Presentation Details
| Natural History of Bleeding, Transfusion, and Antibody Prevalence in a Subset of Hermansky-Pudlak Syndrome Patients: Effects of Freeze-Dried Lyophilized Platelet Derived Hemostat Ex Vivo Keith Moskowitz, Michael Fitzpatrick, Lisa Booth, Maria Abreau-Blanco, Matthew Dickerson, Anna Yu, Anya Derbij, W.Allan Alexander. Cellphire Therapeutics, Inc., Rockville, MD, USA |
Abstract
Background: HPS affects ~1 in 500,000 of the population, ~1500 patients are reported in continental US and Puerto Rico (PR). HPS is an autosomal recessive, multi-genotype, protein storage disorder that clinically presents as oculocutaneous albinism, expressing platelet delta granule deficiency with bleeding from birth, as well as colitis, and premature mortality from pulmonary fibrosis. Providing recommended HLA-matched platelets to treat uncontrolled bleeding is difficult. In practice platelet transfusions are avoided because alloantibody formation reduces eligibility for lung transplant. HLA-Matched, Freeze-Dried, Platelet Derived, Hemostat (FPH-M) is being developed as a potential cellular therapeutic to treat uncontrolled bleeding and potentially reduce alloimmunization risk. Unmatched FPH is in clinical trials (NCT05771831).
Objectives: 1) Assess the natural history of bleeding in two cohorts of HPS subjects from the continental US and PR. 2) Determine the prevalence of antibodies to Class I HLA and platelet antigens in the continental US cohort. 3) Assess the compatibility of blood samples with FPH by crossmatch and hemostatic function of FPH in the presence of allogeneic antibodies.
Methods: Forty-five subjects consented and completed bleeding history surveys and 32 from the continental US provided blood samples. Antibody prevalence was assessed by Luminex and the % calculated Panel Reactive Antibody (% cPRA) determined. Crossmatching with FPH was done by flow cytometry. The thrombin generation assay (TGA) and adhesion under shear over collagen and tissue factor using the Total Thrombus formation Analysis System (T-TAS®) were used to evaluate hemostatic function.
Results: Of 45 subjects, 24% were male, 67% Hispanic or Latino, mean age 42. Of 34 females 58% were post-menopausal. Reported disorders included vascular 91%, ocular 93%, epistaxis 67%, gum bleeding 69%, dental bleeding 80%, bruising 96%, pulmonary bleeding 9% (one requiring transfusion/surgery). Important hemorrhage is common: hematochezia 62%, hematemesis 9%, joint bleeding 6%, intracranial hemorrhage 2%, retinal hemorrhage 7%, and bleeding with spinal tap/epidural 7%, during surgery 44% and 33% with major trauma 27% of whom received transfusions, mean transfusions 11 (range 0-134). 53% of menstruating females had anemia, 12% requiring transfusion while 32% had post-partum hemorrhage, 18% requiring transfusion. Class 1 HLA antibodies were identified in 10 of 32 samples. 60% of those would be incompatible with >50% of Apheresis Platelet Units by % cPRA. Of the ten samples with antibodies, only two (20%) with antibodies to platelet antigens cross-reacted with FPH. Based on the cPRA at least 50% of the samples were expected to be cross-reactive. TGA activity and thrombus formation as measured by TGA and T-TAS of FPH was present in samples from all subjects regardless of antibody presence.
Conclusions: HPS presents with life altering co-morbidities and severe bleeding events that often require platelet transfusions. FPH hemostatic function in an ex vivo human HPS model and in vitro coagulation assays were not affected by single or multiple antibodies. FPH-M may be a future shelf-stable hemostatic alternative for bleeding in HPS patients that reduces the risk of alloimmunization by providing a patient-specific, phenotypically matched platelet hemostatic for transfusion. Further trials are needed to assess FPH in the HPS population.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
Objectives: 1) Assess the natural history of bleeding in two cohorts of HPS subjects from the continental US and PR. 2) Determine the prevalence of antibodies to Class I HLA and platelet antigens in the continental US cohort. 3) Assess the compatibility of blood samples with FPH by crossmatch and hemostatic function of FPH in the presence of allogeneic antibodies.
Methods: Forty-five subjects consented and completed bleeding history surveys and 32 from the continental US provided blood samples. Antibody prevalence was assessed by Luminex and the % calculated Panel Reactive Antibody (% cPRA) determined. Crossmatching with FPH was done by flow cytometry. The thrombin generation assay (TGA) and adhesion under shear over collagen and tissue factor using the Total Thrombus formation Analysis System (T-TAS®) were used to evaluate hemostatic function.
Results: Of 45 subjects, 24% were male, 67% Hispanic or Latino, mean age 42. Of 34 females 58% were post-menopausal. Reported disorders included vascular 91%, ocular 93%, epistaxis 67%, gum bleeding 69%, dental bleeding 80%, bruising 96%, pulmonary bleeding 9% (one requiring transfusion/surgery). Important hemorrhage is common: hematochezia 62%, hematemesis 9%, joint bleeding 6%, intracranial hemorrhage 2%, retinal hemorrhage 7%, and bleeding with spinal tap/epidural 7%, during surgery 44% and 33% with major trauma 27% of whom received transfusions, mean transfusions 11 (range 0-134). 53% of menstruating females had anemia, 12% requiring transfusion while 32% had post-partum hemorrhage, 18% requiring transfusion. Class 1 HLA antibodies were identified in 10 of 32 samples. 60% of those would be incompatible with >50% of Apheresis Platelet Units by % cPRA. Of the ten samples with antibodies, only two (20%) with antibodies to platelet antigens cross-reacted with FPH. Based on the cPRA at least 50% of the samples were expected to be cross-reactive. TGA activity and thrombus formation as measured by TGA and T-TAS of FPH was present in samples from all subjects regardless of antibody presence.
Conclusions: HPS presents with life altering co-morbidities and severe bleeding events that often require platelet transfusions. FPH hemostatic function in an ex vivo human HPS model and in vitro coagulation assays were not affected by single or multiple antibodies. FPH-M may be a future shelf-stable hemostatic alternative for bleeding in HPS patients that reduces the risk of alloimmunization by providing a patient-specific, phenotypically matched platelet hemostatic for transfusion. Further trials are needed to assess FPH in the HPS population.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
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