Hypercoagulability indicated by elevated blood TFPI (tissue factor pathway inhibitor) levels is closely related to severity of septic patients with glucose intolerance

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Background and purpose

Hypercoagulability and endothelial cell activation and/or injury are mutually related and often found in acutely ill septic patients, and recently they have been reported to be related to multiple organ dysfunction syndromes (MODS).It is not clear, however, which parameters indicating coagulopathy are most closely related to MODS. In this report, we analyze correlations among the severity of the illness including MODS and parameters related to coagulopathy including TFPI in acutely ill septic patients, in order not only to ascertain their close relationships but also to find sensitive and predictive markers of the severity of septic patients.

Materials and methods

Five acutely ill septic patients with glucose intolerance were analyzed. Their blood glucose levels were strictly controlled by means of a bedside-type artificial pancreas (AP), STG-22, manufactured by NIKKISOH corporation in Japan. We selected septic patients in whom blood glucose levels were strictly controlled with STG-22, because some parameters related to coagulopathy, including Plasminogen Activator Inhibitor-1 (PAI-1), are influenced by blood glucose levels.

Analyzed items were: (1) regarding the severity of the illness, MOF score as the indicator of the degree of MODS (calculated from the MOF criteria of Japanese Association for Critical Care Medicine), blood thrombomodulin (TM) levels as the indicator of endothelial cell injury; (2) regarding coagulopathy, disseminated intravascular coagulation (DIC) score (calculated from the DIC criteria of the Ministry and Welfare of Japan), platelet count (PLT), fibrinogen, FDP, prothrombin time, TAT, D-dimer, PIC, plasminogen (PLG), Antithrombin (AT), Protein C activity, protein S activity, total PAI-1, tissue plasminogen activator (tPA)-PAI-1 complex, and total TFPI; (3) regarding glucose tolerance, daily mean blood glucose level(BSm), M value (measured by the euglycemic hyperinsulinemic glucose clamp method with AP. The clamped blood glucose level was 80 mg/dl, with the insulin infusion rate of 1.12 mU/kg.min normal range 5–10 mg/kg.min).

Results

(1) Mean of M value and BSm measured within a few days of admission (and during ICU stay) were 4.7± 2.7 mg/kg.min (n=4), 176± 10.7 mg/dl (n=5) [5.7± 3.1 mg/kg.min (n=12), 183.4± 19.4 mg/dl (n=65)], respectively. (2) There was strong positive relationship between MOF score and TM (correlation coefficient r=0.95, n=32, P<0.005). (3) MOF score was correlated with TFPI (r=0.91, n=30), PLT (0.85, n=78), DIC score (0.84, n=78), tPA-PAI (0.76, n=33), AT (0.66, n=32), PLG (0.65, n=33), and PIC (0.53, n=33), (P<0.005).(4) TM was correlated with TFPI (0.89, n=29), tPA-PAI (0.79, n=32), PLT (0.77, n=32), DIC score (0.75, n=32), PLG(0.63, n=32), PIC (0.58, n=32), (P<0.005). (5) DIC score was correlated with PLT (0.73, n=78), TFPI (0.72, n=30), tPA-PAI (0.69, n=33), AT (0.61, n=32), (P<0.005). (6) TFPI was correlated with tPA-PAI (0.76, n=30), PLT (0.70, n=30), PIC (0.50, n=30), (P<0.005).

Interpretation and conclusions

The severity of disease in acutely ill septic patients, indicated by the progression of MODS and endothelial cell injury, was closely related to coagulopathy characterized by hypercoagulability with decreased fibrinolysis. Treatment for hypercoagulability seemed to be justified in severely septic patients. Although the mechanism was unclear, TFPI, which seemed to be a parameter of hypercoagulability and endothelial cell activation, was thought to be a sensitive and possibly predictive marker of the disease severity in septic patients.