• 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, and Luciano Gattinoni.
• Dipartimento di Scienze e Biomediche ed Oncologia Umana, Università degli Studi di Bari Aldo Moro, Bari, Italy.
• Crit. Care Med. 2018 Mar 1; 46 (3): e221-e228.

ObjectiveThrombocytopenia 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.DesignNested 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).SettingForty ICUs in Italy.PatientsThree 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).InterventionsFibrinolytic variables, including fibrinolysis inhibitors and in vivo markers of plasmin generation, were measured on day 1.Measurements And Main ResultsPatients 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.ConclusionsImpaired 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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