PB1287 - Platelet cytoskeletal abnormalities and impaired calcium signaling unveil the bleeding phenotype in Shwachman-Diamond syndrome

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

IT

Ivan Tesakov

Researcher
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia

Co-Author(s)

ED

Ekaterina Deordieva

Immunologist
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia
JK

Julia-Jessica Korobkin

Researcher
Center for Theoretical Problems of Physico-Сhemical Pharmacology
Moscow, Moskva, Russia
EY

Eugenia Yushkova

Junior researcher
Center for Theoretical Problems of Physico-Сhemical Pharmacology
Moscow, Moskva, Russia
AM

Alexey Martyanov

Researcher
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Chapel Hill, North Carolina, United States
AI

Anastasia Ignatova

Research associate
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia
EK

Ekaterina Koltsova

Research associate
Center for Theoretical Problems of Physico-Сhemical Pharmacology
Moscow, Moskva, Russia

Presenting Author(s)

Elena A. Seregina, PhD

Leading Researcher
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia

Co-Author(s)

Alexander Poletaev

Head of the Laboratory of Clinical Hemostasis
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia
NP

Nadezhda Podoplelova

Senior Researcher
Center for Theoretical Problems of Physico-Сhemical Pharmacology
Moscow, Moskva, Russia
MP

Mikhail Panteleev

Director
Center for Theoretical Problems of Physico-Сhemical Pharmacology
Moscow, Moskva, Russia
AS

Anna Shcherbina

Deputy Director of the Institute of Hematology, Immunology and Cell Technologies
Dmitry Rogachev National Medical Research Centеr of Pediatric Hematology, Oncology and Immunology
Moscow, Moskva, Russia
AS

Anastasia N. Sveshnikova

Head of Laboratory
Dmitry Rogachev National Medical Research Center Of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Moscow, Moskva, Russia

Background: Both neutropenia and thrombocytopenia are frequent features of bone marrow failure in Shwachman-Diamond syndrome (SDS). Aberrant F-actin polymerization is known to contribute to granulocyte dysfunction. Despite the potential for hemorrhage, including reported fatal cases, there has been limited study of the bleeding phenotype and the mechanisms of hemostasis impairment in SDS.

Aims: Elucidation of the mechanisms of hemostatic impairments in SDS.

Methods: Seventeen pediatric patients (median age 6.1 years) with genetically confirmed SDS and ten pediatric healthy donors were enrolled in the study. Platelet functionality was assessed by light-transmission aggregometry, flow cytometry and thrombi formation assay. Granulocyte motility was assessed by an ex vivo thromboinflammation test. Routine coagulogram and thrombodynamics test were used to evaluate coagulation status. Evaluation of bleeding propensity was conducted using Pediatric Bleeding Questionnaire (PBQ). The study was performed in accordance with the Declaration of Helsinki and approved by the independent ethics committee.

Results: The majority of patients presented with mild-to-moderate thrombocytopenia and mild bleeding phenotype (median PBQ score 2, range 0 to 5). There was no correlation between the severity of bleeding and platelet count. Bone marrow investigation revealed hypocellularity and diminished proplatelet formation by megakaryocytes. Immunofluorescence microscopy demonstrated platelet cytoskeletal abnormalities, including diffuse distribution of β1-tubulin, filamin, and myosin IIa. Platelet aggregation, along with intracellular calcium mobilization in response to ADP and PAR1-AP, was significantly diminished. Platelet shape change, glycoprotein IIb/IIIa activation, and dense granule secretion in response to strong stimulation were significantly diminished. Mild hypercoagulation was observed in most patients. However, the ability of platelets to form thrombi ex vivo was noticeably decreased. Granulocyte movement in thromboinflammation test was characterized by reduced velocities and randomness.

Conclusion(s): SDS is characterized by a mild bleeding phenotype and pronounced platelet abnormalities, notably involving cytoskeletal defects and impaired calcium signaling. The study was supported by the endowment foundation "Science for Children".