Argatroban Dose Research Articles

Monitoring of Argatroban in Critically Ill Patients: A Prospective Study Comparing Activated Partial Thromboplastin Time, Point-of-Care Viscoelastic Testing with Ecarin Clotting Time and Diluted Thrombin Time to Mass Spectrometry.

The direct thrombin inhibitor argatroban is indicated for the treatment of heparin-induced thrombocytopenia II, but it is also used off-label to treat critically ill patients presenting with heparin resistance, severe antithrombin deficiency, or hypercoagulability. Direct drug monitoring is not routinely available, and argatroban dosing is mainly based on global coagulation assays such as activated partial thromboplastin time (PTT) or diluted thrombin time (TT), both of which have limitations in patients with hypercoagulability. Blood samples were obtained from critically ill patients treated with argatroban. Activated PTT and diluted TT were measured with a STA R Max3 analyzer (STAGO Deutschland GmbH, Germany) using an argatroban-calibrated kit. Ecarin clotting time was measured using a point-of-care viscoelastic test device. Liquid chromatography with tandem mass spectrometry was performed using a reversed-phase column, a solvent gradient, and an API4000 mass spectrometer with electrospray. Correlation was described using Pearson correlation coefficient r and Bayesian multilevel regression to estimate relationships between outcomes and covariates. From June 2021 to March 2022, 205 blood samples from 22 patients were analyzed, allowing for 195 activated PTT-liquid chromatography with tandem mass spectrometry comparisons, 153 ecarin clotting time-liquid chromatography with tandem mass spectrometry comparison, and 105 diluted TT-liquid chromatography with tandem mass spectrometry comparisons. Compared to liquid chromatography with tandem mass spectrometry, performance of argatroban quantification was best for diluted TT (r = 0.91), followed by ecarin clotting time (r = 0.58) and activated PTT (r = 0.48). Regression analysis revealed that patients with sepsis were more prone to argatroban overdosing (coefficient, 4.194; 95% credible interval, 2.220 to 6.792). Although activated PTT monitoring of argatroban is the most commonly used test, in critically ill patients, diluted TT provides more precise measurements. Alternately, point-of-care viscoelastic ecarin clotting time also provides guidance for argatroban dosing to identify overdosing if available. The data also suggested that patients with sepsis are at greater risk for argatroban overdosing.

Association of Argatroban Dose With Coagulation Laboratory Test in Patients on Extracorporeal Membrane Oxygenation: Activated Clotting Time vs Activated Partial Thromboplastin Time.

Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration. This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment. We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin. Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 (P < 0.001) and 0.194 (P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day. A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.

Veno-venous Extracorporeal Membrane Oxygenation: Anesthetic Considerations in Clinical Practice.

After the COVID-19 pandemic, multiple reviews have documented the success of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients who experience hypoxemia but have normal contractility may be switched to veno-venous-ECMO (VV-ECMO). In this review, we present three protocols for anesthesiologists. Firstly, transesophageal echocardiography (TEE) aids in cannulation and weaning off inotropes and fluids. Our main objective is to assist in patient selection for the Avalon Elite single catheter, which is inserted into the right internal jugular vein and terminates in the right atrium. Secondly, we propose appropriate anticoagulant doses. We outline day-to-day monitoring protocols to prevent heparin-induced thrombocytopenia (HIT) or resistance. Once the effects of neuromuscular paralysis subside, sedation should be reduced. Therefore, we describe techniques that may prevent delirium from progressing into permanent cognitive decline. We conducted a PubMed search using the keywords VV-ECMO, TEE, Avalon Elite (Maquet, Germany), and quetiapine. We combined these findings with interviews conducted with nurses and anesthesiologists from two academic ECMO centers, focusing on anticoagulation and sedation. Our qualitative evidence synthesis reveals how TEE confirms cannulation while avoiding right atrial rupture or low flows. Additionally, we discovered that typically, after initial heparinization, activated partial thromboplastin time (PTT) is drawn every 1 to 2 hours or every 6 to 8 hours once stable. Daily thromboelastograms, along with platelet counts and antithrombin III levels, may detect HIT or resistance, respectively. These side effects can be prevented by discontinuing heparin on day two and initiating argatroban at a dose of 1 μg/kg/min while maintaining PTT between 61 - 80 seconds. The argatroban dose is adjusted by 10 - 20% if PTT is between 40 - 60 or 80 - 90 seconds. Perfusionists assist in establishing protocols following manufacturer guidelines. Lastly, we describe the replacement of narcotics and benzodiazepines with dexmedetomidine at a dose of 0.5 to 1 μg/kg/hour, limited by bradycardia, and the use of quetiapine starting at 25 mg per day and gradually increasing up to 200 mg twice a day, limited by prolonged QT interval. The limitation of this review is that it necessarily covers a broad range of ECMO decisions faced by an anesthesiologist. However, its main advantage lies in the identification of straightforward argatroban protocols through interviews, as well as the discovery, via PubMed, of the usefulness of TEE in determining cannula position and contractility estimates for transitioning from VA-ECMO to VV-ECMO. Additionally, we emphasize the benefits in terms of morbidity and mortality of a seldom-discussed sedation supplement, quetiapine, to dexmedetomidine.

Application of argatroban in patients receiving extracorporeal membrane oxygenation support: a case-control study

To evaluate the safety and efficacy of argatroban applied as alternative anticoagulant in critical illness patients underwent extracorporeal membrane oxygenation (ECMO) with contraindications of unfractionated heparin (UFH), and to further explore the effective dose of argatroban. From July 1, 2013 to February 28, 2022, there were 14 patients who admitted in the respiratory intensive care unit (RICU) of Beijing Chao-Yang Hospital received ECMO and used argatroban for anticoagulation (argatroban group). Two of them received argatroban as the initial anticoagulant. The remaining 12 patients used UFH at first, and then switched to argatroban. UFH group included 28 patients who received UFH for anticoagulation after matching the demographic characteristics. Primary endpoint was the prevalence of ECMO-related thrombotic events. Secondary endpoints included the type of thrombotic events, prevalence of ECMO-related major bleeding events, bleeding sites, ICU mortality, mortality during ECMO, liver and kidney function, thrombelastogram, blood transfusion, dosage of argatroban, the dynamic changes of coagulation variables 4 days before and 7 days after argatroban treatment. In argatroban group, there were 8 patients received veno-venous ECMO (VV-ECMO), 2 patients with veno-arterial ECMO (VA-ECMO), and 4 patients with veno-arterio-venous ECMO (VAV-ECMO). In UFH group, VV-ECMO was applied in 23 patients, VA-ECMO and VAV ECMO was established in 3 patients and 2 patients, respectively. In endpoint events, the incidence of ECMO related thrombotic events in argatroban group was slightly higher than that in UFH group (28.6% vs. 21.4%). The ECMO running time in argatroban group was slightly longer than that in UFH group [days: 16 (7, 21) vs. 13 (8, 17)]. The incidence of ECMO-related bleeding events (28.6% vs. 32.1%) and mortality during ECMO (35.7% vs. 46.4%) in argatroban group were slightly lower than those in UFH group. However, the differences were not statistically significant (all P < 0.05). The platelet transfusion in argatroban group was significantly higher than that in UFH group [U: 7.7 (0, 10.0) vs. 0.8 (0, 1.0)]. The coagulation reaction time (R value) in thrombelastography in argatroban group was significantly longer than that in UFH group [minutes: 9.3 (7.2, 10.8) vs. 8.8 (6.3, 9.7)]. The maximum width value [MA value, mm: 48.4 (40.7, 57.9) vs. 52.6 (45.4, 61.5)] and blood clot generation rate [α-Angle (deg): 54.1 (45.4, 62.0) vs. 57.9 (50.2, 69.0)] in the argatroban group were significantly lower than those in the UFH group (all P < 0.05). The activated partial thromboplastin time (APTT) was prolonged after changing from UFH to argatroban in the argatroban group [seconds: 63.5 (58.4, 70.6) vs. 56.7 (53.1, 60.9)]. The PLT level showed a decreasing trend during UFH anticoagulation therapy, and gradually increased after changing to argatroban. D-dimer level was 19.1 (7.0, 28.7) mg/L after switching to argatroban, and then no longer showed an increasing trend. The level of fibrinogen (FIB) showed a decreasing trend during the anticoagulant therapy of UFH (the lowest was 23.6 g/L), and fluctuated between 16.8 and 26.2 g/L after changing to argatroban. The median initial dose of argatroban was 0.049 (0.029, 0.103) μg×kg-1×min-1, which the highest dose was in VV-ECMO patients of [0.092 (0.049, 0.165) μg×kg-1×min-1]. The initial dose of VAV-ECMO was the lowest [0.026 (0.013, 0.041) μg×kg-1×min-1], but without significant difference (P > 0.05). The maintenance dose of argatroban was 0.033 (0.014, 0.090) μg×kg-1×min-1, VV-ECMO patients was significantly higher than those in VA-ECMO and VAV-ECMO patients [μg×kg-1×min-1: 0.102 (0.059, 0.127) vs. 0.036 (0.026, 0.060), 0.013 (0.004, 0.022), both P < 0.05]. Argatroban appears to be a feasible, effective and safety alternative anticoagulant for patients with contraindications to UFH who undergoing ECMO support.

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Heparin-Induced Thrombocytopenia in COVID-19: A Systematic Review.

Background:It has been more than a year since the whole world is struggling with COVID-19 pandemic and may experience resurgences in the near future. Along with severe pneumonia, this disease is notorious for extensive thromboembolic manifestations. That is why experts advocated aggressive anticoagulation as a part of the therapy since the beginning. However, from May 2020 onwards, cases of heparin-induced thrombocytopenia (HIT) are being reported. HIT in itself is an autoimmune entity leading to life-threatening thrombosis in the setting of thrombocytopenia. Continuation of heparin can have disastrous consequences in case of unrecognized HIT. Hence, timely recognition of HIT is of utmost value to modify the anticoagulation strategy and salvaging lives. We performed a systemic review trying to find all reported cases of HIT in COVID-19.Methods:It involved extensive search of the databases including PubMed, Google Scholar, Scopus, and Embase in an attempt to find all reported literature in the last 1 year (November 1, 2019–December 25, 2020) using keywords in various combinations. Literature search resulted in a total of 27 articles and 12 articles were finally selected based on the study design and their relevance pertaining to the intervention done and the outcome of interest. Results:A total of 35 patients were included (mean age 56.7 ± 12.8 years, male-to-female ratio = 2:1). The most frequent comorbidity was hypertension. Fifty-seven percent of cases were with low-molecular weight heparin and the rest with unfractionated heparin. Confirmatory functional assay was done in 85.7% of cases (67% by serotonin-release assay [SRA] and 33% by heparin-induced platelet aggregation [HIPA]). All cases tested with HIPA were positive, while with SRA, only 30% were positive. The most common alternate anticoagulation used was argatroban infusion. The new arterial thrombotic event was seen in only 5.7% of cases as repeat myocardial infarction, stroke, and splenic infarction, while clinically significant bleeding was seen in 17.1% of cases. Fifty percent of bleeding episodes were seen where conventional doses of argatroban were used, while no mortality was seen with low-dose argatroban infusion. However, only 45.7% of patients were discharged, 31.4% of patients died, while the outcome was pending for 23% of patients.Conclusion:Severe endotheliitis and immune dysregulation giving rise to HIT antibodies and antiphospholipid antibodies have been demonstrated in COVID-19 and modifying our therapy becomes indispensable when it is pathogenic with potentially fatal consequences. In the light of interim results of REMAP-CAP study in severe COVID-19 cases where heparin does not improve the outcome, the present anticoagulation strategy needs re-evaluation. Unrecognized HIT can be catastrophic and close clinical monitoring is required for patients on heparin therapy.

Comparison of percent adjusted versus predefined incremental argatroban dosing nomograms in patients with heparin induced thrombocytopenia

IntroductionHeparin-induced thrombocytopenia (HIT) necessitates initiation of non-heparin based anticoagulation to prevent long-term sequelae. Optimal anticoagulation needs to be reached safely and rapidly. The optimal adjustment of argatroban dosing has remained unclear. Materials and methodsThis retrospective cohort study at UI Health screened patients between 1/1/2011 to 3/21/2017. Patients were included if argatroban was administered for 24 h or more for suspected or confirmed HIT. The primary outcome was to compare time to reach 2 consecutive activated partial thromboplastin time within 60 to 100 s (stable therapeutic aPTT) between pre-guideline (dose incremental adjusted) and post-guideline (percent adjusted) nomograms. Secondary outcomes were to characterize safety events and analyze the effect of covariates on the primary outcome. ResultsA total of 231 patients were screened, 29 patients pre-guideline and 24 patients post-guideline were included. The mean ± SD time to reach stable therapeutic aPTT was 17.3 ± 14.4 h pre-guideline and 27.4 ± 23.5 h post-guideline (p=0.08). The mean ± SD number of dose adjustments was 1.5 ± 2.2 pre-guideline and 1.7 ± post-guideline (p = 0.89). ICU admission, hepatic impairment, albumin level, total bilirubin level, weight, and starting argatroban dose did not statistically affect time to stable therapeutic aPTT. There were 3 major bleed events and 3 thrombotic events, all occurred in pre-guideline cohort. ConclusionsNo statistically significant difference in time to reach therapeutic anticoagulation between dosing nomograms or in any safety or clinical outcomes was found. Less stringent, provider-driven argatroban dosing nomograms may have similar efficacy and safety to more aggressive dosing.

Thrombin inhibitor argatroban modulates bone marrow stromal cells behaviors and promotes osteogenesis through canonical Wnt signaling

AimsCoagulation is a common event that play a double-edged role in physiological and pathological process. Anti-coagulation methods were applied in joint surgery or scaffolds implantation to encourage new vascular formation and avoid coagulation block. However, whether anti-coagulation drug perform regulatory roles in bone structure is unknown. This study aims to explore a direct thrombin inhibitor, argatroban, effects on bone marrow stromal cells (BMSCs) and decipher the underlying mechanisms. Materials and methodsArgatroban effects on BMSCs were investigated in vivo and in vitro. The drug was applied in periodontal disease model mice and bone loss was evaluated by μCT and histology. BMSCs were treated with different doses argatroban or vehicle. Cellular reactions were analyzed using wound healing assay, qRT-PCR, Alizarin Red S staining and western blotting. Key findingsWe demonstrated that local injection of argatroban can rescue bone loss in periodontal disease in vivo. To explore the underlying mechanism, we examined that cell proliferation and differentiation capability. Proliferation and migration of BMSCs were both inhibited by applying lower dose of argatroban. Interestingly, without affecting osteoclastogenesis, osteogenic differentiation was significantly induced by argatroban, which were shown by extracellular mineralization and upregulation of early osteoblastic differentiation markers, alkaline phosphatase, Osteocalcin, transcription factors RUNX2 and Osterix. In addition, molecular analysis revealed that argatroban promoted β-catenin nuclear translocation and led to an increase of osteogenesis through activating canonical Wnt signaling. SignificanceTaken together, our results show the novel application of the anti-coagulation compound argatroban in the commitment of BMSCs-based alveolar bone regeneration and remodeling.

HEPARIN-INDUCED THROMBOCYTOPENIA IN A PATIENT WITH ANTI-PHOSPHOLIPID SYNDROME AFTER AORTIC VALVE REPLACEMENT

SESSION TITLE: Medical Student/Resident Critical Care SESSION TYPE: Med Student/Res Case Report PRESENTED ON: October 18-21, 2020 INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a feared complication of heparin exposure due to antibodies against platelet factor 4 (PF4) and heparin. The reported incidence of HIT ranges from 0.1 to 5% in patients exposed to heparin (1). Nearly all patients undergoing cardiac surgery are exposed to heparin and up to 50% of patients who undergo cardiopulmonary bypass develop antibodies to PF4. Though this does not necessarily correlate to a higher incidence, 1-2% of cardiac patients develop HIT. In these patients, alternative agents for anticoagulation are required, presenting unique challenges in monitoring. CASE PRESENTATION: A 44-year-old female with severe aortic insufficiency and moderate aortic stenosis was scheduled for aortic valve replacement (AVR). Her history was notable for anti-phospholipid syndrome (APLS) with an extensive history of thromboses including hepatic, renal, pulmonary and placental thrombosis, maintained on chronic warfarin. The patient had a remote history of HIT; however, pre-operatively she had a negative PF4 antibody and serotonin release assay (SRA), and bridging was done with enoxaparin. She underwent successful AVR with heparin use intra-operatively. Post-operatively, her platelet counts down-trended from 166,000/μL to 78,000/μL. Given her remote history of HIT, repeat antibody and SRA were sent and argatroban was used for post-op anticoagulation. As the patient’s baseline activated partial thromboplastin time (aPTT) was prolonged, argatroban was titrated using thrombin time (TT). Argatroban was started at 0.2 mcg/kg/min. TT was assessed every 6 hours after initiation with titration by 0.1mcg/kg/min until a therapeutic goal of 30-50 seconds was achieved. DISCUSSION: In healthy patients, aPTT is recommended for monitoring the effect of argatroban. However, in the case of APLS, antibodies interfere with coagulation tests that are phospholipid dependent, resulting in a prolonged baseline aPTT. Though there is no established range for the use of TT for monitoring argatroban, a recent study of agatroban in critically ill patients found TT to correlate with plasma drug concentrations (2). Low levels of argatroban were found to correlate with TT that are 30-50 seconds and intermediate plasma levels of argatroban correlate with TT that are approximately 50-100 seconds. Other options include fixed dose argatroban without monitoring of laboratory parameters or using non-phospholipid dependent measures such as thromboelastometry (3). CONCLUSIONS: As is demonstrated in this case, suspected HIT following cardiac surgery can be difficult to manage; this is further compounded in patients with APLS with baseline altered coagulation parameters. When a direct thrombin inhibitor is used, TT monitoring can be considered in patients that cannot be monitored using aPTT. Reference #1: Pishko AM, Cuker A. Heparin-Induced Thrombocytopenia in Cardiac Surgery Patients. Semin Thromb Hemost. 2017; 43(7):691–698. Reference #2: Beiderlinden M, Werner P, Bahlmann A, et al. Monitoring of argatroban and lepirudin anticoagulation in critically ill patients by conventional laboratory parameters and rotational thromboelastometry - a prospectively controlled randomized double-blind clinical trial. BMC Anesthesiol. 2018; 18(1):18. Reference #3: Pendleton, R., Wheeler, M. M., & Rodgers, G. M. Argatroban Dosing of Patients with Heparin-Induced Thrombocytopenia and an Elevated aPTT Due to Antiphospholipid Antibody Syndrome. Annals of Pharmacotherapy. 2006; 40(5): 972–976. DISCLOSURES: No relevant relationships by Ashley Budd, source=Web Response No relevant relationships by Prachi Patel, source=Web Response

Monitoring and Dosing of Argatroban in a Patient With Antiphospholipid Syndrome.

Background: This case reports outlines argatroban dosing and necessary dose adjustments in a 56 year-old male with a past medical history of antiphospholipid syndrome and heparin-induced thrombocytopenia. Method: Argatroban was initiated as a fixed dose of 0.5 µg/kg/min with all initial aPTTs above goal. Argatroban was held for a procedure and re-initiated at 0.25 µg/kg/min. The dose was increased or decreased by 25% from the current rate based on supratherapeutic and subtherapeutic aPTTs, respectively. Results: The patient remained on argatroban for 6 total days, while achieving goal aPTT levels with no VTE or bleeding events. Conclusion: Our patient represents the first reported case of monitoring argatroban with aPTTs in an individual with APS.

Comparison of a predefined dose increment nomogram with a percentage adjustment nomogram in patients receiving argatroban therapy

ObjectiveTo determine the compliance with a predefined dose increment (PDI) nomogram compared with a percentage adjustment (PA) nomogram for the dose titration of argatroban therapy. DesignThis was a single-center, retrospective chart review. Setting and participantsThis study was conducted in a tertiary care teaching hospital. Patients were included if they received argatroban from 2013 to 2016. Outcome measuresThe primary safety outcome was the percentage of appropriate dose titrations. The secondary safety and efficacy outcomes included the median time to therapeutic activated partial thromboplastin time (aPTT), the median argatroban dose once therapeutic, and the median time in the therapeutic, subtherapeutic, and supratherapeutic aPTT ranges, as well as the bleeding and thrombotic events during hospitalization. ResultsSeventy-seven patients were included in the study. There was no statistically significant difference in the percentage of titrations performed appropriately (P = 0.17). The median time to goal aPTT, the dose when first therapeutic, and the time aPTT was subtherapeutic were similar in both the arms. The patients in the PDI arm were on argatroban for a median time of 55 hours compared with 110.5 hours for the patients in the PA arm (P = 0.001). The patients in the PA arm spent more time in the therapeutic range (P < 0.05) and less time in the supratherapeutic range (P < 0.005). ConclusionAlthough there was no difference in the percentage of appropriate dose titrations, the patients in the PA arm spent more time on argatroban, had greater time in the therapeutic aPTT range, and had less time in the supratherapeutic aPTT range. Future studies that include a larger sample size, matching therapeutic aPTT ranges, and similar initial infusion rates would help evaluate further the outcomes between the PDI and PA nomograms.

Argatroban dosing requirements in extracorporeal life support and other critically ill populations

Argatroban is a parenteral direct thrombin inhibitor that requires close monitoring to ensure safety and efficacy. Limited data exist to describe its effect in critically ill patients. This was a retrospective, single-center, cohort study that aimed to compare argatroban dosing requirements in those receiving extracorporeal life support (ECLS), continuous renal replacement therapy (CRRT), or neither. Organ dysfunction was assessed using a modified version of the Sequential Organ Failure Assessment (modSOFA) that incorporated the use of extracorporeal support systems. Eighty patients were included in the study (n = 20, 20, 40 in the ECLS, CRRT, and support-free groups, respectively). The majority of patients were Child-Pugh classification B (73%). Median modSOFA scores were higher in the ECLS (16.5) and CRRT (15.5) groups than in the support-free group (7.5) (P < .001). There was no difference in the primary outcome of first therapeutic argatroban dose between the three groups (0.5 μg/kg/min for each; IQRs 0.25–0.50, 0.11–0.50, and 0.25–0.50, respectively; P = .455). The ECLS group had the lowest mean (0.39 μg/kg/min), minimum (0.20 μg/kg/min), and final (0.43 μg/kg/min) doses. ECLS patients had more supratherapeutic aPTTs and dose changes overall, supporting the need for more frequent anticoagulation monitoring or dose reductions in this population. Total modSOFA score demonstrated a moderate inverse correlation with first therapeutic dose (dose = 0.54 – (modSOFA score × 0.012); R = −0.342, P = .002). Overall, initial argatroban doses of 0.3–0.5 μg/kg/min appear to achieve therapeutic aPTT values in the studied populations.

Use of argatroban in combination with nafamostat mesilate in open-heart surgery for a pediatric patient with heparin-induced thrombocytopenia type II: a case report

BackgroundHeparin-induced thrombocytopenia type II (HIT II) is a rare, immune-mediated complication of heparin therapy and can cause life-threatening thromboembolism. However, perioperative anticoagulation therapy for patients with a complication of HIT II has not been established.Case presentationA 6-year-old boy with tetralogy of Fallot underwent radical intracardiac repair with administration of argatroban at 1 year old due to positive HIT antibody. Reoperation was scheduled for pulmonary valve insufficiency, using argatroban and nafamostat mesilate as anticoagulants. Argatroban has a long onset time and the activated coagulation time (ACT) requires 7–26 h to return to the preadministration level, making hemorrhage control difficult, while half-life of nafamostat mesilate is shorter than that of argatroban. Celite ACT reflects the effects of both argatroban and nafamostat mesilate, but kaolin ACT reflects only the effect of argatroban. Due to the early termination of argatroban administration based on Celite and kaolin ACTs, ACT recovered to ≤ 200 s at 5 h after the end of argatroban administration.ConclusionCelite and kaolin ACTs can be used as markers to obtain close control of the required dose of argatroban in combination with nafamostat mesilate for the management of HIT II patients.

PB2257 USE OF ARGATROBAN AS AN ANTICOAGULANT TREATMENT ALTERNATIVE IN CRITICAL PATIENTS WITH HEPARIN‐INDUCED THROMBOCYTOPENIA. EXPERIENCE IN A THIRD LEVEL HOSPITAL.

Background:Heparin is a widely used drug. The most frequent complication derived from its use is the haemorrhage. However, an uncommon but potentially serious adverse effect is heparin‐induced thrombocytopenia (HIT). The goal of treatment of HIT is to reduce platelet activation and thrombin formation to decrease the risk of thrombosis. Argatroban is the drug of choice in HIT patients as an alternative anticoagulant treatment in critically ill patients with high risk of haemorrhage, postoperative cardiac events or renal failure, since it allows close control of anticoagulation.Aims:To analyze the clinical, laboratory and therapeutic characteristics of patients treated with Argatroban by HIT in our hospitalMethods:Retrospective analysis or patients treated with Argatroban for diagnosed HIT during the last year.Results:Four patients have required treatment with Argatroban for HIT since they required maintenance of anticoagulation due to mitral prosthesis, unstable angina, DVT in the right lower extremity and acute ischemia in the left lower extremity. Median age 68 years (43‐79). All of them were diagnosed with HIT according to the 4T score during their admission to the Intensive Care Unit. PF4/Heparin antibody testing was positive in the four patients.The median number of days from the start of Heparin treatment (2 with unfractioned and 2 with low molecular weight) to the onset of thrombocytopenia was 6 days (1‐8). Median platelets at diagnosis were 73x109/L (49‐82). Median number of days from the start of Argatroban to platelet recovery was 6 days (3‐12). Median number of days of treatment with Argatroban was 9.5 days (2‐18). Argatroban dose was adjusted to maintain aPTT at 1.5‐3.0 times baseline. 3 patients presented thrombotic events, 2 directly related to HIT (1 ischemic stroke and 1 acute ischemia of right upper extremity) and 1 with worsening of reperfusion of the limb. 2 patients required amputation of the limb. No adverse events associated with Argatroban, including haemorrhage, were observed.Summary/Conclusion:HIT is a potentially catastrophic complication of heparin treatment which requires urgent detection and treatment with a non‐heparin anticoagulant such as Argatroban should be initiated. Even in critically ill patients, Argatroban anticoagulation improves clinical outcomes in patients who have HIT, without increasing bleeding risk.

Evaluation of the Use of Argatroban or Bivalirudin for the Management of Suspected Heparin-Induced Thrombocytopenia in the Setting of Continuous Renal Replacement Therapy

Studies have shown an association between continuous renal replacement therapy (CRRT) and thrombocytopenia. Patients on CRRT usually receive unfractionated heparin (UFH), and heparin-induced thrombocytopenia (HIT) is frequently suspected as a potential cause of thrombocytopenia. In the setting of HIT suspicion, changes in anticoagulation may put patients at risk of developing thromboembolic events or adverse medication effects. Purpose: The purpose of this study was to investigate current management of anticoagulation in patients with suspected HIT while on CRRT and identify complications associated with anticoagulation in this setting. Methods: This is a retrospective study of patients on CRRT with suspicion for HIT. Prevalence of HIT and anticoagulant use were collected for all patients. Outcomes included thromboembolic and bleeding events, final therapeutic doses of each anticoagulant, and time to reach therapeutic range. Thromboembolic and bleeding outcomes were compared between anticoagulants. Results: From January 2013 through December 2015, 74 patients were identified with suspicion of HIT while on CRRT. During the period of HIT suspicion, 20 patients received argatroban, 18 received bivalirudin, 1 received fondaparinux, 4 received UFH infusions, 10 received prophylactic dosing subcutaneous UFH, and 21 received no anticoagulation. The median final therapeutic doses of argatroban and bivalirudin were 1.00 μg/kg/min and 0.075 mg/kg/h, respectively, with no difference in time to therapeutic range (17.6 h vs 18.2 h, P = .485). Compared with bivalirudin, patients treated with argatroban had significantly more therapeutic activated partial thromboplastin time (aPTT) values (54.5% vs 42.8%, P = .008). Four patients (20.0%) treated with argatroban and 5 patients (27.8%) treated with bivalirudin experienced major bleeding ( P = .709). Three patients (15.0%) treated with argatroban and 4 patients (22.2%) treated with bivalirudin experienced thromboembolic events ( P = .687). Conclusion: Argatroban and bivalirudin were associated with similar rates of bleeding and thromboembolic events during the period of concurrent CRRT and thrombocytopenia, although patients treated with argatroban had more therapeutic aPTT values.

Use of argatroban for extracorporeal life support in patients with nonheparin-induced thrombocytopenia: Analysis of 10 consecutive patients.

Unfractionated heparin (UFH) is currently the standard anticoagulant used in extracorporeal life support (ECLS). However, severe thrombocytopenia occurs frequently during ECLS use and it may be difficult to determine whether this represents heparin-induced thrombocytopenia (HIT) or not. In this case, UFH cannot be continued. Because a confirmatory laboratory test requires time, argatroban is empirically used if HIT is suspected. However, many patients are not found to have HIT. In non-HIT patients, the effectiveness and safety of argatroban are unclear. Thus, we investigated whether argatroban was safe and useful in patients who were suspected of having HIT and were started on argatroban, but were ultimately found to have non-HIT.We retrospectively reviewed all patients on ECLS who received the anticoagulant argatroban as an alternative to UFH between January 2014 and July 2015. The pretest clinical score (4Ts) was calculated, and a score greater than 4 was considered an indication for argatroban. The target-activated clotting time or activated partial thromboplastin time was 1.5 times the patient's upper normal value. Of 191 patients on ECLS during the study period, 10 (5.2%) were treated with argatroban infusion.No patients were found to have antiplatelet factor 4/heparin antibodies. The average maintenance dose of argatroban was 0.1 μg/kg/min. Platelet counts increased significantly following argatroban administration (P = .02). There were no anticoagulation-related complications such as bleeding or thrombosis.Our results suggest that argatroban is a safe alternative to UFH for patients with non-HIT on ECLS. Argatroban may have a more significant platelet-preserving effect than UFH, regardless of whether HIT is present.

Heparin-Induced Thrombocytopenia in Infants after Heart Surgery.

Heparin-induced thrombocytopenia (HIT) in infants is a rare disorder, and the diagnosis and management of HIT still remains challenging. Argatroban is a synthetic direct thrombin inhibitor (DTI) that is widely used for treating HIT. However, little is known about the efficacy of the activated clotting time (ACT) test in monitoring DTI treatment as an alternative to the routinely used activated partial thromboplastin time (aPTT). Between July 2013 and January 2015, four infants were diagnosed with HIT after surgical correction of congenital anomalies. In all cases, heparin was used during cardiopulmonary bypass (CPB). Diagnosis of HIT was based on the "4 Ts" pretest clinical scoring system, and platelet factor 4 (PF4) antibody was detected using enzyme-linked immunosorbent assay. Argatroban was used in treating HIT. When argatroban was infused, anticoagulation tests (aPTT, prothrombin time [PT], thrombin time [TT], and fibrinogen) were performed every 4 to 12 hours. ACT was used in addition to monitor the anticoagulation effect of argatroban. The target ACT was 1.5 to 3.0 times the baseline. ACT was measured every 2 to 4 hours and remeasured 1 hour after each dosage adjustment. Thrombocytopenia (defined as a 50% decrease in platelet count) occurred during the 3rd to 6th day postoperatively. After the diagnosis of HIT, argatroban was started immediately, and platelet counts stabilized and gradually increased. Anticoagulation effect of argatroban was successful monitored by ACT and aPTT. Poor correlation between the ACT test and aPTT test (R = 0.270, p = 0.092) was noted in one patient. ACT values increased rapidly after 3 to 7 days on argatroban treatment. In most cases, low dosage of argatroban was given ranging from 0.04 to 5.00 μg/kg/min. Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study.

Anticoagulation Management during First Five Days of Infant-Pediatric Extracorporeal Life Support

Anticoagulation during infant-pediatric extracorporeal life support (ECLS) has been a topic of study for many years, but management of anticoagulation is still only partially understood. Adequate anticoagulation during ECLS is imperative for successful outcomes and understanding the individual variables that play part is crucial for properly implementing anticoagulation management strategies. The purpose of our study was to compare the relationships between the variables of activated partial thromboplastin time (aPTT), activated clotting time, international normalized ratio, bleeding, thrombus formation, kaolin + heparinase thromboelastograph alpha angle, kaolin thromboelastograph reaction time (KTEG R-time), heparin dose rates (HDR), antithrombin (AT), anti-Xa, bivalirudin dose rate, argatroban dose rate, interventions, and transfusions. We hypothesized that the relationship between measures of anticoagulation would be influenced by the AT levels, and a therapeutic aPTT (60–80 seconds) could be achieved by increasing, or maintaining, the overall AT above a specific threshold for infant-pediatric patients on ECLS. Thirty-five infant-pediatric patients underwent ECLS between January 2013 and January 2016. The median age was 39 days with an average weight of 3.9 ± 4.3 kg. ECLS parameters collected at least every 24 hours for the first five ECLS days. Parameters recorded by retrospective chart review were analyzed using linear regression and receiver operator characteristic (ROC) analysis. We were unable to report a significant correlation between optimal aPTT and HDR at various AT levels. However, ROC analysis suggested that to maintain an aPTT above 60 seconds, an AT threshold of 42% or higher was observed when the HDR was &gt;12 U/kg/h ROC analysis also determined that no thrombus was associated with an aPTT &gt;64 seconds and decreased bleeding was associated with a KTEG R-time below 30 minutes. Based on these findings, we report multiple correlations that may help develop future standardized infant-pediatric ECLS anticoagulation protocols.

Argatroban dosing in obesity

PurposeObesity is associated with significant alterations in pharmacokinetic and pharmacodynamic properties. The use of weight based anticoagulants such as argatroban may put obese patients at an increased risk of hemorrhagic events. The purpose of this study was to evaluate argatroban dosing requirements in obese vs non-obese patients. MethodsThis single-center, retrospective cohort study included patients ≥18 years with suspected HIT, treated with argatroban for ≥12 h. Patients were stratified by body mass index (BMI) into obese (BMI > 30 kg/m2) and non-obese (BMI ≤ 30 kg/m2) groups. The primary outcome was the median maintenance dose required to achieve two consecutive therapeutic activated partial thromboplastin times. ResultsA total of 121 patients were included. The median BMI in the obese vs non-obese groups was 35.8 vs 24.05 kg/m2 (p < .0001). Although statistically significant, there was no clinically significant difference in median maintenance argatroban dose in obese versus non-obese patients (1 vs 1 μg/kg/min; p = .01). In-hospital major bleeding and in-hospital thrombosis also did not differ between the two groups. ConclusionObese patients require similar median argatroban maintenance doses when compared to non-obese patients. Based on these results argatroban should be dosed using actual body weight regardless of BMI.