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 ≤50x109/L at study entry (n=85); 2) patients with baseline platelet count ≥100x109/L who developed thrombocytopenia (≤50x109/L) within 28 days (n=100); 3) patients with platelet count always ≥100x109/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, while patients without thrombocytopenia (group 3) had milder disease and lower mortality. Fibrinolysis was markedly (and similarly) depressed in groups 1 and 2 as compared to group 3. Major fibrinolytic changes included increased levels of plasminogen activator inhibitor 1 (PAI-1) and extensive activation/consumption of thrombin activatable fibrinolysis inhibitor (TAFI). Most fibrinolytic variables were significantly associated with mortality in univariate models. However, only TAFI level and in vivo markers of fibrinolysis activation, namely plasmin-antiplasmin complex (PAP), and D-dimer, were independently associated with mortality after adjustment for SAPSII score, sex and platelet count. Moreover, the coexistence of impaired fibrinolysis and low platelet count greatly raised the mortality rate. Conclusions: Impaired fibrinolysis, mainly driven by PAI-1 increase and TAFI activation, is an early manifestation of sepsis and may precede the development of thrombocytopenia. TAFI level, in particular, proved to be an independent predictor of mortality, which may improve risk stratification of patients with severe sepsis.