BackgroundRecombinant 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.MethodsPlasma 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.ResultsrTM 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.ConclusionsPlasma APC activity is not increased in septic patients treated with rTM. It is possible that APC acts locally and does not circulate systemically.Electronic supplementary materialThe online version of this article (10.1186/s12959-018-0178-0) contains supplementary material, which is available to authorized users.

NPPV using a helmet is more effective than the other interfaces for WOB in obstructive lung disease.

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.

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Abstract 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.Objective: 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.Methods: 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.Results: 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.

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.Cardiopulmonary bypass (CPB) is important in maintaining the circulation and respiration during cardiac surgery. Abnormal elevation in pressure is a serious complication of CPB and has been reported in 0.03-4.3% cases of CPB 1-9 . This abnormal elevation in pressure has been termed abnormal inlet pressure elevation 1 , abnormal pressure gradient 2 , high-pressure excursion 3 , increased resistance in the oxygenator 4 , oxygenator failure 5,6 , increased internal pressure levels 7 , and oxygenator thrombosis 8 .Abnormal elevation in pressure may occur at three narrowed sections in CPB equipment, including the venous reservoir, oxygenator, and arterial line filter. Previous studies have suggested risk factors for an abnormal elevation in pressure in CPB, such as older age 2 , male sex 1,3 , coronary artery disease 1-3,10 , and polycythemia vera 11 . Hypothermia and alkalemia might also be associated with an abnormal elevation in pressure, although these factors are not sufficient by themselves 3,9 . Fibrin deposition inside CPB equipment might be involved in the underlying mechanism 1,2,6,9,10,12 . However, whether intensification of anticoagulation can ameliorate an abnormal elevation in pressure is unclear because most patients have already received a large amount of unfractionated heparin 1,2,11,12 . Therefore, the precise mechanism of an abnormal elevation in pressure during CPB is unknown.To determine the underlying mechanisms of an abnormal elevation in pressure during CPB, we developed an extracorporeal recirculation circuit in which in-circuit pressure cou...