Platelet distribution width is associated with cardiovascular mortality in an adult general population
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Platelet distribution width (PDW), a marker of platelet size heterogeneity used as a readout of processes leading to platelet production and destruction, was recently reported to tag platelet activation variability. As platelets participate in the pathogenesis of many acute and chronic diseases, we evaluated PDW as a predictor of all-cause and cause-specific mortality. Longitudinal analysis was performed on 17,334 participants (52% women, mean age 55.6±12 years) in the Moli-sani study cohort, without a history of hematological diseases. Baseline PDW measurements were categorized in tertiles, the lowest acting as the reference. A multivariable Cox-proportional hazard model was used to estimate the association between PDW and mortality. Over a median follow-up of 11.6 years (interquartile range 10.7-12.5), 1,535 deaths [37.7% cardiovascular disease (CVD) and 36.5% cancer] were ascertained. As compared to those in the first PDW tertile (14.6-16.0 fL), individuals within the highest tertile (16.6-20.4 fL) had an increased risk of all-cause [hazard ratios (HR):1.20; 95% CI: 1.04-1.37] and CVD mortality (HR:1.29; 1.03-1.62). No association between PDW and cancer mortality was found in the whole sample. Subgroup analyses by two age classes (35-65y, ≥65y) showed that the association of PDW with both all-cause and cancer mortality was more apparent in the elderly (HR:1.34; 1.14-1.58, P for interaction =0.028 and HR:1.37; 1.01-1.85, P for interaction =0.020, respectively). We conclude that PDW-associated increase in CVD mortality risk could be related to accelerated/altered activation, production, or destruction of platelets, leading to several clinical conditions and death. In the elderly, PDW involvement in all-cause and cancer mortality should be further investigated.
Steering committee: Licia Iacoviello, Giovanni de Gaetano, Maria Benedetta Donati. Scientific secretariat: Marialaura Bonaccio, Americo Bonanni, Chiara Cerletti, Simona Costanzo, Amalia De Curtis, Augusto Di Castelnuovo, Alessandro Gialluisi, Francesco Gianfagna, Mariarosaria Persichillo, Teresa Di Prospero. Safety and ethical committee: Jos Vermylen, Renzo Pegoraro, Antonio Spagnolo. External event adjudicating committee: Deodato Assanelli, Livia Rago. Baseline and follow-up data management: Simona Costanzo, Marco Olivieri, Teresa Panzera. Data analysis: Augusto Di Castelnuovo, Marialaura Bonaccio, Simona Costanzo, Simona Esposito, Alessandro Gialluisi, Francesco Gianfagna, Sabatino Orlandi, Emilia Ruggiero, Alfonsina Tirozzi. Biobank, molecular and genetic laboratory: Amalia De Curtis, Sara Magnacca, Fabrizia Noro, Alfonsina Tirozzi. Recruitment staff: Mariarosaria Persichillo, Francesca Bracone, Teresa Panzera. Communication and press office: Americo Bonanni. Regional institutions: Direzione Generale per la Salute - Regione Molise; Azienda Sanitaria Regionale del Molise; Agenzia Regionale per la Protezione Ambientale del Molise; Molise Dati Spa; Offices of vital statistics of the Molise region. Hospitals: Presidi Ospedalieri ASReM: Ospedale A. Cardarelli, Campobasso; Ospedale F. Veneziale, Isernia; Ospedale San Timoteo, Termoli (CB); Ospedale Ss. Rosario, Venafro (IS); Ospedale Vietri, Larino (CB); Ospedale San Francesco Caracciolo, Agnone (IS); Casa di Cura Villa Maria, Campobasso; Ospedale Gemelli Molise, Campobasso; IRCCS Neuromed, Pozzilli (IS), Italy.
Kabat GC, Kim MY, Verma AK, et al. Platelet count and total and cause-specific mortality in the Women's Health Initiative. Ann Epidemiol 2017;27:274-80. DOI: https://doi.org/10.1016/j.annepidem.2017.02.001
Msaouel P, Lam AP, Gundabolu K, et al. Abnormal platelet count is an independent predictor of mortality in the elderly and is influenced by ethnicity. Haematologica 2014;99:930-6. DOI: https://doi.org/10.3324/haematol.2013.101949
Tsai MT, Chen YT, Lin CH, et al. U-shaped mortality curve associated with platelet count among older people: a community-based cohort study. Blood 2015;126:1633-5. DOI: https://doi.org/10.1182/blood-2015-06-654764
Bonaccio M, Di Castelnuovo A, Costanzo S, et al. Age- and sex-based ranges of platelet count and cause-specific mortality risk in an adult general population: prospective findings from the Moli-sani study. Platelets 2018;29:312-5. DOI: https://doi.org/10.1080/09537104.2017.1411584
Bonaccio M, Di Castelnuovo A, Costanzo S, et al. Age-sex-specific ranges of platelet count and all-cause mortality: prospective findings from the MOLI-SANI study. Blood 2016;127:1614-6. DOI: https://doi.org/10.1182/blood-2016-01-692814
Vinholt PJ, Hvas AM, Frederiksen H, et al. Platelet count is associated with cardiovascular disease, cancer and mortality: A population-based cohort study. Thromb Res 2016;148:136-42. DOI: https://doi.org/10.1016/j.thromres.2016.08.012
Thaulow E, Erikssen J, Sandvik L, et al. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991;84:613-7. DOI: https://doi.org/10.1161/01.CIR.84.2.613
van der Bom JG, Heckbert SR, Lumley T, et al. Platelet count and the risk for thrombosis and death in the elderly. J Thromb Haemost 2009;7:399-405. DOI: https://doi.org/10.1111/j.1538-7836.2008.03267.x
Bonaccio M, Di Castelnuovo A, Costanzo S, et al. Mean platelet volume is associated with lower risk of overall and non-vascular mortality in a general population. Results from the Moli-sani study. Thromb Haemost 2017;117:1129-40. DOI: https://doi.org/10.1160/TH16-12-0974
Panova-Noeva M, Schulz A, Hermanns MI, et al. Sex-specific differences in genetic and nongenetic determinants of mean platelet volume: results from the Gutenberg Health Study. Blood 2016;127:251-9. DOI: https://doi.org/10.1182/blood-2015-07-660308
Slavka G, Perkmann T, Haslacher H, et al. Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease. Arterioscler Thromb Vasc Biol 2011;31:1215-8. DOI: https://doi.org/10.1161/ATVBAHA.110.221788
Tzur I, Barchel D, Izhakian S, et al. Platelet distribution width: a novel prognostic marker in an internal medicine ward. J Community Hosp Intern Med Perspect 2019;9:464-70. DOI: https://doi.org/10.1080/20009666.2019.1688095
Sachdev R, Tiwari AK, Goel S, et al. Establishing biological reference intervals for novel platelet parameters (immature platelet fraction, high immature platelet fraction, platelet distribution width, platelet large cell ratio, platelet-X, plateletcrit, and platelet distribution width) and their correlations among each other. Indian J Pathol Microbiol 2014;57:231-5. DOI: https://doi.org/10.4103/0377-4929.134676
Budak YU, Polat M, Huysal K. The use of platelet indices, plateletcrit, mean platelet volume and platelet distribution width in emergency non-traumatic abdominal surgery: a systematic review. Biochem Med (Zagreb) 2016;26:178-93. DOI: https://doi.org/10.11613/BM.2016.020
Wiwanitkit V. Plateletcrit, mean platelet volume, platelet distribution width: its expected values and correlation with parallel red blood cell parameters. Clin Appl Thromb Hemost 2004;10:175-8. DOI: https://doi.org/10.1177/107602960401000208
Vagdatli E, Gounari E, Lazaridou E, et al. Platelet distribution width: a simple, practical and specific marker of activation of coagulation. Hippokratia 2010;14:28-32.
Borkataky S, Jain R, Gupta R, et al. Role of platelet volume indices in the differential diagnosis of thrombocytopenia: a simple and inexpensive method. Hematology 2009;14:182-6. DOI: https://doi.org/10.1179/102453309X426182
Lee E, Kim M, Jeon K, et al. Mean Platelet Volume and Platelet Distribution Width Indicate that Platelets Remain Small for Most of Their Lifespans in Patients with Essential Thrombocythemia. Clin Lab 2019;65. DOI: https://doi.org/10.7754/Clin.Lab.2018.180938
Luzzatto G, de Franchis G, Fabris F, et al. Increased proportion of giant platelets and platelet distribution width are better indicators of altered platelet homeostasis than mean platelet volume in liver cirrhosis. Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115:719-26.
Ntaios G, Papadopoulos A, Chatzinikolaou A, et al. Increased values of mean platelet volume and platelet size deviation width may provide a safe positive diagnosis of idiopathic thrombocytopenic purpura. Acta Haematol 2008;119:173-7. DOI: https://doi.org/10.1159/000135658
Xia W, Chen W, Tu J, et al. Prognostic Value and Clinicopathologic Features of Platelet Distribution Width in Cancer: A Meta-Analysis. Med Sci Monit 2018;24:7130-6. DOI: https://doi.org/10.12659/MSM.913040
Weymann A, Ali-Hasan-Al-Saegh S, Sabashnikov A, et al. Platelets Cellular and Functional Characteristics in Patients with Atrial Fibrillation: A Comprehensive Meta-Analysis and Systematic Review. Med Sci Monit Basic Res 2017;23:58-86. DOI: https://doi.org/10.12659/MSMBR.902557
Budzianowski J, Pieszko K, Burchardt P, et al. The Role of Hematological Indices in Patients with Acute Coronary Syndrome. Dis Markers 2017;2017:3041565. DOI: https://doi.org/10.1155/2017/3041565
Zaccardi F, Rocca B, Pitocco D, et al. Platelet mean volume, distribution width, and count in type 2 diabetes, impaired fasting glucose, and metabolic syndrome: a meta-analysis. Diabetes Metab Res Rev 2015;31:402-10. DOI: https://doi.org/10.1002/dmrr.2625
Izzi B, Tirozzi A, Cerletti C, et al. Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities. Int J Mol Sci 2020;21. DOI: https://doi.org/10.3390/ijms21228817
Izzi BFJJ. Blood platelet heterogeneity at a glance: new insights into the relationship between platelet distribution width and neuropsychiatric disorders. Bleed Thromb Vasc Biol 2023;2. DOI: https://doi.org/10.4081/btvb.2023.65
Izzi B, Gialluisi A, Gianfagna F, et al. Platelet Distribution Width Is Associated with P-Selectin Dependent Platelet Function: Results from the Moli-Family Cohort Study. Cells 2021;10. DOI: https://doi.org/10.3390/cells10102737
Izzi B, Gianfagna F, Yang WY, et al. Variation of PEAR1 DNA methylation influences platelet and leukocyte function. Clin Epigenetics 2019;11:151. DOI: https://doi.org/10.1186/s13148-019-0744-8
Di Castelnuovo A, de Curtis A, Costanzo S, et al. Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study. Haematologica 2013;98:1476-80. DOI: https://doi.org/10.3324/haematol.2012.083410
Iacoviello L, Bonanni A, Costanzo S, et al. The MOLI-SANI Project, a randomized, prospective cohort study in the Molise region in Italy; design, rationale and objectives. Ital J Pub Health 2007:110-8.
Celegen M, Kesici S, Yavuz S, et al. Are platelet indices promising ratios for predicting pediatric septic shock prognosis? Bratisl Lek Listy 2022;123:444-8. DOI: https://doi.org/10.4149/BLL_2022_069
Khadka P, Maharjan G, Chapagain G, et al. Economic and Diagnostic Biomarker Tests of Neonatal Sepsis: A Prospective Study from a Tertiary Care Hospital in a Low-Income Country. Biomed Res Int 2022;2022:5166380. DOI: https://doi.org/10.1155/2022/5166380
Hsieh PY, Hsu KH, Chiang MC, et al. Platelet parameters and the association with morbidity and mortality in Preterm Infants. Pediatr Neonatol 2023;64:68-74. DOI: https://doi.org/10.1016/j.pedneo.2022.06.009
Sato Y, Yoshihisa A, Watanabe K, et al. Association between platelet distribution width and prognosis in patients with heart failure. PLoS One 2020;15:e0244608. DOI: https://doi.org/10.1371/journal.pone.0244608
Ghaffari S, Parvizian N, Pourafkari L, et al. Prognostic value of platelet indices in patients with acute pulmonary thromboembolism. J Cardiovasc Thorac Res 2020;12:56-62. DOI: https://doi.org/10.34172/jcvtr.2020.09
Araz O, Albez FS, Ucar EY, et al. Predictive Value of Mean Platelet Volume for Pulmonary Embolism Recurrence. Lung 2017;195:497-502. DOI: https://doi.org/10.1007/s00408-017-0020-7
Zeng W, Xu B, Wang X, et al. Identification of Prognostic Factors for Recurrence and Mortality in Patients With Acute Pulmonary Embolism. Heart Surg Forum 2022;25:E812-E821. DOI: https://doi.org/10.1532/hsf.4971
Wikan VE, Tondel BG, Morelli VM, et al. Diagnostic Blood Biomarkers for Acute Pulmonary Embolism: A Systematic Review. Diagnostics (Basel) 2023;13. DOI: https://doi.org/10.3390/diagnostics13132301
Kowara M, Grodecki K, Huczek Z, et al. Platelet distribution width predicts left ventricular dysfunction in patients with acute coronary syndromes treated with percutaneous coronary intervention. Kardiol Pol 2017;75:42-7. DOI: https://doi.org/10.5603/KP.a2016.0137
Timoteo AT, Papoila AL, Lousinha A, et al. Predictive impact on medium-term mortality of hematological parameters in Acute Coronary Syndromes: added value on top of GRACE risk score. Eur Heart J Acute Cardiovasc Care 2015;4:172-9. DOI: https://doi.org/10.1177/2048872614547690
Bae MH, Lee JH, Yang DH, et al. White blood cell, hemoglobin and platelet distribution width as short-term prognostic markers in patients with acute myocardial infarction. J Korean Med Sci 2014;29:519-26. DOI: https://doi.org/10.3346/jkms.2014.29.4.519
Rechcinski T, Jasinska A, Forys J, et al. Prognostic value of platelet indices after acute myocardial infarction treated with primary percutaneous coronary intervention. Cardiol J 2013;20:491-8. DOI: https://doi.org/10.5603/CJ.2013.0134
Oguz S. Relationship between First Values of Red Cell Distribution Width, Mean Platelet Volume, Platelet Distribution Width, and Hospital Mortality in Acute Deep Venous Thrombosis. J Coll Physicians Surg Pak 2021;30:379-82. DOI: https://doi.org/10.29271/jcpsp.2021.04.379
Mangalpally KK, Siqueiros-Garcia A, Vaduganathan M, et al. Platelet activation patterns in platelet size sub-populations: differential responses to aspirin in vitro. J Thromb Thrombolysis 2010;30:251-62. DOI: https://doi.org/10.1007/s11239-010-0489-x
Mezzano D, Aranda E, Foradori A. Comparative study of size, total protein, fibrinogen and 5-HT content of human and canine platelet density subpopulations. Thromb Haemost 1986;56:288-92. DOI: https://doi.org/10.1055/s-0038-1661668
Polanowska-Grabowska R, Raha S, Gear AR. Adhesion efficiency, platelet density and size. Br J Haematol 1992;82:715-20. DOI: https://doi.org/10.1111/j.1365-2141.1992.tb06949.x
Frojmovic M, Wong T. Dynamic measurements of the platelet membrane glycoprotein IIb-IIIa receptor for fibrinogen by flow cytometry. II. Platelet size-dependent subpopulations. Biophys J 1991;59:828-37. DOI: https://doi.org/10.1016/S0006-3495(91)82295-0
Handtke S, Steil L, Palankar R, et al. Role of Platelet Size Revisited-Function and Protein Composition of Large and Small Platelets. Thromb Haemost 2019;119:407-20. DOI: https://doi.org/10.1055/s-0039-1677875
Karpatkin S. Heterogeneity of human platelets. I. Metabolic and kinetic evidence suggestive of young and old platelets. J Clin Invest 1969;48:1073-82. DOI: https://doi.org/10.1172/JCI106063
Chamberlain KG, Penington DG. Monoamine oxidase and other mitochondrial enzymes in density subpopulations of human platelets. Thromb Haemost 1988;59:29-33. DOI: https://doi.org/10.1055/s-0038-1642560
Clancy L, Beaulieu LM, Tanriverdi K, Freedman JE. The role of RNA uptake in platelet heterogeneity. Thromb Haemost 2017;117:948-61. DOI: https://doi.org/10.1160/TH16-11-0873
Thompson CB, Jakubowski JA, Quinn PG, et al. Platelet size as a determinant of platelet function. J Lab Clin Med 1983;101:205-13.
Li BY, He SZ, Li WH. Heterogeneity of human platelet density subpopulations in aggregation, secretion of ATP, and cytosolic-free calcium concentration. Zhongguo Yao Li Xue Bao 1996;17:152-5.
Selvadurai MV, Hamilton JR. Structure and function of the open canalicular system - the platelet's specialized internal membrane network. Platelets 2018;29:319-25. DOI: https://doi.org/10.1080/09537104.2018.1431388
Kamisli O, Kamisli S, Kablan Y, et al. The prognostic value of an increased mean platelet volume and platelet distribution width in the early phase of cerebral venous sinus thrombosis. Clin Appl Thromb Hemost 2013;19:29-32. DOI: https://doi.org/10.1177/1076029612453196
Sevuk U, Bahadir MV, Altindag R, et al. Value of serial platelet indices measurements for the prediction of pulmonary embolism in patients with deep venous thrombosis. Ther Clin Risk Manag 2015;11:1243-9. DOI: https://doi.org/10.2147/TCRM.S89355
Ulucan S, Keser A, Kaya Z, et al. Association between PDW and Long Term Major Adverse Cardiac Events in Patients with Acute Coronary Syndrome. Heart Lung Circ 2016;25:29-34. DOI: https://doi.org/10.1016/j.hlc.2015.05.017
Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol 2020;17:137-44. DOI: https://doi.org/10.1038/s41569-019-0247-5
Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 2017;377:111-21. DOI: https://doi.org/10.1056/NEJMoa1701719
Haybar H, Shahrabi S, Ghanavat M, Khodadi E. Clonal hematopoiesis: Genes and underlying mechanisms in cardiovascular disease development. J Cell Physiol 2019;234:8396-401. DOI: https://doi.org/10.1002/jcp.27752
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488-98. DOI: https://doi.org/10.1056/NEJMoa1408617
Kar SP, Quiros PM, Gu M, et al. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat Genet 2022;54:1155-66. DOI: https://doi.org/10.1038/s41588-022-01121-z
Allan HE, Hayman MA, Marcone S, et al. Proteome and functional decline as platelets age in the circulation. J Thromb Haemost 2021;19:3095-112. DOI: https://doi.org/10.1111/jth.15496
Bongiovanni D, Santamaria G, Klug M, et al. Transcriptome Analysis of Reticulated Platelets Reveals a Prothrombotic Profile. Thromb Haemost 2019;119:1795-806. DOI: https://doi.org/10.1055/s-0039-1695009
Cesari F, Marcucci R, Gori AM, et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 2013;109:846-53. DOI: https://doi.org/10.1160/TH12-09-0709
Grove EL, Hvas AM, Mortensen SB, et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011;9:185-91. DOI: https://doi.org/10.1111/j.1538-7836.2010.04115.x
Ibrahim H, Schutt RC, Hannawi B, et al. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014;64:2122-9. DOI: https://doi.org/10.1016/j.jacc.2014.06.1210
Anetsberger A, Blobner M, Haller B, et al. Immature platelets as a novel biomarker for adverse cardiovascular events in patients after non-cardiac surgery. Thromb Haemost 2017;117:1887-95. DOI: https://doi.org/10.1160/TH16-10-0804
Briggs C. Quality counts: new parameters in blood cell counting. Int J Lab Hematol 2009;31:277-97. DOI: https://doi.org/10.1111/j.1751-553X.2009.01160.x
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