Time course of immature platelet count and its relation to thrombocytopenia and mortality in patients with sepsis

Kansuke Koyama, Shinshu Katayama, Tomohiro Muronoi, Ken Tonai, Yuya Goto, Toshitaka Koinuma, Jun Shima, Shin Nunomiya, Kansuke Koyama, Shinshu Katayama, Tomohiro Muronoi, Ken Tonai, Yuya Goto, Toshitaka Koinuma, Jun Shima, Shin Nunomiya

Abstract

Introduction: The pathogenesis of thrombocytopenia in patients with sepsis is not fully understood. The aims of this study were to investigate changes in thrombopoietic activity over time by using absolute immature platelet counts (AIPC) and to examine the impact of platelet production on thrombocytopenia and mortality in patients with sepsis.

Methods: This retrospective observational study included adult patients with sepsis admitted to the intensive care unit at a university hospital. Two hundred five consecutive sepsis patients were stratified into four groups according to nadir platelet count: severe (nadir ≤40×103/μL), moderate (41-80×103/μL), or mild thrombocytopenia (81-120×103/μL), or normal-increased platelet count (>120×103/μL). The development of thrombocytopenia was assessed during the first week; mortality was assessed at day 28.

Result: Of the 205 patients included, 61 (29.8%) developed severe thrombocytopenia. On admission, AIPC did not differ among the four groups. In patients with severe thrombocytopenia, AIPC decreased significantly from days 2 to 7, but remained within or above the normal range in the other three groups (overall group comparison, P<0.0001). Multivariate analysis including coagulation biomarkers revealed that AIPC was independently associated with the development of severe thrombocytopenia (day 3 AIPC, odds ratio 0.49 [95% confidence interval (CI) 0.35-0.66], P<0.0001; day 5 AIPC, 0.59 [95% CI 0.45-0.75], P<0.0001). AIPC was a significant predictor of 28-day mortality in Cox hazard models adjusted for Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores (day 3 AIPC, hazard ratio 0.70 [95% CI 0.52-0.89], P = 0.0029; day 5 AIPC, 0.68 [95% CI 0.49-0.87], P = 0.0012).

Conclusions: Thrombopoietic activity was generally maintained in the acute phase of sepsis. However, a decrease in AIPC after admission was independently associated with the development of severe thrombocytopenia and mortality, suggesting the importance of suppressed thrombopoiesis in the pathophysiology of sepsis-induced thrombocytopenia.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Time course of platelet count…
Fig 1. Time course of platelet count and absolute immature platelet count (AIPC).
Platelet count and AIPC were measured from admission (day 1) to day 7 in patients with sepsis, classified into four groups according to nadir platelet count during the 7 days: severe thrombocytopenia (nadir platelet count ≤40×103/μL); moderate thrombocytopenia (41–80×103/μL); mild thrombocytopenia (81–120×103/μL); and normal-increased platelet count (>120×103/μL). Data are expressed as mean with the 95% confidence interval shown by the error bars. Multiple analysis of variance was among the four groups.
Fig 2. Box plot showing (a) platelet…
Fig 2. Box plot showing (a) platelet and (b) absolute immature platelet count (AIPC).
Platelet count and AIPC on the day of admission (day 1) and at the nadir during the 7 days are shown. Septic patients were classified into four groups according to nadir platelet count during the first 7 days of their ICU stay: severe thrombocytopenia (nadir platelet count ≤40×103/μL); moderate thrombocytopenia (41–80×103/μL); mild thrombocytopenia (81–120×103/μL); and normal-increased platelet counts (>120×103/μL). Multiple pairwise comparison used the Steel–Dwass test.
Fig 3. Time course of coagulation biomarkers…
Fig 3. Time course of coagulation biomarkers from admission (day 1) to day 7 in patients with sepsis.
Septic patients were classified into four groups according to nadir platelet count during the first 7 days of their ICU stay: severe thrombocytopenia (nadir platelet count ≤40×103/μL); moderate thrombocytopenia (41–80×103/μL); mild thrombocytopenia (81–120×103/μL); and normal-increased platelet counts (>120×103/μL). Data are expressed as mean with the 95% confidence interval shown by the error bars.

References

    1. Sharma B, Sharma M, Majumder M, Steier W, Sangal A, Kalawar M. Thrombocytopenia in septic shock patients—a prospective observational study of incidence, risk factors and correlation with clinical outcome. Anaesth Intensive Care. 2007;35(6):874–80.
    1. Larkin CM, Santos-Martinez MJ, Ryan T, Radomski MW. Sepsis-associated thrombocytopenia. Thromb Res. 2016;141:11–6. doi:
    1. Martin CM, Priestap F, Fisher H, Fowler RA, Heyland DK, Keenan SP, et al. A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry. Crit Care Med. 2009;37(1):81–8. doi:
    1. Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, Wilmer A, et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med. 2000;28(6):1871–6.
    1. Moreau D, Timsit JF, Vesin A, Garrouste-Orgeas M, de Lassence A, Zahar JR, et al. Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest. 2007;131(6):1735–41. doi:
    1. Thiery-Antier N, Binquet C, Vinault S, Meziani F, Boisrame-Helms J, Quenot JP, et al. Is Thrombocytopenia an Early Prognostic Marker in Septic Shock? Crit Care Med. 2016;44(4):764–72.
    1. Vandijck DM, Blot SI, De Waele JJ, Hoste EA, Vandewoude KH, Decruyenaere JM. Thrombocytopenia and outcome in critically ill patients with bloodstream infection. Heart Lung. 2010;39(1):21–6. doi:
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–10.
    1. Taylor FB Jr., Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86(5):1327–30.
    1. Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34(3):625–31.
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. doi:
    1. Vincent JL, Yagushi A, Pradier O. Platelet function in sepsis. Crit Care Med. 2002;30(5 Suppl):S313–7.
    1. de Stoppelaar SF, van 't Veer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost. 2014;112(4):666–77. doi:
    1. Koyama K, Madoiwa S, Tanaka S, Koinuma T, Wada M, Sakata A, et al. Evaluation of hemostatic biomarker abnormalities that precede platelet count decline in critically ill patients with sepsis. J Crit Care. 2013;28(5):556–63. doi:
    1. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res. 2012;129(3):290–5. doi:
    1. Taylor FB Jr., Wada H, Kinasewitz G. Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC. Crit Care Med. 2000;28(9 Suppl):S12–9.
    1. Deutsch VR, Tomer A. Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside. Br J Haematol. 2013;161(6):778–93. doi:
    1. Thiolliere F, Serre-Sapin AF, Reignier J, Benedit M, Constantin JM, Lebert C, et al. Epidemiology and outcome of thrombocytopenic patients in the intensive care unit: results of a prospective multicenter study. Intensive Care Med. 2013;39(8):1460–8. doi:
    1. Abe Y, Wada H, Tomatsu H, Sakaguchi A, Nishioka J, Yabu Y, et al. A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF). Thromb Res. 2006;118(4):463–9. doi:
    1. Briggs C, Kunka S, Hart D, Oguni S, Machin SJ. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol. 2004;126(1):93–9. doi:
    1. Pons I, Monteagudo M, Lucchetti G, Munoz L, Perea G, Colomina I, et al. Correlation between immature platelet fraction and reticulated platelets. Usefulness in the etiology diagnosis of thrombocytopenia. Eur J Haematol. 2010;85(2):158–63. doi:
    1. Takami A, Shibayama M, Orito M, Omote M, Okumura H, Yamashita T, et al. Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;39(8):501–7. doi:
    1. Barsam SJ, Psaila B, Forestier M, Page LK, Sloane PA, Geyer JT, et al. Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia. Blood. 2011;117(21):5723–32. doi:
    1. Hoffmann JJ. Reticulated platelets: analytical aspects and clinical utility. Clin Chem Lab Med. 2014;52(8):1107–17. doi:
    1. Kulshrestha M, Sola-Visner M, Widness JA, Veng-Pedersen P, Mager DE. Mathematical model of platelet turnover in thrombocytopenic and nonthrombocytopenic preterm neonates. Am J Physiol Heart Circ Physiol. 2015;308(1):H68–73. doi:
    1. Muronoi T, Koyama K, Nunomiya S, Lefor AK, Wada M, Koinuma T, et al. Immature platelet fraction predicts coagulopathy-related platelet consumption and mortality in patients with sepsis. Thromb Res. 2016;144:169–75. doi:
    1. De Blasi RA, Cardelli P, Costante A, Sandri M, Mercieri M, Arcioni R. Immature platelet fraction in predicting sepsis in critically ill patients. Intensive Care Med. 2013;39(4):636–43. doi:
    1. Di Mario A, Garzia M, Leone F, Arcangeli A, Pagano L, Zini G. Immature platelet fraction (IPF) in hospitalized patients with neutrophilia and suspected bacterial infection. J Infect. 2009;59(3):201–6. doi:
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228. doi:
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–29.
    1. Segre E, Pigozzi L, Lison D, Pivetta E, Bosco O, Vizio B, et al. May thrombopoietin be a useful marker of sepsis severity assessment in patients with SIRS entering the emergency department? Clin Chem Lab Med. 2014;52(10):1479–83. doi:
    1. Zakynthinos SG, Papanikolaou S, Theodoridis T, Zakynthinos EG, Christopoulou-Kokkinou V, Katsaris G, et al. Sepsis severity is the major determinant of circulating thrombopoietin levels in septic patients. Crit Care Med. 2004;32(4):1004–10.
    1. Eissa DS, El-Farrash RA. New insights into thrombopoiesis in neonatal sepsis. Platelets. 2013;24(2):122–8. doi:
    1. Cremer M, Weimann A, Szekessy D, Hammer H, Buhrer C, Dame C. Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis. J Perinatol. 2013;33(8):622–6. doi:
    1. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11(2):R49 doi:
    1. Ishiguro A, Suzuki Y, Mito M, Shimbo T, Matsubara K, Kato T, et al. Elevation of serum thrombopoietin precedes thrombocytosis in acute infections. Br J Haematol. 2002;116(3):612–8.
    1. Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest. 2005;115(12):3339–47. doi:
    1. Stohlawetz P, Folman CC, von dem Borne AE, Pernerstorfer T, Eichler HG, Panzer S, et al. Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost. 1999;81(4):613–7.
    1. Kaser A, Brandacher G, Steurer W, Kaser S, Offner FA, Zoller H, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98(9):2720–5.
    1. Cerutti A, Custodi P, Mduranti, Cazzola M, Balduini CL. Circulating thrombopoietin in reactive conditions behaves like an acute phase reactant. Clin Lab Haematol. 1999;21(4):271–5.
    1. Buyse S, Teixeira L, Galicier L, Mariotte E, Lemiale V, Seguin A, et al. Critical care management of patients with hemophagocytic lymphohistiocytosis. Intensive Care Med. 2010;36(10):1695–702. doi:
    1. Inai K, Noriki S, Iwasaki H, Naiki H. Risk factor analysis for bone marrow histiocytic hyperplasia with hemophagocytosis: an autopsy study. Virchows Arch. 2014;465(1):109–18. doi:
    1. Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A, et al. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care. 2004;8(2):R82–90. doi:
    1. Dhainaut JF, Shorr AF, Macias WL, Kollef MJ, Levi M, Reinhart K, et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med. 2005;33(2):341–8.
    1. Bat T, Leitman SF, Calvo KR, Chauvet D, Dunbar CE. Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion. Transfusion. 2013;53(6):1201–4. doi:

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera