Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural)

Amy D Shapiro¹, Margaret V Ragni², Munira Borhany³, Yasmina L Abajas⁴, Michael D Tarantino⁵, Katharina Holstein⁶, Stacy E Croteau⁷, Riana Liesner⁸, Cristina Tarango⁹, Manuela Carvalho¹⁰, Catherine McGuinn¹¹, Eva Funding¹², Christine L Kempton¹³, Christoph Bidlingmaier¹⁴, Alice Cohen¹⁵, Johannes Oldenburg¹⁶, Susan Kearney¹⁷, Christine Knoll¹⁸, Philip Kuriakose¹⁹, Suchitra Acharya²⁰, Ulrike M Reiss²¹, Roshni Kulkarni²², Michelle Witkop²³, Stefan Lethagen²⁴, Sharyne Donfield²⁵, Petra LeBeau²⁵, Erik Berntorp²⁶, Jan Astermark^{27

28}

Affiliations

¹ Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA.
² Hemophilia Center of Western Pennsylvania, University of Pittsburgh, Pittsburgh, PA, USA.
³ National Institute of Blood Disease and Bone Marrow Transplantation, Karachi, Pakistan.
⁴ Hemophilia and Thrombosis Center, University of North Carolina, Chapel Hill, NC, USA.
⁵ Bleeding and Clotting Disorders Institute, Peoria, IL, USA.
⁶ Medical Department, Haemophilia Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Boston Hemophilia Center, Boston Children's Hospital, Boston, MA, USA.
⁸ Great Ormond Street Hospital for Children, NHS Trust supported by NIHR, GOSH, BRC, London, UK.
⁹ Department of Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁰ Congenital Coagulopathies Reference Centre, Centro Hospitalar Universitário São João, Porto, Portugal.
¹¹ Weill Cornell Medical College, New York, NY, USA.
¹² Department of Hematology, University Hospital Rigshospitalet, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹³ Emory University School of Medicine, Emory University, Atlanta, GA, USA.
¹⁴ Dr. v. Hauner's Childrens University Hospital, Hemophilia Center, LMU Hospital, Munich, Germany.
¹⁵ Newark Beth Israel Medical Center, Newark, NJ, USA.
¹⁶ University Clinic Bonn, Bonn, Germany.
¹⁷ Children's Minnesota Center for Bleeding and Clotting Disorders, Minneapolis, MN, USA.
¹⁸ Phoenix Children's Hospital, Phoenix, AZ, USA.
¹⁹ Henry Ford Hospital, Detroit, MI, USA.
²⁰ Northwell Hemostasis and Thrombosis Center, New York, NY, USA.
²¹ St. Jude Children's Research Hospital, Memphis, TN, USA.
²² Michigan State University, East Lansing, MI, USA.
²³ Northern Regional Bleeding Disorders Center, Munson Medical Center, Traverse City, MI, USA.
²⁴ Sobi, Stockholm, Sweden.
²⁵ Rho, Inc., Durham, NC, USA.
²⁶ Clinical Coagulation Research, Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁷ Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁸ Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden.

PMID: 33278853
DOI: 10.1111/hae.14139

Observational Study

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural)

Amy D Shapiro et al. Haemophilia. 2021 Jan.

. 2021 Jan;27(1):49-59.

doi: 10.1111/hae.14139. Epub 2020 Dec 5.

Authors

Affiliations

¹ Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA.
² Hemophilia Center of Western Pennsylvania, University of Pittsburgh, Pittsburgh, PA, USA.
³ National Institute of Blood Disease and Bone Marrow Transplantation, Karachi, Pakistan.
⁴ Hemophilia and Thrombosis Center, University of North Carolina, Chapel Hill, NC, USA.
⁵ Bleeding and Clotting Disorders Institute, Peoria, IL, USA.
⁶ Medical Department, Haemophilia Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Boston Hemophilia Center, Boston Children's Hospital, Boston, MA, USA.
⁸ Great Ormond Street Hospital for Children, NHS Trust supported by NIHR, GOSH, BRC, London, UK.
⁹ Department of Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁰ Congenital Coagulopathies Reference Centre, Centro Hospitalar Universitário São João, Porto, Portugal.
¹¹ Weill Cornell Medical College, New York, NY, USA.
¹² Department of Hematology, University Hospital Rigshospitalet, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹³ Emory University School of Medicine, Emory University, Atlanta, GA, USA.
¹⁴ Dr. v. Hauner's Childrens University Hospital, Hemophilia Center, LMU Hospital, Munich, Germany.
¹⁵ Newark Beth Israel Medical Center, Newark, NJ, USA.
¹⁶ University Clinic Bonn, Bonn, Germany.
¹⁷ Children's Minnesota Center for Bleeding and Clotting Disorders, Minneapolis, MN, USA.
¹⁸ Phoenix Children's Hospital, Phoenix, AZ, USA.
¹⁹ Henry Ford Hospital, Detroit, MI, USA.
²⁰ Northwell Hemostasis and Thrombosis Center, New York, NY, USA.
²¹ St. Jude Children's Research Hospital, Memphis, TN, USA.
²² Michigan State University, East Lansing, MI, USA.
²³ Northern Regional Bleeding Disorders Center, Munson Medical Center, Traverse City, MI, USA.
²⁴ Sobi, Stockholm, Sweden.
²⁵ Rho, Inc., Durham, NC, USA.
²⁶ Clinical Coagulation Research, Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁷ Department of Translational Medicine, Lund University, Malmö, Sweden.
²⁸ Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden.

PMID: 33278853
DOI: 10.1111/hae.14139

Abstract

Introduction: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research.

Aim: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations.

Methods: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing.

Results: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis.

Conclusion: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Keywords: FIX inhibitors; factor IX deficiency; haemophilia B; joint range-of-motion; quality-of-life; treatment.

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References

REFERENCES

1. Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood. 2000;96(2):437-442.
1. Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White GC II. Inhibitors to Coagulation Factors. Vol 386. New York: Springer Science & Business Media; 1995.
1. Katz J. Prevalence of factor IX inhibitors among patients with haemophilia B: results of a large-scale North American survey. Haemophilia. 1996;2(1):28-31.
1. Sultan Y. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group. Thromb Haemost. 1992;67(6):600-602.
1. Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992;339(8793):594-598.

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Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural)

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Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural)

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