Altered platelet quality and dynamics in patients undergoing hemodialysis

Abstract

Patients undergoing hemodialysis (HD) are at high risk for both atherothrombosis and hemorrhage. Compared to healthy individuals, these patients show significant alterations in platelet dynamics, potentially contributing to cardiovascular complications and bleeding. This review presents a hypothesis-generating model to elucidate the mechanisms of platelet turnover, reactivity, and premature aging in HD patients. It also examines the roles of pulmonary thrombopoiesis, inflammation, and oxidative stress in platelet dysfunction. Furthermore, the review highlights the importance of platelet heterogeneity and proposes a strategy for developing personalized antiplatelet therapies for HD patients. Future research directions, such as single-cell analyses, are recommended to enhance understanding of platelet dynamics in HD and improve patient care.

Keywords

Clonal hematopoiesis / extramedullary hematopoiesis / hematopoietic stem cells / inflammation / megakaryocytes / oxidative stress

References

[1] Natale P,Saglimbene VM.Antiplatelet agents for chronic kidney disease.Cochrane Database Syst Rev2022;2:CD008834 PMCID:PMC8883339

[2] Jain N,Dai J.Age modifies intracranial and gastrointestinal bleeding risk from P2Y₁₂ inhibitors in patients receiving dialysis.Kidney3602022;3:1374-83 PMCID:PMC9416835

[3] Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.Am J Kidney Dis2005;45:16-153

[4] Holden RM,Wang M,Day AG.Major bleeding in hemodialysis patients.Clin J Am Soc Nephrol2008;3:105-10 PMCID:PMC2390984

[5] Claudio P.Nephrotic syndrome: pathophysiology and consequences.J Nephrol2023;36:2179-90

[6] Gritters M,Grooteman MP.Platelet activation in clinical haemodialysis: LMWH as a major contributor to bio-incompatibility?.Nephrol Dial Transplant2008;23:2911-7

[7] Martin JF.A theory of rapid evolutionary change explaining the de novo appearance of megakaryocytes and platelets in mammals.J Cell Sci2022;135:jcs260286 PMCID:PMC10112974

[8] Trowbridge EA.A computer model of the random binary sequential division of megakaryocyte cytoplasm to produce platelets.Phys Med Biol1984;29:1477-87

[9] Kuter DJ.The biology of thrombopoietin and thrombopoietin receptor agonists.Int J Hematol2013;98:10-23

[10] Dowling MR,Henley KJ,Kile BT.Platelet senescence is regulated by an internal timer, not damage inflicted by hits.Blood2010;116:1776-8

[11] Ingram M.Reticulated platelets following acute blood loss.Br J Haematol1969;17:225-9

[12] Hancock V,Lelchuk R.The relationship between human megakaryocyte nuclear DNA content and gene expression.Br J Haematol1993;85:692-7

[13] Martin JF,Mathur A,Choudry FA.The causal role of megakaryocyte-platelet hyperactivity in acute coronary syndromes.Nat Rev Cardiol2012;9:658-70

[14] Debili N,Katz A,Breton-Gorius J.Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34⁺ cells.Blood1993;82:84-95

[15] Hacein-Bey-Abina S,Bessoles S.Erythropoietin is a major regulator of thrombopoiesis in thrombopoietin-dependent and -independent contexts.Exp Hematol2020;88:15-27

[16] Nishimura S,Kunishima S.IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.J Cell Biol2015;209:453-66 PMCID:PMC4427781

[17] Hasegawa T,Akizawa T.Anemia in conventional hemodialysis: finding the optimal treatment balance.Semin Dial2018;31:599-606

[18] Anding K,Rost JM,Jacobs E.The influence of uraemia and haemodialysis on neutrophil phagocytosis and antimicrobial killing.Nephrol Dial Transplant2003;18:2067-73

[19] Kato S,Honda H.Aspects of immune dysfunction in end-stage renal disease.Clin J Am Soc Nephrol2008;3:1526-33 PMCID:PMC4571158

[20] Lisowska KA,Dębska-Ślizień A.T cell subpopulations and cytokine levels in hemodialysis patients.Hum Immunol2022;83:134-43

[21] van Bladel ER,Walter D.Platelets of patients with chronic kidney disease demonstrate deficient platelet reactivity in vitro.BMC Nephrol2012;13:127 PMCID:PMC3473261

[22] Kaw D.Platelet dysfunction and end-stage renal disease.Semin Dial2006;19:317-22

[23] Galbusera M,Boccardo P.Treatment of bleeding in dialysis patients.Semin Dial2009;22:279-86

[24] Baaten CCFMJ,Henning T,Jankowski J.Platelet function in CKD: a systematic review and meta-analysis.J Am Soc Nephrol2021;32:1583-98 PMCID:PMC8425648

[25] Vaziri ND,Crum A.Effect of uremia on structure and function of immune system.J Ren Nutr2012;22:149-56 PMCID:PMC3246616

[26] Hedges SJ,Hooper JS,Busti AJ.Evidence-based treatment recommendations for uremic bleeding.Nat Clin Pract Nephrol2007;3:138-53

[27] Daugirdas JT.Hemodialysis effect on platelet count and function and hemodialysis-associated thrombocytopenia.Kidney Int2012;82:147-57

[28] Aggarwal A,Rimmer JM.Biphasic effects of hemodialysis on platelet reactivity in patients with end-stage renal disease: a potential contributor to cardiovascular risk.Am J Kidney Dis2002;40:315-22

[29] Gawaz MP,Schmidt B.Platelet-leukocyte aggregation during hemodialysis.Kidney Int1994;46:489-95

[30] Ashman N,Fan SL,Yaqoob MM.Increased platelet-monocyte aggregates and cardiovascular disease in end-stage renal failure patients.Nephrol Dial Transplant2003;18:2088-96

[31] Schoorl M,Nubé MJ.Platelet depletion, platelet activation and coagulation during treatment with hemodialysis.Scand J Clin Lab Invest2011;71:240-7

[32] Schoorl M,Bartels PC.Changes in platelet volume, morphology and RNA content in subjects treated with haemodialysis.Scand J Clin Lab Invest2008;68:335-42

[33] Schoorl M,Gritters M,Musters R.Electron microscopic observation in case of platelet activation in a chronic haemodialysis subject.Hematol Rep2011;3:e15 PMCID:PMC3238486

[34] Schoorl M,Bartels PC.Aspects of platelet disturbances in haemodialysis patients.Clin Kidney J2013;6:266-71 PMCID:PMC3941307

[35] Sloos PH,van't Veer C.Platelet dysfunction after trauma: from mechanisms to targeted treatment.Transfusion2022;62 Suppl 1:S281-300 PMCID:PMC9546174

[36] Jurk K,Van Aken H.Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-transmembrane thrombin receptor (PAR-1).Thromb Haemost2004;91:334-44

[37] Riedl J,Marosi C.Decreased platelet reactivity in patients with cancer is associated with high risk of venous thromboembolism and poor prognosis.Thromb Haemost2017;117:90-8 PMCID:PMC6522348

[38] Dewanjee MK,Cavagnaro CF.In vitro and in vivo evaluation of the comparative thrombogenicity of cellulose acetate hemodialyzers with radiolabeled platelets.ASAIO J1994;40:49-55

[39] Popescu NI,Lupu F.Disseminated intravascular coagulation and its immune mechanisms.Blood2022;139:1973-86 PMCID:PMC8972096

[40] Arepally GM.Heparin-induced thrombocytopenia: a focus on thrombosis.Arterioscler Thromb Vasc Biol2021;41:141-52 PMCID:PMC7769912

[41] Joly BS,Veyradier A.Thrombotic thrombocytopenic purpura.Blood2017;129:2836-46

[42] Martin JF,Trowbridge EA.Acute and chronic changes in platelet volume and count after cardiopulmonary bypass induced thrombocytopenia in man.Thromb Haemost1987;57:55-8

[43] Kim S,Fonarow GC.Mean platelet volume and mortality risk in a national incident hemodialysis cohort.Int J Cardiol2016;220:862-70 PMCID:PMC5929115

[44] Cho A,Lee YK.Effects of aspirin resistance and mean platelet volume on vascular access failure in hemodialysis patients.Korean J Intern Med2019;34:1304-12 PMCID:PMC6823566

[45] International Atomic Energy Agency. Radiolabelled autologous cells: methods and standardization for clinical use. Vienna: International Atomic Energy Agency; 2015. Available from: https://www-pub.iaea.org/MTCD/Publications/PDF/Pub1437web-26591607.pdf [Last accessed on 1 June 2023].

[46] Araújo NC.The spleen size in patients undergoing hemodialysis.J Bras Nefrol2021;43:61-7 PMCID:PMC8061966

[47] Hakim RM.Hemodialysis-associated platelet activation and thrombocytopenia.Am J Med1985;78:575-80

[48] Linthorst GE,van Olden RW.Plasma thrombopoietin levels in patients with chronic renal failure.Hematol J2002;3:38-42

[49] Ando M,Suda A,Nihei H.New insights into the thrombopoietic status of patients on dialysis through the evaluation of megakaryocytopoiesis in bone marrow and of endogenous thrombopoietin levels.Blood2001;97:915-21

[50] Mahlknecht U.Age-related changes in peripheral blood counts in humans.Exp Ther Med2010;1:1019-25 PMCID:PMC3446744

[51] Toyoda Y,Takeda Y.Significance of mild thrombocytopenia in maintenance hemodialysis patients; a retrospective cohort study.Platelets2022;33:735-42

[52] Panova-Noeva M,Nagler M.Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies.EBioMedicine2020;60:102978 PMCID:PMC7494681

[53] Zimmermann N,Wenk A,Gams E.Is cardiopulmonary bypass a reason for aspirin resistance after coronary artery bypass grafting?.Eur J Cardiothorac Surg2005;27:606-10

[54] Gäckler A,Lisman T.Evaluation of hemostasis in patients with end-stage renal disease.PLoS One2019;14:e0212237 PMCID:PMC6382154

[55] Mitic BP,Hosokawa K.Platelet thrombus formation in patients with end-stage renal disease before and after hemodialysis as measured by the total thrombus-formation analysis system.Int Urol Nephrol2022;54:2695-702 PMCID:PMC9463292

[56] Jain N,Kumar A,Ware J.Role of platelets in chronic kidney disease.J Am Soc Nephrol2021;32:1551-8 PMCID:PMC8425650

[57] Chuang YC,Yang LC.Significance of platelet activation in vascular access survival of haemodialysis patients.Nephrol Dial Transplant2003;18:947-54

[58] Eknoyan G,Glueck HI.Platelet function in renal failure.N Engl J Med1969;280:677-81

[59] Parguiña AF,Agra RM.Proteins involved in platelet signaling are differentially regulated in acute coronary syndrome: a proteomic study.PLoS One2010;5:e13404 PMCID:PMC2954807

[60] López-Farré AJ,Azcona L.Proteomic changes related to “bewildered” circulating platelets in the acute coronary syndrome.Proteomics2011;11:3335-48

[61] Goudswaard LJ,Khalil J.Alterations in platelet proteome signature and impaired platelet integrin α_IIbβ₃ activation in patients with COVID-19.J Thromb Haemost2023;21:1307-21 PMCID:PMC9883069

[62] Trugilho MRO,Gesto JSM.Platelet proteome reveals features of cell death, antiviral response and viral replication in covid-19.Cell Death Discov2022;8:324 PMCID:PMC9287722

[63] Tateno K,Hirose M,Kanda M.Abstract 11022: progressive thrombocytopenia in critical limb ischemia as a novel cardiovascular rsk.Circulation2019;140:A11022

[64] Benlachgar N,Masrar A,Harmouche H.Immature platelets: a review of the available evidence.Thromb Res2020;195:43-50

[65] Himmelfarb J,McMonagle E.Increased reticulated platelets in dialysis patients.Kidney Int1997;51:834-9

[66] Tàssies D,Cases A.Reticulated platelets in uremic patients: effect of hemodialysis and continuous ambulatory peritoneal dialysis.Am J Hematol1995;50:161-6

[67] Tàssies D,Cases A,Escolar G.Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: association with early improvement in platelet function.Am J Hematol1998;59:105-9

[68] Baaten CCFMJ,van der Meijden PEJ.Platelet populations and priming in hematological diseases.Blood Rev2017;31:389-99

[69] Gafter U,Malachi T,Djaldetti M.Platelet count and thrombopoietic activity in patients with chronic renal failure.Nephron1987;45:207-10

[70] Levine RF,Shoff PK,Tenza D.Circulating megakaryocytes: delivery of large numbers of intact, mature megakaryocytes to the lungs.Eur J Haematol1993;51:233-46

[71] Davis RE,Levin J.Localization of megakaryocytes in normal mice and following administration of platelet antiserum, 5-fluorouracil, or radiostrontium: evidence for the site of platelet production.Exp Hematol1997;25:638-48

[72] Zucker-Franklin D.Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept.Am J Pathol2000;157:69-74 PMCID:PMC1850212

[73] Weyrich AS.Platelets in lung biology.Annu Rev Physiol2013;75:569-91 PMCID:PMC3670819

[74] Aabo K.Megakaryocytes in pulmonary blood vessels. I. Incidence at autopsy, clinicopathological relations especially to disseminated intravascular coagulation.Acta Pathol Microbiol Scand A1978;86:285-91

[75] Pedersen NT.Occurrence of megakaryocytes in various vessels and their retention in the pulmonary capillaries in man.Scand J Haematol1978;21:369-75

[76] Lefrançais E,Caudrillier A.The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.Nature2017;544:105-9 PMCID:PMC5663284

[77] Rao DS,Mohini R.Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia.N Engl J Med1993;328:171-5

[78] Weng CH,Hu CC,Wang IK.Bone marrow pathology predicts mortality in chronic hemodialysis patients.Biomed Res Int2015;2015:160382 PMCID:PMC4354719

[79] Yilmaz M,Kaya E,Huddam B.Evaluation of bone marrow findings in hemodialysis patients with erythropoietin-resistant anemia.Ther Apher Dial2024;28:218-24

[80] Pariser DN,Ture SK.Lung megakaryocytes are immune modulatory cells.J Clin Invest2021;131:137377 PMCID:PMC7773372

[81] Yeung AK,Hon S,Murphy GJ.Lung megakaryocytes display distinct transcriptional and phenotypic properties.Blood Adv2020;4:6204-17 PMCID:PMC7757004

[82] Qiu J,Dong Z.Lung megakaryocytes engulf inhaled airborne particles to promote intrapulmonary inflammation and extrapulmonary distribution.Nat Commun2024;15:7396 PMCID:PMC11349891

[83] Gelon L,Lefrançais E.Occurrence and role of lung megakaryocytes in infection and inflammation.Front Immunol2022;13:1029223 PMCID:PMC9745136

[84] Gritters M,Schoorl M.Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis.Nephrol Dial Transplant2006;21:153-9

[85] Liakopoulos V,Zarogiannis S,Mertens PR.Oxidative stress in hemodialysis: causative mechanisms, clinical implications, and possible therapeutic interventions.Semin Dial2019;32:58-71

[86] Himmelfarb J,Holbrook D,Hakim RM.Intradialytic granulocyte reactive oxygen species production: a prospective, crossover trial.J Am Soc Nephrol1993;4:178-86

[87] Meyring-Wösten A,Campos I.Erythrocyte sodium sensitivity and eryptosis in chronic hemodialysis patients.Kidney Blood Press Res2017;42:314-26

[88] Pernow J,Yang J.Red blood cell dysfunction: a new player in cardiovascular disease.Cardiovasc Res2019;115:1596-605

[89] Liakopoulos V,Gorny X,Mertens PR.Oxidative stress in hemodialysis patients: a review of the literature.Oxid Med Cell Longev2017;2017:3081856 PMCID:PMC5613374

[90] Arthur JF,Andrews RK.Platelet hyperreactivity in diabetes: focus on GPVI signaling-are useful drugs already available?.Diabetes2017;66:7-13

[91] Chatterjee M,Schlotterbeck J.Regulation of oxidized platelet lipidome: implications for coronary artery disease.Eur Heart J2017;38:1993-2005

[92] Melk A.Cell senescence and its implications for nephrology.J Am Soc Nephrol2001;12:385-93

[93] Carracedo J,Vida C.Mechanisms of cardiovascular disorders in patients with chronic kidney disease: a process related to accelerated senescence.Front Cell Dev Biol2020;8:185 PMCID:PMC7099607

[94] Stenvinkel P,Lindholm B.Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.Nephrol Dial Transplant2004;19:972-6

[95] Di Micco R, Krizhanovsky V, Baker D, d’Adda di Fagagna F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat Rev Mol Cell Biol2021;22:75-95 PMCID:PMC8344376

[96] Zhang L,Yousefzadeh MJ,Robbins PD.Cellular senescence: a key therapeutic target in aging and diseases.J Clin Invest2022;132:e158450 PMCID:PMC9337830

[97] Ramírez R,Soriano S.Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis.Am J Kidney Dis2005;45:353-9

[98] Hirashio S,Doi S.Telomeric g-tail length and hospitalization for cardiovascular events in hemodialysis patients.Clin J Am Soc Nephrol2014;9:2117-22 PMCID:PMC4255409

[99] He S.Senescence in health and disease.Cell2017;169:1000-11 PMCID:PMC5643029

[100] Ong SM,Dang TM.The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence.Cell Death Dis2018;9:266 PMCID:PMC5833376

[101] Le Blanc J, Lordkipanidzé M. Platelet function in aging.Front Cardiovasc Med2019;6:109 PMCID:PMC6692461

[102] Davizon-Castillo P,Aguila S.TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.Blood2019;134:727-40 PMCID:PMC6716075

[103] Yamamoto T.Pathological mechanisms of kidney disease in ageing.Nat Rev Nephrol2024;20:603-15

[104] Besancenot R,Tonetti C.A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation.PLoS Biol2010;8:e1000476 PMCID:PMC2935456

[105] Thongon N,Santoni A.Hematopoiesis under telomere attrition at the single-cell resolution.Nat Commun2021;12:6850 PMCID:PMC8617077

[106] Gekas C.CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age.Blood2013;121:4463-72

[107] Sanjuan-Pla A,Jensen CT.Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.Nature2013;502:232-6

[108] Pang WW,Sahoo D.Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.Proc Natl Acad Sci USA2011;108:20012-7 PMCID:PMC3250139

[109] Choudry FA.Epigenetic control of haematopoietic stem cell aging and its clinical implications.Stem Cells Int2016;2016:5797521 PMCID:PMC4670691

[110] Carrelha J,Winroth A.Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells.Nat Immunol2024;25:1007-19 PMCID:PMC11147777

[111] Poscablo DM,Smith-Berdan S.An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis.Cell2024;187:3090-107.e21

[112] Meade TW,Thompson SG,Haines AP.Epidemiological characteristics of platelet aggregability.Br Med J1985;290:428-32 PMCID:PMC1417797

[113] Simon LM,Nagalla S.Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics.Blood2014;123:e37-45 PMCID:PMC3990915

[114] Campbell RA,Bhatnagar A.Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging.J Immunol2018;200:295-304 PMCID:PMC5736423

[115] Jaiswal S,Flannick J.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med2014;371:2488-98 PMCID:PMC4306669

[116] Genovese G,Handsaker RE.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med2014;371:2477-87 PMCID:PMC4290021

[117] Jaiswal S,Silver AJ.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med2017;377:111-21 PMCID:PMC6717509

[118] Sano S,Walsh K.Clonal hematopoiesis and its impact on cardiovascular disease.Circ J2018;83:2-11 PMCID:PMC6310086

[119] Vlasschaert C,Chong M.Association of clonal hematopoiesis of indeterminate potential with worse kidney function and anemia in two cohorts of patients with advanced chronic kidney disease.J Am Soc Nephrol2022;33:985-95 PMCID:PMC9063886

[120] Veninga A,Heemskerk JWM,van der Meijden PEJ.Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding.Haematologica2020;105:2020-31

[121] Kristiansen MH,Skov V.JAK2V617F mutation is highly prevalent in patients with ischemic stroke: a case-control study.Blood Adv2023;7:5825-34 PMCID:PMC10561044

[122] Hinckley J.Genetic basis of congenital platelet disorders.Hematol Am Soc Hematol Educ Program2014;2014:337-42

[123] Caiado F,Manz MG.Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection.J Exp Med2021;218:e20201541 PMCID:PMC8210622

[124] Pietras EM.Inflammation: a key regulator of hematopoietic stem cell fate in health and disease.Blood2017;130:1693-8 PMCID:PMC5639485

[125] Sezaki M,Wang Y,Umemoto T.Immuno-modulation of hematopoietic stem and progenitor cells in inflammation.Front Immunol2020;11:585367 PMCID:PMC7732516

[126] Bochenek ML,Schäfer K.Endothelial cell senescence and thrombosis: ageing clots.Thromb Res2016;147:36-45

[127] Sasaki K,Kabata D.Oxidative stress and inflammation as predictors of mortality and cardiovascular events in hemodialysis patients: the DREAM cohort.J Atheroscler Thromb2021;28:249-60 PMCID:PMC8049144

[128] Cianciolo G,Donati G.Intra- and post-dialytic platelet activation and PDGF-AB release: cellulose diacetate vs polysulfone membranes.Nephrol Dial Transplant2001;16:1222-9

[129] Kessler M,Nguyen P.Anticoagulation in chronic hemodialysis: progress toward an optimal approach.Semin Dial2015;28:474-89

[130] Ponchia PI,Farag M.Antiplatelet therapy in end-stage renal disease patients on maintenance dialysis: a state-of-the-art review.Cardiovasc Drugs Ther2023;37:975-87

[131] Mitchell E,Williams N.Clonal dynamics of haematopoiesis across the human lifespan.Nature2022;606:343-50 PMCID:PMC9177428

[132] Koupenova M,Corkrey HA.Circulating platelets as mediators of immunity, inflammation, and thrombosis.Circ Res2018;122:337-51 PMCID:PMC5777300

[133] Molnar MZ,Kovesdy CP.High platelet count as a link between renal cachexia and cardiovascular mortality in end-stage renal disease patients.Am J Clin Nutr2011;94:945-54 PMCID:PMC3155928

[134] Blair TA,Frelinger AL 3rd.Mass cytometry reveals distinct platelet subtypes in healthy subjects and novel alterations in surface glycoproteins in glanzmann thrombasthenia.Sci Rep2018;8:10300 PMCID:PMC6037710

[135] David Amir EA,Tadmor MD.viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia.Nat Biotechnol2013;31:545-52 PMCID:PMC4076922

[136] Jain V,Wu J,Gregory SG.Single cell RNA-seq analysis of human red cells.Front Physiol2022;13:828700 PMCID:PMC9065680