Platelet Heterogeneity in Myeloproliferative Neoplasms

Thomas, Spencer A.; Krishnan, Anandi

doi:10.1161/atvbaha.121.316373

Cited by 9 publications

(5 citation statements)

References 123 publications

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“…The time from whole blood collection to platelet isolation was similar between healthy donors and MPN patients. For next generation RNA-sequencing (RNA-seq), 1×10 9 isolated platelets lysed in Trizol were processed following established procedures 21,22,25 for RNA isolation (RNA integrity numbers >7.0), extraction and library preparation. Twelve pooled samples with individual indices were run on an Illumina HiSeq 4000 (Patterned flow cell with Hiseq4000 SBS v3 chemistry) as 2 X 75bp paired end sequencing with a coverage goal of 40M reads/sample.…”

Section: Methodsmentioning

confidence: 99%

SIRPα controls CD47-dependent platelet clearance in mice and humans

Shoham,

Yiu,

Hansen

et al. 2023

Preprint

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Over the last decade, more data has revealed that increased surface expression of the “don’t eat me” CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRPα can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRPα signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRPα axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRPα axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at theSIRPAlocus that impact platelet levels in humans such that higherSIRPAgene expression is associated with higher platelet levels.SIRPAexpression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy.Key pointsPlatelet homeostasis is regulated through the CD47-SIRPα axis and therapeutic blockade to disrupt this interaction impacts platelet levelsCommon genetic variants atSIRPAlocus associate with platelet levels

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Section: Methodsmentioning

confidence: 99%

SIRPα controls CD47-dependent platelet clearance in mice and humans

Shoham,

Yiu,

Hansen

et al. 2023

Preprint

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“…Heterogeneity in platelet function in bone marrow disorders is of interest, especially in the context of potential megakaryocyte heterogeneity. Some of our own work [ 4 , 7 , [82] , [83] , [84] , [85] ] has been in this area, in myeloproliferative neoplasms (MPNs) and clonal hematopoietic stem and progenitor cell malignancies characterized by aberrant megakaryocyte proliferation and thrombocytosis [ 86 , 87 ]. Patients with MPNs, including essential thrombocythemia, polycythemia vera, and myelofibrosis, experience progressively more severe clinical features, including complications with thrombosis and hemostasis and an increased propensity for transformation to acute myeloid leukemia [ 88 ].…”

Section: Platelet Heterogeneity At the Individual Level: Inherited Ac...mentioning

confidence: 99%

Heterogeneity of platelets and their responses

Thomas,

Kelliher,

Krishnan

2024

Research and Practice in Thrombosis and Haemostasis

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“…The molecular explanation for these losses remains undefined, but may be linked to disturbances in bone marrow cellularity and megakaryocyte maturation. 77 As GPIb-IX-V and the collagen/fibrin receptor GPVI also contribute to efficient thrombus generation by binding thrombin and other coagulation proteins, 78 79 80 81 any alteration to normal levels of platelet adhesion receptors due to changes in megakaryocyte maturity could disrupt efficient thrombin generation at the platelet surface.…”

Section: Platelet Dysfunction In Wmmentioning

confidence: 99%

Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation

et al. 2022

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Waldenström Macroglobulinaemia (WM) is a rare, incurable, low-grade, B cell lymphoma. Symptomatic disease commonly results from marrow or organ infiltration and hyperviscosity secondary to IgM paraprotein, manifesting as anaemia, bleeding and neurological symptoms among others. The causes of the bleeding phenotype in WM remain obscure but are likely to involve several intersecting mechanisms. Evidence of defects in platelet function is lacking in the literature, but factors impacting platelet function and coagulation pathways such as hyperviscosity, vascular bed disturbances, abnormal haematopoiesis, acquired von Willebrand Factor (VWF) syndrome and cryoglobulinaemia may contribute to bleeding. Understanding the pathophysiological mechanisms behind bleeding are important, as common WM therapies including chemo-immunotherapy and Bruton’s tyrosine kinase inhibitors, carry attendant bleeding risks. Furthermore, due to the relatively indolent nature of this lymphoma, most patients diagnosed with WM are often older and have one or more comorbidities requiring treatment with anticoagulant or antiplatelet drugs. It is thus important to understand the origin of the WM bleeding phenotype to better stratify patients according to their bleeding risk and thus enhance confidence in clinical decisions regarding treatment management. In this review, we detail the evidence for various contributing factors to the bleeding phenotype in WM and focus on current and emerging diagnostic tools that will aid evaluation and management of bleeding in these patients.

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Platelet Heterogeneity in Myeloproliferative Neoplasms

Cited by 9 publications

References 123 publications

SIRPα controls CD47-dependent platelet clearance in mice and humans

SIRPα controls CD47-dependent platelet clearance in mice and humans

Heterogeneity of platelets and their responses

Bleeding Propensity in Waldenström Macroglobulinemia: Potential Causes and Evaluation

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