Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis

Fabrizio Semeraro, Mario Colucci, Pietro Caironi, Serge Masson, Concetta T Ammollo, Roberto Teli, Nicola Semeraro, Michela Magnoli, Giovanni Salati, Michele Isetta, Mauro Panigada, Tommaso Tonetti, Gianni Tognoni, Roberto Latini, Antonio Pesenti, Luciano Gattinoni

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis.

DESIGN: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial).

SETTING: Forty ICUs in Italy.

PATIENTS: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95).

INTERVENTIONS: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1.

MEASUREMENTS AND MAIN RESULTS: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality.

CONCLUSIONS: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

Original languageEnglish
Pages (from-to)e221-e228
JournalCritical Care Medicine
Volume46
Issue number3
DOIs
Publication statusPublished - Mar 2018

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Sepsis
Blood Platelets
Carboxypeptidase B2
Fibrinolysis
Mortality
Platelet Count
Thrombocytopenia
Fibrinolysin
Plasminogen Activator Inhibitor 1
Albumins
Hemostatic Disorders
Antifibrinolytic Agents
Septic Shock
Italy
Multicenter Studies
Randomized Controlled Trials

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Semeraro, F., Colucci, M., Caironi, P., Masson, S., Ammollo, C. T., Teli, R., ... Gattinoni, L. (2018). Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis. Critical Care Medicine, 46(3), e221-e228. https://doi.org/10.1097/CCM.0000000000002919

Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis. / Semeraro, Fabrizio; Colucci, Mario; Caironi, Pietro; Masson, Serge; Ammollo, Concetta T; Teli, Roberto; Semeraro, Nicola; Magnoli, Michela; Salati, Giovanni; Isetta, Michele; Panigada, Mauro; Tonetti, Tommaso; Tognoni, Gianni; Latini, Roberto; Pesenti, Antonio; Gattinoni, Luciano.

In: Critical Care Medicine, Vol. 46, No. 3, 03.2018, p. e221-e228.

Research output: Contribution to journalArticle

Semeraro, F, Colucci, M, Caironi, P, Masson, S, Ammollo, CT, Teli, R, Semeraro, N, Magnoli, M, Salati, G, Isetta, M, Panigada, M, Tonetti, T, Tognoni, G, Latini, R, Pesenti, A & Gattinoni, L 2018, 'Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis', Critical Care Medicine, vol. 46, no. 3, pp. e221-e228. https://doi.org/10.1097/CCM.0000000000002919
Semeraro F, Colucci M, Caironi P, Masson S, Ammollo CT, Teli R et al. Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis. Critical Care Medicine. 2018 Mar;46(3):e221-e228. https://doi.org/10.1097/CCM.0000000000002919
Semeraro, Fabrizio ; Colucci, Mario ; Caironi, Pietro ; Masson, Serge ; Ammollo, Concetta T ; Teli, Roberto ; Semeraro, Nicola ; Magnoli, Michela ; Salati, Giovanni ; Isetta, Michele ; Panigada, Mauro ; Tonetti, Tommaso ; Tognoni, Gianni ; Latini, Roberto ; Pesenti, Antonio ; Gattinoni, Luciano. / Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis. In: Critical Care Medicine. 2018 ; Vol. 46, No. 3. pp. e221-e228.
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AU - Semeraro, Fabrizio

AU - Colucci, Mario

AU - Caironi, Pietro

AU - Masson, Serge

AU - Ammollo, Concetta T

AU - Teli, Roberto

AU - Semeraro, Nicola

AU - Magnoli, Michela

AU - Salati, Giovanni

AU - Isetta, Michele

AU - Panigada, Mauro

AU - Tonetti, Tommaso

AU - Tognoni, Gianni

AU - Latini, Roberto

AU - Pesenti, Antonio

AU - Gattinoni, Luciano

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N2 - OBJECTIVE: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis.DESIGN: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial).SETTING: Forty ICUs in Italy.PATIENTS: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95).INTERVENTIONS: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1.MEASUREMENTS AND MAIN RESULTS: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality.CONCLUSIONS: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

AB - OBJECTIVE: Thrombocytopenia is the most common hemostatic disorder during sepsis and is associated with high mortality. We examined whether fibrinolytic changes precede incident thrombocytopenia and predict outcome in patients with severe sepsis.DESIGN: Nested study from the multicenter, randomized, controlled trial on the efficacy of albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial).SETTING: Forty ICUs in Italy.PATIENTS: Three groups of patients were selected: 1) patients with platelet count less than or equal to 50 × 10/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 10/L who developed thrombocytopenia (≤ 50 × 10/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 10/L (n = 95).INTERVENTIONS: Fibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1.MEASUREMENTS AND MAIN RESULTS: Patients with early thrombocytopenia (group 1) and those who developed it later (group 2) had similar illness severity and 90-day mortality, whereas patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared with group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor. Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only thrombin activatable fibrinolysis inhibitor level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex, and D-dimer, were independently associated with mortality after adjustment for Simplified Acute Physiology Score-II score, sex, and platelet count. Furthermore, the coexistence of impaired fibrinolysis and low platelets was associated with an even greater mortality.CONCLUSIONS: Impaired fibrinolysis, mainly driven by plasminogen activator inhibitor-1 increase and thrombin activatable fibrinolysis inhibitor activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. Thrombin activatable fibrinolysis inhibitor level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.

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