The Factor II (FII) Expression Quantitative Trait Locus (eQTL) Prothrombin G20210A Is Pleiotropically Associated with Plasma Fibrinogen Levels and Has a Profound Effect on Obesity in Mexican Americans of South Texas

Abstract The literature on risk factors for venous thromboembolism (VTE) is replete with complex combinations of genetic and environmental determinants. Here we apply statistical genetic models to data from Mexican Americans of South Texas participating in the San Antonio Family Study (SAFS) to help disentangle some of this complexity. The SAFS has data for nearly 50 large extended pedigrees (Figure A) that are extensively phenotyped, especially for traits related to the pathophysiology of cardiovascular disease. Using a linear mixed model approach, while accounting for age, sex, and their interactions (including age-squared, age-by-sex, and age-squared-by-sex) as confounders, we found significant heritability for plasma FII (46%; N=640; p=6.9E-12) and fibrinogen (28%; N=759; p=1.6E-06) coagulant activity levels and that the Prothrombin G20210A mutation was significantly associated with both traits (FII: p=0.002; fibrinogen: p=0.037; Figure B). We also examined a dichotomous obesity variable based on the Adult Treatment Panel III criterion of sex-specific waist circumferences (>102 cm in males; >88 cm females) denoted as OBWC. Under a threshold and liability model, we found a significant heritability of the liability of OBWC (71%; N=654; p=4.4E-08) and that Prothrombin G20210A was a significant predictor (p=0.031), while still adjusting for age, sex, and their interactions. As can be seen in Figure C, the G20210A mutation profoundly impacts the liability of OBWC such that obesity prevalence, where the prevalence parameter is denoted by Kp in the figure, increases by 27% from individuals homozygous for the major G-allele (G/G) with a prevalence of 34% to heterozygous (G/A) individuals with a prevalence of 61%. To the best of our knowledge, this appears to be the largest single-allele-dose effect for obesity reported in the literature. We next performed bivariate trait analysis (each time accounting for age, sex, and their interactions as confounders) to discover potentially meaningful correlations between the three traits of interest and to see if these would influence their association with G20210A. Under a bivariate model for any two traits, denoted as trait A and B say, the parameters of the following equation are estimated: r_p(A,B) = r_g(A,B)*sqrt(h2_A)*sqrt(h2_B) + r_e(A,B)* sqrt(1-h2_A)*sqrt(1-h2_B), where r_p(A,B), r_g(A,B), and r_e(A,B) respectively denote the phenotypic, genetic, and environmental correlation coefficients of A and B, and where h2_A and h2_B denote the trait heritabilities. Moreover, we can test their significance using likelihood-based inferential statistics. For the FII and OBWC bivariate analysis, none of the correlation coefficients were significant. For the fibrinogen and OBWC bivariate analysis, we found significant phenotypic (r_p=0.24; p=2.0E-05) and genetic (r_g=0.41; p=0.024) correlations. For the FII and fibrinogen bivariate analysis, we found significant phenotypic (r_p=0.26; p=3.1E-10) and environmental (r_e=0.28; p=0.003) correlations. For all bivariate analyses, the Prothrombin G20210A mutation was always a significant predictor for both traits of any given pair. In conclusion, Prothrombin G20210A is pleiotropically associated with plasma FII and fibrinogen coagulant activity levels, and OBWC, and profoundly impacts the prevalence of obesity in our sample. The associations of the prothrombin G20210A mutation are not affected by the consideration of inter-correlations between the three traits examined and thus appears to be fairly robust. Figure 1 Figure 1. Disclosures DeFronzo: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Intarcia: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

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The G505A Nonsynonymous Single-Nucleotide Polymorphism (SNP) in TAFI, the Gene Encoding Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Is Pleiotropically Associated with TAFI Antigen Levels and Coronary Heart Disease (CHD) in Mexican Americans of South Texas

Blood ◽

10.1182/blood-2021-151968 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3217-3217

Author(s):

Shuchita Jhaveri ◽

Vincent P. Diego ◽

Hoang Anh Thi Nguyen ◽

Satish Kumar ◽

Marcio A. Almeida ◽

...

Keyword(s):

Board Of Directors ◽

Mexican Americans ◽

Research Funding ◽

Mixed Model ◽

South Texas ◽

Elisa Assay ◽

Systematic Bias ◽

Advisory Committees ◽

P Values ◽

Increased Risk

Abstract Studies have reported that the G505A nonsynonymous (ns)-SNP encoding the Ala147Thr amino acid substitution in TAFI, is associated with a reduction in risk of venous thrombosis and myocardial infarction. Interestingly, homozygosity for the A-allele (AA) of G505A is associated with increased TAFI antigen (TAFI:Ag) levels in plasma. In our study of the genetic determinants of cardiovascular disease (CVD) in Mexican Americans of South Texas, we performed an exome-wide scan in relation to plasma TAFI antigen levels in 784 individuals. While accounting for age, sex, and their interactions as confounders in linear mixed model, we found a heritability of 59% for TAFI:Ag levels (p=1.4E-19), and that ns-SNP G505A was the only variant showing exome-wide significance (p=3.5E-14; Figure A). Figure B shows the quantile-quantile distribution of the p-values from all the exome-wide tests. Clearly, the p-value distribution reveals that there is no systematic bias that may act to skew the p-values, and that the lone exception¾in agreement between observed and expected quantiles¾is due to this TAFI SNP, which strongly suggests a truly significant effect. Consistent with previous reports, the regression coefficient for G505A as a predictor of TAFI:Ag levels showed them to be increasing from the homozygous for the major G-allele (GG), to the heterozygous individuals (GA), to the individuals homozygous for the minor A-allele (AA) (Figure B). We also investigated if G505A is associated with our CHD variable. Using a statistical genetic model for the liability to disease conditional on a threshold, which is equivalent to a probit mixed model, we found that the G505A ns-SNP in TAFI, encoding TAFI Ala147Thr, is significantly associated with a reduction in the risk of CHD (p=0.002). As observed in existing literature, potential limitations of this study include the ELISA assay used for the quantification of TAFI levels. Some ELISA assays measure proTAFI, TAFIa, and TAFIi. However, recent evidence suggests that there may be cross reactivity between TAFIa and TAFIi. This can result in measuring ongoing TAFI activation peptides and elevated levels of TAFIa which ultimately goes on to make resistant fibrin. This is likely the marker that results in the increased risk of venous thromboembolism. To mitigate this confounding factor, an ELISA assay specific to measuring TAFI antigen is needed. In conclusion, we found that TAFI G505A is pleiotropically associated with TAFI:Ag levels and risk of CHD. Figure 1 Figure 1. Disclosures DeFronzo: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Intarcia: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

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Predicting FIX Activity in Prophylaxis Patients Using Recombinant FIX Fc Fusion Protein for Treatment of Bleeding Episodes

Blood ◽

10.1182/blood.v124.21.2842.2842 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2842-2842

Author(s):

Jerry S Powell ◽

Margareth Ozelo ◽

Margaret V. Ragni ◽

John Pasi ◽

David J. Perry ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Activity Levels ◽

Factor Activity ◽

Median Dose ◽

Employment Equity ◽

Advisory Committees ◽

Educational Support ◽

Bleeding Episodes ◽

Equity Ownership

Abstract Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of bleeding episodes in patients with severe hemophilia B. There is currently a lack of data on factor activity levels in patients that treat bleeding episodes while adhering to a prophylactic regimen. The phase 3 B-LONG study (Powell et al. NEJM 2013) demonstrated that recombinant factor IX Fc fusion protein (rFIXFc) had a prolonged half-life relative to recombinant FIX, and that rFIXFc was efficacious and safe for prophylaxis and treatment of bleeding in subjects with hemophilia B; previous reports have evaluated treatment of bleeding in all subjects in B-LONG, including those receiving episodic treatment with rFIXFc. The purpose of this analysis was to assess the efficacy of rFIXFc for the treatment of bleeding in patients that received rFIXFc prophylaxis in the B-LONG study. Additionally, FIX activity levels were predicted under scenarios where treatment of bleeding occurred in close proximity to prophylactic doses using a population pharmacokinetic (PK) modeling approach. Methods: B-LONG included previously treated male subjects ≥12 years of age that had moderately-severe to severe hemophilia B (≤2 IU/dL endogenous FIX activity). Treatment of bleeding was assessed in subjects receiving weekly prophylaxis (Arm 1) and individualized interval prophylaxis (Arm 2). The number of bleeds, median dose per infusion to treat a bleed, and number of infusions to resolve bleeds were evaluated. Predicted activity levels were generated for 1000 hypothetical patients using a three-compartment population PK model that was developed using PK data from B-LONG (n=123) and a phase 1/2a study of rFIXFc (n=12). Factor activity was predicted assuming that bleeds were treated with 50 IU/kg rFIXFc either 24 hours before or 24 hours after a scheduled prophylactic dose for patients on regimens of 50 IU/kg weekly (at steady-state). The treatment of bleeding dose was selected because it was in the recommended range in the B-LONG study and was consistent with the median dose per infusion used in B-LONG. The 50 IU/kg weekly regimen was the most common starting prophylactic regimen in B-LONG; 24 hours was selected to approximate the shortest time interval between separate treatment of bleeding and prophylactic doses. Results: In Arm 1 of B-LONG, bleeding episodes were reported in 47 of 61 subjects, and there were 167 episodes in total. In Arm 2, 67 episodes were reported in 15 of 26 subjects. The median annualized bleeding rate (ABR) was 2.95 in Arm 1 (median spontaneous ABR 1.04) and 1.38 in Arm 2 (median spontaneous ABR 0.88). In Arm 1, 85% of bleeding episodes resolved with 1 infusion and the median dose per infusion was 47.11 IU/kg (interquartile range [IQR] 31.75-56.03). In Arm 2, 85.1% of bleeding episodes resolved with 1 infusion and the median dose per infusion was 44.78 IU/kg (IQR 33.63-74.33). rFIXFc was generally well-tolerated, and there were no vascular thrombotic events reported in any arm of the B-LONG study. The predicted median Cmax from the population PK model was in the normal range for both scenarios (Table 1; Figure 1). Figure 1A: FIX activity over time for hypothetical patients that treat a bleeding episode while on prophylactic regimens. Graphs correspond to scenarios as labelled in Table 1. Figure 1A:. FIX activity over time for hypothetical patients that treat a bleeding episode while on prophylactic regimens. Graphs correspond to scenarios as labelled in Table 1. Figure 1B Figure 1B. Conclusions: Predictions of factor activity from a population PK model showed that the vast majority of patients maintained factor activity within the normal range when rFIXFc was dosed in close proximity for both prophylaxis and to treat a bleeding episode. These predictions also indicated that maximum plasma concentration was achieved rapidly. An analysis of bleeding episodes in subjects specifically from the prophylaxis arms of B-LONG showed that rFIXFc was a safe and efficacious treatment for bleeding in patients on prophylactic regimens. Disclosures Powell: Bayer: Research Funding; Baxter Healthcare: Research Funding; Biogen Idec: Research Funding; CSL Behring: Research Funding; Novo Nordisk: Research Funding. Ozelo:Bayer: Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk Haemophilia Foundation: Research Funding. Ragni:Pfizer: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy, Drug Safety Monitoring Board, Drug Safety Monitoring Board Other; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biogen Idec: Consultancy, Research Funding; Spark Therapeutics: Research Funding; Vascular Medicine Institute, PIttsburgh, PA: Research Funding. Pasi:Bayer: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Educational Support and Travel Grants, Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Educational Support and Travel Grants, Educational Support and Travel Grants Other; OctaPharma: Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees; Pfizer: Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees. Perry:Biogen Idec: Consultancy, Research Funding; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Baxter: Honoraria. Zhu:Biogen Idec: Employment, Equity Ownership. Mei:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Robinson:Biogen Idec: Employment, Equity Ownership.

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Circulating Cytokines and Markers of Iron Metabolism in Myelofibrosis Patients Treated with Momelotininb: Correlatives from the Ym-387-II Study

Blood ◽

10.1182/blood.v126.23.1600.1600 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1600-1600 ◽

Cited By ~ 2

Author(s):

Vikas Gupta ◽

Ruben A. Mesa ◽

Michael W Deininger ◽

Candido E. Rivera ◽

Shireen Sirhan ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Inflammatory Cytokines ◽

Iron Metabolism ◽

Research Funding ◽

Correlation Coefficients ◽

Exploratory Analysis ◽

Spearman Correlation ◽

Advisory Committees ◽

Jak2v617f Allele Burden

Abstract Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, progressive bone marrow fibrosis and shortened survival. Inflammatory cytokines are associated with the disease and monitoring cytokine levels provides information about response to therapy. Momelotinib (MMB) is a JAK1/2 inhibitor under investigation for the treatment of MF that has been shown to be safe and efficacious while providing an anemia benefit to MF patients in the phase I/II studies: CCL09101 (ASH 2013) and YM387-II (EHA 2014). AIMS: To perform an exploratory analysis of the association between cytokines and anemia-related laboratories, 8 week transfusion response, spleen response by MRI at 24 weeks and total symptom score (TSS) reduction (≥50% decrease at week 24) and JAK2 mutation status, in the phase I/II, open-label YM387II trial. METHODS: 61 patients were enrolled and received MMB treatment. Whole blood samples were collected at baseline, 6 and 24 hours post-dose on day 1, and weeks 8 and 20. Plasma levels of 25 cytokines were analyzed by ELISA or MSD. Comparison of post-treatment data with baseline was carried out using Wilcoxon signed rank tests. Significant change from baseline was declared when ≥ 20% change from baseline was observed with Bonferroni adjusted p < 0.05. As this was an exploratory evaluation, comparison between treatment responders and non-responders was carried out using Wilcoxon rank sum test with no multiple testing corrections. Correlations between the cytokines and main biological parameters were investigated using Spearman correlation coefficients. RESULTS: JAK2V617F allele burden. The prevalence of JAK2V617F-positive patients was 68%. A statistically significant decline in JAK2V617F allele burden from baseline in this subgroup was observed at week 12 (median decrease 16.6%; p = 0.0063; n=21) and week 24 (median decrease 21.1%; p = 0.0019; n=18). Higher baseline IGFBP1 was associated with JAK2V617 mutation (48.2% higher in JAK2 mutated patients than in wildtype patients; p = 0.027). Cytokines and iron metabolism markers at baseline At baseline, hepcidin and IL-8 were anti-correlated with anemia-related markers such as transferrin and hemoglobin (Hb) (Spearman correlation coefficients < -0.5). IL-6, CRP and IL-10 showed strong, positive correlation (Spearman correlation coefficients > 0.5). Lower baseline IL-6 was associated with 24 week spleen response (42.3% lower in responders, p = 0.005); higher baseline thrombopoeitin (TPO) was associated with transfusion response at 8 week (3-fold higher in responders, p = 0.002). Baseline ferritin was 63.7% lower in TSS responders compared to non-responders (p = 0.015). On-treatment changes of cytokines and iron markers A significant decrease was observed in CRP, EPO, IL-6, IL-10, IL-12, TNFRII and TNFα following MMB treatment. IL-6 was reduced 30.3% as early as 6 hrs after first dose of MMB and CRP levels were reduced 27.3% after 24 hrs after treatment and continued to decline to 75% by week 4. A peak of IGFBP1 at 24h and increased TPO were observed. Decreased IL-12 and increased IL-8 at week 8 was significantly associated with 24 week spleen response (p < 0.05). Decline of CRP at week 8 was associated with TSS response (p = 0.045). Hb stayed at or above baseline for 6 months. An early peak of Hb was observed at Day 15 which was correlated with a significant increase in red blood cells and decrease in reticulocytes. CONCLUSIONS: In this exploratory analysis, a rapid and sustained reduction in inflammatory cytokines was observed with MMB treatment as expected based on the mechanism of action of MMB through JAK1/2 inhibition. Data from this study suggest an association between IGFBP1 and JAK/STAT signaling in myelofibrosis that will need to be explored in future studies with larger sample sets. Individual baseline biomarkers were correlated with MMB response, but no single biomarker was associated with all responses. Changes in IL-12 and IL-8 were significantly correlated with 24 week spleen response. The Day 15 data suggest that MMB treatment facilitates erythrocyte maturation. These observations, as well as a panel of iron metabolism markers and cellular signaling pathways, will be investigated in a planned Phase 2 translational biology study of MMB in transfusion-dependent subjects with MF (Gilead Sci: GS-US-352-1672). Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Deininger:Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zhang:Gilead Sciences: Employment. Xiao:Gilead Sciences: Employment. Collins:Gilead Science: Employment. Kwei:Gilead Sciences: Employment. Joshi:Gilead Sciences: Employment. Brachmann:Gilead Sciences: Employment.

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Quantitative Assessment of Physical Activity in Adults with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-154451 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3102-3102

Author(s):

Foluso Joy Ogunsile ◽

Nicky Harris ◽

David T Redden ◽

Jeffrey D. Lebensburger ◽

Julie Kanter

Keyword(s):

Physical Activity ◽

Physical Fitness ◽

Board Of Directors ◽

Sickle Cell ◽

Self Efficacy ◽

The Other ◽

Moderate Intensity ◽

Activity Levels ◽

Advisory Committees ◽

Physical Activity Levels

Abstract Cardiopulmonary disease is a leading cause of death for adults with sickle cell disease (SCD) and targeted therapies to modify cardiopulmonary disease currently do not exist. Physical fitness is an important predictor of cardiovascular morbidity and overall survival. More specifically, individuals who have lower fitness are at a higher risk for poor cardiovascular outcomes and premature death. Previous studies show that adults with SCD have lower physical fitness levels compared to the general population and deconditioning is one of the reasons cited for lower fitness in SCD. Fortunately, increasing physical activity can improve physical fitness and can result in better daily functioning, disease-related symptomatology, and cardiovascular outcomes in other chronic disease populations. Thus, evaluating the amount of physical activity in SCD provides an excellent opportunity to explore strategies to improve physical fitness which could have larger implications to cardiovascular health in SCD. The objective of this study is to determine physical activity levels in addition to identifying barriers, facilitators, and attitudes towards physical activity in an adult population with SCD. Methods: We obtained consent from 110 ambulatory adults with SCD (age=19-68 yrs; 69% female; 77% HbSS) during routine visits at an adult comprehensive sickle cell center. Participants completed validated quantitative assessments (International Physical Activity Questionnaire, CDC Barriers to Exercise Survey, and Determinants of Physical Activity) to determine weekly physical activity levels and to identify barriers, facilitators, and attitudes towards physical activity. High self-efficacy is a marker of resilience to sustaining physical activity, so we evaluated self-efficacy using a scale tailored to SCD, the Sickle Cell Self-Efficacy Scale. Information regarding genotype, gender, age, pain medication use, disease-modifying therapy, hospital admissions, and acute care visits were obtained from the electronic medical record. Physical activity levels were stratified into three groups: (1) sub-adequate( < 3 days of low to moderate-intensity exercise), (2) adequate(3 days of moderate-intensity activity or > 4 days of low-intensity activity), and (3) optimal ( ≥4 days of moderate-intensity activity). We compared proportions across the three groups using chi-square analysis. To compare scales across the three groups, we used the non-parametric Kruskal-Wallis test. Results: 94 completed entries and 16 partial entries were analyzed at the conclusion of the study. Only 21.8% (n=24) of the participants reported optimal levels of physical activity. There were more males in the optimal activity group (N=18/24, p=<0.0001) compared to the other groups, but there was not a significant difference between genotype and age among the three groups. Among the barriers evaluated, lacking energy was identified more often in the sub-adequate group compared to the other two (Table 1). Other important barriers to physical activity such as lack of time, social influence, and so forth were identified more often in the sub-adequate group than the optimal group but this was not statistically significant (Table 1). Facilitators to physical activity and self-efficacy scores did not differ tremendously between the three groups. Interestingly, participants in the optimal sub-category were more likely to use short-acting pain medications compared to the other groups (Table 1). However, there were no significant differences between use of long-acting pain medications, the use of disease-modifying therapy, and hospital admissions among the physical activity groups. Limitations: The quantitative surveys were validated in the general population which may not include the needs specific to SCD. Self-reported physical activity levels are subjective and consequently subjected to recall bias. Conclusion: This is the first report of physical activity levels in US adults with SCD. The majority of SCD participants reported sub-optimal levels of activity and currently do not meet the national guidelines of physical activity in the US. This study underscores the importance of implementing strategies such as regular exercise to increase physical activity in SCD. Gender-differences in physical activity, pain medication use, and fatigue as barriers and facilitators to physical activity will need to be studied further. Figure 1 Figure 1. Disclosures Ogunsile: Global Blood Therapeutics: Consultancy, Other: Disease-Specific Presentations on SCD; Clearview Research Institute: Consultancy, Honoraria; Novartis: Consultancy, Other: Treatment-Specific Therapy on Crizanlizumab ; Forma: Consultancy, Other: Attended one Advisory Board Meeting . Lebensburger: Novartis: Consultancy; Bio Products Laboratory: Consultancy. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

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GO-8: Preliminary Results of a Phase I/II Dose Escalation Trial of Gene Therapy for Haemophilia a Using a Novel Human Factor VIII Variant

Blood ◽

10.1182/blood-2018-99-118256 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 489-489 ◽

Cited By ~ 8

Author(s):

Amit C Nathwani ◽

Edward Tuddenham ◽

Pratima Chowdary ◽

Jenny McIntosh ◽

Doyoung Lee ◽

...

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Phase I ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Activity Levels ◽

Advisory Committees ◽

Preliminary Results ◽

Fviii Activity

Abstract Background: Haemophilia A (HA), the most common inherited bleeding disorder, is well suited for gene therapy because a modest increase in the plasma factor VIII (FVIII) levels to ≥1% of normal levels will substantially ameliorate the bleeding diathesis and improve quality of life. Earlier gene transfer strategies for FVIII replacement approaches using plasmid electroporation, retroviral vector, or adenoviral vector failed to achieve persistent phenotypic correction of bleeding. We have recently shown that a single peripheral vein administration of adeno-associated viral (AAV) vectors expressing the FIX transgene results in stable long-term expression of transgenic FIX at therapeutic levels without long term toxicity in patients with severe haemophilia B (ClinicalTrials.gov:NCT00979238). However, the use of AAV vectors for HA gene therapy has been limited by inefficient expression of transgenic FVIII and the large size of the FVIII cDNA. To overcome these obstacles, we developed two AAV-FVIII expression cassettes containing a small synthetic liver specific promoter (HLP) driving the expression of codon optimized FVIII variants. These vectors mediated therapeutic expression of FVIII in murine and non-human primate models (McIntosh et al 2013). The first of these constructs, AAV-HLP-hFVIII-SQ, encoding a B-domain deleted FVIII variant, was recently shown (Rangarajan et al, 2017) to mediate sustained (>1 year) normalisation of factor VIII activity in six of seven participants following a single intravenous infusion of AAV serotype 5 pseudotyped vector. However, high vector doses (6x1013 vector genomes/kg [vg/kg]) were required for efficacy, possibly because this product was manufactured using the insect cell/baculovirus system. In this report we describe the preliminary results of our on-going Phase I/II clinical trial (GO-8) evaluating the second FVIII cassette (AAV-HLP-hFVIII-V3), which contains a 17 amino-acid peptide comprising six N-linked glycosylation motifs from the human FVIII B-domain that are highly conserved through evolution. In murine studies, AAV-HLP-hFVIII-V3 mediated expression of FVIII at 3-fold higher levels when compared to AAV-HLP-hFVIII-SQ. Methods: The safety and efficacy of a single intravenous infusion of AAV8-HLP-hFVIII-V3, pseudotyped with AAV serotype 8 capsid was assessed in three adult men with severe hemophilia A (FVIII activity levels ≤1% of normal) in the context of an Investigator led, Phase I/II, open-label, non-randomized, dose-escalation trial (ClinicalTrials.gov: NCT03001830GO-8). The first subject received a dose of 6x1011vg/kg and the subsequent two patients each received a dose of 2x1012vg/kg. AAV8-HLP-hFVIII-V3 was manufactured in mammalian HEK 293T cells. The subjects have been followed up for 13-47 weeks after vector administration. Results: Peripheral vein administration of AAV8-HLP-hFVIII-V3 was well tolerated in all patients with no infusion-related reactions. Transgenic FVIII was detectable within two weeks and was more than 5 IU/dl by 6 weeks of gene transfer in all three subjects. Factor VIII activity (one stage clotting assay) levels have remained stable at 7±1IU/dl in patient 1 over a period of 47 weeks. The second participant is 20 weeks following administration of 2x1012 vg/kg of AAV8-HLP-hFVIII-V3 and has steady-state FVIII activity of 6±2IU/dl. In the third subject, who was also treated at a dose of 2x1012 vg/kg, the steady state FVIII activity is almost 10 times higher at 69±7 IU/dl. Elevation of serum alanine aminotransferase was observed in patients 1 and 3 at between weeks 4-6 after gene transfer, reaching peak levels that were 1.5 X upper limit of the normal range. Both patients were treated with corticosteroids within 48 hours of the onset of transaminitis with no loss of transgene expression. No participant has developed a FVIII inhibitor. Conclusion: Our preliminary results from the ongoing Phase I/II study demonstrate FVIII activity levels >5% in all three subjects with normalization of FVIII:C levels in one patient. These levels are sufficient to reduce/prevent spontaneous hemorrhage and have been achieved using relatively lower doses of AAV8-HLP-FVIII-V3 than reported previously with a related FVIII expression cassette. No Grade III (CTCAE v4.03) or greater adverse events have been observed over a period of 47 weeks after administration of AAV8-HLP-hFVIII-V3. Disclosures Nathwani: Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tuddenham:Freeline: Consultancy; BioMarin: Consultancy, Patents & Royalties. Chowdary:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Consultancy. McIntosh:Freeline: Consultancy.

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Bendamustine and Rituximab Versus Dexamethasone, Rituximab and Cyclophosphamide in Patients with Waldenstrom Macroglobulinemia (WM)

Blood ◽

10.1182/blood.v128.22.2968.2968 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2968-2968 ◽

Cited By ~ 3

Author(s):

Jonas Paludo ◽

Jithma P Abeykoon ◽

Amber B Hesse ◽

Amanda Shreders ◽

Sikander Ailawadhi ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Progressive Disease ◽

Controlled Trial ◽

Bivariate Analysis ◽

Time To Event ◽

Advisory Committees ◽

Best Response

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

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Association Of Bleeding Tendency With Time Under Target FIX Activity Levels In Severe Hemophilia B Patients Treated With Recombinant Factor IX Fc Fusion Protein

Blood ◽

10.1182/blood.v122.21.2349.2349 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2349-2349 ◽

Cited By ~ 5

Author(s):

Amy Shapiro ◽

James Potts ◽

Shuanglian Li ◽

Leonard A. Valentino ◽

Lei Diao ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia B ◽

Activity Levels ◽

Bleeding Tendency ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Episodic Treatment ◽

Equity Ownership

Abstract Introduction The goal of prophylactic treatment with coagulation factor replacement in hemophilia patients has been to convert severe hemophilia, defined as <1% endogenous factor activity levels, to moderate (1% to 5%) and mild (5 to 40%) disease. It has been reported that increased time spent under 1% FVIII activity was associated with an increase in total bleeding episodes and hemarthroses in patients with severe hemophilia A (Collins PW, J Thromb Haemost 2009). Since no studies to date have documented this association for FIX activity in patients with severe hemophilia B, we examined the bleeding tendency in relation to FIX activity using data from the B-LONG study. The B-LONG study evaluated the pharmacokinetics (PK), safety, and efficacy of a recombinant FIX Fc fusion protein (rFIXFc) in severe hemophilia B patients (Powell J, J Thromb Haemost 2013). Briefly, the B-LONG study had 4 treatment arms: weekly prophylaxis, tailored prophylaxis, episodic treatment, and perioperative management. The corresponding median annualized bleeding rates for the first 3 treatment arms were 2.95, 1.38, and 17.69, respectively. Methods A 3-compartmental population PK model of rFIXFc was developed based on activity-time profiles in 12 subjects from a Phase 1/2a study and 123 subjects (>12 years) from B-LONG, collected over ≤ 52 weeks of treatment (Diao L, EAHAD 2013). Individual post-hoc PK parameters were then derived to construct continuous FIX activity-time profiles for each dose administered over the course of the study for all subjects in B-LONG. The cumulative time under target 1%, 3%, and 5% FIX level for each individual on study was calculated and normalized to obtain annualized time under the respective target FIX level. Negative binomial regression models were used to evaluate associations between the number of bleeding events (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1%, 3%, and 5% of FIX activity for all subjects in B-LONG. Models were adjusted for age, body mass index, baseline HIV and HCV status, FIX genotype, number of bleeding episodes in the 12 months prior to study entry, and each subject's time on study. Results The multivariable negative binomial regression analysis estimated that overall bleeding events increased with increased time spent under 1% of FIX activity (p<0.001). The association, however, is largely driven by subjects on episodic treatment. The median annualized time under 1% for subjects on episodic treatment was 171 days, in contrast to the median of 0 days for subjects on either weekly prophylaxis or tailored prophylaxis, respectively, as the tailored PK-driven dosing regimens were designed to maintain a target trough above 1%. The association is consistent with the distribution of bleeding events, most of which occurred at predicted FIX activity levels under 1% in subjects on episodic treatment. Since the distribution of predicted FIX trough levels in subjects on prophylaxis were largely in the range of 1% to 5%, the analysis was repeated for cumulative time under 3% and 5%. Both analyses found statistically significant increases in predicted bleeding events as time spent below the respective FIX activity levels increased (Figure 1). The significant association was also observed for spontaneous, traumatic, or joint bleeds analyzed separately for all 3 target FIX activity levels. When comparing across thresholds (1% vs. 3% vs. 5%), the predicted bleeding rate was significantly reduced and the predicted probability of being bleed-free improved as the trough increased. Additionally, the odds of having joint bleeds increased significantly with increasing time spent under the respective target trough (1%, 3%, or 5%). Conclusions This is the first study to demonstrate a correlation between increased time spent under a target therapeutic FIX activity level (1%, 3% or 5%) and increased bleeding tendency, as well as a reduced probability of being bleed-free in patients treated with rFIXFc, suggesting that rFIXFc can provide protection from bleeding in a manner similar to endogenous FIX. These findings also confirm the importance of a minimum therapeutic threshold of 1% and provide additional support for establishing effective rFIXFc prophylaxis using population PK simulation. Disclosures: Shapiro: Baxter: Consultancy, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Valentino:Baxter Healthcare: Consultancy; Bayer: Consultancy; Biogen Idec: Consultancy; GTC Biotherapeutics: Consultancy; Inspiration Biopharmaceuticals: Consultancy; Novo Nordisk: Consultancy. Diao:Biogen Idec: Employment, Equity Ownership. Wang:Biogen Idec: Employment. Robinson:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.

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The Propagation of Hemophilic Arthropathy - the Role of Abnormal Angiogenesis and Vascular Remodeling in Recurrent Joint Bleeding in Adults with Hemophilia

Blood ◽

10.1182/blood.v126.23.3538.3538 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3538-3538

Author(s):

Kidder Wesley ◽

Eric Y Chang ◽

Colleen Moran ◽

Steven Rose ◽

Annette von Drygalski

Keyword(s):

Board Of Directors ◽

Vascular Remodeling ◽

Research Funding ◽

Clotting Factor ◽

Activity Levels ◽

Factor Activity ◽

Vascular Changes ◽

Advisory Committees ◽

Hemophilic Arthropathy ◽

Equity Ownership

Abstract Neoangiogenesis and vascular remodeling in the hypertrophic synovium of arthropathic hemophilic joints may disturb vascular integrity and contribute to repeated bleeding (A von Drygalski, et al. Vascular Remodeling Underlies Re-Bleeding in Hemophilic Arthropathy; ASH 2015; Abstract ID 78677). However, it is difficult to distinguish the importance of the contribution of abnormal vascular structures to hemophilic joint bleeding from the contribution of low clotting factor levels. This is because most prophylactic clotting factor replacement strategies are designed to avoid trough levels below 1-5%, but not to fully correct the factor deficiency. This report reveals the importance of aberrant angiogenesis for joint bleeding in two hemophilia patients whose clotting factor activity levels were constantly normal or near normal. The first patient had severe Hemophilia A with normalized Factor (f)VIII activity levels after liver transplantation 6 years previously. Abnormal vascularization of elbows, knees and ankles (absent bleeding) was detected by musculoskeletal ultrasound and Power Doppler (PD). Three months after the baseline exam the patient experienced severe elbow bleeding associated with new vascular changes on PD. These changes were characterized by pronounced confluent, patchy vascular signals and numerous enlarged and thickened vessels by angiography consistent with acute and chronic vascular remodeling. Bleeding could not be controlled by increasing fVIII activity to supra-normal levels, and ultimately required synovial embolization. The second patient has severe Hemophilia B and presented shortly after left knee joint replacement with fluctuating knee bleeding for many months associated with pronounced dynamic vascular changes on PD. Neither bleeding nor vascular changes were prevented by daily fIX treatment which maintained near normal plasma fIX activity levels. Within one year, additional chronic bleeding with vascular changes developed in the left elbow and left ankle and remained unresponsive to intense factor replacement. These cases provide several insights. First, vascular changes in hemophilic arthropathy persist and evolve in dynamic fashion even in the presence of normal clotting factor activities. Second, vascular disturbance and leakiness contributed to bleeding independent of clotting factor activity levels as exemplified by the first patient and as suggested by the second patient. Third, the sequence of bleeding events in the second patient suggests that at least some of the observed vascular abnormalities are mediated systemically. These observations provide clinical evidence in support of the hypothesis that neoangiogenesis and vascular remodeling contribute to hemophilic joint bleeding and should lead to new studies of the pathophysiology of vascular remodeling in such joints. Targeting angiogenesis may emerge as a new treatment strategy to enhance the effectiveness of clotting factor replacement hemophilic arthropathy. Disclosures Chang: Biogen: Research Funding. Rose:Sirtex Medical: Equity Ownership, Honoraria; XLSciTech: Consultancy; Surefire Medical: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Embolx: Consultancy. von Drygalski:Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Pharmacokinetic Characterisation Of Recombinant FXIII Across Age Groups In Patients With FXIII Subunit A Congenital Deficiency

Blood ◽

10.1182/blood.v122.21.3613.3613 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3613-3613

Author(s):

Brigitte Brand-Staufer ◽

Manuel Carção ◽

Bryce A. Kerlin ◽

Diane Nugent ◽

Andrew Will ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Geometric Mean ◽

Age Groups ◽

Activity Levels ◽

Phase 3 ◽

Advisory Committees ◽

Post Dose ◽

Congenital Deficiency ◽

Fxiii Activity

Abstract Introduction Three trials, F13CD-1725, F13CD-3760 and F13CD-3720 have investigated the pharmacokinetics (PK) of recombinant FXIII (rFXIII), given at a dose of 35 IU/kg once monthly, in a total of 54 patients with FXIII congenital deficiency (Inbal A et al Blood 2012;119(22):5111-5117; Williams M et al Haemophilia 2013;DOI:10.1111/hae.12224; Kerlin B et al JTH 2013;11(Suppl 2):235-236). The aim of the current analysis was to assess and compare the PK characteristics of rFXIII among trials and 3 different age groups of patients (1-<6, 6-17 and ≥18 years). Methods All patients were dosed with rFXIII 35 IU/kg every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval (28 to 30-day period) in the 3 trials: in the pivotal phase 3 trial, F13CD-1725, at 1 hour, 14 and 28 days post-dose; in the paediatric F13CD-3760 trial at 0.5 and 24 hours and 7, 14, 21 and 30 days post-dose; and in the F13CD-3720 phase 3 extension trial at 1 and 2 hours and 3, 7, 14, 21 and 28 days post-dose. Prior to the PK assessment, all but 2 patients had received treatment with repeated doses of either plasma derived FXIII products or rFXIII, thus all PK measurements were performed at steady-state. The Berichrom® FXIII activity assay was used for measurement of FXIII activity. PK parameters were calculated using non-compartmental statistical methods, without baseline adjustment. The results include data from a total of 54 patients, aged 1 to 60 years; 41 in the F13CD-1725 trial, 23 in the F13CD-3720 trial (including 16 patients who also participated in F13CD-1725), and 6 in the F13CD-3760 trial. Results The non-compartmental PK parameters (Cmax, Ctrough, AUC0-28/30d, t1/2) were similar across the 3 age groups (Table 1). Post-hoc, pairwise t-tests across the age groups of log-transformed data did not demonstrate any statistically significant differences, when adjusting p-values for multiple testing. Additionally, separate ANOVA analyses of each of the parameters, showed no significant differences across the groups. The geometric mean half-life ranged from 11.6 to 15.0 days (Figure 1), and the trough FXIII activity levels ranged from 0.15 to 0.21 IU/mL (Figure 2). The geometric mean recoveries were also in the same range; 0.015 (F13CD-1725), 0.013 (F13CD-3760) and 0.020 (F13CD-3720) (IU/mL)/(IU/kg). Furthermore, it could be demonstrated that the mean PK profiles were similar for the 3 trials, and that Cmax and Ctrough values, as well as FXIII exposures (AUC), were constant over time, based on results from patients participating in both the F13CD-1725 and the F13CD-3720 trial. Conclusion The PK profile of rFXIII, after dosing with 35 IU/kg of rFXIII, was independent of age and comparable between trials. It was further demonstrated that FXIII trough activity levels were constant over time, when comparing the individual levels of FXIII activity in patients participating in both the F13CD-1725 and the F13CD-3720 trials. Despite rather large individual variation (CV of up to 38%) in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU/mL during the entire duration of the trials. The results support that monthly dosing with 35 IU/kg of rFXIII to patients with FXIII subunit A deficiency, regardless of age, is adequate for prophylaxis. Nevertheless individual PK measurements to determine optimal dose and dosing frequency should be considered due to patient variation. Disclosures: Brand-Staufer: Bayer HealthCare: Travel support, Travel support Other; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel support Other; Bayer: DMC Chair for a Bayer study Other. Carção:Octapharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, Travel Support. Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel Support., Travel Support. Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Scientific Advisory Board. Travel Support., Speakers Bureau, Travel Support. Other; Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Support., Travel Support. Other; Biogen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel Support., Travel Support. Other; Bayer : Honoraria, Research Funding, Travel Support. , Travel Support. Other; Baxter: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Support. Other. Kerlin:Bayer HealthCare: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Research Funding. Nugent:Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bayer: Honoraria. Will:Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Williams:Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Travel support., Travel support. Other; Bayer: Travel support, Travel support Other; Baxter: Membership on an entity’s Board of Directors or advisory committees, Travel support. Other. Rosholm:Novo Nordisk: Employment. Sandberg Lundblad:Novo Nordisk: Employment.

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The Effects of Tranexamic Acid on Bleed Control, Coagulopathy and Survival with Trauma in Anemic Mice

Blood ◽

10.1182/blood-2021-148060 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3174-3174

Author(s):

Bilgimol Chumappumkal Joseph ◽

Richard FW Barnes ◽

Annette von Drygalski

Keyword(s):

Iron Deficiency ◽

Blood Loss ◽

Tranexamic Acid ◽

Board Of Directors ◽

Iron Content ◽

Research Funding ◽

Activity Levels ◽

Advisory Committees ◽

Liver Laceration ◽

Fviii Activity

Abstract Clinical evidence suggests that anemia increases surgical bleeding and is associated with poor outcomes. Globally, ~ 50% of anemia is attributed to iron deficiency as the most common nutritional disorder. To study the effects of iron deficiency anemia (IDA) on traumatic bleeding we developed a mouse model of IDA and traumatic injury, and tested the effects of prophylactic tranexamic acid (TXA), on blood loss, coagulopathy and survival. Materials and Methods C57BL/6J mice, both male and female, were fed with usual laboratory ("control mice") or iron deficient (4ppm iron) chow ("IDA mice") starting at 3 weeks of age. After 6 weeks, IDA was documented by blood count, red cell indices and liver iron content. Mice then were subjected to an established liver laceration model causing severe bleeding. Blood loss (weighing blood-soaked sponges in the abdominal cavity), seven-day survival and coagulation parameters (APTT, activity levels of Factor (F) V, FVIII, Fibrinogen) were determined at 15 and 60 minutes after liver laceration for "IDA" and "control mice", treated or not treated five minutes prior to injury with TXA (10mg/kg). All data were expressed as median and were compared using Mann-Whitney test. Results Compared to "control" mice, "IDA mice" developed hypochromic and microcytic anemia with a significantly lower mean hematocrit (32±1.7% vs 49±1.2%, p≤0.0001) and hepatic iron content (75.9±19.8µg/g vs 22.4±9.4 µg/g, p≤0.0001). "IDA mice" demonstrated significantly more bleeding after liver laceration compared to "control mice." Most of the bleeding had occurred at 15 minutes after injury with little incremental bleeding at 60 minutes. The blood loss in "IDA mice" was greater at both time points compared to "control mice" (15 minutes: 21.5±2.3µl/g vs 15.9±2.6µl/g, p≤0.0001; 60 minutes: 24.5±1.6µl/g vs 20.7±1.9µl/g, p≤0.0001). TXA reduced bleeding significantly in "IDA mice" at 15 and 60 min to ~15µl/g. In "control mice", bleed improvement was only present at 60 min (also reduced to ~15µl/g), without improvement below the ~15µl/g baseline threshold at 15 min. Coagulopathy developed in both groups over 60 min, with similar prolongation of the APTT from baseline (23.9±1.5s to 36.0±4.9s in "IDA mice"; 22.8±1.3s 35.0±3.8s in "control mice"), substantial depletion of FV and FVIII activity levels and partial reduction of fibrinogen. TXA administration normalized the APTT only in "control mice" at 60 minutes, but not in "IDA mice", although TXA reconstituted FV and fibrinogen to ~100% activity, with FVIII activity of ~50% in both groups. Survival of "IDA mice" was lower compared to "control mice" (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion Enhanced bleeding and poorer survival was observed in "IDA mice" compared to "control mice" after liver laceration at similar degrees of coagulopathy. Prophylactic TXA corrected bleeding and reduced mortality in "IDA mice" to values similar to those observed for "control mice" despite incomplete correction of the coagulopathy in "IDA mice". This suggests that TXA may be of particular importance in the face of anemia, by mechanisms that may go beyond hemostasis correction alone, warranting further investigation. Disclosures von Drygalski: CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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