Immature platelets as a novel biomarker for adverse cardiovascular events in patients after non-cardiac surgery
24 October 2016
Accepted after major revision: 24 June 2017
08 November 2017 (online)
This study evaluates whether immature platelets (IPF) determined in the post anesthesia care unit (PACU) can predict major adverse cardiovascular events (MACE) or other thromboembolic events after intermediate and high-risk surgery. IPF are increased in patients with acute coronary syndrome and recently gained interest as novel biomarker for risk stratification. In this prospective observational trial 732 patients undergoing intermediate or high-risk non-cardiac surgery were enrolled (NCT02097602). IPF was measured preoperatively and postoperatively in the PACU. Primary outcome was a composite endpoint defined as MACE, deep vein thrombosis or pulmonary embolism during hospital stay (modMACE). A cut off for IPF identifying a threshold between a low and high risk for modMACE was calculated by logrank optimization. A multivariate Cox regression was calculated in a forward stepwise manner to assess the relation between this IPF cut off and modMACE as well as other established risk factors (inclusion if p<0.05). Preoperatively, there were no differences in IPF between patients with and without modMACE (3.1% [2.2% – 4.7%](median [interquartile range]) vs. 2.8% [1.9% – 4.3%]. Patients with modMACE (28 of 730 patients; 3.8%) had higher IPF values in the PACU compared to patients without modMACE (3.6% [2.6–6%] vs. 2.9% [2–4.4%]; p=0.011). The optimal cut off of IPF > 5.4% was associated with an increased risk for modMACE after adjustment for covariates (hazard ratio: 2.528; 95% confidence interval: 1.156 to 5.528, p=0.02). In conclusion, IPF is an independent predictor of modMACE after surgery and might improve risk stratification of surgical patients.
Institution where the work was performed and funded: Klinikum rechts der Isar der Technischen Universität München, Ismaningerstr. 22, 81675 Munich, Germany.
- 1 Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpatient surgery. N Engl J Med 2009; 361: 1368-1375.
- 2 Sheetz KH, Dimick JB, Ghaferi AA. The Association between hospital care intensity and surgical outcomes in medicare patients. J Am Med Assoc Surg 2014; 149: 1254-1259.
- 3 Silber JH, Williams SV, Krakauer H. et al. Hospital and patient characteristics associated with death after surgery: a study of adverse occurrence and failure to rescue. Med Care 1992; 30: 615-629.
- 4 Sabaté S, Mases A, Guilera N. et al. ncidence and predictors of major perioperative adverse cardiac and cerebrovascular events in non-cardiac surgery. Br J Anaesth 2011; 107: 879-890.
- 5 Eikelboom JW, Warkentin TE. Immature platelet count: part of the cardiologist’s complete blood count?. J Am Coll Cardiol 2014; 64: 2130-2132.
- 6 Grove EL, Hvas A-M, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156.
- 7 Lakkis N, Dokainish H, Abuzahra M. et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004; 44: 2091-2093.
- 8 Ibrahim H, Schutt RC, Hannawi B. et al. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014; 64: 2122-2129.
- 9 Ault KA, Rinder HM, Mitchell J. et al. The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 1992; 98: 637-646.
- 10 Harrison P, Goodall AH. “Message in the platelet”- more than just vestigial mRNA. Platelets 2008; 19: 395-404.
- 11 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: 251-262.
- 12 McBane RD. Gonzalez C, Hodg DO. et al. Propensity for young reticulated platelet recruitment into arterial thrombi. J Thromb Thrombolysis 2014; 37: 148-154.
- 13 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: 846-853.
- 14 Nakamura T, Uchiyama S, Yamazaki M. et al. Flow cytometric analysis of reticulated platelets in patients with ischemic stroke. Thromb Res 2002; 106: 171-177.
- 15 Fleisher LA, Beckman JA, Brown KA. et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol 2007; 50: 159-241.
- 16 Thygesen K, Alpert JS, Jaffe AS. et al. the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation 2012; 126: 2020-2533
- 17 American Society of Anesthesiologists (last approved by the ASA House of Delegates on October 15, 2014) Available at: http://www.asahq.org/resources/clinical-information/asa-physical-status-classification-system
- 18 Meintker L, Haimerl M, Ringwald J. et al. Measurement of immature platelets with Abbott CD-Sapphire and Sysmex XE-5000 in haematology and oncology patients. Clin Chem Lab Med 2013; 51: 2125-2131.
- 19 Gengireddy C, Rectenwald JR, Upchurch GR. et al. Risk factors and clinical importance of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007; 45: 335-342.
- 20 Fleischmann KE, Goldman L, Young B. et al. Association between cardiac and noncardiac complications in patients undergoing noncardiac surgery: outcomes and effects on length of stay. Am J Med 2003; 115: 515-520.
- 21 Harrell F. Regression modeling strategies: with applications to linear models, logistic and ordinal regression, and survival analysis. Springer: 2015
- 22 Lange S, Bender M. Linear regression and correlation. Dtsch Med Wochenschr 2007; 132: e9-e11.
- 23 Altman DG, Lausen B, Sauerbrei W. et al. Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. JNCI J Natl Cancer Inst 1994; 86: 829-835.
- 24 Prause G, Ratzenhofer-Comenda B, Pierer G. et al. Can ASA grade or Goldman’s cardiac risk index predict peri-operative mortality? A study of 16227 patients. Anaesthesia 1997; 52: 203-206.
- 25 Mussallam KM, Tamim HM, Richards T. et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet 2011; 378: 1396-1407.
- 26 Friedman J, Trevor H, Tibshirani R. The elements of statistical learning. Vol. 1 Springer, Berlin: Springer series in statistics; 2001
- 27 Breiman L, Friedman JH, Olshen RA. et al. Classification and Regression Trees. CRC Press; 1984
- 28 Lee TH, Marcantonio ER, Mangione CM. et al. Derivation and Prospective Validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999; 100: 1043-1049.
- 29 Moonesinghe SR, Mythen MG, Das P. et al. Risk stratification tools for predicting morbidity and mortality in adult patients undergoing major surgery. Anesthesiology 2013; 119: 959-981.
- 30 Le Manach Y, Collins G, Rodseth R. et al. Preoperative Score to Predict Postoperative Mortality (POSPOM): Derivation and Validation. Anesthesiology 2016; 124: 570-579.
- 31 Kristensen SD, Knuuti J, Saraste A. et al. ESC/ESA guidelines on non-cardiac surgery: Cardiovascular assessment and management: The joint task force on non-cardiac surgery: Cardiovascular assessment and management of the European society of cardiology (esc) and the european society of anaesthesiology (esa). Eur Heart J 2014; 35: 2383-2431.
- 32 Haynes AB, Regenbogen SE, Weiser TG. et al. Surgical outcome measurement for a global patient population: validation of the Surgical Apgar Score in 8 countries. Surgery 2011; 149: 519-524.
- 33 Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. J Am Med Assoc 2012; 307: 2295-2304.
- 34 van Waes JA, Grobben RB, Nathoe HM. et al. One-Year Mortality, Causes of Death, and Cardiac Interventions in Patients with Postoperative Myocardial Injury. Anesth Analg 2016; 123: 29-37.
- 35 Sessler DI, Sigl JC, Kelley SD. et al. Hospital stay and mortality are increased in patients having a „triple low“ of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia. Anesthesiology 2012; 116: 1195-1203.
- 36 Bernard AC, Davenport DL, Chang PK. et al. Intraoperative transfusion of 1 U to 2 U packed red blood cells is associated with increased 30-day mortality, surgical- site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg 2009; 208: 931-937.
- 37 Pearse RM, Moreno RP, Bauer P. et al. Mortality after surgery in Europe: a 7 day cohort study. Lancet 2012; 380: 1059-1065.
- 38 Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation 2007; 115: 928-935.
- 39 Chen S, Du C, Shen M. et al. Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation. Blood 2016; 127: 1024-1035.
- 40 Hobisch-Hagen P, Jelkmann W, Mayr A. et al. Low platelet count and elevated serum thrombopoietin after severe trauma. Eur J Haematol 2000; 64: 157-163.
- 41 Watt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: A systematic review. Surgery 2015; 157: 362-380.
- 42 Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000; 85: 109-117.
- 43 Larsen SB, Grove EL, Würtz M. et al. The influence of low-grade inflammation on platelets in patients with stable coronary artery disease. Thromb Haemost 2015; 114: 519-529.
- 44 Peng J, Friese P, Wolf RF. et al. Relative reactivity of platelets from Thrombopoietin- and IL-6-treated dogs. Blood 1996; 10: 4158-4163.