Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.

There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.

Effect of antithrombin III among patients with disseminated intravascular coagulation in obstetrics: a nationwide observational study in Japan.

OBJECTIVE: Pregnant women may develop disseminated intravascular coagulation (DIC), possibly resulting in massive maternal haemorrhage and perinatal death. The Japan guideline recommends use of antithrombin III (ATIII) for DIC in obstetrics; however, its effect remains uncertain. The present study aimed to investigate the effect of ATIII for DIC in obstetrics, using a national inpatient database in Japan. DESIGN: Nationwide observational study. SETTING: Japan. POPULATION: We used the Diagnosis Procedure Combination inpatient database to identify patients who delivered at hospital and were diagnosed with DIC from July 2010 to March 2018. METHODS: Propensity score matching analyses were performed to compare in-hospital maternal mortality and hysterectomy during hospitalisation between users and non-users of ATIII on the day of delivery. MAIN OUTCOME MEASURES: In-hospital mortality, hysterectomy. RESULTS: A total of 9920 patients were enrolled, including 4329 patients (44%) who used ATIII and 5511 patients (56%) who did not use ATIII. One-to-one propensity score matching created 3290 pairs. In-hospital maternal mortality did not differ significantly between the propensity-matched groups (0.3% in the ATIII group versus 0.5% in the control group; odds ratio 0.73; 95% CI 0.35-1.54). A significantly lower proportion of patients in the ATIII group, compared with those in the control group, underwent hysterectomy during hospitalisation (5.3% versus 8.7%; absolute risk difference -2.9%; 95% CI -4.2 to -1.6%). CONCLUSIONS: Although the present study did not show a mortality-reducing effect of ATIII for patients with DIC in obstetrics, it may have clinical benefit in terms of reducing the number of patients undergoing hysterectomy. TWEETABLE ABSTRACT: This study did not show mortality-reducing effect of antithrombin III for patients with DIC in obstetrics.

Management Practices for Asparaginase-associated Coagulopathy: A Survey of Pediatric Oncologists.

BACKGROUND: Coagulopathy and thrombosis are well-described complications of asparaginase therapy. However, treatment practices in pediatric hematology/oncology (PHO) patients vary widely as evidence-based guidelines for clinical management of these complications in this population are lacking. OBJECTIVE: The objective of this study was to assess management practices of asparaginase-related coagulopathy by pediatric hematologist/oncologist attending physicians. DESIGN/METHOD: Email survey sent to 2327 PHO physicians primarily practicing in the United States. RESULTS: Two hundred eighty-five (12.2%) attending physicians completed the survey. Only 4.6% (n=13/285) routinely prescribe prophylactic anticoagulation during induction chemotherapy for leukemia. Slightly more than half (n=145/250, 50.9%) of all providers perform baseline coagulation studies. Most providers that were surveyed (n=185/285, 64.9%) only replete coagulant factors if the patient experiences bleeding or bruising. One hundred thirty (n=130/285, 45.6%) physicians replace low fibrinogen. The median fibrinogen replacement was 100 mg/dL (range: 40 to 200 mg/dL) with the median target of at least 100 mg/dL (range: 50 to 200 mg/dL). A minority of physicians (n=39/250, 13.7%) replace low antithrombin. The median antithrombin cutoff activity level was 60% (range: 40% to 100%) with a median target of 75% (range: 40% to 125%). CONCLUSIONS: There is a significant variation in PHO physician practices for monitoring and management of asparaginase-associated hemostatic derangements. Evidence-based guidelines have the potential to standardize practices.

A Retrospective Analysis of Antithrombin III Replacement Therapy for the Treatment of Hepatic Sinusoidal Obstruction Syndrome in Children Following Hematopoietic Stem Cell Transplantation.

Hepatic sinusoidal obstruction syndrome (SOS) remains a serious complication of hematopoietic stem cell transplantation (HSCT). In this single institution retrospective case series, 18 children developed SOS after HSCT. Patients were treated with antithrombin III (ATIII), defibrotide, or ATIII followed by defibrotide. Twelve of 13 patients who were treated with ATIII therapy alone had complete resolution of SOS, including 4 of 5 children with severe SOS. In this limited cohort, ATIII was safe and successfully prevented progression of hepatic SOS following HSCT in the majority of children at our center.

[Dissolution and maintenance of portal vein thrombosis with antithrombin III and edoxaban in liver cirrhosis:a case report].

A male patient in his 70s was referred to our department. He was found to have alcoholic liver cirrhosis, esophageal varices, and portal vein thrombosis. Antithrombin III (ATIII) formulation was administered. The thrombus was almost completely lysed 2 days after administration. Because portal vein thrombosis could recur, edoxaban, a direct oral anticoagulant (DOAC), was introduced to prevent recurrence. After 4 months, he showed no recurrence of portal vein thrombosis. In the present case, the combination of an ATIII formulation as initial treatment and edoxaban as maintenance therapy was safe and effective. The combination of ATIII and edoxaban may be a treatment option for patients with portal vein thrombosis.

Endothelial dysfunction a significant marker of adverse clinical outcome in patients with atrial fibrillation after cardioembolic stroke.

AIM: To study the prognostic significance of endothelial dysfunction (ED) markers in the development of adverse clinical outcome (death) in patients with atrial fibrillation (AF) within a year after cardioembolic stroke. MATERIALS AND METHODS: 260 patients with newly diagnosed (nAF), paroxysmal, persistent and permanent forms of AF who underwent stroke were included. Duration of observation-12 months. V1 - the beginning of the study: V2 - 180 (±5) days and V3 - 360 (±5) evaluated the level of von Willebrand factor (fW), antithrombin III (AT III) and plasminogen. RESULTS: During the year of follow-up, patients with AF who underwent and had a high mortality rate. During the whole period 38 (14.6%) patients died, 15 (23.0%) - in the group with nAF, 6 (9.2%) - in the group with paroxysmal AF, 7 (10.8%) - in the group with persistent AF and 10 (15.4%) - in the group with permanent AF. After a year of follow-up, the level of fW in patients with nAF was higher than in patients of all groups, and statistically significant in patients with paroxysmal and persistent forms of AF. At III was important in the group of patients with nAF and with a constant form of AF, in the same groups there was no statistically significant increase in a year of follow-up. It was found that in survivors with nAF at III (73.54±8.67%) higher (p=0.002) compared with the dead (65.77±6.01%). In the group of patients with paroxysmal AF in survivors of III (77.75±10.15%) higher (p=0.031) compared with the dead (69.25±5.80%). In patients with persistent AF, the survivors of III (76.57±9.09%) were higher (p=0.002) compared to the dead (65.60±2.21%). Taking into account the results of the analysis of the dynamics of ed markers, it can be assumed that AT III is the most accurate prognostic marker for the studied cohort of patients. CONCLUSION: Detection and correction of ED in AF in patients within a year after stroke can optimize the tactics of management of patients and improve the prognosis of the diseas.

[Pulmonary embolism in a girl with nephrotic syndrome and factor V Leiden - case report]. / Zatorowosc plucna u dziewczynki z zespolem nerczycowym i czynnikiem V Leiden ­ opis przypadku.

Thromboembolic complications are found in 2-3% of children with nephrotic syndrome (NS); this increased risk is caused by hypovolemia, hemoconcentration, increased number and activity of platelets, hyperfibrinogenemia and loss of coagulation inhibitors. Risk is even higher in case of additional factors e.g. congenital thrombophilia. CASE REPORT: Girl with NS aged 17 11/12 years was admitted to hospital due to respiratory tract infection with cough and back pain. NS started 9 months earlier and she had two bouts of disease, and was treated only with prednisone (current dose - 60 mg/48h). On admission she was without any abnormalities on auscultation, with BP 111/65 mmHg, HR 80 bpm, satO2 99%. Lab results showed the increase of WBC 18.3×103/µL, D-dimers 23038 µg/L and proteinuria 900 mg/dL. Other values of examined parameters were in normal limits. Chest X-ray and ECG were also normal. Presumptive diagnosis of pulmonary embolism was made and the patient was given 1000IU of antithrombin III and nadroparine (2x90IU/kg/24h s.c.). In ECHO the occlusion of left pulmonary artery and preserved blood flow in right were revealed. In angioCT clot nearly filling lumen of left pulmonary artery, clot in intermediate part of right pulmonary artery, and focus of pulmonary infarction in 10th segment of left lung were found. Doppler USG of lower limb veins did not reveal thrombi or perforator vein incompetence. Treatment with nadroparine was continued, and rapid improvement of clinical condition and disappearance of pain and cough were observed. Mycophenolate mofetil was added, which resulted in subsidence of proteinuria. Rivaroxaban was used in prophylaxis of recurrences of thromboembolism. Tests for thrombophilia revealed factor V Leiden in patient.

SerpinC1/Antithrombin III in kidney-related diseases.

The gene SerpinC1 encodes a serine protease inhibitor named antithrombin III (ATIII). This protease demonstrates both anticoagulant and anti-inflammatory action. ATIII is the most important coagulation factor inhibitor, and even minor changes in ATIII can significantly alter the risk of thromboembolism. ATIII can also suppress inflammation via a coagulation-dependent or -independent effect. Moreover, apart from ATIII deficiency, ATIII and its gene SerpinC1 may also be related to many diseases (e.g. hypertension, kidney diseases). The present review summarizes how ATIII affects the progress of kidney disease and its mechanism. Further studies are required to investigate how ATIII affects renal function and the treatment.

Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia.

BACKGROUND: Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. METHODS: Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression. RESULTS: Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia. CONCLUSIONS: Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients.

Antithrombin III for critically ill patients.

BACKGROUND: Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown. This review was published in 2008 and updated in 2015. OBJECTIVES: To examine:1. The effect of AT III on mortality in critically ill participants.2. The benefits and harms of AT III.We investigated complications specific and not specific to the trial intervention, bleeding events, the effect on sepsis and disseminated intravascular coagulation (DIC) and the length of stay in the intensive care unit (ICU) and in hospital in general. SEARCH METHODS: We searched the following databases from inception to 27 August 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid SP), EMBASE (Ovid SP,), CAB, BIOSIS and CINAHL. We contacted the main authors of trials to ask for any missed, unreported or ongoing trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We contacted the investigators and the trial authors in order to retrieve missing data. In this updated review we include trials only published as abstracts. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was mortality. Two authors each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetrics, and paediatrics), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed trial sequential analysis (TSA) to establish the implications for further research. MAIN RESULTS: We included 30 RCTs with a total of 3933 participants (3882 in the primary outcome analyses).Combining all trials, regardless of bias, showed no statistically significant effect of AT III on mortality with a RR of 0.95 (95% CI 0.88 to 1.03), I² statistic = 0%, fixed-effect model, 29 trials, 3882 participants, moderate quality of evidence). For trials with low risk of bias the RR was 0.96 (95% Cl 0.88 to 1.04, I² statistic = 0%, fixed-effect model, 9 trials, 2915 participants) and for high risk of bias RR 0.94 (95% Cl 0.77 to 1.14, I² statistic = 0%, fixed-effect model, 20 trials, 967 participants).For participants with severe sepsis and DIC the RR for mortality was non-significant, 0.95 (95% Cl 0.88 to 1.03, I² statistic = 0%, fixed-effect model, 12 trials, 2858 participants, moderate quality of evidence).We conducted 14 subgroup and sensitivity analyses with respect to the different domains of risk of bias, but detected no statistically significant benefit in any subgroup analyses.Our secondary objective was to assess the benefits and harms of AT III. For complications specific to the trial intervention the RR was 1.26 (95% Cl 0.83 to 1.92, I² statistic = 0%, random-effect model, 3 trials, 2454 participants, very low quality of evidence). For complications not specific to the trial intervention, the RR was 0.71 (95% Cl 0.08 to 6.11, I² statistic = 28%, random-effects model, 2 trials, 65 participants, very low quality of evidence). For complications other than bleeding, the RR was 0.72 ( 95% Cl 0.42 to 1.25, I² statistic = 0%, fixed-effect model, 3 trials, 187 participants, very low quality of evidence). Eleven trials investigated bleeding events and we found a statistically significant increase, RR 1.58 (95% CI 1.35 to 1.84, I² statistic = 0%, fixed-effect model, 11 trials, 3019 participants, moderate quality of evidence) in the AT III group. The amount of red blood cells administered had a mean difference (MD) of 138.49 (95% Cl -391.35 to 668.34, I² statistic = 84%, random-effect model, 4 trials, 137 participants, very low quality of evidence). The effect of AT III in patients with multiple organ failure (MOF) was a MD of -1.24 (95% Cl -2.18 to -0.29, I² statistic = 48%, random-effects model, 3 trials, 156 participants, very low quality of evidence) and for patients with an Acute Physiology and Chronic Health Evaluation score (APACHE) at II and III the MD was -2.18 (95% Cl -4.36 to -0.00, I² statistic = 0%, fixed-effect model, 3 trials, 102 participants, very low quality of evidence). The incidence of respiratory failure had a RR of 0.93 (95% Cl 0.76 to 1.14, I² statistic = 32%, random-effects model, 6 trials, 2591 participants, moderate quality of evidence). AT III had no statistically significant impact on the duration of mechanical ventilation (MD 2.20 days, 95% Cl -1.21 to 5.60, I² statistic = 0%, fixed-effect model, 3 trials, 190 participants, very low quality of evidence); on the length of stay in the ICU (MD 0.24, 95% Cl -1.34 to 1.83, I² statistic = 0%, fixed-effect model, 7 trials, 376 participants, very low quality of evidence) or on the length of stay in hospital in general (MD 1.10, 95% Cl -7.16 to 9.36), I² statistic = 74%, 4 trials, 202 participants, very low quality of evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to support AT III substitution in any category of critically ill participants including the subset of patients with sepsis and DIC. We did not find a statistically significant effect of AT III on mortality, but AT III increased the risk of bleeding events. Subgroup analyses performed according to duration of intervention, length of follow-up, different patient groups, and use of adjuvant heparin did not show differences in the estimates of intervention effects. The majority of included trials were at high risk of bias (GRADE; very low quality of evidence for most of the analyses). Hence a large RCT of AT III is needed, without adjuvant heparin among critically ill patients such as those with severe sepsis and DIC, with prespecified inclusion criteria and good bias protection.

Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis.

OBJECTIVE: To characterize features of antithrombin concentrate (ATC) use in children receiving unfractionated heparin (UFH) therapy for acute thrombosis. STUDY DESIGN: All pediatric patients at Texas Children's Hospital who received ATC in the context of UFH therapy for acute thrombosis during February 2011 to May 2013 were analyzed. RESULTS: Fifty-one children received ATC during UFH therapy for acute thrombosis. Median age was 3 months (IQR 1 to 18 months). Clinical indications included venous (53%), arterial (37%), venous and arterial (6%), and intracardiac (4%) thrombosis. Median baseline antithrombin (AT) level was 61% and UFH dose was 26 U/kg/h. The median dose of ATC was 49.9 IU/kg (IQR 32.6 to 50.0 IU/kg). Although most patients (86%) did not undergo a change in UFH dose, there was a significant increase in both AT and anti-factor Xa level after the first dose of ATC (P < .001 for both). There was no correlation between ATC dose or increment in AT level above baseline and the achievement of targeted anticoagulation by anti-factor X activity level. Adverse bleeding events occurred in 10% of patients. CONCLUSIONS: There was a significant change in AT and anti-factor Xa activity level after a single dose of ATC despite little to no change in dose of UFH. ATC appears to facilitate anticoagulation with UFH in some children with acute thrombosis but the degree of response is variable and dependent on factors identified in this study. Bleeding and other theoretical risks must be carefully considered.

Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation.

BACKGROUND: Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy. OBJECTIVES: We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT. SEARCH METHODS: We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results. AUTHORS' CONCLUSIONS: There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.

Administration of antithrombin III attenuates posthepatectomy liver failure in hepatocellular carcinoma.

BACKGROUND/AIMS: Coagulopathy can cause disseminated intravascular coagulation and posthepatectomy liver failure. Posthepatectomy liver failure predicts a poor prognosis after hepatectomy for hepatocellular carcinoma. Although antithrombin III reduces hypercoagulation, the impact of postoperative antithrombin III administration remains unknown. The aim of this study was to determine whether postoperative antithrombin III administration protects against the development of coagulation disorders. METHODS: Data from 164 patients who received antithrombin III and 169 who did following curative hepatectomy for hepatocellular carcinoma were retrospectively collected and analyzed. To overcome bias due to different distributions of covariates for the two groups, a one-to-one match was created using propensity score analysis. After matching, patient outcomes were analyzed. RESULTS: A multivariate analysis of the whole group revealed that antithrombin III activity of <50% on postoperative day 1 was an independent risk factor for posthepatectomy liver failure. After one-to-one matching, the rate of posthepatectomy liver failure was significantly lower in the AT-III-treated group than in the non-AT-III-treated group (16.3% (7/43) vs. 44.2% (19/43), p < 0.01). CONCLUSIONS: Antithrombin III may attenuate posthepatectomy liver failure in hepatocellular carcinoma, possibly by suppressing coagulopathy.

Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

Retrospective evaluation of antithrombin III supplementation in neonates and infants receiving enoxaparin for treatment of thrombosis.

BACKGROUND: Thromboembolic events are occurring at increasing rates in neonates and infants. At Children's Mercy Hospitals and Clinics, antithrombin III (AT3) concentrates are often used in combination with enoxaparin to supplement physiologically low AT3 levels. Theoretically, AT3 enhances the anticoagulant activity of enoxaparin and results in decreased time to therapeutic anti-Xa levels. No data exist on use of AT3 for this indication. PROCEDURE: This retrospective study compared time to therapeutic anti-Xa levels in patients <1 year of age receiving enoxaparin with AT3 (Group 1) and without AT3 (Group 2) for treatment of thrombosis. Primary objective was to compare time to therapeutic anti-Xa levels (0.5-1 U/ml) between groups. Secondary objectives included comparison of the initial and therapeutic dose of enoxaparin, enoxaparin dose changes, AT3 supplementation, and level monitoring. Bleeding events and cost were also evaluated. Statistical tests included Schuirmann's two one-sided tests for equivalence and general linear models/logistic regression for independent effects of age, critical illness, and timing of AT3. RESULTS: Mean time to therapeutic anti-Xa levels were not equivalent between Groups 1 and 2 (80.7 vs. 65.2 hours; P = 0.28). Initial enoxaparin dose and number of dose changes were equivalent. Group 1 required higher doses of enoxaparin to achieve therapeutic anti-Xa levels. Age, critical illness, and timing of AT3 had no effect on time to therapeutic anti-Xa levels. Bleeding events were not equivalent between Groups 1 and 2 (14.3% vs. 3.9%; P = 0.55). CONCLUSION: Supplementation with AT3 did not decrease time to therapeutic anti-Xa levels, added significant cost, and was associated with increased bleeding events.

[Therapy with high-doses of antithrombin III in patients with septic shock and agranulocytosis].

OBJECTIVE: The aim of the study was to assess efficacy of high-doses ofantithrombin 111 (AT) for treatment of septic shock in patients with an agranulocytosis. DESIGN: Prospective, controlled study. PATIENTS: 29 patients from 18 to 74 years old, with blood diseases complicated with septic shock Dates of study: from 2006 to 2012. METHODS: The patients were randomized into two groups. Group-1 included 14 patients, who did not receive AT and group-2 included 15 patients who received AT. RESULTS: Demographic indicators, condition severity according to APACHE II, level of thrombocytopenia, levels ofplasma procalcitonin, interleukin-6 (IL-6) and C-reactive protein (CRP) were the same in both groups. Level of AT was decreased in both groups; however it was higher in the group-1 (50% vs. 60%, p < 0.05). In the group-1, microorganisms were found in the blood of 9 patients. In the group-2, the microorganisms were found in the blood of 11 patients. Inflammation markers were decreased after the treatment of septic shock in both groups (p<0.05). The decreasing of procalcitonin in group-1 was from 43.8 to 1 ng/ml in 14 days and from 12.8 to 1.6 ng/ml in 7 days in group-2. The decreasing of CRP in group-1 was from 224 to 114 mg/l in 7 days and from 146 to 60 mg/l in 14 days in group-2. The decreasing of IL-6 in group-1 was from 1617 to 100 pg/ml in 3 days and from 5895 to 77 pg/ml in 7 days in group-2. A level of AT was increased only in group-2 (under 12% per day). 28-day survival was higher in group-2 (60 +/- 13% vs. 45 +/- 13%, p<0.05). We did not find any complications of the treatment with AT concentrate. CONCLUSION: Treatment of septic shock with high-doses of antithrombin III was effective and safe in patients with an agranulocytosis.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Antithrombin attenuates vascular leakage via inhibiting neutrophil activation in acute lung injury.

OBJECTIVE: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. DESIGN: Randomized controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Eighteen chronically instrumented sheep. INTERVENTIONS: Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. MEASUREMENTS AND MAIN RESULTS: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. CONCLUSIONS: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

Effect of recombinant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation.

From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n = 23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n = 11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment for coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (P = 0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy.