Anticoagulation Monitoring Using Activated Clotting Time in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis of Correlation Coefficients.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to maintain the circuit patency. However, the use of anticoagulation carries a risk of severe hemorrhage, necessitating rigorous monitoring. Activated clotting time (ACT) is a widely used monitoring tool; however, the evidence of its correlation with unfractionated heparin (UFH) infusion dose is limited. Here we aimed to analyze the correlation between ACT and UFH infusion during ECMO. DESIGN: Systematic literature review and meta-analysis of correlation coefficients (Scopus and PubMed, up to July 13, 2024). PROSPERO: CRD42023448888 SETTING: All retrospective and prospective studies PARTICIPANTS: Patients receiving ECMO support INTERVENTION: Anticoagulation monitoring during ECMO support MEASUREMENTS AND MAIN RESULTS: Nineteen studies were included in the analysis, and the meta-analysis encompassed 16 studies. The vast majority of studies (n = 15) found a weak correlation, and no study reported a strong correlation between ACT and UFH infusion dose. The meta-analysis (n = 12,625 samples) identified a weak correlation, with a pooled estimate of correlation coefficients of 0.132 (95% confidence interval 0.03-0.23). The most common adverse events were hemorrhage (pooled incidence, 45%) and thrombosis (30%), and 47% of the patients died during their hospital stay. CONCLUSIONS: Even though ACT is a widely used UFH monitoring tool in ECMO patients, our meta-analysis found a weak correlation between ACT and UFH infusion dose. New trials are needed to investigate the role of emerging tools and to clarify the most appropriate monitoring strategy for patients receiving ECMO support.

Anticoagulation Strategies in Pediatric Cardiopulmonary Bypass, Weight-Based vs. Concentration-Based Approaches.

Pediatric patients undergoing cardiopulmonary bypass (CPB) require adequate anticoagulation to combat hemostatic activation. Heparin is used to bind and catalyze antithrombin III (ATIII) that works to inhibit clot formation. To dose heparin, a weight-based (WB) or patient-specific concentration-based (PSCB) method can be used. The WB protocol calculates the dose based on the patients' weight and uses an activated clotting time (ACT) test to ensure anticoagulation. The ACT has limitations during CPB especially for pediatric patients who have immature hemostatic systems. The PSCB method predicts the patients' response to heparin by projecting a heparin dose-response (HDR) curve. Some investigators have found benefit to using the PSCB method but further investigation into how well the HDR predicts the heparin response is needed. A literature review was conducted for studies that looked at heparin management strategies in pediatric CPB patients between 1992 and 2020. Articles that focused on pediatric physiology, heparin management strategies, and anticoagulation were included. Articles older than 1990 were excluded. The literature review highlights that utilizing the PSCB approach more adequately anticoagulated patients. The WB protocol was found to have several flaws due to its reliance on the ACT, especially in infants. The results show that further investigation is needed to understand why there is benefit to using the PSCB approach. Observing the association between the HDR curve and subsequent heparin concentrations could determine how accurately it predicts the patients' response to heparin and why there is benefit to using this method.

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO.

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics.

Whole Blood Point-of-Care Testing for Incomplete Reversal With Idarucizumab in Supratherapeutic Dabigatran.

BACKGROUND: Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results. METHODS: Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 µg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM). RESULTS: At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added. CONCLUSIONS: Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.

An in vitro study of coagulation properties in refrigerated whole blood and reconstituted whole blood.

OBJECTIVE: Fresh whole blood (WB) has been used in military applications and cardiac surgery. We undertook a study of the coagulation properties of refrigerated WB stored for 21 days and compared them with the properties of reconstituted WB. STUDY DESIGN AND METHODS: Ten WB units were obtained from healthy volunteer donors and stored at 4 ± 2°C. Samples were obtained on Days 1, 2, 4, 6, 8, 10, 14 and 21 from the WB units. Ten units of reconstituted WB were prepared with a ratio of red cells, platelets and plasma of 1:1:1. Tests included complete blood count, electrolyte, routine coagulation, blood coagulation factor and thromboelastography. RESULTS: There was a progressive decline in Hb, WBC, PLT, sodium and coagulation factors but a progressive increase in APTT, PT and potassium in WB. The concentrations of factor (F)V and FVIII as well as FII and FX of WB were higher before Days 4, 2, 8 and 14, respectively, compared with the concentrations of reconstituted WB. The concentrations of FVII, FIX, FXI and FXII in WB were found to be equal to or higher than those in reconstituted WB throughout the course of 21 days. TEG variables in all WB units were normal throughout the course of 10 days. The mean PT and APTT of WB were lower than those of reconstituted WB before Days 14 and 10, respectively. CONCLUSION: This study suggests that the coagulation properties of refrigerated WB were equal to or superior to those of reconstituted WB for a minimum of 10 days.

Assessment of Heparin Anticoagulation Measured Using i-STAT and Hemochron Activated Clotting Time.

OBJECTIVE: Adequate anticoagulation, measured using activated clotting time (ACT), is important during vascular and cardiac surgeries. Unfractionated heparin is the most common anticoagulant used. The purpose of this analysis was to compare the i-STAT ACT (iACT) to the Hemochron ACT (hACT), both of which were then compared to anti-factor Xa (anti-Xa) assay, a representation of heparin level and activity. DESIGN: Prospective study. SETTING: Tertiary care cardiovascular center. PARTICIPANTS: Eleven consecutive elective adult cardiac surgical patients. INTERVENTIONS: Prior to cardiopulmonary bypass, ACTs were measured using i-STAT and Hemochron technologies and compared to each other and to anti-Xa assay prior to and during a cumulative administration of heparin. Data were compared using bias analyses. MEASUREMENTS AND MAIN RESULTS: Heparin (300 U/kg) was administered in quarterly doses. Coagulation labs were collected prior to and 3 minutes after each quarterly dose of heparin. The baseline ACTs for i-STAT and Hemochron were 147 and 142 seconds, respectively. A significant association was found between iACT and hACT (p = 0.002). The iACT measurements underestimated hACT at ACT levels >180 seconds or anti-Xa levels >0.75 U/mL. No significant difference was found between ACT data at anti-Xa levels <0.5 U/mL. CONCLUSION: There was a good association between the iACT and hACT; however, the 2 tests are not equivalent. Overall, the iACT underestimated the hACT. Agreement between the ACT technologies was good at lower ACTs and anti-Xa levels, but declined with an anti-Xa >0.75 U/mL.

Adjusted calculation model of heparin management during cardiopulmonary bypass in obese patients: A randomised controlled trial.

BACKGROUND: Anticoagulation during cardiopulmonary bypass (CPB) is usually adapted to total body weight (TBW). This may be inaccurate in obese patients and lead to heparin overdose with a risk of bleeding. OBJECTIVES: To validate the efficacy and safety of an adjusted calculation model of heparin dosing based on ideal body weight (IBW) rather than TBW in obese CPB patients, with an expected target mean plasma heparin concentration of 4.5 IU ml after onset of CPB in the experimental group. DESIGN: Randomised controlled study. SETTING: University hospital. PATIENTS: Sixty obese patients (BMI ≥ 30 kg m) scheduled for CPB were included from January to June 2016. INTERVENTIONS: Patients received a bolus dose of unfractionated heparin of either 300 IU kg of TBW or 340 IU kg of IBW before onset of CPB. Additional adjusted boluses were injected to maintain an activated clotting time (ACT) of at least 400 s. MAIN OUTCOME MEASURES: Plasma heparin concentration and ACT were measured at different time points. Total heparin doses and transfusion requirements were recorded. RESULTS: The target heparin concentration of 4.5 IU ml was reached in the IBW group at the onset of CPB and maintained at all time points during CPB. Heparin concentrations were significantly higher in the TBW group after the bolus (6.52 ±â€Š0.97 vs. 4.54 ±â€Š1.13 IU ml, P < 0.001) and after cardioplegia (5.10 ±â€Š1.03 vs. 4.31 ±â€Š1.00 IU ml, P = 0.02). Total heparin doses were significantly higher in the TBW group. Mean ACT was significantly lower in the IBW group but remained over 400 s during CPB. The correlation between heparin and ACT was poor. Peri-operative bleeding and transfusion requirements were comparable. No thrombotic event occurred in the CPB circuit. CONCLUSION: The current IBW-adjusted regimen of heparin administration may be used efficiently in obese CPB patients, thereby avoiding overdose which cannot be accurately assessed by ACT monitoring alone. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02675647.

Clinical Evaluation of Measuring the ACT during Elective Cardiac Surgery with Two Different Devices.

Unfractionated heparin is the mainstay of anticoagulation during cardiac surgery on cardiopulmonary bypass (CPB) due to its low cost, quick onset, and ease of reversal. Since over 30 years, the activated clotting time (ACT) has been used to assess the level of heparin activity both before and after CPB. We compared two different methods of measuring the ACT: i-STAT, which uses amperometric detection of thrombin cleavage, and Hemochron Jr, which is based on detecting viscoelastic changes in blood. We included 402 patients from three institutions (Papworth Hospital, Cambridge, UK; Groote Schuur, Cape Town, South Africa; University Hospital Basel, Basel, Switzerland) undergoing elective cardiac surgery on CPB in our study. We analyzed duplicate samples on both devices at all standard measuring points during the procedure. The correlation coefficient between two Hemochron and two i-STAT devices was .9165 and .9857, respectively. The within-subject coefficient of variation (WSCV) ranged from 8.2 to 13.6% for the Hemochron and from 4.1 to 9.1% for the i-STAT. We found that the number of occasions where one of the duplicate readings was >1,000 seconds while the other was below or close to the clinically significant threshold of 400 seconds were higher for the Hemochron. We found the i-STAT to systematically return higher measurements. We conclude that the i-STAT provides a more reliable test for heparin activity and assesses safe anticoagulation during cardiac surgery on pump. The fact the that the i-STAT reads higher than the Hemochron leads to the recommendation to validate the methods against each other before changing devices.

Changes in heparin dose response slope during cardiac surgery: possible result in inaccuracy in predicting heparin bolus dose requirement to achieve target ACT.

INTRODUCTION: The substantial interpatient variability in heparin requirement has led to the use of a heparin dose response (HDR) technique. The accuracy of Hepcon-based heparin administration in achieving a target activated clotting time (ACT) using an HDR slope remains controversial. METHODS: We prospectively studied 86 adult patients scheduled for cardiac surgery requiring cardiopulmonary bypass. The total dose of calculated heparin required for patient and pump priming was administered simultaneously to achieve a target ACT of 450 s for HDR on the Hepcon HMS system. Blood samples were obtained after the induction of anesthesia, at 3 min after heparin administration and after the initiation of CPB to measure kaolin ACT, HDR slope, whole-blood heparin concentration based on the HDR slope and anti-Xa heparin concentration, antithrombin and complete blood count. RESULTS: The target ACT of 450 s was not achieved in 68.6% of patients. Compared with patients who achieved the target ACT, those who failed to achieve their target ACT had a significantly higher platelet count at baseline. Correlation between the HDR slope and heparin sensitivity was poor. Projected heparin concentration and anti-Xa heparin concentration are not interchangeable based on the Bland-Altman analysis. CONCLUSION: It can be hypothesized that the wide discrepancy in HDR slope versus heparin sensitivity may be explained by an inaccurate prediction of the plasma heparin level and/or the change in HDR of individual patients, depending on in vivo factors such as extravascular sequestration of heparin, decreased intrinsic antithrombin activity level and platelet count and/or activity.

Point-of-care testing of activated clotting time in the ICU: is it relevant?

BACKGROUND: Over the past 50 years there have been significant advances in both the clinical techniques and equipment used in the intensive care environment. One traditionally used point-of-care test is activated clotting time (ACT), a coagulation test primarily used during cardiopulmonary bypass surgery to monitor the anticoagulation effects of heparin. The ACT test has since emerged into the intensive care environment to guide clinical assessment and management of haemostasis in postoperative cardiac patients. OBJECTIVES: The aim of this integrative systematic review was to critique the available research evaluating the effectiveness of ACT point-of-care testing in the intensive care unit for adult patients following cardiopulmonary bypass and cardiac surgery and any impacts this may have on nursing care. METHODS: A systematic search of Medline, CINAHL and PubMed was undertaken. RESULTS: The search identified five research papers reporting on the use of ACT point-of-care testing in the intensive care unit for adult cardiac surgical patients. Meta-analysis was not performed due to the lack of homogeneity between the papers included. CONCLUSIONS: There was a lack of clear evidence for the use of the ACT point-of-care test after cardiac surgery in the intensive care environment. This review has highlighted that conventional laboratory tests are generally more accurate and reliable than this point-of-care test in guiding nursing care management.

Bedside monitoring of anticoagulation in chronic haemodialysis patients treated with tinzaparin.

BACKGROUND: During haemodialysis, anticoagulants are required to prevent clotting in the extracorporeal circuit. Low-molecular weight heparins (LMWH) are frequently used because of the ease of a single injection at the start of dialysis. Disadvantages of LMWH include the lack of a reliable bedside assay for measuring their anticoagulant effect. METHODS: We investigated a bedside test for LMWH activity. The relationship between anti-Xa (chromogenic assay) and Hemonox point-of-care assay was evaluated in 21 dialysis patients (12 men and 9 women) with a median age of 71 years, receiving tinzaparin at the start of a haemodiafiltration session. RESULTS: At the start, before tinzaparin administration, median (interquartile ranges) of Hemonox values were 74 (67-82) s. Thirty minutes after tinzaparin administration, Hemonox values were increased to 496 (360-736) s, followed by a decrease to 149 (135-301) s after 120 min, 102 (97-144) s after 180 min and 92 (83-100) s after 240 min. Corresponding anti-Xa activities were 0 (0-0), 1.12 (0.9-1.29), 0.74 (0.57-0.96), 0.47 (0.31-0.7) and 0.31(0.16-0.49) IU/mL. Hemonox values showed an exponential relation to anti-Xa levels. Interchangeability of tests was shown by Bland-Altman plot. CONCLUSION: Point-of-care Hemonox test is a valuable bedside method for monitoring anti-Xa activity in dialysis patients anticoagulated with tinzaparin.

Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation*.

OBJECTIVE: To assess the utility of activated clotting time, activated partial thromboplastin time, and anti-Factor Xa assay for the monitoring and dosing of heparin in pediatric patients requiring support with extracorporeal membrane oxygenation. DESIGN: Retrospective chart review. SETTING: PICU in a single, tertiary care, academic children's hospital. PATIENTS: Seventeen patients (age 1 d to 13.9 yr, median 0.83 yr) managed on pulmonary and cardiac extracorporeal membrane oxygenation between March 2010 and August 2012 by a single surgeon. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twice daily measurements of anti-Factor Xa assay, activated clotting time, and activated partial thromboplastin time were determined from the same blood specimen. Data were analyzed using SAS system v9.2. Fourteen patients (82.4%) were successfully weaned from extracorporeal membrane oxygenation and 12 (70.6%) were discharged from the hospital. Pearson correlations were used to compare heparin dose and activated clotting time, activated partial thromboplastin time, and anti-Factor Xa assay. Analysis showed negative Pearson correlations in 11 of 17 patients between the activated clotting time and heparin, as compared with seven of 17 for activated partial thromboplastin time and only one for heparin and anti-Factor Xa assay. Only four patients had moderate to strong positive correlations between activated clotting time and heparin as compared with a moderate to strong positive correlation in 10 patients for anti-Factor Xa assay and heparin. CONCLUSIONS: The anti-Factor Xa assay correlated better with heparin dosing than activated clotting time or activated partial thromboplastin time. Activated clotting time has a poor correlation to heparin doses commonly associated with extracorporeal membrane oxygenation. In pediatric extracorporeal membrane oxygenation, anti-Factor Xa assay may be a more valuable monitor of heparin administration.

Heparinase thromboelastography compared with activated coagulation time for protamine titration after cardiopulmonary bypass.

OBJECTIVE: The present study is a comparison of two point-of-care (POC) tests as endpoints of protamine titration after CPB. The authors hypothesized that using the heparinase-kaolin thromboelastography (TEG-HK) R-time difference would more readily identify residual heparin necessitating additional protamine than when using activated coagulation time (ACT). The primary endpoint was the between-group difference in protamine dose. Whether this approach would lessen postoperative bleeding and sequelae also was investigated. DESIGN: Single center, blinded, prospective, randomized study. SETTING: University teaching hospital. PARTICIPANTS: Eighty-two adult patients for on-pump coronary artery bypass and/or valve surgery. INTERVENTIONS: Patients were randomized. In the ACT group, protamine was titrated until ACT did not exceed baseline by more than 10%. In the TEG group, a TEG-HK R-time difference less than 20% was targeted. Protamine was repeated to achieve the endpoints. Clinicians in the ACT group were blinded to TEG data and vice versa. MEASUREMENTS AND MAIN RESULTS: There was no between-group difference in total protamine dose (3.9 ± 0.6 and 4.2 ± 0.7; 95% CI of the difference between means: -0.544 to 0.008 mg/kg; p = 0.057) or protamine:heparin ratios (1.3:1 and 1.4:1; 95% CI of the difference between means: -0.05 to 0.03 mg/mg; p = 0.653). In the ACT group, 17% of patients required a second protamine dose, and in the TEG group, 24% of patients required a second protamine dose. No between-group differences in the postoperative transfusion requirements or intensive care unit length of stay were demonstrated. CONCLUSION: No difference was identified in protamine dosing using either ACT or TEG-HK R-time difference as endpoints. Heparinase TEG may be useful for monitoring heparin reversal.

[Coagulation profiles during cardiac surgery].

OBJECTIVE: To evaluate patients' hemostasis after cardiac surgery using thromboelastometric and impedance aggregometry. MATERIALS AND METHODS: 66 patients were examined intraoperatively. Comparison group included 45 blood donors. Hemostasis was tested for thromboelastometricRotem Gamma with the assessment of external (exTem) and internal (inTem) pathways of coagulation tests performed detection of heparin (hepTem) and cytochalasin-D-inactivation of platelets (fibTem) to assess the level of fibrinogen. Collagen-induced platelet aggregation was determined in an aggregometer CHRONO-LOG (USA). RESULTS: Significant deviations of the parameters of hemostasis were detected in 52 of the 66 studied patients. In group-1 (23 patients) revealed a residual effect of heparin. The effect manifested prolongation CT (clotting time) inTem to an average of 241 +/- 15 s, compared with CT hepTem--181 +/- 7. Patients in this group were in need of additional administration of protamine sulfate. Postoperative bleeding and resternotomia were observed in 3 patients of group-1. In group-2 (25 patients) CT inTem was 216 +/- 21 with significantly fewer CT hepTem (272 +/- 26). The data indicated excess of protamine sulfate. Platelets aggregation decreased compared to the norm. According to the obtained results, the addition of protamine sulfate is not required, however, in 7 cases the protamine sulfate was administered in a dose of 8.9 +/- 0.8 mg in 6 cases resternotomiya required. In the third group (n = 6) bleeding was observed in 4 patients. The difference in CT-hepCT was significant. Significant variations were revealed in the tests of the activity of the extrinsic pathway of coagulation and cytochalasin-D-induced inactivation of platelets: exMCF- 42 +/- 2 mm (normal 57 +/- 15 mm), fibMCF 5.0 +/- 0.3 mm (norm 12.8 +/- 4.3 mm). The concentration of platelets and their aggregation activity was sharply reduced. Disorders of hemostasis in the third group, designated as dilution coagulopathy. CONCLUSION: Turning thromboelastometric and impedance aggregometry in the study of the coagulation profile of patients undergoing cardiac surgery in postperfusion period brings valuable information and allows a differentiated treatment of hemostasis disorders.

Factors Affecting the Discrepancy Between Coagulation Times on Extracorporeal Circulation Using Unfractionated Heparin in Children and Young Adults.

In unfractionated heparin (UFH) monitoring during extracorporeal circulation, the traditional measures of activated clotting time (ACT) or activated partial thromboplastin time (APTT) may diverge, confounding anticoagulant adjustments. We aimed to explore the factors explaining this discrepancy in children and young adults. This retrospective observational study, conducted at an urban regional tertiary hospital, included consecutive pediatric patients who received UFH during extracorporeal circulation (continuous kidney replacement therapy or extracorporeal membrane oxygenation) between April 2017 and March 2021. After patients whose ACT and APTT were not measured simultaneously or who were also taking other anticoagulants were excluded, we analyzed 94 samples from 23 patients. To explain the discrepancy between ACT and APTT, regression equations were created using a generalized linear model (family = gamma, link = logarithmic) with ACT as the response variable. Other explanatory variables included age, platelet count, and antithrombin. Compared to APTT alone as an explanatory variable, the Akaike information criterion and pseudo-coefficient of determination improved from 855 to 625 and from 0.01 to 0.42, respectively, when these explanatory variables were used. In conclusion, we identified several factors that may explain some of the discrepancy between ACT and APTT in the routinely measured tests. Evaluation of these factors may aid in appropriate adjustments in anticoagulation therapy.

Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery.

OBJECTIVES: To assess the incidence of incomplete heparin reversal and heparin rebound after cardiac surgery with cardiopulmonary bypass (CPB) and the ability of the activated coagulation time (ACT) and thromboelastography (TEG) to detect these phenomena. DESIGN: Prospective single-center study. SETTING: University hospital. PARTICIPANTS: Forty-one patients undergoing elective cardiac surgery with CPB and with normal preoperative TEG parameters. INTERVENTIONS: ACT, TEG, and plasma heparin levels were measured in all patients at 5 different times between 20 minutes and 3 hours after protamine administration. The variability of TEG reaction time (R) with and without heparinase (delta-R [DR]) was used to detect the presence of residual heparin. MEASUREMENTS AND MAIN RESULTS: Plasma heparin expressed as anti-FXa activity was detected in 180 (88%) samples. At univariate analysis, ACT, R-kaolin (R-k), and DR significantly correlated with plasma heparin concentration (respectively, p = 0.007, p = 0.006, and p = 0.002). At multivariate analysis, R-k and DR remained associated with plasma heparin concentration (respectively, p = 0.014 and p = 0.004). Greater quartiles of heparin were associated with higher values of R-k and DR. Combined procedures had significantly lower DR than isolated procedures (p = 0.017), and CPB time and heparinization time positively correlated with R-k (respectively, p = 0.044 and p = 0.022). No association was observed between heparin concentration, ACT, and TEG parameters with postoperative bleeding and need for blood and blood components transfusions. CONCLUSIONS: Heparin rebound and incomplete heparin reversal are very common phenomena after cardiac surgery with CPB; ACT is not able to detect residual heparin activity, whereas TEG analysis with and without heparinase allows the diagnosis of heparin rebound.

Non-recovery of ACT in a patient with heparin-induced thrombocytopenia type II during mitral valve replacement using argatroban anticoagulation.

Argatroban was used as the anticoagulant during cardiopulmonary bypass (CPB) in a patient with heparin-induced thrombocytopenia (HIT) type II undergoing mitral valve replacement. Dosage was reduced because of preoperative congestive liver disorder. Perioperative coagulability was poor, and, ultimately, failure of hemostasis led to a fatal outcome. Although argatroban use as an anticoagulant for HIT is reported, the optimal dose has not been established. During long-term CPB, increasing the total dosage may extend anticoagulant ability, leading to dose dependence. Because no antagonist for argatroban exists, failure of hemostasis might occur.

Multiple electrode whole blood aggregometry, PFA-100, and in vivo bleeding time for the point-of-care assessment of aspirin-induced platelet dysfunction in the preoperative setting.

BACKGROUND: Acquired platelet dysfunction due to aspirin ingestion may increase bleeding tendency during surgery. Thus, we examined the diagnostic accuracy of in vivo bleeding time (BT) and 2 platelet function assays for the preoperative assessment of a residual antiplatelet effect in patients treated with aspirin. METHODS: Consecutive patients scheduled for surgery were prospectively enrolled in this study. The patients' last aspirin ingestion had occurred within the previous 48 hours before blood sampling in the "full aspirin effect" group, between 48 and 96 hours before in the "variable aspirin effect" group, and >96 hours before in the "recovered aspirin effect" group. The control group had not taken any aspirin. Multiple electrode aggregometry, platelet function analyzer (PFA)-100, and in vivo BT were performed to assess the effects of aspirin. One-way analysis of variance on ranks with a post hoc multiple-comparison procedure (Dunn) was used to detect differences among the groups. Categorical data were compared using the z test. Receiver operating characteristic (ROC) curves were created to determine the diagnostic accuracy of the platelet function assays investigated. The area under the ROC curve (AUC), sensitivity, and specificity of the assays were calculated. The level of statistical significance was set at P < 0.05. RESULTS: Three hundred ninety-four patients were included in the analysis (133 control and 261 aspirin-treated patients). All 3 methods were able to detect the antiplatelet effect of aspirin in the full aspirin effect group. Furthermore, no difference in the measurement values between the recovered aspirin effect and control group was found, irrespective of the assay performed. Measurement values in the variable aspirin effect group were different from those of the control group in the ASPItest using multiple electrode aggregometry and COL-EPI using PFA-100 but not in BT. ROC analysis showed the highest diagnostic accuracy in excluding the residual aspirin effect in the ASPItest (AUC 0.81, P < 0.001), followed by COL-EPI (AUC 0.78, P < 0.001) and BT (AUC 0.56, P = 0.05). The cutoff value of 53 U in the ASPItest excluded the effect of aspirin with a sensitivity of 88% and specificity of 71%. CONCLUSIONS: The full therapeutic antiplatelet effects of aspirin can be expected within 48 hours of the patient's last aspirin ingestion. Platelet function recovered in our study if aspirin cessation occurred >96 hours (4 days) before; thus, in these patients, preoperative platelet function testing is not useful. To quantify any residual aspirin effect in patients who ceased their intake of aspirin between 48 and 96 hours before surgery, the ASPItest might have the highest diagnostic accuracy.

A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change.

The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4×4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose-proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring.