title: Independent adjudicator assessments of platelet refractoriness and rFVIIa efficacy in bleeding episodes and surgeries from the multinational Glanzmann's thrombasthenia registry.
abstract: Glanzmann's thrombasthenia (GT) is a rare congenital bleeding disorder associated with decreased platelet aggregation due to qualitative/quantitative deficiencies of the fibrinogen receptor. Severe bleeding episodes and perioperative bleeding are typically managed with platelet transfusions, although patients can develop anti-platelet antibodies or experience clinical refractoriness. The GT Registry (GTR) was established to collect efficacy/safety data on hemostatic treatments for GT, including recombinant factor VIIa (rFVIIa). At the request of the United States Food and Drug Administration, three hematology experts evaluated platelet refractoriness, antibody status, and rFVIIa efficacy data on a case-by-case basis to support a potential indication for rFVIIa in GT. Adjudication included 195 patients with 810 events (619 severe bleeding episodes, 192 surgeries), and a consensus algorithm was developed to describe adjudicators' coding of refractoriness and antibody status based on treatment patterns over time. Most rFVIIa-treated events were in patients without refractoriness or antibodies. Adjudicators rated most rFVIIa-treated bleeding episodes as successful (251/266, 94.4%; rFVIIa only, 101/109, 92.7%; rFVIIa ± platelets ± other agents, 150/157, 95.5%); efficacy was consistent in patients with platelet refractoriness ± antibodies (75/79, 94.9%), antibodies only (10/10, 100.0%), and neither/unknown (166/177, 93.8%). Adjudicators also rated most rFVIIa-treated surgeries as successful (159/160, 99.4%; rFVIIa only, 65/66, 98.5%; rFVIIa ± platelets ± other agents, 94/94, 100.0%); efficacy was consistent in patients with platelet refractoriness ± antibodies (69/70, 98.6%), antibodies only (24/24, 100.0%), and neither/unknown (66/66, 100.0%). Unblinding the adjudicators to investigator efficacy ratings changed few assessments. Doses of rFVIIa were narrowly distributed, regardless of other hemostatic agents used.
authors.affiliation: Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-2805-1016
authors.initials: M
authors.lastname: Recht
authors.affiliation: Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.
authors.forename: Madhvi
authors.initials: M
authors.lastname: Rajpurkar
authors.affiliation: Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Chitlur
authors.affiliation: Centre for Haemophilia and Rare Congenital Bleeding Disorders, University Hospitals Paris-Sud, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
authors.forename: Roseline
authors.initials: R
authors.lastname: d'Oiron
authors.affiliation: Department of Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University Medical Center, Dusseldorf, Germany and Center for Laboratory Medicine, Blood Coagulation and Transfusion Medicine (LBT), Dusseldorf, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Zotz
authors.affiliation: Federico II University, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Minno
authors.affiliation: Clinical Development, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, New Jersey, USA.
authors.forename: David L
authors.identifier: http://orcid.org/0000-0002-4499-1526
authors.initials: DL
authors.lastname: Cooper
authors.affiliation: University of Calgary and Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Calgary, Alberta, Canada.
authors.forename: Man-Chiu
authors.initials: MC
authors.lastname: Poon
mesh_terms: D000293:Adolescent; D001792:Blood Platelets / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003029:Coagulants / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D015942:Factor VIIa / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use; D013514:Surgical Procedures, Operative / Q000009:adverse effects*; D013915:Thrombasthenia / Q000150:complications* / Q000175:diagnosis / Q000601:surgery; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003029:Coagulants; D007518:Isoantibodies; D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa