ADAMTS13 in pediatric sepsis: a prognostic biomarker with potential therapeutic implications
Tóm tắt
Growing evidence implicates a pro-thrombotic state, caused by ADAMTS13 deficiency, in sepsis-associated organ dysfunction, but pediatric data is limited. Our purpose was to evaluate association of ADAMTS13 with prognosis of pediatric sepsis. This was prospective observational study, conducted on 70 children with sepsis and 18 healthy controls. Patients were classified upon Pediatric Intensive Care Unit (PICU) admission into sepsis, severe sepsis, and septic shock groups. Serum ADAMTS13 was measured within 24 h of admission. The primary outcome was all-cause PICU mortality. ADAMTS13 was lower among patients than controls [median and interquartile range (IQR): 1.30 (0.88–3.13ng/mL) vs. 6.00 (5.55–6.50 ng/mL); p < 0.001]. ADAMTS13 was lower in both severe sepsis and septic shock than sepsis [median (IQR): 0.90 (0.80–1.75 ng/mL); 1.0 ng/ml (0.90–1.20); and 2.80 (1.00–3.85ng/mL), p = 0.026 and 0.006 respectively]. ADAMTS13 was lower among non-survivors compared with survivors [median (IQR): 0.9 (0.80–1.18 ng/mL) vs. 2.45 (0.98–3.50 ng/mL); p < 0.001]. ADAMTS13 had area under Receiver Operating Characteristic Curve (AUC) of 0.77 for mortality prediction. Lower ADAMTS13 level was associated with mechanical ventilation; vasoactive medications; acute respiratory distress syndrome; and multiple organ dysfunction syndrome. ADAMTS13 correlated with pediatric Sequential Organ Failure Assessment (pSOFA) score (rs = -0.46, p < 0.001); vasoactive infusion days ((rs = -0.48, p < 0.001); and vasoactive-inotropic score on day1 (rs = -0.43, p < 0.001) and day2 ((rs = -0.41; p < 0.001). In pediatric sepsis, lower ADAMTS13 level is a risk factor for organ dysfunction and mortality, lending theoretical foundations to therapeutic interventions aiming at reversing the pro-thrombotic state in sepsis.
Tài liệu tham khảo
Schlapbach LJ, Straney L, Alexander J et al (2015) Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002–13: a multicentre retrospective cohort study. Lancet Infect Dis 15:46–54
Levi M, Scully M, Singer M (2018) The role of ADAMTS-13 in the coagulopathy of sepsis. J Thromb Haemost 16:646–651
Bernardo A, Ball C, Nolasco L et al (2004) Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 104:100–106
Uemura M, Tatsumi K, Matsumoto M et al (2005) Localization of ADAMTS13 to the stellate cells of human liver. Blood 106:922–924
Shelat SG, Ai J, Zheng XL (2005) Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Semin Thromb Hemost 31:659–672
Chen J, Chung DW (2018) Inflammation, von Willebrand factor, and ADAMTS13. Blood 132:141–147
Mikuła T, Kozłowska J, Stańczak W et al (2018) Serum ADAMTS-13 Levels as an Indicator of Portal Vein Thrombosis. Gastroenterol Res Pract 2018:3287491
Maino A, Siegerink B, Lotta LA et al (2015) Plasma ADAMTS-13 levels and the risk of myocardial infarction: an individual patient data meta-analysis. J Thromb Haemost 13:1396–1404
Beltrami-Moreira M, DeSancho MT (2022) Delayed diagnosis of congenital thrombotic thrombocytopenic purpura in a patient with recurrent strokes. J Thromb Thrombolysis 53:734–738
Nguyen TC, Liu A, Liu L et al (2007) Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica 92:121–124
Lin JJ, Chan OW, Hsiao HJ et al (2016) Decreased ADAMTS 13 Activity is associated with disease severity and outcome in pediatric severe sepsis. Medicine (Baltimore) 95:e3374
Bongers TN, Emonts M, de Maat MP et al (2010) Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome. Thromb Haemost 103:1181–1187
Zeineddin A, Dong JF, Wu F et al (2021) Role of Von Willebrand factor after injury: It may do more than we think. Shock 55:717–722
Hugenholtz GC, Adelmeijer J, Meijers JC et al (2013) An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology 58:752–761
Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2–8
Slater A, Shann F, Pearson G (2003) PIM2: a revised versionof the Paediatric index of mortality. Intensive Care Med 29:278–285
Matics TJ, Sanchez-Pinto LN (2017) Adaptation and Validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children. JAMA Pediatr 171:e172352
Nguyen HV, Havalad V, Aponte-Patel L et al (2013) Temporary biventricular pacing decreases the vasoactive-inotropic score after cardiac surgery: a substudy of a randomized clinical trial. J Thorac Cardiovasc Surg 146:296–301
Davis AL, Carcillo JA, Aneja RK et al (2017) American college of critical care medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med 45:1061–1093
Kremer Hovinga JA, Zeerleder S, Kessler P et al (2007) ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost 5:2284–2290
Martin K, Borgel D, Lerolle N et al (2007) Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 35:2375–2382
Ono T, Mimuro J, Madoiwa S et al (2006) Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 107:528–534
Ghimire S, Ravi S, Budhathoki R et al (2021) Current understanding and future implications of sepsis-induced thrombocytopenia. Eur J Haematol 106:301–305
Karim F, Adil SN, Afaq B et al (2013) Deficiency of ADAMTS-13 in pediatric patients with severe sepsis and impact on in-hospital mortality. BMC Pediatr 13:44
Kokame K, Matsumoto M, Soejima K et al (2002) Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 99:11902–11907
Banno F, Kokame K, Okuda T et al (2006) Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 107:3161–3166
Levy B, Lacolley P, Regnault V (2007) ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin) and endothelial dysfunction in sepsis: marker or culprit? Crit Care Med 35:2453–2454
Ouyang Y, Wang Y, Liu B et al (2019) Effects of antiplatelet therapy on the mortality rate of patients with sepsis: a meta-analysis. J Crit Care 50:162–168
Nicolai L, Gaertner F, Massberg S (2019) Platelets in host defense: experimental and clinical insights. Trends Immunol 40:922–938
Weiss SL, Peters MJ, Alhazzani W et al (2020) Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med 21:e52–e106