PB0776 - Characterization of the effects of hydroxyurea and crizanlizumab on plasma immunothrombosis biomarkers in patients with sickle cell disease

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Veronica Bochenek

Research Technician
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States

Co-Author(s)

JW

Jessica Wu

Medical Student
Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
Philadelphia, Pennsylvania, United States
Anh T. Ngo, PhD

Postdoc
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States
NL

Nate Levine

Research Technician
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
MK

M. Anna Kowalska

Scientist III
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
OA

Osheiza Abdulmalik

Research Associate II
Division of Hematology, Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
MR

Marjorie Risman

Senior Research Coordinator & Project Manager
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine
Philadelphia, Pennsylvania, United States
JW

Joellen Weaver

Technical Director
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine
Philadelphia, Pennsylvania, United States
AR

Andrea H. Roe

Assistant Professor
Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
Philadelphia, Pennsylvania, United States
Kandace Gollomp

Assistant Professor
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
Philadelphia, Pennsylvania, United States

Background: For decades, hydroxyurea was the only drug known to reduce the frequency of pain crises in sickle cell disease (SCD), until 2019 when the anti-P-selectin antibody, crizanlizumab, was approved for use. The effect of these treatments on inflammation and cellular activation in SCD has not yet been fully characterized.

Aims: To determine how treatment with hydroxyurea and crizanlizumab impact markers of inflammation, platelet activation, thrombosis, neutrophil degranulation, and NET release in patients with SCD.

Methods: Frozen plasma samples from 31 patients with SCD and 9 patients with sickle cell trait (SCT) collected during routine medical visits, were obtained from the Penn Medicine BioBank. SCD genotypes included SS (n=16), SC (n=10), Sß thalassemia (n=3), and unknown (n=2). Clinical laboratory data was extracted by the biobank. A fluorescent plate assay was used to measure plasma cell free DNA, and commercial ELISAs were used to measure thrombin anti-thrombin (TAT) complexes, myeloperoxidase (MPO), citrullinated histones (Cit-H3), β-thromboglobulin (BTG), and platelet factor 4 (PF4) and markers of complement activation.

Results: PF4 and MPO were significantly elevated in patients with sickle cell disease compared to controls with SCT. Patients treated with hydroxyurea did not exhibit a decrease in markers of inflammation, complement activation, or NETosis, irrespective of genotype. Patients on crizanlizumab had decreased markers of NETosis (Cit-H3), platelet activation (BTG and PF4), inflammation (CRP), and thrombosis (TAT).

Conclusion(s): In this cohort, we did not detect significant differences in markers of neutrophil degranulation, platelet activation, or NETosis between patients of different SCD genotype or those prescribed hydroxyurea. However, patients treated with the P-selectin inhibitor crizanlizumab had decreased markers for all these readouts. These results suggest that P-selectin blockade may have broad effects on inflammation and cellular activation in SCD, and further study is merited to characterize its effect on immunothrombosis and end-organ injury over time.