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Mitochondrial dysfunction in platelets from patients with JAK2 V617F essential thrombocythemia and polycythemia vera underlie thrombo-hemorrhagic complications

1University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States, 2Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States, 3Department of Pediatrics Hematology/Oncology and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States, 4Department of Surgery, University of Colorado Anschutz Medical Campus/Vitalant Research Institute, Aurora, Colorado, United States, 5Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States, 6Division of Hematology, University of Washington/Bloodworks NW Research Institute, Seattle, Washington, United States, 7Department of Pediatrics Hematology/Oncology and Bone Marrow Transplantation, Hemophilia and Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Abstract Number: OC 66.5

Meeting: ISTH 2022 Congress

Theme: Hemostatic Systems in Cancer, Inflammation and Immunity » Platelets and Inflammation

Background: Myeloproliferative neoplasms are a group of pro-inflammatory clonal hematopoietic disorders. Patients with JAK2 V617F essential thrombocythemia (ET) and polycythemia vera (PV) experience thrombo-hemorrhagic events. We have previously identified that platelets from patients with ET/PV exhibit dysmorphic mitochondria. In light of these changes, we hypothesize that platelet metabolism and function are altered.

Aims: We sought to identify and characterize the metabolic and functional alterations of platelets from patients with JAK2 V617F ET/PV.

Methods: Platelets from sex and age-matched healthy controls and individuals with ET/PV were studied. Platelet activation, calcium mobilization and mitochondrial polarization were determined by flow cytometry. Thrombus formation under flow was measured with the Total Thrombus-formation Analysis System analyzer. Platelet bioenergetics were studied with the Seahorse extracellular flux analyzer. Semi-quantitative metabolomics was performed using the Vanquish UHPLC system. Clot retraction analysis was calculated by weight of extruded serum.

Results: ET/PV platelets demonstrated elevated cytoplasmic calcium under resting conditions and after stimulation with thrombin (Figure 1A). ET/PV platelets displayed greater membrane depolarization when compared to healthy controls (p=0.03). ET/PV platelets also exhibited decreased basal respiration and ATP-linked respiration (Figure 1B) and reduced ADP and ATP pools (Figure 1C). Functionally, ET/PV platelets exposed more procoagulant phosphatidylserine on the outer membrane leaflet and, under arterial flow conditions, formed thrombi faster (Figure 2A-B). Despite the accelerated clot formation, platelet contraction was significantly decreased in ET/PV platelets (p=0.04).

Conclusion(s): We show that JAK2 V617F ET/PV platelets have dysfunctional mitochondria (i.e., perturbed calcium flux and loss of mitochondrial membrane potential), leading to defective energy production. Energy-demanding processes such as maintaining plasma membrane phospholipid polarity and clot retraction may be disrupted in ET/PV platelets leading to a procoagulant phenotype, accelerated thrombus formation, and an unstable clot. Our findings may explain why patients with ET/PV are at an increased risk for thrombo-hemorrhagic complications.

To cite this abstract in AMA style:

Esparza O, McMahon B, Hernandez G, Le D, Kelher M, Nemkov T, D'Alessandro A, Lopez J, Davizon-Castillo P. Mitochondrial dysfunction in platelets from patients with JAK2 V617F essential thrombocythemia and polycythemia vera underlie thrombo-hemorrhagic complications [abstract]. https://abstracts.isth.org/abstract/mitochondrial-dysfunction-in-platelets-from-patients-with-jak2-v617f-essential-thrombocythemia-and-polycythemia-vera-underlie-thrombo-hemorrhagic-complications/. Accessed September 27, 2022.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/mitochondrial-dysfunction-in-platelets-from-patients-with-jak2-v617f-essential-thrombocythemia-and-polycythemia-vera-underlie-thrombo-hemorrhagic-complications/