Administration Of Antithrombin Research Articles

Clinical outcomes of antithrombin III supplementation in an overt disseminated intravascular coagulation: a longitudinal single-institutional experience and retrospective analysis.

Antithrombin is a small plasma glycoprotein synthesized in the liver that belongs to the serpin family of serine protease inhibitors and inactivates several enzymes in the coagulation pathway. It plays a leading major factor on coagulation pathway, therefore administration of antithrombin is essential to treat serious clinical conditions such as disseminated intravascular coagulation (DIC). Despite the theoretical benefits of antithrombin supplementation, the optimal antithrombin activity for heparin efficacy and the benefits of antithrombin supplementation in various disease entities are not yet fully understood. The strict administration guidelines on antithrombin III in cases of DIC by the National Health Insurance Service and the Ministry of Food and Drug Safety complied as follows: antithrombin levels below 20 mg/dL in adults; antithrombin activity below 70% of normal in adults; total administration period of antithrombin must be carefully limited to within maximum 3 days, and the total administration dose must be below 7,000 international unit (IU), (loading dose, 1,000 IU in 1 hour: maintenance dose, 500 IU every 6 hours for 3 days). We identified 76 eligible for analysis according to the above-mentioned criteria in our institution (male/female, 59/17). Forty-four were identified to the non-survivor group and 32 patients were recognized as the survivor group. The baseline parameters in the non-survivor and survivor groups were comparable with no significant differences in age (66.5±18.1 vs. 66.0±16.2 years, P=0.90), sex (32/12 vs. 27/5, P=0.35), hospital length of stay (31.1±34.5 vs. 31.2±26.1 days, P=0.99), sequential organ failure assessment (SOFA) (7.3±2.5 vs. 6.6±2.0, P=0.22), simplified acute physiology score II (SAPS II) (46.0±8.8 vs. 43.5±9.2, P=0.23), cause for DIC (P=0.95), and underlying disease (P=0.38). The levels of antithrombin III on the day just before the administration significantly lower in the non-survivor groups than in the survivor groups (50.1%±13.6% vs. 57.6%±12.5%, P=0.01). The hemoglobin level in the 2nd day and 7th day after antithrombin III administration was significantly different between the non-survivor and survivor groups (9.9±1.9 vs. 11.0±2.0 g/dL, P=0.01, and 9.4±1.8 vs. 10.5±1.6 g/dL, P=0.006). The antithrombin III levels on the day of administration [area under the curve (AUC) =0.672] demonstrated significantly better prediction of mortality than the A antithrombin III levels on 1st day (AUC =0.552), the 2nd day (AUC =0.624), and 7th day (AUC =0.593). Our study suggests that the antithrombin administration may be effective tools for DIC treatment, and may be more positively considered, especially in the cases of DIC, which is a frequent complication of septic shock, sepsis, and other critical disease entities and which is associated with a high level of mortality. Furthermore, our study also suggests that the total doses and periods of antithrombin administration, which recommended by national guidelines, may be insufficient, therefore prolongation of period and increase of total dose of antithrombin supplement might be necessary.

Efficacy of antithrombin administration for patients with sepsis: A systematic review, meta-analysis, and meta-regression.

There have been inconsistent reports regarding the effect of antithrombin on sepsis; furthermore, there are limited reports on how dosage affects therapeutic efficacy. Thus, we aimed to perform a systematic review and meta-analysis of the use of antithrombin for sepsis and a meta-regression analysis of antithrombin dosage. We included randomized controlled trials (RCTs) and observational studies of adult patients with sepsis who received antithrombin. Outcomes included all-cause mortality and serious bleeding complications. Statistical analyses and data synthesis were performed using a random-effects model; further, meta-regression and funnel plots were used to explore heterogeneity and biases. Seven RCTs and six observational studies were included. Most patients in the RCTs and observational studies had severe sepsis and septic-disseminated intravascular coagulation (DIC), respectively. A meta-analysis using RCTs showed no significant differences in mortality between the antithrombin and control groups. However, the meta-analysis of observational studies indicated a trend of decreasing mortality rates with antithrombin administration (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.68-0.92; p = 0.002). Bleeding complications were significantly higher in the antithrombin group than in the control group in both study types (OR, 1.90; 95% CI, 1.52-2.37; p < 0.01). The meta-regression analysis showed no correlation between antithrombin dosage and mortality. A meta-analysis of RCTs confirmed no survival benefit of antithrombin, whereas that of observational studies, which mostly focused on septic DIC, showed a significant beneficial effect on improving outcomes. Indications of antithrombin should be considered based on its beneficial and harmful effects.

Investigation of real-world heparin resistance and anticoagulation management prior to cardiopulmonary bypass: report from a nationwide survey by the Japanese Association for Thoracic Surgery heparin resistance working group

ObjectiveHeparin resistance is often encountered during cardiopulmonary bypass. Heparin dose and activated clotting time target values for the initiation of cardiopulmonary bypass are not yet universally standardized; further no consensus exists on the management of heparin resistance. This study aimed to investigate the current real-world practice on heparin management and anticoagulant treatment for heparin resistance in Japan.MethodsA questionnaire survey was conducted at medical institutions nationwide with which The Japanese Society of Extra-Corporeal Technology in Medicine members are affiliated, targeting surgical cases with cardiopulmonary bypass performed from January 2019 through December 2019.ResultsAmong 69% (230/332) of the participating institutions, the criterion for heparin resistance was defined as “the target activated clotting time value not reached even with an additional dose of heparin administration”. Cases of heparin resistance were reported in 89.8% (202/225) of the responded institutions. Of note, 75% (106/141) of the responded institutions reported heparin resistance associated with antithrombin activity ≥ 80%. Antithrombin concentrate was used in 38.4% (238/619 responses) or third dose of heparin in 37.8% (234/619 responses) for advanced heparin resistance treatment. Antithrombin concentrate was found to be effective in resolving heparin resistance in patients having normal, as well as lower antithrombin activity.ConclusionHeparin resistance has occurred in many cardiovascular centers, even among patients with normal antithrombin activities. Interestingly, the administration of antithrombin concentrate resolved heparin resistance, regardless of the baseline antithrombin activity value.

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study

BackgroundThe development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of “high disease severity” in addition to “sepsis with DIC” has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize “severe” sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy.MethodsThis retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination.ResultsIn total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy.ConclusionsThe combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis.Trial registration: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

Antithrombin substitution practice in pediatric cardiac surgery: A European survey.

The antithrombin concentration of neonates is approximately half that of adults. Low preoperative antithrombin concentration in this population have been associated with increased transfusion requirements.1 Similarly, low antithrombin concentration result in poor response to unfractionated heparin and inability to establish adequate anticoagulation during extracorporeal circulation (e.g., cardiopulmonary bypass, CPB), placing patients at risk for thrombosis.2 Despite obvious mode of action, there are no well-described clinical benefits of antithrombin usage in clinical practice. The aim of this survey was to identify the practice of antithrombin usage in pediatric cardiac surgery across Europe. The authors developed a 55-item electronic questionnaire to evaluate the following areas: the local practice of antithrombin management and substitution, including antithrombin monitoring and target levels, antithrombin administration techniques, and monitoring of anticoagulation. The survey was endorsed by the European Association of Cardiothoracic Anesthesiology and Intensive Care (EACTAIC) and distributed among its members. Respondents had to identify themselves as pediatric cardiac anesthetists before they were allowed to enter the questionnaire. A total of 118 responses were received. The half of respondents confirmed that they were currently working as pediatric cardiac anesthesiologists and were allowed to participate in the survey. Sixty-eight percent of participants (39/57) regularly measure antithrombin concentration and 79% (31/39) regularly substitute antithrombin in different pathophysiological scenarios in pediatric congenital heart surgery (Table 1). Thirty-two percent (12/37) substitute antithrombin in all cardiac surgery cases with low antithrombin concentration. In the setting of CPB, 41% (15/37) substitute antithrombin. In patients <6 months of age scheduled for cardiac surgery, half of the respondents (54%, 20/37) not routinely substitute antithrombin. In pediatric patients with low antithrombin concentration on veno-arterial extracorporeal membrane oxygenation (ECMO), 78% (29/37) replace antithrombin. In all cardiac patients (with or without cardiac surgery), more than 65% (21/32) of respondents measure antithrombin concentration only when specifically indicated, 28% (9/32) before administration, and 25% (8/32) preoperatively (in case of cardiac surgery). In patients on veno-arterial ECMO, 50% (16/32) measure antithrombin once daily, 31% (10/32) before administration, 28% (9/32) only on specific indication, 25% (8/32) after administration or before ECMO implantation, respectively. The primary strategy for antithrombin concentration below target was immediate substitution in 54% (14/26) of respondents. Twenty-seven (7/26) percent opted for repeated measurements to make a final decision. In a situation with low antithrombin concentration and known heparin resistance, 100% (31/31) of responders substitute antithrombin. In a situation with known heparin resistance and unmeasured antithrombin concentration, half of the participants (52%, 16/31) did not substitute antithrombin. In unclear clinical situations with suspected low antithrombin concentration (e.g., disseminated intravascular coagulation), 77% (24/31) did not substitute antithrombin without a previous level measurement. Antithrombin substitution occurred in 66% (18/27) using calculations as provided by the manufacturer, in 22% (6/27) using a standard dose (e.g., 500 U antithrombin concentrate), and in 11% (3/27) using a calculation based on a custom formula. Antithrombin substitution - YES - Antithrombin substitution - NO - Antithrombin substitution - no answer - In this European survey examining the use of antithrombin in pediatric cardiac patients, we found widespread use of antithrombin measurement and substitution strategies. The most important areas for antithrombin monitoring and substitution were ECMO, in patients with inadequate elevation of activated clotting time during cardiac surgery with CPB, and in patients with known heparin resistance in combination with low antithrombin concentration. The most common consensus in the literature regarding antithrombin administration is inadequate response to heparin.3, 4 In our survey, antithrombin was substituted in all cases when a low antithrombin concentration was present in combination with detected heparin resistance. Regarding the use of antithrombin in different procedures without surgery, this study confirms large differences between institutions. One possible explanation is the lack of evidence in the literature for the use of antithrombin in specific cardiac lesions including specific cardiac surgery populations as for example cyanotic patients with high hematocrit. This survey underlines again the need for further, adequately powered studies regarding antithrombin monitoring and substitution in the pediatric cardiac patients undergoing surgery or interventions. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

193: PROGRAM-WIDE TRANSITION FROM HEPARIN TO BIVALIRUDIN ANTICOAGULATION IN ADULT ECMO: A COST ANALYSIS

Introduction: Bivalirudin is becoming an increasingly popular alternative to heparin for extracorporeal membrane oxygenation (ECMO) anticoagulation due to its short half-life, organ-independent metabolism, thrombin inhibition without the need for a co-factor, and its ability to bind clot-bound and freely circulating thrombin. The objective of this study was to compare the cost implications of bivalirudin and heparin during adult ECMO support. Methods: A retrospective analysis of adults supported on ECMO who received heparin or bivalirudin for anticoagulation between January 2014 and January 2022 at Mayo Clinic was performed. In November 2017, the Mayo Clinic ECMO program transitioned from heparin to bivalirudin as the primary anticoagulant of choice, which separated the pre- and post-transition groups. Cost data were estimated using Wholesale Acquisition Costs and laboratory reimbursement schedules. Cost data were normalized to duration of ECMO support, compared between the pre- and post-transition groups, and were summarized in United States Dollar ($). Results: A total of 126 patients (123 heparin, 3 bivalirudin) in the pre-transition period and 275 patients (82 heparin, 193 bivalirudin) in the post-transition period were included. Antithrombin administration was more frequent in the pre-transition group (31% vs. 12%, p < 0.0001), as were number of coagulation assays per ECMO day (6.1 vs. 5.4, p = 0.0004). The post-transition group had significantly less costs from antithrombin assessments ($1.03 vs. $11.78, p < 0.0001) and antithrombin supplementation ($0 [IQR $0, $0] vs. $0 [IQR $0, $312.82], p < 0.0001) per day of ECMO support. The aggregate costs per patient were similar in the heparin ($333 vs. $248, p = 0.5690) and bivalirudin ($2723 vs $1720, p = 0.4659) groups pre- and post-transition, respectively. Survival at 28-days was greater in the post-transition group (75% vs. 64%, p = 0.0286). Conclusions: Antithrombin assessment and supplementation comprised a majority of anticoagulant-related costs in heparin-based ECMO patients, which was significantly reduced following transition to bivalirudin-based anticoagulation. When considering laboratory and drug costs in aggregate, there is a favorable association between bivalirudin and heparin anticoagulation in adult ECMO patients.

The relationship between antithrombin administration and inflammation during veno-venous ECMO

Veno-venous Extracorporeal Membrane Oxygenation (ECMO) is used in the most severe cases of respiratory failure and further exacerbates the patients’ inflammatory status. Antithrombin is supplemented during ECMO for its anticoagulant effects, but it also deploys anti-inflammatory properties. In this pre-specified ancillary study of the GATRA trial [NCT03208270] we aimed to evaluate the relationship between antithrombin and inflammation during ECMO. Forty-six patients were included in the study, 23 were randomized to receive antithrombin to maintain a level of 80–120% (study group) and 23 were randomized not to be supplemented (control group). Anticoagulation was provided in both groups with heparin infusion. Six cytokines were measured at 5 timepoints from prior to ECMO start to 7 days after ECMO removal. Cytokines decreased during the study but overall were not very different in the two groups. Testing the interaction between the study group and timepoints suggests that the administration of antithrombin led to a more rapid decrease over time of IL-6, IL-1β, TNF-⍺ and Pro-ADM. Plasma levels of antithrombin (either endogenous or exogenous) were negatively associated with all cytokines. Inflammation decreases during ECMO but a causal effect of antithrombin administration on the reduction of inflammation (and its clinical relevance) must be confirmed by appropriately powered studies.

Age-related differences in the survival benefit of the administration of antithrombin, recombinant human thrombomodulin, or their combination in sepsis

Disseminated intravascular coagulation (DIC) is one of the major organ dysfunctions associated with sepsis. This retrospective secondary analysis comprised data from a prospective multicenter study to investigate the age-related differences in the survival benefit of anticoagulant therapy in sepsis according to the DIC diagnostic criteria. Adult patients with severe sepsis based on the Sepsis-2 criteria were enrolled and divided into the following groups: (1) anticoagulant group (patients who received anticoagulant therapy) and (2) non-anticoagulant group (patients who did not receive anticoagulant therapy). Patients in the former group were administered antithrombin, recombinant human thrombomodulin, or their combination. The increases in the risk of hospital mortality were suppressed in the high-DIC-score patients aged 60–70 years receiving anticoagulant therapy. No favorable association of anti-coagulant therapy with hospital mortality was observed in patients aged 50 years and 80 years. Furthermore, anticoagulant therapy in the lower-DIC-score range increased the risk of hospital mortality in patients aged 50–60 years. In conclusion, anticoagulant therapy was associated with decreased hospital mortality according to a higher DIC score in septic patients aged 60–70 years. Anticoagulant therapy, however, was not associated with a better outcome in relatively younger and older patients with sepsis.

Antimicrobial Prophylaxis and Anticoagulation Therapy in Pediatric ECMO: A Survey Study.

The purpose was to characterize antimicrobial and anticoagulation therapies used in health systems with children receiving extracorporeal membrane oxygenation (ECMO). An anonymous electronic survey assessing health system demographics and antimicrobial and anticoagulation therapies during ECMO was distributed to the American College of Clinical Pharmacy Pediatric Practice and Research Network and the Pediatric Pharmacy Association Critical Care Special Interest Group. The primary objective was to identify the number of respondents using antimicrobial prophylaxis for ECMO cannulation and ECMO runs. Secondary objectives included the first- and second-line anticoagulants and anticoagulation laboratory parameters. Additionally, the antimicrobial regimens and the dosing and administration of antithrombin III (AT III) with systemic anticoagulation were collected. Descriptive statistics were employed. The questionnaire was completed by 38 respondents from 33 health systems; respondents practiced in the pediatric ICU (n = 20; 52.6%), cardiovascular ICU (n = 14; 36.8%), and neonatal ICU (n = 4; 10.5%). Twenty-eight (73.6%) respondents use antimicrobial prophylaxis during ECMO cannulation or ECMO runs, with most units using cefazolin monotherapy. Thirty-five (92.1%) respondents use heparin as the first-line anticoagulant and used a variety of laboratory tests including anti-factor Xa, activated clotting time, and activated partial thromboplastin time. The most common second-line anticoagulant was bivalirudin (n = 24; 63.2%). Thirty-six (94.7%) respondents use AT III with heparin, with most patients receiving AT III dosing calculated based on a formula for the desired AT III concentration. The majority of respondents use antimicrobial prophylaxis, but variations in the regimens were noted. Heparin was the most common anticoagulant, but variations in laboratory monitoring and concomitant use of AT III were found.

Plasma Proteolytic Cascade Activation and Control during Neonatal Cardiopulmonary Bypass Surgery

Introduction: As blood passes through the cardiopulmonary bypass (CPB) circuit, foreign surface exposure activates cells producing tissue factor expression and microparticles that induce procoagulant and pro-inflammatory responses. In the neonate, higher pump flow rates, longer bypass times and decreased levels of endogenous plasma proteins, make plasma proteolytic cascades vulnerable to uncontrolled activation. Changes in the plasma concentrations and structures of five plasma protease inhibitors regulating coagulation, inflammation, fibrinolysis and complement were examined in neonates undergoing CPB to understand how deregulation of proteolytic cascades may contribute to excessive bleeding, which continues to be a common problem in these patients.Methods: Blood samples were obtained at baseline (Draw 1), on CPB (Draw 2), following protamine (Draw 3) and in the intensive care unit (Draw 4). Plasma total protein and the concentrations of the serpins, antitrypsin, antithrombin, antiplasmin and C1-inhibitior, and the Kunitz inhibitor, tissue factor pathway inhibitor (TFPI) were measured. Serpin structures were examined using transverse urea gradient (TUG) gels. TFPI degradation was examined by SDS-PAGE. Excessive bleeding was defined by meeting one or more of the following: ≥ 84 mL/kg total chest tube output (CTO) in the first 24 hours, ≥ 7 mL/kg/hr CTO for ≥2 consecutive hours in the first 12 hours, or re-exploration in the first 24 hours for bleeding or tamponade.Results: Of 44 neonates, 16 (36%) were classified as bleeders. The total plasma protein concentration was 60% that of adults at Draw 1. Adult plasma transfusion increased total protein by 43%, 59% and 32% at Draws 2, 3 and 4. The concentration of each inhibitor changed over the course of surgery (p<0.001 for all). Antitrypsin, an inhibitor of inflammation, and C1-inhibitor, an inhibitor of complement, are acute phase proteins. C1-Inhibitor increased in neonates by 56% and 81% at Draws 2 and 3, returning to baseline at Draw 4. However, antitrypsin decreased 30% between Draws 1 and 2, and remained low at Draws 3 and 4, suggesting it is consumed during surgery. Antithrombin and antiplasmin inhibit coagulation and fibrinolysis, respectively. Changes in antithrombin concentration mirrored those of total protein, while antiplasmin remained stable or decreased, again suggesting consumption. TFPI inhibits coagulation. It is a heparin-releasable protein that increased 5-fold at Draw 2, and remained 4-fold and 3-fold elevated following protamine at Draws 3 and 4. Comparisons of neonates who bled with those who did not revealed that antithrombin was higher in those bleeding at Draw 2 (p=0.031). There was no difference between groups in other inhibitors. TUG gels produce a unique unfolding signature for each serpin and differentiate virgin, proteolytically cleaved, protease complexed and polymerized forms. TUG signatures revealed only virgin antitrypsin, C1-inhibitor and antiplasmin at all 4 draws. Heparin administration at Draw 2 produced antithrombin-FXa and antithrombin-thrombin complexes, as well as proteolytically cleaved forms of antithrombin. These were also variably present at Draws 3 and 4. Western blots for TFPI revealed the appearance of degraded forms at Draws 3 and 4 in some patients.Conclusions: C1-inhibitor concentration increased during surgery, consistent with it being an acute phase reactant. Changes in antithrombin concentration mirrored the conversion to adult plasma, while antitrypsin and antiplasmin decreased in concentration suggesting consumption and clearance. Structural analysis of serpins, other than antithrombin, revealed only the virgin form, indicating the absence of widespread, unregulated proteolysis by plasma proteolytic cascades. Antithrombin displayed complexed and cleaved forms following heparin administration, consistent with its role as an anticoagulant during surgery. TFPI increased 5-fold following heparin administration and remained 3-fold elevated at Draw 4. A portion of this elevation could be attributed to proteolytic degradation, but it is unclear why levels remained so high following protamine reversal. TFPI levels were not different between neonates who bled or not. In contrast, elevated antithrombin levels at Draw 2 were more common in neonates who bled, suggesting that administration of recombinant antithrombin may worsen bleeding in these patients. DisclosuresMast:Novo Nordisk: Research Funding.

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

BackgroundPosthepatectomy 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. MethodsThe 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). ResultsTreatment 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. ConclusionThis study showed that the administration of antithrombin III resulted in no significant difference in preventing posthepatectomy liver failure, possibly through suppressing coagulopathy.

高用量アンチトロンビン投与が血小板機能と凝固機能に及ぼす影響(The influence of a high dose antithrombin on the platelet function and blood coagulability)

要旨【目的】KyberSept trialのサブグループ解析では，アンチトロンビン高用量投与群はプラセボ群に比べて有意に死亡率が低かった。しかし，高用量アンチトロンビン投与による，凝固系への影響に関しては詳しく知られていない。今回アンチトロンビン高濃度検体の凝固特性について調査を行った。【対象】健常者10人より血液検体を採取し，アンチトロンビン製剤を添加することでアンチトロンビン濃度が異なる検体を作成した。凝固特性の調査には生体内での反応に近づけるため，全血を利用するT–TAS®およびROTEM®を使用した。【結果】血小板機能を反映するPL測定では，血栓閉塞開始時間はアンチトロンビン濃度に依存し有意差をもって延長した。AR測定でも同様に，血栓閉塞開始時間はアンチトロンビン濃度に依存し延長した。また血栓閉塞時間もアンチトロンビン濃度に依存し延長した。健常検体内では十分量存在し飽和状態と考えられていたアンチトロンビンであるが，高用量投与された場合には抗凝固作用が増強することが証明された。さらに，T–TAS®を用いたPL測定を行うことで，血小板血栓形成能にも抑制効果が認められることが証明された。【結語】アンチトロンビンは濃度依存性に抗凝固作用を発揮する。また血小板粘着能に対しても影響を及ぼしており，濃度依存性に血小板血栓形成能を抑制する。

Antithrombin use and mortality in patients with stage IV solid tumor-associated disseminated intravascular coagulation: a nationwide observational study in Japan

BackgroundTerminal-stage solid tumors are one of the main causes of disseminated intravascular coagulation (DIC); effective therapeutic strategies are therefore warranted. This study aimed to investigate the association between mortality and antithrombin therapy in patients with stage IV solid tumor-associated DIC using a large nationwide inpatient database.MethodsFrom July 2010 to March 2018, patients with stage IV solid tumor-associated DIC in the general wards, intensive care unit, or high care unit were identified using the Japanese Diagnosis Procedure Combination Inpatient Database. Patients who received antithrombin within 3 days of admission were allocated to the antithrombin group, while the remaining patients were allocated to the control group. One-to-four propensity score matching analyses were applied to compare outcomes. The primary outcome was the 28-day in-hospital mortality.ResultsOf the 25,299 eligible patients, 919 patients had received antithrombin within 3 days of admission and were matched with 3676 patients in the control group. There were no significant differences in the 28-day mortality between the two groups (control vs. antithrombin: 28.9% vs. 30.3%; hazard ratio, 1.08; 95% confidence interval, 0.95–1.23). There were no significant differences in the organ failure score and the proportion of critical bleeding between the two groups. Subgroup analyses showed that the effects of antithrombin were not significantly different among different tumor types.ConclusionUsing a nationwide Japanese inpatient database, this study showed that there is no association between antithrombin administration and 28-day mortality in patients with stage IV solid tumor-associated DIC. Therefore, establishing other therapeutic strategies for solid tumor-associated DIC is required.

Antithrombin use during pediatric cardiac extracorporeal membrane oxygenation admission: insights from a national database.

The frequency of extracorporeal membrane oxygenation in pediatric patients continues to increase, especially in patients with complex congenital heart disease. Providing adequate anticoagulation is necessary for patients on extracorporeal membrane oxygenation and is achieved with adequate heparin administration. Antithrombin is administered to potentiate heparin's effects. However, the efficacy of antithrombin supplementation is unclear and a clear clinical benefit has not been established. We present a large retrospective study examining the effects of antithrombin on pediatric patients receiving extracorporeal membrane oxygenation. Data for this study were obtained from the Pediatric Health Information System and Pediatric Health Information System+ databases from 2004 to 2015. Pediatric patients receiving extracorporeal membrane oxygenation with a congenital heart disease diagnosis were included and divided into groups that did or did not utilize antithrombin. For all admissions, the following were captured: age of admission, gender, year of admission, length of stay, billed charges, inpatient mortality, the presence of specific congenital malformations of the heart, specific cardiac surgeries, and comorbidities. A total of 9,193 admissions were included and 865 (9.4%) utilized antithrombin. Between groups, there were significantly different frequencies of co-morbidities, cardiac lesion types and antithrombin usage over the study period. There were significantly lower odds in the antithrombin group of venous thrombosis. Antithrombin was not significantly associated with hemorrhage; however, antithrombin was associated with increased inpatient mortality and a decrease in length of stay and billed charges. Antithrombin administration is associated with increased mortality, a shorter length of stay, and decreased billing cost. Recently, antithrombin usage has been decreasing-potentially due to the reported lack of clinical benefit. Together, these results reinforce that antithrombin may not be indicated for all pediatric extracorporeal membrane oxygenation patients.

Antithrombin III treatment for portal vein thrombosis after living donor liver transplantation: a case report

BackgroundThere have been no reports on the effectiveness of the administration of antithrombin III (AT III) for post-transplant portal vein thrombosis (PVT). We herein report a case of post-transplant PVT that was resolved by AT III treatment after living donor liver transplantation (LDLT).Case presentationThe patient was a 57-year-old man who had been diagnosed with decompensate liver cirrhosis by hepatitis C virus infection. He presented with repeated hepatic coma and refractory ascites. Computed tomography (CT) revealed PVT of Yerdel classification grade II before LDLT. He underwent ABO-identical LDLT using a right lobe graft. A liver function test revealed elevated liver enzyme levels on post-operative day (POD) 14. The CT examination on POD 15 revealed PVT in the left side of the main portal vein at the side of left gastric vein ligation. AT III treatment from POD 15 to POD 24 was performed. Magnetic resonance imaging revealed that the PVT had decreased 10% on POD 27. Furthermore, AT III treatment from POD 28 to POD 32 was performed. The CT examination demonstrated the disappearance of PVT on POD 69 and thereafter, he had no recurrence of PVT on 10 post-operative month (POM).ConclusionsThe present case suggests that the administration of AT III is safe and suitable for the treatment of post-transplant PVT.

Application of goal-directed therapy for the use of concentrated antithrombin for heparin resistance during cardiac surgery.

The maintenance of anticoagulation in adult patients undergoing cardiopulmonary bypass is dependent upon a number of factors, including heparin concentration and adequate antithrombin activity. Inadequate anticoagulation increases the risk of thrombosis and jeopardizes both vascular and extracorporeal circuit integrity. The purpose of this study was to evaluate a goal-directed approach for the use of antithrombin in patients who were resistant to heparin. Following institutional review board approval, data were obtained from quality improvement records. A goal-directed protocol for antithrombin was established based upon heparin dosing (400 IU kg-1 body weight) and achieving an activated clotting time of ⩾500 seconds prior to cardiopulmonary bypass. Two groups of patients were identified as those receiving antithrombin and those not receiving antithrombin. Outcome measures included activated clotting time values and transfusion rates. Consecutive patients (n = 140) were included in the study with 10 (7.1%) in the antithrombin group. The average antithrombin dose was 1,029.0 ± 164.5 IU and all patients had restoration to the activated clotting time levels. Patients in the antithrombin group were on preoperative heparin therapy (80.0% vs. 24.6%, p = 0.001). Prior to cardiopulmonary bypass the activated clotting time values were lower in the antithrombin group (417.7 ± 56.1 seconds vs. 581.1 ± 169.8 seconds, p = 0.003). Antithrombin patients had a lower heparin sensitivity index (0.55 ± 0.17 vs. 1.05 ± 0.44 seconds heparin-1 IU kg-1, p = 0.001), received more total heparin (961.3 ± 158.5 IU kg-1 vs. 677.5 ± 199.0 IU kg-1, p = 0.001), more cardiopulmonary bypass heparin (22,500 ± 10,300 IU vs. 12,100 ± 13,200 IU, p = 0.016), and more protamine (5.4 ± 1.2 vs. 4.1 ± 1.1 mg kg-1, p = 0.003). The intraoperative transfusion rate was higher in the antithrombin group (70.0% vs. 35.4%, p = 0.035), but no differences were seen postoperatively. Utilization of a goal-directed algorithm for the administration of antithrombin for the treatment of heparin resistance is effective in patients undergoing cardiac surgery.

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

AimsThrombin 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 methodsA 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 findingsTreatment 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. SignificanceTreatment 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.

A narrative review of antithrombin use during veno-venous extracorporeal membrane oxygenation in adults: rationale, current use, effects on anticoagulation, and outcomes.

During extracorporeal membrane oxygenation, the large contact surface between the blood and the extracorporeal circuit causes a continuous activation of coagulation and inflammation. Unfractionated heparin, a glycosaminoglycan that must bind to antithrombin as a cofactor, is currently the standard anticoagulant adopted during extracorporeal membrane oxygenation. Antithrombin, beyond being a potent natural anticoagulant, acts in the cross-talk between coagulation and inflammatory system through anticoagulation and coagulation-independent effects. In this review, we describe, in the adult setting of veno-venous extracorporeal membrane oxygenation, the pathophysiological rationale for antithrombin use, the current practice of administration, and the effects of antithrombin on anticoagulation, bleeding, and outcomes. Studies on adults (18 years or older) on veno-venous extracorporeal membrane oxygenation published from 1995 to 2018 in order to evaluate the use of antithrombin. In adults on veno-venous extracorporeal membrane oxygenation, antithrombin supplementation has a highly pathophysiological rationale since coagulation factor consumption, systemic inflammatory response syndrome, and endothelial activation are triggered by extracorporeal membrane oxygenation. Eleven articles are focused on the topic but among the authors there is no consensus on the threshold for supplementation (ranging from 70% to 80%) as well as on the dose (rarely standardized) and time of administration (bolus vs continuous infusion). Consistently, antithrombin is considered able to achieve better anticoagulation targets in or not in the presence of heparin resistance. The impact of antithrombin administration on bleeding still shows contrasting results. Antithrombin use in veno-venous extracorporeal membrane oxygenation should be investigated on the threshold for supplementation, dose, and time of administration.

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

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. 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. 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. 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.

Administration of Andexanet Alfa for Direct Factor Xa Inhibitor Reversal Precludes Therapeutic Heparinization for Cardiopulmonary Bypass

Normal hemostasis is desired prior to invasive procedures such as surgery. For emergent surgeries, where waiting for an anticoagulant to wear off is not an option, reversal agents or antidotes are often administered. However, for cardiac surgery requiring cardiopulmonary bypass (CPB), hemostatic needs vary throughout the procedure. Early in the procedure, normal hemostasis is preferred for skin incision, sternotomy, and cannulation. However, during CPB, strong anticoagulation is needed, typically with unfractionated heparin (UFH), to prevent thrombosis in the circuit. Thus, any anticoagulant reversal agent administered prior to cardiopulmonary bypass must not interfere with heparinization. Andexanet alfa (AnXa) is the only FDA-approved reversal agent for oral direct factor Xa (FXa) inhibitors. AnXa is a recombinant FXa variant that lacks the membrane-binding Gla domain and is catalytically inactive due to mutation of the active site serine 195 residue to alanine. It retains active site conformation, and therefore binds active site inhibitors like rivaroxaban, apixaban, and edoxaban, with high affinity. When administered in stoichiometric quantities, it can rapidly sequester direct factor Xa inhibitors and thereby neutralize their effects. However, AnXa has also been reported to reverse the anticoagulant effects of indirect FXa inhibitors, including low molecular weight heparin, fondaparinux, and UFH, both in vitro and in vivo. Given its biochemical properties and mechanism of action, we hypothesized that administration of AnXa would severely limit the anticoagulant efficacy of UFH and delay safe initiation of CPB. To evaluate this, we measured activated clotting times (ACT) in whole blood from healthy volunteers (N=8) supplemented with varying concentrations of AnXa, UFH, and rivaroxaban. As expected, 4 U/mL UFH, a frequently cited therapeutic concentration for CPB, prolonged the ACT to 418±45s, compared to a baseline ACT of 117±8s. For reference, an ACT of 400s is typically considered the minimum safe level of anticoagulation needed for CPB. In comparison, "low dose" AnXa, 2 mM, in the presence of 4 U/mL UFH and typical blood concentrations of rivaroxaban, 500 nM, resulted in an average ACT of 189±26s, well below the level needed for CPB. In an attempt to overcome the effects of AnXa, we repeated these experiments with supratherapeutic levels of UFH, 16 U/mL, in the presence of 2mM AnXa and rivaroxaban, which prolonged the ACT to 376±36s, but was not reliably above the 400 s threshold. In the absence of AnXa, 16 U/mL heparin resulted in an ACT near 1000 s. In patients who have recently taken rivaroxaban, a "high dose" of AnXa, approximately 4 mM, is typically used. 4 mM AnXa in the presence of 4 U/mL or 16 U/mL UFH and 500 nM rivaroxaban yielded ACT values of 139±17s and 184±27s, respectively. Administration of recombinant antithrombin III (AT) was not able to overcome the effects of AnXa. To help elucidate the mechanism by which AnXa hinders heparinization, we measured the kinetics of FXa inhibition by AT in the presence of heparin. As shown in Figure 1, AnXa slows the rate of FXa-AT complex formation in a dose-dependent manner. When the stoichiometry of the reaction is taken into consideration, this indicates that AnXa sequesters heparin in a ternary complex with AT which thereby prevents heparin from being free to potentiate AT's interaction with endogenous FXa. Together, these data suggest that therapeutic heparinization after administration of AnXa is, at best, challenging, if not impossible. From a clinical perspective, this information is crucial in emergent cases as providers will either need to choose alternative anticoagulation strategies for CPB (such as argatroban, bivalirudin, or an emerging FXIa or FXIIa inhibitor), or avoid AnXa and tolerate increased bleeding upon sternotomy prior to CPB. Further, it poses an important safety concern as patients requiring emergent cardiac surgery are often hemodynamically unstable and delays in initiation of CPB due to inability to therapeutically heparinize following AnXa administration could adversely affect outcomes. We are currently evaluating whether the effects of AnXa on heparinization translate to increased thrombosis on CPB oxygenator membranes using an in vitro extracorporeal circulation model. Disclosures Patel: Edward's Life Sciences: Other: Speaker. Camire:Pfizer: Research Funding.