An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature.

BACKGROUND: Administration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet. CASE PRESENTATION: We report a series of 8 patient's TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC. Using plasma samples from clinical studies conducted from May 2016-March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors. CONCLUSIONS: Plasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation.

Leukocyte-derived extracellular DNA contributes to abnormal pressure elevation in the extracorporeal circulation circuit.

An abnormal elevation in pressure is a serious complication involving the extracorporeal circulation circuit. Clot formation might be associated with this complication, but the precise mechanism of an abnormal elevation in pressure has not been identified. We investigated sufficient conditions for in-circuit elevation in pressure using an ex vivo re-circulation circuit with porcine blood. Specifically, we investigated the effect of blood conditions, the type of anticoagulation, and pro-inflammatory stimulation on in-circuit pressure. We also examined the cause of an abnormal elevation of in-circuit pressure by specifically degrading DNA, RNA, or protein components of an obstructed filter and by using immunofluorescent techniques. Neither a change in temperature nor change in pH in the blood increased in-circuit pressure. In contrast, long-term storage of blood, pro-inflammatory stimulation by phorbol myristate acetate, and heparin administration significantly increased in-circuit pressure. Abnormal in-circuit elevation in pressure was associated with deposition of extracellular DNA on the outlet surface of the filter. Administration of DNase resulted in a rapid decline of in-circuit pressure. In an ex vivo re-circulation circuit system, extracellular DNA deposition on the filter is responsible for an abnormal in-circuit elevation in pressure. Senescent leukocytes, stimulated leukocytes, and heparin exposure are associated with extracellular DNA deposition.

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been used for the treatment of disseminated intravascular coagulation in Japan, and an international phase III clinical trial for rTM is currently in progress. rTM mainly exerts its anticoagulant effects through an activated protein C (APC)-dependent mechanism, but the circulating APC levels after rTM treatment have not been clarified. This prospective observational study investigated plasma APC levels after rTM treatment. METHODS: Plasma levels of soluble thrombomodulin, thrombin-antithrombin complex (TAT), protein C, and APC were measured in eight septic patients treated with rTM. APC generation in vitro was assessed in the presence or absence of rTM. RESULTS: rTM significantly increased thrombin-mediated APC generation in vitro. In septic patients, soluble thrombomodulin levels were significantly increased during a 30-60-min period of rTM treatment and TAT levels were decreased. However, APC activity was not increased during the treatment period. CONCLUSIONS: Plasma APC activity is not increased in septic patients treated with rTM. It is possible that APC acts locally and does not circulate systemically.

Work of breathing using different interfaces in spontaneous positive pressure ventilation: helmet, face-mask, and endotracheal tube.

PURPOSE: Noninvasive positive pressure ventilation (NPPV) using a helmet is expected to cause inspiratory trigger delay due to the large collapsible and compliant chamber. We compared the work of breathing (WOB) of NPPV using a helmet or a full face-mask with that of invasive ventilation by tracheal intubation. METHODS: We used a lung model capable of simulating spontaneous breathing (LUNGOO; Air Water Inc., Japan). LUNGOO was set at compliance (C) = 50 mL/cmH2O and resistance (R) = 5 cmH2O/L/s for normal lung simulation, C = 20 mL/cmH2O and R = 5 cmH2O/L/s for restrictive lung, and C = 50 mL/cmH2O and R = 20 cmH2O/L/s for obstructive lung. Muscle pressure was fixed at 25 cmH2O and respiratory rate at 20 bpm. Pressure support ventilation and continuous positive airway pressure were performed with each interface placed on a dummy head made of reinforced plastic that was connected to LUNGOO. We tested the inspiratory WOB difference between the interfaces with various combinations of ventilator settings (positive end-expiratory pressure 5 cmH2O; pressure support 0, 5, and 10 cmH2O). RESULTS: In the normal lung and restrictive lung models, WOB decreased more with the face-mask than the helmet, especially when accompanied by the level of pressure support. In the obstructive lung model, WOB with the helmet decreased compared with the other two interfaces. In the mixed lung model, there were no significant differences in WOB between the three interfaces. CONCLUSION: NPPV using a helmet is more effective than the other interfaces for WOB in obstructive lung disease.