene were examined by PCR. Among 477 hemophilia A patients, missense mutations were found in 196 (41%), intron 22 inversions in 139 (29%), frameshifts in 50 (10%), nonsense mutations in 41 (9%), large deletions in 18 (4%), intron 1 inversions in 9 (2%), splice site changes in 5 (0.6%), and insertion in 1 (0.2%). Two mutations were identified in 4 (0.8%). No mutation was identified in 18 (4%). 124/139 of int22 inversions were reported to result in severe hemophilia, as well as 18/18 large deletions, 44/50 frameshifts, 37/41 nonsense mutations, and 8/9 int1 inversions. Of 196 missense mutations, 56 resulted in severe disease, 55 in moderate, and 80 in mild. History of inhibitor was reported in 79 patients, 22.4% of those with severe, 11.8% of those with moderate, and 2.4% of those with mild disease. Inhibitors occurred in 61% of those with large deletions, 26% of intron 22 inversions, 22% of nonsense mutations, 14% of frameshifts, 11% of intron 1 inversions, 6% of missense mutations, 20% of splice site changes, and 11% of those with no mutation identified. 173 distinct mutations were observed, 81 of which have not been reported previously in the Hemophilia A Mutation Database (HAMSTeRS). Among the patients enrolled in the study, black patients with hemophilia A were more likely to have a history of inhibitor than white patients (p=0.02). In hemophilia B patients, the promoter, coding regions, and intron-exon junctions of the factor IX (F9) gene were resequenced as above. Among 123 hemophilia B patients, 90 (73%) had missense mutations, 9 (7%) had frameshift mutations, 8 (7%) had nonsense mutations, and 3 (2%) had deletions. Two enrolled patients had history of FIX inhibitor, one with a large deletion and one a missense mutation. Centralized testing with high-throughput systems allows genotype to be used as a variable in ongoing studies of inhibitor risk. This project is supported by the CDC Foundation through a grant from Wyeth Pharmaceuticals, which had no role in data analysis or abstract preparation.

Platelet-Derived Codon-Optimized Hyperfunctional FIX Gene Therapy of Hemophilia B Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3751-3751
Author(s):  
Jocelyn A. Schroeder ◽  
Mary A. Jozwiak ◽  
Paul E. Monahan ◽  
Qizhen Shi
Keyword(s):  
Gene Therapy ◽  
Immune Tolerance ◽  
Conflicts Of Interest ◽  
Insertion Site ◽  
Hemoglobin Level ◽  
Factor Ix ◽  
Hemophilia B ◽  
Specific Gene ◽  
Activity Levels ◽  
Gene Therapy Protocol

Abstract Our previous studies demonstrate that targeting factor IX (FIX) expression to platelets under control of the platelet-specific αIIb promoter (2bF9) can restore hemostasis and induce immune tolerance in hemophilia B (HB) (FIXnull) mice (Chen, et al. Mol Ther 2014). However, functional platelet-FIX activity levels in transduced mice were only around 3% in whole blood even when a lethal 11Gy total body irradiation (TBI) was employed. To reduce potential toxicities associated with this gene therapy protocol from preconditioning and insertion site-mediated mutagenesis, it is desirable to optimize our vector for better clinical efficacy and safety. Recent studies have demonstrated that the combined effect of codon optimization and hyperfunctional FIX Padua can significantly enhance the efficacy of hepatocyte-targeted FIX gene therapy in HB. Thus, we engineered a novel lentiviral vector, 2bCoF9R338L, in which codon-optimized FIX Padua was used to replace the normal FIX expression cassette in our 2bF9 construct. FIXnull mice that we used in this study were originally developed by Lin, et al. (Blood 1997). Platelet-FIX expression was introduced by 2bCoF9R338L lentivirus transduction and syngeneic transplantation under a clinically relevant non-myeloablative preconditioning regimen 6.6Gy TBI. The levels of FIX expression were determined by ELISA for FIX antigen (FIX:Ag) and chromogenic assay for functional FIX activity (FIX:C). Both antigen and activity levels of FIX in platelets from 2bCoF9R338L-transduced recipients were significantly higher than those from normal 2bF9LV-transduced animals. There are approximately a 5.8-fold higher antigen (10.9±3.9 vs. 1.9±1.3 mU/108 platelets) and 28-fold activity (29.1±9.8 vs. 1.1±0.3 mU/108 platelets) levels, respectively, in the 2bCoF9R338L group compared to the 2bF9 group. Flow cytometry analysis showed that 17.7±5.8% of platelets expressed hFIX, which was not significantly different from the 2bF9 group (14.8±10.7%), demonstrating that lentivirus harboring 2bCoF9R338L has similar transduction efficiency as the 2bF9 lentivirus. To assess whether the bleeding phenotype was rescued in FIXnull mice after receiving 2bCoF9R338L-transduced HSCs, we used a 6-hour tail bleeding test. All 2bCoF9R338L-transduced recipients' tail bleeding clotted within 6 hours with a clotting time of 2.5±0.6 hours and the remaining hemoglobin level of 69.3±8.8%, which were not significantly different from those of the wild type controls (1.9±0.3 hours and 67.2±4.2%). In contrast, none of the FIXnull control mice clotted within 6 hours and the remaining hemoglobin level (40.5±1.9%) was significantly lower than in the 2bCoF9R338L group. To investigate whether anti-FIX immune tolerance was induced in 2bCoF9R338L-transduced recipients, 6 months after HSCT, animals were immunized with recombinant human FIX (rhF9) at a dose of 200 U/kg via intraperitoneal injection two times with a 3-week interval, and the anti-FIX inhibitory antibodies (inhibitors) were determined by Bethesda assay. We found that none of the FIXnull mice that received 2bCoF9R338L-transduced HSCs developed anti-FIX inhibitors even after extensive rhF9 immunization in the presence of adjuvant. In contrast, all FIXnull control mice developed anti-FIX inhibitors when the same immunization protocol was employed. Of note, anaphylaxis can occur in these FIXnull mice with rhF9 infusion if the immune system was primed by FIX. To confirm that platelet-FIX expression is sustained in 2bCoF9R338L-transduced recipients, sequential transplantation was carried out using bone marrow from primary recipients that received 2bCoF9R338L-transduced HSCs. Platelet lysate FIX assays showed that hyperfunctional platelet-FIX was sustained in the secondary recipients resulting in phenotypic correction and immune tolerance in the secondary transplantation FIXnull recipients. Together, our data strongly suggest that immune tolerance is induced in FIXnull mice after 2bCoF9R338L gene therapy. In summary, we have demonstrated that we are able to significantly augment platelet-FIX expression utilizing codon-optimized FIX Padua for platelet-specific gene therapy of HB, resulting in phenotypic correction and immune tolerance induction in FIXnull mice. Our data suggest that platelet-targeted codon-optimized gain-of-function FIX gene therapy is a promising approach for gene therapy of HB. Disclosures No relevant conflicts of interest to declare.

scholarly journals Carrier Detection in Hemophilia B.

1977 ◽  
Author(s):  
E. Briët ◽  
R.M. Bertina ◽  
N.H. van Tilburg ◽  
J.J. Veltkamp
Keyword(s):  
Oral Contraceptives ◽  
Neutralization Test ◽  
A Priori ◽  
Rabbit Antiserum ◽  
Neutralization Assay ◽  
Factor Ix ◽  
Hemophilia B ◽  
Carrier Detection ◽  
Activity Levels ◽  
Normal Women

We examined 37 obligatory carriers of hemophilia B and 40 normal women. The levels of both factor IX activity and factor IX antigen were determined. The factor IX antigen levels were assayed in an inhibitor neutralization test in which a rabbit antiserum was used. 12 out of the 37 carriers had oral contraceptives and so did 20 out of the 40 normals.Higher levels of both factor IX activity and factor IX antigen were found in the women, carriers as well as normals, using oral contraceptives. In carrier detection programs, therefore, a distinction should be made between women using the pill and those wo do not. The attempt to discriminate between carriers and normals on basis of factor IX activity and antigen levels proved to be as unsatisfactory as it was on the basis of factor IX activity levels only. The overlapping area of normals and carriers was smaller in the group of women on oral contraceptive medication. On the basis of our findings we expect that we can detect with a 90% confidence 17 carriers and 17 normals in a group of 100 potential carriers with an a priori chance on carriership of 50%. The detection rate is somewhat higher for women using oral contraception. The assay of factor IX antigen by means of the inhibitor neutralization assay does not appear to improve carrier detection.Results with an immuno-electrophoretic assay of factor IX antigen will be discussed.

scholarly journals Collected Experience of the Pennsylvania Hemophilia Program

1977 ◽  
Author(s):  
S.S. Shapiro ◽  
M.E. Eyster ◽  
J. Lewis
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Severe Disease ◽  
Factor Ix ◽  
Hemophilia B ◽  
Home Therapy ◽  
Product Usage ◽  
Number Of Patients ◽  
Total State ◽  
Actual Prevalence

The Pennsylvania Hemophilia Program was initiated in March 1973, with the establishment of 9 Hemophilia Centers throughout the state. From an initial enrollment of 150, the number of patients has grown to 669 as of October 1976. Of these, 491 have Hemophilia A and 91 have Hemophilia B, a prevalence rate of 4.2 and 0.76 per 100,000, respectively in the total state population of some 11,800,000. A total of 210 patients (36%) with Hemophilia A or B are on home therapy programs. Two hundred fifty-five patients with Hemophilia A (52%) have severe disease, of whom 160 (63%) are on home therapy. Thirty-six patients with Hemophilia B (40%) have severe disease, of whom 22 (61%) are on home therapy. The remaining patients are treated in-center as necessary. Thirty-seven patients (7.5%) with Hemophilia A have inhibitors to Factor VIII, while only 1 of 91 patients with Hemophilia B has an inhibitor to Factor IX. Total Factor VIII and Factor IX usage for hemophiliacs in the past year was 15,040,000 and 1,282,000 biological units, respectively. At current prices, this represents $1.5 million for Factor VIII and approximately $150,000 for Factor IX. The average annual use of Factor VIII in severe Hemophilia A, excluding surgery, was 44,300 units/patient for patients on home therapy and 32,000 units/patient for patients on Center therapy. These figures are roughly comparable when corrected for patient age (14% of home therapy patients but 28% of Center therapy patients under the age of 10). These observations suggest that the actual prevalence rates of Hemophilia A and B are lower than previously quoted, that more patients with milder disease exist than expected and that home and Center therapy require equal product usage.

Results of Genetic Analysis of 11,341 Participants Enrolled in the My Life, Our Future (MLOF) Hemophilia Genotyping Initiative

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Jill M Johnsen ◽  
Shelley N Fletcher ◽  
Angela Dove ◽  
Haley McCracken ◽  
Beth K Martin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Severe Disease ◽  
Clinical Results ◽  
Hemophilia B ◽  
Bleeding Disorders ◽  
Severe Hemophilia ◽  
Common Variants ◽  
Advisory Committees ◽  
Large Deletions

Background Hemophilia A (HA) and hemophilia B (HB) are rare X-linked bleeding disorders. Hemophilia genotype is important to inform reproductive planning, pregnancy, neonatal management, inhibitor risk, disease severity, and understanding of disease mechanisms. MyLifeOurFuture (MLOF) was formed as a collaboration between the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF), Bloodworks (BW), and Biogen. Together with participating hemophilia treatment centers (HTCs), MLOF provided hemophilia genotype analysis for patients in the U.S. and created a Research Repository. Methods HTCs contracted through ATHN, enrolled patients, obtained samples, and provided clinical results to patients. ATHN offered provider education, secure infrastructure for clinical data collection, and access for research proposals. NHF educated the bleeding disorders community about the initiative and supported recruitment. Biogen provided scientific collaboration and financial support. BW served as the central genotyping laboratory and houses the research sample repository. Genotyping was performed using a custom next generation sequencing screen followed by confirmation with a second method. Clinical results were returned to providers. Results 107 HTCs enrolled 11,341 patients for testing: 8976 for HA (6180 males, 2796 females), 2358 for HB (1616 males, 742 females), 3 for HA/HB, 4 for hemophilia NOS. Clinically reportable variants were detected in 98.2%% of male HA and 98.1% of male HB patients. 1919 unique variants were found, 1486 in F8 and 433 in F9. Of these, 744 were novel (F8 n=610, F9 n=134). Two variants were detected in 95 patients, including 36 females. In severe HA (n=3419), the most common variants were F8 inversions (44.7%), missense (16.8%), frameshift (16.1%), stop-gain (11.3%), large structural variants (SV) (5.7%), and splice (3.4%). In severe HB (n=564), the most common variants were missense (46.8%), stop-gain (24.1%), frameshift (9.4%), SV (8.3%), and splice (4.1%). Missense variants were the most common variants found in non-severe HA (81.1%) and HB (88.2%). Inhibitor information is reported for 6986 MLOF patients (HA n=5583; HB n=1403) in the ATHNdataset. Inhibitors were more common in severe disease than non-severe disease in HA [29.8% (n=950/3193) vs. 9.0% (n=216/2390)] and HB [12.4% (n=63/508) vs. 1.9% (n=17/895)]. In severe HA, inhibitors were reported in ~50% of patients with large deletions (n=77/80), complex intron 22 inversions (n=9/17), or no variant found (n=7/14). Other gene-disrupting genotypes had intermediate inhibitor rates (25-36%): intron 1 inversions, intron 22 type 1 and type 2 inversions, stop-gain, splice, and frameshift. Lower rates (~7-14%) were reported with in-frame insertion-deletions, missense, and large duplications. In severe hemophilia B, inhibitors were most common with large deletions (57%, n=24/42). Conclusions We here report our analysis of the complete dataset of MLOF, the largest hemophilia genetics project performed to date. Clinically reportable DNA variants were identified in nearly all patients. Our findings support the need for comprehensive gene sequencing and SV detection. Deletions, complex inversions, and "No variant found" were the highest risk genotypes for inhibitors in severe hemophilia. The incidence of discovery of novel variation was high (38%) and continued throughout the study, indicating additional variation remains undiscovered. In summary, MLOF has been a successful nationwide collaboration to genotype two rare bleeding disorders at a scale not previously done. This effort has contributed significantly towards identifying and better understanding DNA variation in the F8 and F9 genes in hemophilia. Disclosures Johnsen: Octapharma: Research Funding. Pierce:Voyager Therapeutics: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy; Decibel Therapeutics: Consultancy; Third Rock Ventures: Consultancy; Takeda: Consultancy; Geneception: Consultancy; Generation Bio: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioMarin: Consultancy; Ambys Medicines: Consultancy; World Federation of Hemophilia.: Membership on an entity's Board of Directors or advisory committees. Recht:Genentech: Consultancy, Other: personal fees, Research Funding; CSL Behring: Consultancy, Other: personal fees; uniQure: Consultancy, Other: personal fees, Research Funding; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Spark: Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Pfizer: Consultancy, Other: personal fees. Konkle:BioMarin: Consultancy; Sanofi: Consultancy, Research Funding; Sigilon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Baxalta: Research Funding; Spark: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Roche: Consultancy.

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