Platelet Drop and Fibrinolytic Shutdown in Patients With Sepsis

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 × 109/L at study entry (n = 85); 2) patients with baseline platelet count greater than or equal to 100 × 109/L who developed thrombocytopenia (≤ 50 × 109/L) within 28 days (n = 100); 3) patients with platelet count always more than or equal to 100 × 109/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. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported by grants from the Italian Medicines Agency (AIFA, grant FARM6JS3R5, 2006), the Italian Ministry of Health (Ricerca Finalizzata 2011–2012, grant RF-2011-02348358), and by a grant from Università degli Studi di Bari Aldo Moro. Dr. Colucci received support for article research from Università degli Studi di Bari Aldo Moro (IT). Drs. Gattinoni, Masson, Teli, Magnoli, Latini, and Pesenti's institutions received funding from Italian Medicines Agency (AIFA, grant FARM6JS3R5, 2006) and Italian Ministry of Health (Ricerca Finalizzata 2011–2012, grant RF-2011-02348358). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mario.colucci@uniba.it Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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