Intraprocedural Thrombotic Events during Percutaneous Coronary Intervention Due to Acquired Antithrombin Deficiency-related Heparin Resistance Successfully Treated with Antithrombin Gamma Supplementation.

A 75-year-old man receiving treatment for necrotizing pancreatitis developed septic disseminated intravascular coagulation and acute coronary syndrome (ACS). During percutaneous coronary intervention (PCI), a large amount of fresh thrombi appeared after balloon dilatation for the ACS-culprit lesion. Given the low plasma antithrombin (AT) activity and poorly prolonged activated clotting time (ACT), we suspected that acquired AT deficiency-related heparin resistance (HR) was responsible for the thrombus formation. Administration of AT gamma markedly improved ACT, and we successfully completed PCI. We suggest that AT gamma be considered a treatment option for AT deficiency-related HR and subsequent intraprocedural thrombotic events.

Impact of Antithrombin Activity Levels Following Recombinant Antithrombin Gamma Therapy in Patients with Sepsis-Induced Disseminated Intravascular Coagulation.

Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels <70% were treated with rAT between May 2018 and December 2020. The recovery rates from DIC were 32.2% and 63.3% on day 3 and 5 post administration, respectively. Recovery and survival rates were significantly higher in patients who achieved AT activity ≥70% or 80% on day 3 post administration. Receiver operating characteristic curve analysis revealed that the cutoff values of post-treatment AT activity on day 3 for 28-day survival and 5-day recovery from DIC were 79.5% and 81.5%, respectively. Patients who did not achieve AT activity ≥80% on day 3 presented a lower base level of AT activity and lower dose supplementation. Our results suggest that targeted AT activity should be at least 70%, and ideally 80%, and sufficient doses to maintain this activity are required to achieve better outcomes.

A randomized phase 3 trial evaluating antithrombin gamma treatment in Japanese patients with early-onset severe preeclampsia (KOUNO-TORI study): Study protocol.

INTRODUCTION: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. Several studies have demonstrated the beneficial effects of antithrombin replacement in patients with preeclampsia. Here, we describe the study protocol of KOUNO-TORI (KW-3357 randOmized, mUlti-center, double-bliNd, placebO-controlled phase 3 sTudy in patients with early Onset pReeclampsIa) to evaluate recombinant human antithrombin gamma (rhAT-gamma) for the treatment of early-onset severe de novo preeclampsia. MATERIAL AND METHODS: Patients with early-onset severe de novo preeclampsia who are ≥24 to <32 weeks pregnant at the time of registration and have an antithrombin activity of ≤100% at screening are included. The target population is selected based on a reanalysis of the data of a previous plasma-derived antithrombin phase 3 study. Primary endpoint is the prolongation of pregnancy from the initiation of rhAT-gamma treatment to the pregnancy termination. Secondary endpoints include gestational age in terms of achievement of 32- and 34-weeks'gestation, and gestational age in terms of achievement of 28 weeks' gestation for patients enrolled at <28 weeks' gestation. Maternal, fetal, and neonatal outcomes will be assessed. DISCUSSION: As we have selected a specifically defined target population based on reanalysis of data of a previous plasma-derived antithrombin phase 3 study, the results of our study are expected to provide efficacy and safety data concerning rhAT-gamma treatment in Japanese patients. This study could help identify an effective novel treatment for such patients with early-onset severe preeclampsia for whom appropriate treatment is unavailable.

Comparison of Protective Effects of Recombinant Antithrombin Gamma and Plasma-Derived Antithrombin on Sepsis-Induced Disseminated Intravascular Coagulation and Multiple Organ Failure.

In Japan, the dose of the new recombinant antithrombin III concentrate (rAT-gamma) is titrated according to patient body weight (BW), while conventional plasma-derived antithrombin concentrates (AT) are administered as a fixed dose. Therefore, it is anticipated that rAT-gamma could produce better treatment effects than AT. The aim of this study was to compare the organ protective effects of doses of rAT-gamma and AT administered in clinical practice for septic disseminated intravascular coagulation (DIC) and multiple organ failure. This study was performed at a single university hospital in Japan. A total of 49 patients with antithrombin deficiency secondary to septic DIC who were administered either rAT-gamma (n = 26) or AT (n = 23) were retrospectively analyzed to assess the dose of supplemental antithrombin concentrates, plasma antithrombin activity, Japanese Association for Acute Medicine (JAAM)-DIC score, and modified Sequential Organ Failure Assessment (SOFA) score on days 0, 3 and 6. The AT-equivalent dose per kg BW of rAT-gamma (equal to the initial rAT-gamma dose per kg BW divided by 1.2) was significantly higher than the dose per kg BW of AT (AT 23.4 ± 5.1 vs. rAT 28.9 ± 3.9 IU/kg/day; P < 0.001). Consequently, serial increases in plasma antithrombin levels occurred more rapidly in the rAT-gamma group (P = 0.036). JAAM DIC and modified SOFA scores revealed significantly greater improvement in the rAT versus the AT group (JAAM DIC score: P = 0.042, mSOFA score: P = 0.005). The results of this study suggest that AT supplementation adjusted for patient BW might further improve septic DIC and multiple organ failure.

Antithrombin gamma attenuates macrophage/microglial activation and brain damage after transient focal cerebral ischemia in mice.

AIMS: Thrombin formation is increased in patients with acute cerebral ischemic stroke, and augments coagulation and inflammation in the brain. Administration of antithrombin (AT) was previously reported to be protective against renal and myocardial ischemic injury. Thus, we hypothesized that treatment with AT would be neuroprotective against cerebral ischemic injury. This study evaluated the effects of AT treatment on ischemic inflammation and brain damage in mice subjected to middle cerebral artery occlusion (MCAO). MAIN METHODS: A mouse model of 4-hour MCAO was used to induce ischemic brain injury. Recombinant AT gamma was administered intravenously immediately after reperfusion at 4 h after MCAO. Infarct volume, neurological deficit, and regional cerebral blood flow (rCBF) were measured at 24 h after MCAO. To evaluate the effect of AT gamma on ischemic inflammation, we measured the number of Iba1-positive cells (marker of macrophage/microglial activation) and levels of proinflammatory cytokines. Further, we investigated the direct anti-inflammatory effects of rAT in the J774.1 cell line. KEY FINDINGS: Treatment with AT gamma (480 U/kg) reduced infarct volume and neurological deficit, and improved rCBF, in MCAO mice. Moreover, AT gamma treatment decreased the number of Iba1-positive cells and levels of proinflammatory cytokines. In vitro, treatment with thrombin significantly increased proinflammatory cytokine levels, which was significantly reduced by pretreatment with AT gamma. SIGNIFICANCE: Treatment with AT showed neuroprotective effects via anticoagulation actions, as well as direct anti-inflammatory effects on macrophage/microglial activation. These data suggest that AT may be a useful new therapeutic option for cerebral ischemia.