Abstract
Purpose
Sepsis and its progression are known to have a major influence on the coagulation system. Current coagulation tests are of limited use when assessing coagulation in sepsis patients. This study aims to assess the potential for a new functional biomarker of clot microstructure, fractal dimension, to identify changes in the mechanical properties of clot microstructure across the sepsis spectrum (sepsis, severe sepsis and septic shock).
Methods
A total of 100 patients that presented acutely to a large teaching hospital were included in this prospective observational study (50 sepsis, 20 severe sepsis and 30 septic shock) against a matched control of 44 healthy volunteers. Fractal analysis was performed, as well as standard markers of coagulation, and six plasma markers of inflammation.
Results
Fractal dimension was significantly higher in the sepsis and severe sepsis groups than the healthy control (1.78 ± 0.07 and 1.80 ± 0.05, respectively vs 1.74 ± 0.03) (p < 0.001), indicating a significant increase in mechanical clot strength and elasticity consistent with a hypercoagulable state. Conversely, fractal dimension was significantly lower in septic shock (1.66 ± 0.10, p < 0.001), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state. This corresponded with a significant increase in the inflammatory response.
Conclusions
This study confirms that clot microstructure is significantly altered through the various stages of sepsis. Of particular importance was the marked change in clot development between severe sepsis and septic shock, which has not been previously reported.
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References
Schouten M, Wiersinga WJ, Levi M, Van Der Poll T (2006) Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 79:536–545
Dhainaut J-F, Shorr AF, Macias WL, Kollef MJ, Levi M, Reinhart K, Nelson DR (2005) Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 33:341–348
Ranieri VM, Thompson BT, Barie PS, Dhainaut J-F, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055–2064
Rimmer E, Kumar A, Doucette S, Marshall J, Dial S, Gurka D, Dellinger RP, Sharma S, Penner C, Kramer A, Wood K, Ronald J, Kumar A, Turgeon AF, Houston DS, Zarychanski R (2012) Activated protein C and septic shock: a propensity-matched cohort study. Crit Care Med 40:2974–2981
Abraham E, Opal S, Demeyer I, Lo A, Svoboda P, Laterre F, Simon S, Light B, Peckelsen C, De Deyne C, Percell SR, Shu V, Poole L, Creasey AA (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238–247
Lipets EN, Ataullakhanov FI (2015) Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk. Thromb J 13:4
Meybohm P, Zacharowski K, Weber CF (2013) Point-of-care coagulation management in intensive care medicine. Crit Care 17:218
Favaloro EJ, (Adcock) Funk DM, Lippi G (2012) Pre-analytical variables in coagulation testing associated with diagnostic errors in hemostasis. Lab Med 43:1–10
Evans PA, Hawkins K, Morris RHK, Thirumalai N, Munro R, Wakeman L, Lawrence MJ, Williams PR (2010) Gel point and fractal microstructure of incipient blood clots are significant new markers of hemostasis for healthy and anticoagulated blood. Blood 116:3341–3346
Davies NA, Harrison NK, Morris RHK, Noble S, Lawrence MJ, DSilva LA, Broome L, Brown MR, Hawkins KM, Williams PR, Davidson S, Evans PA (2015) Fractal dimension (d f) as a new structural biomarker of clot microstructure in different stages of lung cancer. Thromb Haemost 114:1251–1259
Stanford SN, Sabra A, DSilva LA, Lawrence M, Morris R, Storton S, Brown M, Evans V, Hawkins K, Williams P, Davidson SJ, Wani M, Potter JF, Evans PF (2015) The changes in clot microstructure in patients with ischaemic stroke and the effects of therapeutic intervention: a prospective observational study. BMC Neurol 15:35
Davies G, Pillai S, Mills G, Aubrey R, Morris K, Williams P, Evans P (2016) Fractal dimension: a new biomarker for quantifying clot microstructure in patients across the sepsis spectrum. Crit Care 20(Suppl 2):P031
Bone R, Balk R, Cerra F, Dellinger R, Fein A, Knaus W, Schein R, Sibbald W (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 20:864–874
Bernard GR, Vincent J-L, Laterre P-F, Larosa SP, Dhainaut J-F, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein c for severe sepsis. N Engl J Med 344:699–709
Lawrence MJ, Marsden N, Mothukuri R, Morris RHK, Davies G, Hawkins K, Curtis DJ, Brown MR, Williams PR, Evans PA (2016) The effects of temperature on clot microstructure and strength in healthy volunteers. Anesth Analg 122:21–26
Evans PA, Hawkins K, Lawrence M, Williams RL, Barrow MS, Thirumalai N, Williams PR (2008) Rheometry and associated techniques for blood coagulation studies. Med Eng Phys 30:671–679
Evans PA, Hawkins K, Lawrence M, Barrow MS, Williams PR, Williams RL (2008) Studies of whole blood coagulation by oscillatory shear, thromboelastography and free oscillation rheometry. Clin Hemorheol Microcirc 38:267–277
Curtis DJ, Brown MR, Hawkins K, Evans PA, Lawrence MJ, Rees P, Williams PR (2011) Rheometrical and molecular dynamics simulation studies of incipient clot formation in fibrin-thrombin gels: an activation limited aggregation approach. J Nonnewton Fluid Mech 166:932–938
Brown MR, Curtis DJ, Rees P, Summers HD, Hawkins K, Evans PA, Williams PR (2012) Fractal discrimination of random fractal aggregates and its application in biomarker analysis for blood coagulation. Chaos Solit Fractals 45:1025–1032
Lawrence MJ, Kumar S, Hawkins K, Boden S, Rutt H, Mills G, Sabra A, Morris RHK, Davidson SJ, Badiei N, Brown MR, Williams PR, Evans PA (2014) A new structural biomarker that quantifies and predicts changes in clot strength and quality in a model of progressive haemodilution. Thromb Res 134:488–494
Lawrence MJ, Sabra A, Thomas P, Obaid DR, DSilva LA, Morris RHK, Hawkins K, Brown MR, Williams PR, Davidson SJ, Chase AJ, Smith D, Evans PA (2015) Fractal dimension: a novel clot microstructure biomarker use in ST elevation myocardial infarction patients. Atherosclerosis 240:402–407
Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, Vadas L, Pugin J (2001) Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 164:396–402
Andersen MG, Hvas CL, Tonnesen E, Hvas AM (2014) Thromboelastometry as a supplementary tool for evaluation of hemostasis in severe sepsis and septic shock. Acta Anaesthesiol Scand 58:525–533
Dirkmann D, Hanke AA, Gorlinger K, Peters J (2008) Hypothermia and acidosis synergistically impair coagulation in whole human blood. Anesth Analg 106:1627–1632
Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S (2000) Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 28:451–457
Donze JD, Ridker PM, Finlayson SRG, Bates DW (2012) Impact of sepsis on risk of postoperative arterial and venous thromboses: large prospective cohort study. BMJ 349:g5334
Massion PB, Peters P, Ledoux D, Zimermann V, Canivet J-L, Massion PP, Damas P, Gothot A (2012) Persistent hypocoagulability in patients with septic shock predicts greater hospital mortality: impact of impaired thrombin generation. Intensive Care Med 38:1326–1335
Davies GR, Mills GM, Lawrence M, Battle C, Morris K, Hawkins K, Williams PR, Davidson S, Thomas D, Evans PA (2014) The role of whole blood impedance aggregometry and its utilisation in the diagnosis and prognosis of patients with systemic inflammatory response syndrome and sepsis in acute critical illness. PLoS One 9:e108589
Annane D, Timsit JF, Mégarbane B, Martin C, Misset B, Mourvillier B, Siami S, Chagnon J-L, Constantin J-M, Petitpas F, Souweine B, Amathieu R, Forceville X, Charpentier C, Tesnière A, Chastre J, Bohe J, Colin G, Cariou A, Renault A, Brun-Buisson C, Bellissant E (2013) Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am J Respir Crit Care Med 187:1091–1097
Hvidt LN, Perner A (2012) High dosage of dextran 70 is associated with severe bleeding in patients admitted to the intensive care unit for septic shock. Dan Med J 59:1–5
Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816–823
Collet JP, Allali Y, Lesty C, Tanguy ML, Silvain J, Ankri A, Blanchet B, Dumaine R, Gianetti J, Payot L, Weisel JW, Montalescot G (2006) Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 26:2567–2573
Acknowledgments
This study was funded by the National Institute for Social Care and Health Research (NISCHR) and was also part-funded by the European Social Fund (ESF) through the European Union’s Convergence programme administered by the Welsh Government. Our thanks go to the staff in the Emergency Department, Intensive Therapy Unit and Haemostasis Biomedical Research Unit of Morriston Hospital for their invaluable support.
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PAE and PRW have signed the International Committee of Medical Journal Editors (ICMJE) form for declaration of interest and have declared all conflict of interests. All other authors declare no competing conflicts of interest.
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Take-home message: Clot microstructure is significantly altered across the sepsis spectrum. This ranges from a highly dense fibrin structure in sepsis and severe sepsis to a significantly weaker, tenuous fibrin structure in septic shock.
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Davies, G.R., Pillai, S., Lawrence, M. et al. The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study. Intensive Care Med 42, 1990–1998 (2016). https://doi.org/10.1007/s00134-016-4496-z
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DOI: https://doi.org/10.1007/s00134-016-4496-z