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Published in: Critical Care 1/2020

01-12-2020 | Septicemia | Research

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock

Authors: Klaus Stahl, Julius J. Schmidt, Benjamin Seeliger, Bernhard M. W. Schmidt, Tobias Welte, Hermann Haller, Marius M. Hoeper, Ulrich Budde, Christian Bode, Sascha David

Published in: Critical Care | Issue 1/2020

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Abstract

Background

A dysbalanced coagulation system is part of the pathological host response to infection in sepsis. Activation of pro-coagulant pathways and attenuation of anti-coagulant activity ultimately lead to microvascular stasis and consequent organ failure. No treatment approaches specifically targeting this axis are available. We explored the effects of therapeutic plasma exchange (TPE) on microvascular coagulation dysbalance in septic shock.

Methods

We conducted a prospective single-center study enrolling 31 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE > 0.4 μg/kg/min). Clinical and biochemical data, including measurement of protein C; a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13); and von Willebrand factor antigen (vWF:Ag), were obtained before and after TPE against fresh frozen plasma.

Results

Antithrombotic acting proteins such as antithrombin-III (ATIII) and protein C were markedly reduced in septic patients, but their activity increased after TPE (ATIII, 51% (41–61) vs. 63% (48–70), p = 0.029; protein C, 47% (38–60) vs. 62% (54–69), p = 0.029). Median ADAMTS13 activity was increased by TPE from 27 (21–42) % before to 47 (38–62) % after TPE (p < 0.001). In contrast, vWF:Ag was elevated and could be reduced by TPE (353 (206–492) IU/dL vs. 170 (117–232) IU/dL, p < 0.001). Regression analysis yielded a correlation between ADAMTS13 activity and platelet count (p = 0.001, R2 = 0.316).

Conclusions

Septic shock was associated with activation of pro-coagulant pathways and simultaneous depletion of anti-coagulant factors. TPE partially attenuated this dysbalance by removing pro- and by replacing anti-coagulant factors.

Trial registration

ClinicalTrials.gov, NCT03065751. Retrospectively registered on 28 February 2017.
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Literature
1.
go back to reference 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.CrossRef 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.CrossRef
2.
go back to reference Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007;33(4):606–18.CrossRef Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007;33(4):606–18.CrossRef
3.
go back to reference Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(21):2063.PubMed Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(21):2063.PubMed
4.
go back to reference Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101(10):3765–77.CrossRef Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101(10):3765–77.CrossRef
5.
go back to reference Powars D, Larsen R, Johnson J, Hulbert T, Sun T, Patch MJ, et al. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis. 1993;17(2):254–61.CrossRef Powars D, Larsen R, Johnson J, Hulbert T, Sun T, Patch MJ, et al. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis. 1993;17(2):254–61.CrossRef
6.
go back to reference Lorente JA, Garcia-Frade LJ, Landin L, de Pablo R, Torrado C, Renes E, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103(5):1536–42.CrossRef Lorente JA, Garcia-Frade LJ, Landin L, de Pablo R, Torrado C, Renes E, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103(5):1536–42.CrossRef
7.
go back to reference White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood. 2000;96(12):3719–24.CrossRef White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood. 2000;96(12):3719–24.CrossRef
8.
go back to reference Knoebl P, Schellongowski P, Staudinger T, Sperr WR, Scheibenpflug C. Treatment of infection-associated purpura fulminans with protein C zymogen is associated with a high survival rate. Blood. 2013;122(21):3606.CrossRef Knoebl P, Schellongowski P, Staudinger T, Sperr WR, Scheibenpflug C. Treatment of infection-associated purpura fulminans with protein C zymogen is associated with a high survival rate. Blood. 2013;122(21):3606.CrossRef
9.
go back to reference Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709.CrossRef Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709.CrossRef
10.
go back to reference Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64.CrossRef Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366(22):2055–64.CrossRef
11.
go back to reference Crawley JT, de Groot R, Xiang Y, Luken BM, Lane DA. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood. 2011;118(12):3212–21.CrossRef Crawley JT, de Groot R, Xiang Y, Luken BM, Lane DA. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood. 2011;118(12):3212–21.CrossRef
12.
go back to reference Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488–94.CrossRef Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488–94.CrossRef
13.
go back to reference Aibar J, Castro P, Espinosa G, Fernandez S, Hernandez C, Rinaudo M, et al. ADAMTS-13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome. Shock. 2015;43(6):556–62.CrossRef Aibar J, Castro P, Espinosa G, Fernandez S, Hernandez C, Rinaudo M, et al. ADAMTS-13 in critically ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome. Shock. 2015;43(6):556–62.CrossRef
14.
go back to reference Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Losche W, et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica. 2008;93(1):137–40.CrossRef Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Losche W, et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica. 2008;93(1):137–40.CrossRef
15.
go back to reference Kremer Hovinga JA, Zeerleder S, Kessler P, Romani de Wit T, van Mourik JA, Hack CE, et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost. 2007;5(11):2284–90.CrossRef Kremer Hovinga JA, Zeerleder S, Kessler P, Romani de Wit T, van Mourik JA, Hack CE, et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost. 2007;5(11):2284–90.CrossRef
16.
go back to reference Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagulation Fibrinolysis. 2014;25(3):206–16.CrossRef Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagulation Fibrinolysis. 2014;25(3):206–16.CrossRef
17.
go back to reference Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura Y, Ishiwata A, et al. 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. 2006;107(2):528–34.CrossRef Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura Y, Ishiwata A, et al. 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. 2006;107(2):528–34.CrossRef
18.
go back to reference Peigne V, Azoulay E, Coquet I, Mariotte E, Darmon M, Legendre P, et al. The prognostic value of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency in septic shock patients involves interleukin-6 and is not dependent on disseminated intravascular coagulation. Crit Care. 2013;17(6):R273.CrossRef Peigne V, Azoulay E, Coquet I, Mariotte E, Darmon M, Legendre P, et al. The prognostic value of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency in septic shock patients involves interleukin-6 and is not dependent on disseminated intravascular coagulation. Crit Care. 2013;17(6):R273.CrossRef
19.
go back to reference Lin JJ, Chan OW, Hsiao HJ, Wang Y, Hsia SH, Chiu CH. Decreased ADAMTS 13 activity is associated with disease severity and outcome in pediatric severe sepsis. Medicine (Baltimore). 2016;95(16):e3374.CrossRef Lin JJ, Chan OW, Hsiao HJ, Wang Y, Hsia SH, Chiu CH. Decreased ADAMTS 13 activity is associated with disease severity and outcome in pediatric severe sepsis. Medicine (Baltimore). 2016;95(16):e3374.CrossRef
20.
go back to reference Claus RA, Bockmeyer CL, Budde U, Kentouche K, Sossdorf M, Hilberg T, et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost. 2009;101(2):239–47.CrossRef Claus RA, Bockmeyer CL, Budde U, Kentouche K, Sossdorf M, Hilberg T, et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost. 2009;101(2):239–47.CrossRef
21.
go back to reference Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018;22(1):285.CrossRef Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018;22(1):285.CrossRef
22.
go back to reference Sloan SR, Andrzejewski C Jr, Aqui NA, Kiss JE, Krause PJ, Park YA. Role of therapeutic apheresis in infectious and inflammatory diseases: current knowledge and unanswered questions. J Clin Apher. 2015;30(5):259–64.CrossRef Sloan SR, Andrzejewski C Jr, Aqui NA, Kiss JE, Krause PJ, Park YA. Role of therapeutic apheresis in infectious and inflammatory diseases: current knowledge and unanswered questions. J Clin Apher. 2015;30(5):259–64.CrossRef
23.
go back to reference David S, Hoeper MM, Kielstein JT. Plasma exchange in treatment refractory septic shock: presentation of a therapeutic add-on strategy. Medizinische Klinik, Intensivmedizin und Notfallmedizin. 2017;112(1):42–6.CrossRef David S, Hoeper MM, Kielstein JT. Plasma exchange in treatment refractory septic shock: presentation of a therapeutic add-on strategy. Medizinische Klinik, Intensivmedizin und Notfallmedizin. 2017;112(1):42–6.CrossRef
24.
go back to reference Cejka J. Enzyme immunoassay for factor VIII-related antigen. Clin Chem. 1982;28(6):1356–8.CrossRef Cejka J. Enzyme immunoassay for factor VIII-related antigen. Clin Chem. 1982;28(6):1356–8.CrossRef
25.
go back to reference Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost. 2008;6(5):762–71.CrossRef Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost. 2008;6(5):762–71.CrossRef
26.
go back to reference Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017;7(9):e017046.CrossRef Iba T, Nisio MD, Levy JH, Kitamura N, Thachil J. New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey. BMJ Open. 2017;7(9):e017046.CrossRef
27.
go back to reference 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.CrossRef 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.CrossRef
28.
go back to reference 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.CrossRef 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.CrossRef
29.
go back to reference Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019;17(11):1989–94.CrossRef Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019;17(11):1989–94.CrossRef
30.
go back to reference Ding R, Wang Z, Lin Y, Liu B, Zhang Z, Ma X. Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: a retrospective study. Blood Coagul Fibrinolysis. 2018;29(6):551–8.CrossRef Ding R, Wang Z, Lin Y, Liu B, Zhang Z, Ma X. Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: a retrospective study. Blood Coagul Fibrinolysis. 2018;29(6):551–8.CrossRef
Metadata
Title
Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock
Authors
Klaus Stahl
Julius J. Schmidt
Benjamin Seeliger
Bernhard M. W. Schmidt
Tobias Welte
Hermann Haller
Marius M. Hoeper
Ulrich Budde
Christian Bode
Sascha David
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2020
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-2799-5

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