A multicenter randomized controlled trial comparing administration of antithrombin III after liver resection (HiSCO-05 trial).

BACKGROUND: Posthepatectomy liver failure is a poor prognostic factor after hepatectomy. Various preventive treatments have been tried; however, there are no clinical trials that use posthepatectomy liver failure as the primary endpoint, and the clinical effects of posthepatectomy liver failure have not been fully verified. The aim of this study was to investigate whether administration of antithrombin III can prevent posthepatectomy liver failure in patients with coagulopathy after hepatectomy. This study also evaluated the safety of AT-III administration after hepatectomy. METHODS: The current study enrolled 141 patients diagnosed with coagulopathy after hepatectomy between October 2015 and September 2018 at 7 hospitals in Hiroshima, Japan (HiSCO group). Patients were randomized to undergo either administration of antithrombin III (n = 64) or non-administration (n = 77). The primary endpoint was the incidence of posthepatectomy liver failure. This randomized controlled trial was registered with the University Medical Information Network Clinical Trial Registry (UMIN000018852). RESULTS: Treatment for postoperative coagulopathy was performed safely without adverse events. The incidence of posthepatectomy liver failure was similar in both treatment groups (nonadministration of antithrombin III group, 28.5%, versus administration of antithrombin III group, 28.1%; P = .953) The rate of morbidity was higher in the administration group than the non-administrated group (17.2% vs 11.7%, P = .351). Following the multivariate analysis of the whole study group, body mass index ≥25, total bilirubin ≥1.5 mg/dL, and the disseminated intravascular coagulation score ≥5 postoperatively were the independent risk factors for posthepatectomy liver failure. CONCLUSION: This study showed that the administration of antithrombin III resulted in no significant difference in preventing posthepatectomy liver failure, possibly through suppressing coagulopathy.

Low level of postoperative plasma antithrombin III is associated with portal vein thrombosis after liver surgery.

PURPOSE: Although decreased antithrombin-III (AT-III) is a risk factor for portal vein thrombosis (PVT) in patients with liver cirrhosis, the association between postoperative PVT and postoperative AT-III levels is unknown in patients undergoing hepatectomy. METHODS: Patients who underwent hepatectomy between 2015 and 2018 were retrospectively analyzed. Postoperative PVT was assessed on CT at days 6-9 after hepatectomy. One-to-one propensity score (PS) matching was used to match the baseline characteristics. RESULTS: Of the 295 patients included in this analysis, 19 patients (6.4%) were diagnosed with postoperative PVT. The AT-III level on postoperative day (POD) 3 predicted postoperative PVT with a sensitivity/specificity of 74%/59% (AUC, 0.644; cut-off value, 60%; p = 0.032). Multivariate analysis revealed that AT-III levels ≤ 60% on POD3 (OR, 3.01; 95% CI 1.02-8.89; p = 0.046), cirrhosis (OR, 5.88; 95% CI 1.92-18.0; p = 0.002) and right-sided hepatectomy (OR, 4.16; 95% CI 1.45-11.9; p = 0.0079) were significant risk factors for postoperative PVT. After PS matching, 56 patients with and without AT-III supplementation were analyzed. The two groups had a similar incidence of PVT (p = 0.489). CONCLUSIONS: Patients with AT-III levels ≤ 60% on POD3 should be carefully followed up regarding postoperative PVT. Our results did not support the efficacy of routine AT-III supplementation for the prophylaxis of postoperative PVT.

Exogenous supplementation of antithrombin III in adult and pediatric patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. METHODS: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at -6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. RESULTS: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at -6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL (p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL (p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h (p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h (p-value: 0.188) for adults. CONCLUSION: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.

Successful administration of recombinant human antithrombin in a pregnant Japanese woman with hereditary antithrombin deficiency.

OBJECTIVE: Hereditary antithrombin (AT) deficiency increases the risk of venous thromboembolism (VTE) in pregnant woman. We report the first case of administration of recombinant human antithrombin (rhAT) to a pregnant Japanese woman with AT deficiency. CASE REPORT: A 30-year-old woman, gravida 2 para 0, was referred to our hospital because of AT deficiency. Unfractionated heparin was administered from 13 weeks of gestation and rhAT was administered from labor onset. A cesarean section was performed and the patient and her baby were healthy, with no sequelae. CONCLUSION: We concluded that rhAT was effective for preventing VTE during delivery, with no potential infection risks.

Capped antithrombin III dosing is cost effective in the management of asparaginase-associated thrombosis.

Asparaginase therapy induces a transient antithrombin III (ATIII) deficiency, which contributes to the risk of asparaginase-induced thrombosis. At Cincinnati Children's Hospital Medical Center, management of asparaginase-induced thrombosis includes ATIII supplementation during therapeutic anticoagulation with enoxaparin. Due to the expense associated with ATIII, a capped dosing approach for ATIII was evaluated in this population. Peak ATIII levels were obtained following capped doses to evaluate response. In this pilot evaluation, 11 patients received a total of 138 capped doses for a total cost savings of $803 782. This pilot evaluation represents the first reported analysis of capped ATIII dosing in oncology patients.

Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis.

BACKGROUND: Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis. METHODS: We induced the development of liver tumor in AT-insufficient (AT+/-) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4. RESULTS: Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/-. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group. CONCLUSIONS: AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.

Revisiting antithrombin in health and disease, congenital deficiencies and genetic variants, and laboratory studies on α and ß forms.

Antithrombin [AT] is the main inhibitor for activated plasma coagulation serine esterases, inhibiting thrombin, Factors Xa and IXa, but also Factors XIIa, XIa, VIIa, kallicrein, and plasmin. Its activity is highly enhanced by heparin, through binding to the pentasaccharide sequences, for inhibition of all coagulation proteases, except thrombin, which inhibition requires its additional binding to the heparin polysaccharide chain. However, AT is the major inhibitor of thrombin in the blood circulation. Congenital or acquired deficiencies of AT expose affected patients to an increased risk of developing unprovoked and recurrent thrombo-embolic diseases. Antithrombin can be measured with various laboratory techniques, by either immunological or functional methods. Earlier, a radial immunodiffusion immunoassay allowed measurement of the protein antigenic content. Functional assays are mainly designed with Anti-Thrombin or Anti-Factor Xa chromogenic methods and are useful for detecting genetic molecular mutations with decreased inhibitory activity and contributed to study the conformational changes of antithrombin and its variants, which potentially regulate the activity of this serine protease inhibitor. These assays are not equivalent in terms of diagnosing protein abnormalities, associated with increased thrombotic incidence, and they have variable performance for reflecting impaired antithrombin binding capacity for heparin, reduced progressive inhibition of serine proteases, or accelerated switch rates to the latent and less active forms. A small proportion of AT (<10%) is present in blood in the ß-form, with a lower oligosaccharide content, a lower Molecular Weight, a higher binding rate to endothelial glycosaminoglycans, and a higher anticoagulant activity, hence requiring specific laboratory methods for its measurement. The ß-AT form is then of critical importance for controlling blood activation by tissue injury and preventing development of thrombo-embolic diseases. This article reviews the performance characteristics of the currently available assays, and their usefulness for monitoring the use of AT concentrates in intensive care units, disseminated intravascular coagulation or severe infections, to restore the anticoagulant protective effect of heparin by supplementing the requested AT concentration. The issues of automation, harmonization and standardization are also revisited and discussed.

Strategy for Cardiovascular Surgery in Patients with Antithrombin III Deficiency.

Antithrombin III (ATIII) deficiency is a rare disorder in which thrombosis can be induced by stimuli that do not usually lead to thrombus formation, including minor injuries and surgery. Therefore, patients with ATIII deficiency undergoing cardiovascular surgery that involves heparinization require careful perioperative management. We experienced five patients with ATIII deficiency who underwent cardiovascular surgery and were managed with ATIII replacement. By administration of ATIII concentrate, preoperative ATIII activity was maintained at ≥120% and postoperative ATIII activity at ≥80%. All five patients were treated successfully without postoperative complications such as hemorrhage or thrombosis. In patients with ATIII deficiency undergoing cardiac surgery, it is important to perform ATIII replacement to achieve preoperative ATIII activity ≥120% and postoperative ATIII activity ≥80%, while the activated clotting time (ACT) is maintained at >400 seconds during cardiopulmonary bypass. In addition, long-term postoperative anticoagulant therapy is necessary in hereditary ATIII deficiency patients with a history of thrombosis.

Identification of Cost-Saving Opportunities for the Use of Antithrombin III in Adult and Pediatric Patients.

Thrombate III is a human plasma-derived antithrombin III (AT-III) often utilized in patients on extracorporeal membrane oxygenation (ECMO) with suspected AT-III-mediated heparin resistance. It is supplied as 500-U and 1000-U vials, costing US$4.66 per unit. Literature is limited in describing the clinical value of AT-III in relation to its high cost. The primary objective was to determine conditions of use and associated cost of potentially unnecessary utilization of AT-III at The Johns Hopkins Hospital. Secondary objectives included evaluating the effect of AT-III on anticoagulation parameters and the overall cost utilized and wasted on AT-III. A retrospective cohort study was performed. The primary end point was the total cost associated with potentially unnecessary utilization of AT-III. There were 326 doses of AT-III administered to 65 patients in 2014. There were 177 (54%) potentially unnecessary doses associated with a cost of US$541 634. Antithrombin III repletion significantly increased median AT-III levels in non-ECMO and ECMO patients compared to baseline (non-ECMO: 62% vs 81%, P < .01; ECMO: 63% vs 81%, P < .01); however, 37.3% of ECMO and 49% of non-ECMO patients had therapeutic anticoagulation monitoring parameters prior to administration. A total cost of US$688 478 was spent on administered AT-III and US$417 194 (38%) was wasted. Utilizing restriction criteria and a new dosing strategy potentially results in estimated annual savings of US$556 000. Utilizing restriction criteria and alternative dosing strategies to mitigate waste and unnecessary use has the potential to result in significant cost savings.

Outcomes of Geriatric Trauma Patients on Preinjury Anticoagulation: A Multicenter Study.

Outpatient anticoagulation in the geriatric trauma patient is a challenging clinical problem. The aim of this study is to determine clinical outcomes associated with class of preinjury anticoagulants (PA) used by this population. This is a multicenter retrospective cohort study among four Level II trauma centers. A total of 1642 patients were evaluated; 684 patients were on anticoagulation and 958 patients were not. Patients on PA were compared with those who were not. Drug classes were divided into thromboxane A2 inhibitors, vitamin K factor-dependent inhibitors, antithrombin III activation, platelet P2Y12 inhibitors, and thrombin inhibitors. Multivariate regression was used to adjust for age, gender, race, mechanism of injury, and Injury Severity Score. No single or combination of anticoagulation agents had a significant association with mortality; however, there were positive trends toward increased mortality were noted for all antiplatelet groups involving thromboxane A2 inhibitors and platelet P2Y12 inhibitors classes. The likelihood of complications was significantly higher with platelet P2Y12 inhibitors adjusted odds ratio (aOR) 2.39 [95% confidence interval (CI) 1.32, 4.3]. The likelihood of blood transfusion was increased with vitamin K inhibitors aOR 2.89 (95% CI 1.3, 6.5), P2Y12 inhibitors aOR 2.76 (95% CI 1.12, 6.76), and combined thromboxane A2 and P2Y12 inhibitors aOR 2.89 (95% CI 1.13, 7.46). P2Y12 inhibitors were also more likely associated with traumatic brain injury aOR 2.16 (95% CI 1.01, 4.6). All classes of PA were associated with solid organ injury. There were no significant differences in the use of antiplatelet agents between patients with major indications for PA and those without major indications. Geriatric trauma patients on outpatient anticoagulants have a higher likelihood of developing complications, packed red blood cell transfusions, traumatic brain injury, and solid organ injury. Attention should be paid to patients on platelet P2Y12 inhibitors, vitamin K inhibitors, and thromboxane A2 inhibitor agents combined with platelet P2Y12 inhibitors. Opportunities exist to address the use of antiplatelet agents among patients without major indications to improve patient outcomes.

Antithrombin III Protects Against Contrast-Induced Nephropathy.

We previously reported that insufficiency of antithrombin III (ATIII), the major anti-coagulation molecule in vivo, exacerbated renal ischemia-reperfusion injury in animal models and possibly humans. In the present study, we investigated the relationship between ATIII level and contrast induced nephropathy (CIN) in patients and examined therapeutic effect of ATIII on CIN in Sprague-Dawley rats. Patients with low ATIII activity presented a higher incidence of acute kidney injury (AKI) following coronary angiography. ATIII (500µg/kg) was intravenously injected before or after the induction of AKI in rats. Our data demonstrated ATIII significantly attenuated the elevation of serum creatinine, blood urea nitrogen, and renal histological injury. The beneficial effects of ATIII were accompanied by diminished renal inflammatory response, oxidative stress, cell apoptosis and improved renal blood flow in rats. In conclusion, ATIII appears to attenuate CIN through inhibiting inflammation, oxidative stress, apoptosis and improving renal blood flow. ATIII administration may represent a promising strategy for the prevention and treatment of contrast-induced AKI.

The Use of Recombinant Antithrombin III in Pediatric and Neonatal ECMO Patients.

A retrospective review of 77 pediatric and neonatal extracorporeal membranous oxygenation (ECMO) patients who received recombinant antithrombin III (ATIII) for ATIII activity greater than 80% was conducted. Anticoagulation management was per institutional protocol. An ATIII activity greater than 80% was targeted. Diagnosis, reason for ECMO cannulation, blood product usage, heparin dosing, ATIII activity and doses, thrombotic and bleeding complications, hours on ECMO, and mortality were recorded. We calculated patient-level summary statistics and assessed differences between groups using χ tests (categorical variables) and Wilcoxon rank sum tests (continuous variables). Hierarchical generalized linear models were developed to model bleeding and thrombotic complications. The majority (n = 75) received venoarterial ECMO and had cardiac diagnoses (n = 62). Antithrombin III activity was below 80% for an average of 5.2 hours per patient. Antithrombin III activity less than 80% was not associated with thrombotic complications (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 0.97-1.06, p = 0.86). Antithrombin III activity greater than 80% was not associated with bleeding complications (OR = 1.06, 95% CI = 1.01-1.11, p = 0.44). Duration of ECMO was an independent predictor of thrombotic complications (OR = 1.08, 95% CI = 1.02-1.11, p = 0.02). There were no independent predictors of bleeding complications. Antithrombin III activity correlated with anti Xa activity (r = 0.367, p < 0.001) but not with other measures of anticoagulation or with heparin dose (r = 0.16, p = 0.165). ATIII activity was not associated with bleeding, thrombosis, or heparin dose. Antithrombin III activity was associated with anti Xa activity but not with traditional measures of anticoagulation. Antithrombin III replacement for an activity less than 80% did not increase bleeding.

[Atrial Septal Defect with Hereditary Deficiency of Antithrombin III].

A 41-year-old female with hereditary deficiency of antithrombin III (ATIII) was diagnosed with atrial septal defect( ASD) and scheduled for the closure of ASD. She had been taking warfarin since she suffered from deep vein thrombosis 10 years ago. Preoperative management of anticoagulation included discontinuation of warfarin, and supplementation of antithrombin with heparin infusion. On the day of operation, antithrombin activity was maintained above 80% by administering antithrombin, and closure of ASD was carried out under standard cardiopulmonary bypass support using heparin. Heparin infusion was continued with antithrombin supplementation until prothrombin time-international normalized ratio(PT-INR) recovered to around 2.5 with warfarin. Her intra-and postoperative courses did not show any thromboembolic events, and she was discharged 20 days after the surgery.

High dose antithrombin supplementation in early preeclampsia: A randomized, double blind, placebo-controlled study.

INTRODUCTION: Antithrombin levels are often reduced in preeclampsia and infusion of antithrombin concentrates has been reported to prolong gestation in severe preeclampsia. We aimed to evaluate efficacy and safety of high-dose antithrombin (ATIII) supplementation in patients with single pregnancies and preeclampsia occurring before 30 weeks of gestation. MATERIALS AND METHODS: In November 2004 a double-blind, placebo-controlled trial (code KB033) was started in 13 Italian centers. The planned sample size was of 240 patients (intention-to-treat, ITT population) to detect a 30% relative risk reduction of the primary endpoint, composite perinatal morbidity. Eligible patients were randomized to high dose AT (3000 IU/daily, ATIII Kedrion S.p.A., Italy), or placebo (1% glycine) for 7 days or less until delivery, whichever came first. The per-protocol (PP) population was restricted to patients receiving at least two days of treatment. RESULTS: The study was terminated by the sponsor in October 2007 after the enrolment of 38 evaluable patients - 20 randomized to high dose AT and 18 to placebo, 27 treated for 2 days or more - out of 164 screened patients. Enrolment failures were mainly represented by requirement for immediate delivery and consent refusal (91 patients). The primary endpoint occurred in 15 of 38 patients (39.5%), with a relative risk in the AT arm of 0.85 (95% CI 0.42-1.75) and 0.79 (95% CI 0.30-2.11) in the ITT and PP populations, respectively. Living neonates in the two arms had similar weight at birth, Apgar scores, and duration of hospitalization in neonatal ICU. In mothers, AT supplementation was associated with reduced blood loss at delivery and with surrogate laboratory markers (LDH, d-dimer). CONCLUSIONS: The results of this markedly underpowered trial, albeit suggestive of a potential maternal benefit, cannot support high-dose AT supplementation to improve fetal/neonatal outcomes in early preeclampsia.

[Experience in treating portal thromboses in patients with chronic myeloproliferative diseases].

Patients with myeloproliferative diseases (MPD) are noted to be at high risk for portal thromboses. This problem gives rise to disability if it is untimely treated or resistant to therapy. The paper gives the experience of the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, in using antithrombin III in MPD patients (3 patients with primary myelofibrosis, 3 with essential thrombocythemia) and acute and subacute portal vein thromboses resistant to therapy with direct anticoagulants. In all 5 cases, the use of antithrombin III in combination with low-molecular-weight heparin showed a positive clinical effect as rapid relief of pain syndrome and comparatively early (3-week to 1.5-2-month) recanalization of thrombosed vessels. Three clinical cases are described in detail.

Recombinant Human Antithrombin in Pregnant Patients with Hereditary Antithrombin Deficiency: Integrated Analysis of Clinical Data.

OBJECTIVES: The purpose of this analysis was to evaluate the use of recombinant human antithrombin (rhAT) in preventing venous thromboembolism (VTE) in pregnant patients with hereditary AT deficiency (HATD). STUDY DESIGN: Data from two clinical trials were pooled. Dosing of rhAT was based on body weight and baseline AT activity, started up to 24 hours before scheduled induction or cesarean delivery, or at the onset of labor. RESULTS: A total of 21 pregnant HATD patients were enrolled. Mean rhAT therapy duration was 4.3 days and dose was 245.1 IU/kg/day. All patients achieved target mean AT activity (80-120% of normal) during rhAT therapy. There were no confirmed VTEs during rhAT treatment or within 7 ( ± 1) days after dosing. Two VTE events (one deep vein thrombosis and one pulmonary embolism) occurred 11 and 14 days after discontinuation of rhAT, in patients managed with prophylactic doses of heparin or low-molecular-weight heparin following delivery. CONCLUSION: rhAT was safe and effective in pregnant HATD patients when administered during the peripartum period, the period of highest VTE risk and a time when anticoagulation therapy is normally withheld. Pregnant HATD patients may benefit from therapeutic, rather than prophylactic, doses of anticoagulation after delivery to protect against postpartum VTE.

A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates.

Neonates have low levels of antithrombin. Inadequate anticoagulation during cardiopulmonary bypass (CPB) due to low antithrombin activity may result in a poor preservation of the coagulation system during bypass. We hypothesize that antithrombin replacement to neonates prior to CPB will preserve the hemostatic system and result in less postoperative bleeding. A randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted. Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy.

Management of Heparin-Resistant Patients with Benefits? Maximizing Biocompatibility in Cardiopulmonary Bypass: Combining ATryn® Recombinant Antithrombin III and Carmeda® Heparin-Bonded Perfusion Circuits: A Case Series.

As many as 25% of our cardiopulmonary bypass (CPB) patients have a diminished heparin response and fail to reach a therapeutic activated clotting time (ACT). We treat a majority of these patients with antithrombin III (ATryn®, recombinant antithrombin III [rhAT], rEVO Biologics). Our current CPB circuit uses Medtronic Carmeda® coating. We observed less post-operative bleeding in a number of patients treated with rhAT. We theorized that adding rhAT would allow patients with diminished heparin response to safely achieve a therapeutic ACT. On the basis of our postoperative bleeding observations, we wondered if using rhAT with a heparin-bonded CPB circuit enhanced its biocompatibility and perhaps improved patient outcomes. Data were collected on 15 patients undergoing CPB who received antithrombin III (AT) replacement therapy for diminished heparin response. We used patient data from 2012, prior to rhAT usage for comparison. All patients achieved therapeutic ACT after rhAT administration. We also observed decreased postoperative atrial fibrillation rates, improved platelet preservation, decreased intensive care unit and ventilator times in patients receiving rhAT compared to rates commonly observed at our center. Heparin-resistant patients can be treated with rhAT to achieve therapeutic ACTs. Our observations suggest that the use of rhAT in conjunction with Carmeda® heparin-bonded circuits may also have a positive benefit on some of the well-established negative clinical consequences of CPB and improve patient outcomes.

Initial experience with recombinant antithrombin to treat antithrombin deficiency in patients on extracorporeal membrane oxygenation.

Acquired antithrombin (AT) deficiency has been associated with patients on extracorporeal membrane oxygenation (ECMO) as a result of hemodilution, blood coagulation activation, and the use of heparin. Replacement of AT has been typically utilized through the use of fresh-frozen plasma or AT concentrate. Antithrombin alfa (ATryn) is a recombinant form of AT (rAT) with an identical amino acid sequence as that of plasma-derived antithrombin. The primary objective of this study is to examine the relationship of rAT dose to measured plasma antithrombin activity in a small series of patients who received rAT while on ECMO. A retrospective chart review was performed of all patients at Medical City Children's Hospital who received ATryn while supported on ECMO between December 2011 and April 2012. Five patients were identified and the patients' weight, bolus dose of ATryn, drip rate of ATryn, and AT blood levels were collected for analysis. The median age of these patients was 1 month (range, 1 day to 3.75 years). Because no dosing guidelines exist for pediatric ECMO, a starting dose of ATryn was chosen based on the manufacturer's labeled indication (prevention of thromboembolic events in patients with AT hereditary deficiency). The median dose of rAT was 368 IU/kg/day (range, 104-520 IU/kg/day) to obtain AT activity level of 80-120%. The average time to reach the targeted AT activity level (80-120%) was 12.7 hours (range, 11-17 hours). Our findings suggest that the published ATryn dose may be inadequate to reach desired AT activity concentrations for pediatric patients on ECMO. Difference in patient population, use of extracorporeal circuits, and the use of heparin are likely explanations for this finding. We would also recommend frequent checking of AT levels while delivering this drug because making timely adjustments is necessary for achieving and maintaining the target AT activity level.

Impact of withdrawing antithrombin III administration from management of septic patients with or without disseminated intravascular coagulation.

Antithrombin III (ATIII) of low doses (1500-3000 units per day for 3-5 days) has been used for treatment of disseminated intravascular coagulation (DIC) for decades in Japan. In this study, we have examined the impact of ATIII practice change on outcome in critically ill patients with sepsis and DIC. From April 2005 to September 2008, all septic patients admitted to our ICU were divided into two groups: before withdrawing ATIII (period 1) and after withdrawing ATIII (period 2). Patients treated with ATIII in the period 1 and those not treated with ATIII in the period 2 were then matched according to the similar Acute Physiology and Chronic Health Evaluation II scores (± 3) and the same diagnosis grouping. Sensitivity analysis was also conducted for patients with DIC. Forty-one out of 98 patients (41.8%) in the period 1 and only one out of 80 patients (1.3%) in the period 2 were treated with ATIII. Thirty pairs of the patients were matched. There was no difference between the two groups regarding the platelet counts and Sepsis-related Organ Failure Assessment scores at day 1 and day 4. A subgroup analysis was conducted with 12 patients diagnosed with DIC out of the 30 pairs. There was no difference between the two DIC groups for platelet counts, Sepsis-related organ failure assessment scores and DIC score at day 1 and also day 4. Although not significant, hospital mortality tended lower in the period 2. This study found that withdrawing ATIII administration from management of septic patients with or without DIC did not influence outcome.