Haemostasis Change in Intensive Care Patients with Severe Sepsis and Patients with Organ Failure without Sepsis

Despite recent advances in understanding the pathophysiology of sepsis, multiple organ failure remains one of the leading causes of death in intensive care units (ICUs). A wide range of coagulation abnormalities have been observed in patients diagnosed with severe sepsis (SS). Its magnitude in relationship to organ failure without sepsis is less well documented. In this study, we examined and compared the results of plasma levels of coagulation tests and thrombin generation (calibrated automated thrombography (CAT) in patients with sepsis, patients with organ failure (OF) without sepsis and controls. We investigated whether the CAT and procoagulant phospholipids would be good prognostic markers and whether these markers would show a significant correlation with coagulation disorders.

21 patients with severe sepsis, 24 non-sepsis patients with organ failure were compared with 30 healthy subjects as controls. The delay between the onset of SS or OF and blood sampling was less than 12 hours. Analytical determinations of prothrombin time, activated partial thromboplastin time, and the levels of factors V,VII,VIII,X antithrombin, fibrinogen, protein C, protein S, D-Dimers were analysed using the STA-R analyser (Diagnostica Stago, France), Tissue factor activity (TFa) and thrombomodulin activity (TMa) were measured with two home-test. Free tissue factor pathway inhibitor (fTFPI), Soluble endothelial protein C receptor (sEPCR), and soluble thrombomodulin antigen were measured by ELISA assays (Diagnostica Stago, France). CAT was performed on PPP using PPP-reagent 5pM (Thrombinoscope, The Netherlands). Procoagulant phospholipids (PPL) were evaluated using the STA Procoag PPL assay (Diagnostica Stago, France).

The mean levels of factors V, VII, X, antithrombin, protein S, protein C, sEPCR were decreased in both SS and OF (p<0.001) compared with controls. Protein S, factor VII and X were significantly lower in the SS group than in the OF group (p<0.05). Factor VIII, D-Di, and fibrinogen level were increased in SS and OF groups (p<0.001). Activity and antigen thrombomodulin were significantly higher in SS and OF groups (p<0.01) than in healthy subjects, with no difference between patients groups. TFa was strongly increased in SS and OF (p<0.001) and not compensated by any increase in TFPI. We also observed that TF/fTFPI ratio were significantly increased in the SS and OF groups (p<0.001). Elevated thrombin generation was observed in patients with SS and OF. In particular lag-time and time to peak were prolonged (p<0.05), peak thrombin was significantly decreased only in SS group. However the mean total amount of thrombin generated in the groups of patients by endogenous Thrombin Potential (ETP) was equivalent to healthy controls. Procoagulant phospholipids were significantly higher in SS and OF groups than controls (p<0.001 and p<0.05 respectively). Non-surviving patients showed higher ETP, D-Di, TFa, PPL than survivors in both groups (p<0.05). No difference in fTFPI levels were observed between patients with negative outcome and survivors in the two groups of patients. IL-6 levels as inflammatory status were higher in SS and OF than in healthy controls, with a more pronounced increase in SS group. The levels of IL-6 were more important in non-survivors compared with survivors (p<0.05).

This study suggests that severe septic and non septic patients with organ failure have similar coagulation abnormalities independently of the triggering event. Marked TFa generation was not adequately balanced by TFPI and inflammation may synergistically play a role in the pathogenesis of OF and death. Thrombin generation results showed that while the total amount of thrombin generated (ETP) was unchanged the initiation of thrombin generation was delayed and peak thrombin was reduced. This could be explained by the decreased levels of FVII, X, II causing a delay in the generation of thrombin. PPL and TGT may be useful in determining clinical outcome in patients and perhaps as a predictive parameter for an increased risk of bleeding or thrombotic complications in these patients. Their role to develop useful new markers in the management of patients remains to be defined.

Van Dreden:Diagnostica Stago: Employment. Woodhams:Diagnostica Stago: Employment. Lenormand:Hospital: Employment. Vasse:hospital: Employment.