F8 and HLA-II Haplotypes in the Hispanic Population: Implications for Inhibitor Risk Development in Hispanic Hemophilia A Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3365-3365
Author(s):  
Benjamin Kim ◽  
Zuben E. Sauna ◽  
Melanie A. Carless ◽  
Joanne E. Curran ◽  
Kevin R. Viel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Mexican Americans ◽  
Mexican American ◽  
Hemophilia A ◽  
Hispanic Americans ◽  
The United States ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Inhibitor Development ◽  
Black And White

Abstract Abstract 3365 Background: A recent study suggested an increased rate of inhibitor development among Hispanic compared to White hemophilia A (HA) patients; however, a possible mechanism was not proposed or explored. In light of findings implicating a role for race-specific distributions of factor VIII (F8) and class-II human-leukocyte antigen (HLA-II) haplotypes on the disparate risk of inhibitor development in the Black HA population, we sought to determine the distributions of F8 and HLA-II haplotypes among Hispanic Americans and compare them to that of Black and White Americans. Methods: Using archived genomic DNA samples from the 194 unrelated founders of the San Antonio Family Heart Study (SAFHS), a collection of 1431 people from 41 large Mexican American families, we re-sequenced all exons of F8 to genotype the known nonsynonymous-single nucleotide polymorphisms (ns-SNPs) and identify any novel ns-SNPs. We then performed high-resolution HLA-II genotyping to identify each founders' pair of HLA-DRB1 alleles to compare them against those found in other ethnic groups. Results: Among the 291 potentially distinct Mexican American X-chromosomes evaluated, we identified the H2 F8 haplotype, defined by D1241E, in 25.0% of the subjects, which is in between that observed in the White (7.4%) and Black (37.4%) populations. We also found H3 F8, defined by D1241E and M2238V, in two subjects, who represent the first non-Black individuals reported to carry this haplotype. Furthermore, we discovered a previously unreported ns-SNP (H1919N), whose minor allele was found in only one male and defines a ninth wild-type F8 haplotype (H9). Regarding HLA-II alleles, the distribution among Mexican Americans in the present study was quite different from those found in Black and White individuals in the National Marrow Donor Program registry (see Figure). Three of the 4 most common HLA-II alleles in the Mexican Americans (DRB1*0802, DRB1*0407 and DRB1*1406) were seen in < 1% of both Blacks and Whites. Discussion: This is the first study to report the haplotypic prevalence of F8 and HLA-II alleles in Mexican Americans, the largest Hispanic ethnic group in the United States. By informing specific wild-type factor VIII (FVIII) peptides for use in HLA-II binding and T-cell stimulation assays, these results may help to identify high risk combinations of FVIII therapeutics and individual HLA-II repertoires that contribute to the higher rate of inhibitor development observed in Mexican versus Caucasian American HA patients. Disclosures: Viel: Histonis, Incorporated: Employment. Howard:Haplomics, Inc.: Equity Ownership.

scholarly journals A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2180-2186 ◽  
Author(s):  
FR Rosendaal ◽  
HK Nieuwenhuis ◽  
HM van den Berg ◽  
H Heijboer ◽  
EP Mauser- Bunschoten ◽  
...  
Keyword(s):  
The Netherlands ◽  
Factor Viii ◽  
Hemophilia A ◽  
The United States ◽  
Clotting Factor ◽  
National Study ◽  
Time Interval ◽  
Factor Viii Inhibitor ◽  
Sudden Increase ◽  
Inhibitor Development

Abstract The development of antibodies to factor VIII (inhibitors) in response to clotting-factor concentrates administration in hemophilia is common during the first few years of treatment but rare in multitransfused patients. We have investigated the possible association of a recently introduced factor VIII concentrate (Factor VIII CPS-P) in The Netherlands with the occurrence of inhibitors. To this effect, we conducted two studies. First, we performed a national multicenter study in which clinical information and inhibitor test results were obtained for 447 hemophilia A patients over the period 1988 through 1991. Secondly, for a baseline comparison we estimated the frequency of inhibitor development in a closely followed cohort of 144 patients, from 1984 through 1989. Before the introduction of Factor VIII CPS-P, the incidence of new inhibitors was 4.4/1,000 patient-years in the national study from March 1988 through May 1990, and 3.9/1,000 patient- years in the cohort followed from 1984 through 1989. These figures are similar to the incidence of new inhibitors that was found in a large cohort of patients in the United States followed in the 1970s. In the period that the new concentrate Factor VIII CPS-P was on the market, from June 1990 through November 1991, 11 clinically relevant inhibitors were detected, which yielded an incidence over this interval of 20.1/1,000 patient-years, a 4.5-fold increase compared with the previous interval (C195: 1.4 to 14.3). Nine of these 11 patients had in their lifetime received over 250 infusions with factor VIII preparations. whereas all of the inhibitors detected in the previous time interval, and all of the 24 inhibitor patients described in the US study, had received less than 250 infusions in their lifetime. All patients who developed inhibitors after June 1990 had been exposed to Factor VIII CPS-P, whereas only 75% of the patients who did not develop an inhibitor had been exposed to this product. In a prospective extension of the study, with a second inhibitor measurement after 3 months, we found that one additional inhibitor had developed during 52.5 patient-years of Factor VIII CPS-P use. In conclusion, there has been a sudden increase in the frequency of inhibitor patients, for a large part among multitransfused patients. It seems more than likely that this increase is associated with the introduction of a new factor VIII concentrate in The Netherlands.(ABSTRACT TRUNCATED AT 400 WORDS)

A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2180-2186
Author(s):  
FR Rosendaal ◽  
HK Nieuwenhuis ◽  
HM van den Berg ◽  
H Heijboer ◽  
EP Mauser- Bunschoten ◽  
...  
Keyword(s):  
The Netherlands ◽  
Factor Viii ◽  
Hemophilia A ◽  
The United States ◽  
Clotting Factor ◽  
National Study ◽  
Time Interval ◽  
Factor Viii Inhibitor ◽  
Sudden Increase ◽  
Inhibitor Development

The development of antibodies to factor VIII (inhibitors) in response to clotting-factor concentrates administration in hemophilia is common during the first few years of treatment but rare in multitransfused patients. We have investigated the possible association of a recently introduced factor VIII concentrate (Factor VIII CPS-P) in The Netherlands with the occurrence of inhibitors. To this effect, we conducted two studies. First, we performed a national multicenter study in which clinical information and inhibitor test results were obtained for 447 hemophilia A patients over the period 1988 through 1991. Secondly, for a baseline comparison we estimated the frequency of inhibitor development in a closely followed cohort of 144 patients, from 1984 through 1989. Before the introduction of Factor VIII CPS-P, the incidence of new inhibitors was 4.4/1,000 patient-years in the national study from March 1988 through May 1990, and 3.9/1,000 patient- years in the cohort followed from 1984 through 1989. These figures are similar to the incidence of new inhibitors that was found in a large cohort of patients in the United States followed in the 1970s. In the period that the new concentrate Factor VIII CPS-P was on the market, from June 1990 through November 1991, 11 clinically relevant inhibitors were detected, which yielded an incidence over this interval of 20.1/1,000 patient-years, a 4.5-fold increase compared with the previous interval (C195: 1.4 to 14.3). Nine of these 11 patients had in their lifetime received over 250 infusions with factor VIII preparations. whereas all of the inhibitors detected in the previous time interval, and all of the 24 inhibitor patients described in the US study, had received less than 250 infusions in their lifetime. All patients who developed inhibitors after June 1990 had been exposed to Factor VIII CPS-P, whereas only 75% of the patients who did not develop an inhibitor had been exposed to this product. In a prospective extension of the study, with a second inhibitor measurement after 3 months, we found that one additional inhibitor had developed during 52.5 patient-years of Factor VIII CPS-P use. In conclusion, there has been a sudden increase in the frequency of inhibitor patients, for a large part among multitransfused patients. It seems more than likely that this increase is associated with the introduction of a new factor VIII concentrate in The Netherlands.(ABSTRACT TRUNCATED AT 400 WORDS)

Good Neighbor in the American Historical Imagination: Mexican American Intellectual Thought in the Fight for Civil Rights, 1930s–1940s

2021 ◽  
Author(s):  
Natalie Mendoza
Keyword(s):  
United States ◽  
Civil Rights ◽  
Identity Formation ◽  
Mexican Americans ◽  
Mexican American ◽  
The United States ◽  
Historical Narrative ◽  
Historical Imagination ◽  
American Intellectual ◽  
Good Neighbor

Abstract This article argues that historical narrative has held a significant role in Mexican American identity formation and civil rights activism by examining the way Mexican Americans in the 1930s and 1940s used history to claim full citizenship status in Texas. In particular, it centers on how George I. Sánchez (1906–1972), a scholar of Latin American education, revised historical narrative by weaving history and foreign policy together through a pragmatic lens. To educators and federal officials, Sánchez used this revisionist history to advocate for Mexican Americans, insisting that the Good Neighbor policy presented the United States with the chance to translate into reality the democratic ideals long professed in the American historical imagination. The example of Sánchez also prompts us to reexamine the historiography in our present day: How do we define the tradition and trajectory of Mexican American intellectual thought in U.S. history? This article posits that when Sánchez and other Mexican Americans thought about their community’s collective identity and civil rights issues through history, they were contributing to a longer conversation driven by questions about identity formation and equality that first emerged at the end of the U.S. War with Mexico in 1848. These questions remain salient in the present, indicating the need for a historiographic examination that will change how we imagine the tradition of intellectual thought in the United States.

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Mexican American Faculty in Research Universities: Can the Next Generation Beat the Odds?

2017 ◽  
Vol 3 (4) ◽  
pp. 458-473 ◽  
Author(s):  
Ruth Enid Zambrana ◽  
Brianne A. Dávila ◽  
Michelle M. Espino ◽  
Lisa M. Lapeyrouse ◽  
R. Burciaga Valdez ◽  
...  
Keyword(s):  
Social Capital ◽  
Research Universities ◽  
Mexican Americans ◽  
Mexican American ◽  
Maternal Education ◽  
Educational Aspirations ◽  
Implicit Bias ◽  
The United States ◽  
National Study ◽  
Underrepresented Minority

Mexican Americans represent the largest Latina/o subpopulation and have the lowest levels of educational attainment in the United States. Mexican Americans are underrepresented in all professional fields, including academia, and thus warrant attention. The purposes of this study are to describe the experiences of early and mid-career Mexican American faculty, emphasizing key sources of inspiration, support, and mentoring, perceived discrimination, and their coping responses; assess the ways in which these factors influence their careers; and examine differences by gender and maternal education. Mixed methods were used to obtain information from 133 Mexican American faculty who participated in a larger national study of underrepresented minority (URM) faculty at research universities. Five major findings emerged: (1) early life course support sustained and encouraged educational aspirations, (2) mentorship from significant others provided valuable advice in developing social capital throughout higher education and early faculty experiences, (3) female respondents were more likely to report inadequate mentoring and higher levels of distress due to recurrent experiences of racially gendered discrimination, (4) strategies of resistance reveal high levels of emotional labor as respondents deconstruct the hidden curriculum to perform effectively in environments that are imbued with implicit bias, and (5) maternal education contributed to improved mentoring experiences and active resistance strategies. The findings suggest that expanding social capital–driven strategies and increasing understanding of persistent anti-Mexican social policy that leads to misidentification and implicit bias are key in retention and professional success for Mexican American faculty.

scholarly journals Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A

Blood ◽  
2014 ◽  
Vol 124 (15) ◽  
pp. 2333-2336 ◽  
Author(s):  
Giancarlo Castaman ◽  
Karin Fijnvandraat
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Biological Response ◽  
Interindividual Variation ◽  
Clinical Use ◽  
Clinical Predictors ◽  
Inhibitor Development ◽  
Prevention And Treatment ◽  
Selection Of

Abstract The risk for inhibitor development in mild hemophilia A (factor VIII levels between 5 and 40 U/dL) is larger than previously anticipated, continues throughout life, and is particularly associated with certain mutations in F8. Desmopressin may reduce inhibitor risk by avoiding exposure to FVIII concentrates, but the heterogenous biological response to desmopressin, showing large interindividual variation, may limit its clinical use. However, predictors of desmopressin response have been recently identified, allowing the selection of the best candidates to this treatment.

THE RISK OF INHIBITOR DEVELOPMENT IN 1104 PATIENTS WITH HEMOPHILIA A ACCORDING TO FACTOR VIII GENOTYPE

2007 ◽  
Vol 5 ◽  
pp. O-S-064-O-S-064
Author(s):  
J. Boekhorst ◽  
G. Rastegar Lari ◽  
R. d'Oiron ◽  
J.M. Costa ◽  
I.R.O. Novakova ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Inhibitor Development

Latino/a and African American Relations

2016 ◽  
Author(s):  
Brian D. Behnken
Keyword(s):  
United States ◽  
African Americans ◽  
Civil Rights ◽  
Puerto Rican ◽  
Civil Rights Movement ◽  
Mexican American ◽  
Black People ◽  
The United States ◽  
Civil Rights Era ◽  
Black And White

African Americans and Latino/as have had a long history of social interactions that have been strongly affected by the broader sense of race in the United States. Race in the United States has typically been constructed as a binary of black and white. Latino/as do not fit neatly into this binary. Some Latino/as have argued for a white racial identity, which has at times frustrated their relationships with black people. For African Americans and Latino/as, segregation often presented barriers to good working relationships. The two groups were often segregated from each other, making them mutually invisible. This invisibility did not make for good relations. Latino/as and blacks found new avenues for improving their relationships during the civil rights era, from the 1940s to the 1970s. A number of civil rights protests generated coalitions that brought the two communities together in concerted campaigns. This was especially the case for militant groups such as the Black Panther Party, the Mexican American Brown Berets, and the Puerto Rican Young Lords, as well as in the Poor People’s Campaign. Interactions among African Americans and Mexican American, Puerto Rican, and Cuban/Cuban American illustrate the deep and often convoluted sense of race consciousness in American history, especially during the time of the civil rights movement.

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Joint Damage ◽  
Coagulation Factor ◽  
The United States ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

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