Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients

Abstract

Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.

Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation

“…Although reduced activity of antithrombin is usually viewed as one of the diagnostic indicators of DIC (5,6), this ®nding is not speci®c to DIC in septic patients. The measurement of selected inhibitors of coagulation, including antithrombin and protein C, provide more useful prognostic information for these patients (3,4,13). This is the ®rst report to demonstrate that the markedly reduced plasma activity of antithrombin and protein C is not due to consumption coagulopathy in septic patients with DIC.…”

“…Sepsis is another important underlying disease responsible for DIC, and the most striking reduction in plasma antithrombin activity is often observed in septic patients with DIC (12,13). In this paper, we have attempted to clarify the etiology of this reduced antithrombin activity in septic patients with DIC, speci®cally investigating whether the decrease in plasma antithrombin activity is due to consumption coagulopathy.…”

Antithrombin and mortality in severe pneumonia patients with sepsis‐associated disseminated intravascular coagulation: an observational nationwide study

“…DIC is characterized by reduced levels of endogenous coagulation inhibitors such as antithrombin (AT). A previous study suggested that marked reductions in serum AT levels are associated with unfavorable outcomes in septic patients [8]. Therefore, therapeutic supplementation of AT was suggested for severe sepsis and septic shock in the 1990s [9][10][11].…”

Tissue factor‐dependent blood coagulation is enhanced following delivery irrespective of the mode of delivery

“…It is of interest that in the present study FVIIa levels rose in parallel with levels of TF. One would expect FVIIa to decrease due to the formation of the FVIIa-TF complex, as seen in sepsis [18,19]. Of relevance, Kondo et al [20] found the FVIIa-TF complex to be inhibited by a placental anticoagulant protein.…”