The use of the activated clotting time for monitoring heparin therapy in critically ill patients

OBJECTIVE: To determine the correlation between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) in patients receiving intravenous unfractionated heparin therapy, and the accuracy of the ACT in predicting the level of anticoagulation. DESIGN: Paired aPTT and ACT measurements were obtained from a convenience sample of critically ill patients requiring intravenous unfractionated heparin. The aPTT was determined in the hospital laboratory and ACT measurements were performed with a portable device. SETTING: The intensive care unit of Ghent University Hospital, a tertiary care facility with 54 beds. PATIENTS AND PARTICIPANTS: Twenty-eight patients were studied prospectively; a total of 105 paired samples were obtained. The indication for heparin therapy was cerebral ischemia in 8, various cardiac conditions in 10, pulmonary embolism in 3, continuous hemofiltration in 3, and peripheral arterial thrombosis in 4. RESULTS: There was a significant correlation between aPTT and ACT. Analysis of variance showed a significant difference in ACT between different levels of anticoagulation, aPTT shorter than 60 s (group 1), aPTT 60-90 s (group 2), and aPTT longer than 90 s (group 3): 142+/-16.7 s in group 1 vs. 155+/-29.6 and 192+/-39.1 in groups 2 and 3. CONCLUSIONS: The correlation between the aPTT and the ACT in this ICU setting is poor; ACT cannot differentiate between low and therapeutic levels of anticoagulation. The use of the ACT for monitoring low to moderate doses of heparin in ICU patients cannot be recommended.     

Evaluation of the TAS analyzer and the low-range heparin management test in patients undergoing extracorporeal membrane oxygenation

BACKGROUND: The new Low-Range Heparin Management Test (LHMT), a method for point-of-care testing (POCT) of heparinization, has been designed to function at the low to moderate heparin concentrations typically found in patients undergoing extracorporeal membrane oxygenation (ECMO). In this study, the new method is compared with two POCT methods and a laboratory-based anti-Xa assay. METHODS: We obtained 760 whole blood samples from 13 patients undergoing ECMO. All samples were tested immediately by the LHMT, the Activated Clotting Time (ACT) test, and its low-range counterpart (ACT-LR). Aliquots from the same blood draw were frozen for later anti-Xa analysis using the Diagnostica Stago method on the Roche Cobas Fara-II. RESULTS: The precision was best for duplicate citrated LHMT samples (CV = 3.1%). LHMT clotting times (overall median, 162 s) were typically shorter than ACT or ACT-LR times (247 and 235 s, respectively). The relationship between the LHMT and the other POCT methods differed significantly from patient to patient (P <0.0001), and a meaningful single relationship between the methods could not be obtained. The overall correlation coefficient between clotting time values and actual heparin concentrations was < or = 0.48 for each of the instruments tested, although time plots of each analyzer's data suggested that they detected heparin dosage changes within single patients. CONCLUSIONS: The performance of the LHMT on the TAS Analyzer is equivalent to that of currently commercially available POCT methods. The lack of agreement between absolute clotting time values and heparin concentrations suggests the need for reexamination of current ECMO patient management strategy.     

Comparing methods of establishing the aPTT therapeutic range of heparin

BACKGROUND: The American College of Chest Physicians (ACCP) recommends that the activated partial thromboplastin time (aPTT) therapeutic range for unfractionated heparin be defined as the aPTT corresponding to a heparin concentration of 0.3-0.7 micro/mL by heparin anti-factor Xa assay. This recommendation suggests that a therapeutic range defined in this manner should be superior to traditional empiric therapeutic ranges of 1.5-2.5 times the control. A pilot study was conducted to evaluate the ACCP recommendation for heparin monitoring. OBJECTIVE: To compare heparin dosage adjustments guided by a heparin concentration-derived therapeutic range (HCDTR) with those influenced by traditional empiric therapeutic ranges for the aPTT. METHODS: This study was conducted in 2 phases. In phase 1, the various aPTT therapeutic ranges were established and/or defined. The first empiric therapeutic range (E1) was established by performing an aPTT test on healthy volunteers. This E1 was defined as 1.5-2.5 times the mean normal aPTT. A second empiric therapeutic range (E2) was defined as 1.5-2.5 times the patient's baseline aPTT. The aPTT HCDTR had been defined in a previous study as 48-61 seconds. In phase 2, heparin dosage adjustment decisions guided by each empiric range and the HCDTR for the aPTT were compared with heparin dosage adjustment decisions guided by actual heparin concentrations. Decisions were in agreement when both the aPTT result and plasma heparin concentration indicated the same dosage change. Forty patients had a bedside aPTT determined prior to receiving continuous infusion heparin and again within 48 hours of heparin initiation. Plasma heparin concentration by anti-factor Xa assay was performed on the blood samples obtained after heparin initiation. Heparin dosage adjustment decisions were evaluated by determining the agreement of each aPTT test result with the corresponding plasma heparin concentration. An overall level of agreement (defined as the % of decisions that were in agreement) for each aPTT therapeutic range was determined. RESULTS: The level of agreement in dosage adjustment decisions between heparin concentration and E1, E2, and HCDTR was 28/40 (70%), 28/39 (72%), and 23/40 (58%), respectively (p = 0.34). Heparin dosage adjustment decisions based on an aPTT HCDTR did not significantly differ from heparin dosage adjustment decisions guided by traditional empiric therapeutic ranges for a bedside aPTT. CONCLUSIONS: This pilot study showed similar heparin dosage adjustment decisions using an empiric aPTT therapeutic range versus a heparin concentration-derived aPTT therapeutic range.     

Whole blood activated clotting time in infants during extracorporeal membrane oxygenation

Bleeding complications are the principal cause of morbidity and mortality in infants treated with extracorporeal membrane oxygenation (ECMO). The whole blood activated clotting time (ACT) test is used universally to monitor heparin therapy during this procedure. To enhance our understanding of this test and improve our management of anticoagulation, we studied the relationship between the ACT and blood heparin concentration in nine infants during ECMO. The activated clotting time correlated with the simultaneously determined heparin concentration (r = .55, p less than .001 for all patients samples; r = .92, p less than .001 for mean patients values). Within the range of values found in our patients, platelet count, fibrinogen, and fibrin degradation products did not affect the ACT-heparin concentration relationship. However, the interpretation of an individual ACT result was limited by its low precision: the mean difference of duplicate determinations was 9.2%, and the estimation of heparin concentration by a single ACT had a coefficient of variation of 32%. Two commercially available techniques using different activators gave results that differed numerically but correlated well with each other. Both provided similar precision in the estimation of heparin concentration. The ACT is a low cost, bedside test whose accuracy and precision allow the achievement of target heparin concentrations required in infants during ECMO. Multiple determinations, either in duplicate or serially, are needed to achieve satisfactory precision. These data will be useful in designing future studies to determine the optimal serum heparin concentration to provide adequate anticoagulation, but avoid bleeding complications.     

Anticoagulation monitoring part 2: Unfractionated heparin and low-molecular-weight heparin

OBJECTIVE: To review the availability, mechanisms, limitations, and clinical application of point-of-care (POC) devices used in monitoring anticoagulation with unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs). DATA SOURCES: Articles were identified through a MEDLINE search (1966-August 2004), device manufacturer Web sites, additional references listed in articles and Web sites, and abstracts from scientific meetings. STUDY SELECTION AND DATA EXTRACTION: English-language literature from clinical trials was reviewed to evaluate the accuracy, reliability, and clinical application of POC monitoring devices. DATA SYNTHESIS: The activated partial thromboplastin time (aPTT) and activated clotting time (ACT) are common tests for monitoring anticoagulation with UFH. Multiple devices are available for POC aPTT, ACT, and heparin concentration testing. The aPTT therapeutic range for UFH will vary depending upon the reagent and instrument employed. Although recommended by the American College of Chest Physicians Seventh Conference on Antithrombotic and Thrombolytic Therapy, establishing a heparin concentration-derived therapeutic range for UFH is rarely performed. Additional research evaluating anti-factor Xa monitoring of LMWHs using POC testing is necessary. CONCLUSIONS: Multiple POC devices are available to monitor anticoagulation with UFH. For each test, there is some variability in results between devices and between reagents used in the same device. Despite these limitations, POC anticoagulation monitoring of UFH using aPTT and, more often, ACT is common in clinical practice, particularly when evaluating anticoagulation associated with interventional cardiology procedures and cardiopulmonary bypass surgery.     

Heparin monitoring during cardiac surgery. Part 1: Validation of whole-blood heparin concentration and activated clotting time

There is limited published data on the agreement between techniques for monitoring heparin levels. The aim of this study was to validate the Hepcon/HMS, with particular focus on the agreement with laboratory anti-Xa assay. The performances of two ACT instruments--Hemochron and HemoTec--were also evaluated, including an assessment for interchangeability. Blood samples from 42 adult cardiopulmonary bypass (CPB) patients were analysed for activated clotting time (ACT), whole-blood heparin concentration (Hepcon/HMS) and anti-factor Xa (anti-Xa) plasma heparin concentration. Agreement between measures was determined using the method of Bland and Altman. Simple analysis of agreement between the Hepcon and anti-Xa heparin revealed the Hepcon has a mean bias of -0.46 U/mL, with the limits of agreement +/- 1.12 U/mL. The comparison between ACT instruments indicated a mean difference of -96 seconds for the HemoTec, with limits of +/- 265 seconds. The Hepcon/ HMS instrument displayed satisfactory agreement with anti-Xa plasma heparin concentration, as the expected variation would not be expected to cause problems in the clinical setting. Agreement between the two measurements of ACT may be satisfactory, provided each is assigned a different target value.     

Comparison of ACT point-of-care measurements: repeatability and agreement

BACKGROUND: Accurate control of heparin anticoagulation is necessary during all stages of cardiopulmonary bypass (CPB). The activated clotting time, first described by Hattersley in 1966, is mostly used for determination of anticoagulation. Either celite or kaolin are used as activators. An ACT value of 480 sec is proposed to be the safe minimum level for anticoagulation during CPB. This study was designed to determine if the activated coagulation time (ACT) values of each analyser separately are repeatable, and to determine whether there exists a significant difference in ACT values measured by three different analysers: the GEM PCL (Instrumentation Laboratory), the Hemochron 801 (International Technidyne Corporation) and the ACT II Automated Coagulation Timer (Medtronic). METHODS: All patients underwent cardiovascular surgical procedures requiring heparinisation (200-300 IU/kg). Blood samples for the measurement of the ACT were taken from all patients before and after heparinisation, during CPB, and after protamine administration. All samples were measured in duplicate with the three different analysers. To compare the activated clotting time data, the method described by Bland and Altman was used. The Pearson correlation coefficient was used to determine whether the differences were related to the average ACTs. p-Values <0.05 were considered statistically significant. RESULTS: The results showed that the three tested ACT analysers met the requirements of repeatability. The mean differences and standard deviations of the ACT values measured with the GEM PCL, the Hemochron 801, and the ACT II analyser were, respectively, -8.78 +/- 37.61, -19.77 +/- 68.82, and -6.23 +/- 39.21, with p-values=0.177, 0.081 and 0.384, respectively. The Pearson correlation coefficients were too low (-0.012, -0.221 and -0.241, respectively) to show any correlation between the differences and the means. The ACT values measured with the Hemochron 801 were not significantly different from the ACT values measured with the ACT II analyser: deltaACT =-34.09 +/- 146.68, with p=0.132. However, the GEM PCL did not agree with the Hemochron 801: deltaACT= -80.2 +/- 143.06, with p=0.001, or the ACT II analyser: deltaACT= -119.13 +/- 138.51, with p<0.001. A rather strong correlation was evident between the differences and the means measured with the GEM PCL compared with the Hemochron 801 (r=0.68) and the ACT II analyser (r=0.76). CONCLUSIONS: All analysers used celite or kaolin as activator. However, it was evident that the ACT measurements depended also on the analyser that had been chosen. A precaution that ACT values could not always be interpreted in the same way seems to be necessary.     

Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test

Patients undergoing cardiopulmonary bypass (CPB) require anticoagulation with heparin to avoid thrombosis within the bypass circuit. The common method used to monitor the degree of anticoagulation is the activated clotting time (ACT). We evaluated a novel point of care device, the TAS (Pharmanetics, Raleigh, NC, USA) heparin management test (HMT), for its suitability in monitoring anticoagulation during CPB. In vitro analysis showed a dose-response (r2=0.988) of the HMT from 0.078-10.0 U/ml heparin, covering the range of heparin used during cardiac surgery (2-5 U/ml). Fifty randomly selected patients undergoing CPB were studied. Preheparin clotting times for these patients were 143+/-32 s for the HMT and 146+/-18 s for the ACT; 435+/-60 s HMT and 438+/-39 s ACT during CPB; 145+/-50 s HMT and 128+/-14 s ACT post-protamine (r2=0.797). epsilon-Aminocaproic acid treatment for inhibition of fibrinolysis did not affect the HMT. We conclude that the HMT correlates well with the ACT and may be useful for monitoring heparin during CPB. Advantages of the HMT are small sample volume and good sensitivity to heparin.     

Monitoring high-dose heparin levels by ACT and HMT during extracorporeal circulation: diagnostic accuracy of three compact monitors

The correct monitoring of heparin therapy and its reversal determines the successful conduct of cardiovascular surgery with extracorporeal circulation (ECC). The activated coagulation time (ACT) and the heparin management test (HMT) are the most frequently used tests in the operating room. Three compact monitors for ACT or HMT are here evaluated. Forty samples were obtained, at 10-min intervals, from eight patients during ECC. The ACT or HMT was immediately performed using: Hemochron juniors ACT, CoaguCeck Pro (ACT) and Rapid Point Coag (HMT). Data were compared between them and with the heparin levels, measured as anti-Xa. The simple least squares linear regression among, respectively, Hemochron Junior ACT, CoaguCeck Pro ACT, Rapid Point Coag HMT and anti-Xa activity were i=452.3, s=15.2, Sy/x=37.5, r=0.18; i=411.9, s=22.1, Sy/x=48.7, r=0.21 and i=479.4, s=9.0, Sy/x=9.3; r=0.41. CoaguCeck Pro ACT results were above the upper detection limit (500 s) in 37 of 40 determinations. The comparison between ACT Hemocron and HMT Rapid Point Coag shows i=35.7, s=0.9, Sy/x=35.4, r=0.68, with a bias of 29.0 s (CI: 17.9-40.1), 95% of agreement between -41.5 s (CI: -60.7 to -22.3) and 99.5 s (CI: 80.4-118.7). Taking a concentration of 2.0 U/ml of heparin to discriminate between high- and low-risk conditions, receiver-operator characteristic (ROC) curve was used to rank the performance of the methods. Areas under the ROC curve+/-SE for Hemochron Junior ACT and Rapid Point Coag HMT were 0.629+/-0.097 and 0.543+/-0.096. The results obtained by HMT appear similar to those obtained by the ACT for monitoring high-dose heparin therapy in patients undergoing ECC. HMT appeared to perform better than ACT in measuring the heparin effect, while the ROC analysis gives a little more accuracy for ACT. Neither of the two methods is able to achieve enough evidence of diagnostic accuracy. Since these tests are widely used, and there are no laboratory alternatives, a real comparison with the outcome of the patients should be helpful for an evidence-based evaluation of these point-of-care tests.     

Changing systems for measuring activated clotting times: impact on the clinical practice of heparin anticoagulation during cardiac surgery

BACKGROUND: The activated clotting time (ACT) is a standard monitor for heparin anticoagulation during cardiopulmonary bypass (CPB). This study determines the effect of upgrading our ACT system on our clinical practice with regards to the conduct and safety of heparin anticoagulation during cardiopulmonary bypass. METHODS: We compared the intraoperative heparin doses required for all adult cardiac surgery patients (n=1240) and postoperative bleeding for a subset of primary aortocoronary bypass (CABG) surgery procedures (n=285) from cohorts before and after the change in ACT systems. RESULTS: The heparin dose needed to exceed our target ACT of 480 sec for the duration of CPB was higher (45000 vs. 40000 units; p<0.0001), and the mean ACT during CPB was lower (557 vs. 618 sec; p<0.05) using the new ACT system. Furthermore, this coincided with decreased postoperative bleeding in the CABG subset (median value of 417 vs. 575 ml over 12 h; p<0.0005). CONCLUSIONS: We demonstrated that the introduction of the Actalyke ACT system significantly altered our clinical practice by increasing the heparin dose required to exceed our target ACT during CPB. Prospective study to determine the effect of Actalyke ACT system monitoring on hemostasis after cardiac surgery is merited.     

Measurement of the activated clotting time during cardiopulmonary bypass: differences between Hemotec ACT and Hemochron Jr apparatus

BACKGROUND: Measurement of the activated clotting time (ACT) represents a standard method for coagulatory assessments. The test employs specific agents to trigger the coagulation process. The present study aimed to compare kaolin (Hemotec) versus a combination of silica, kaolin and phospholipid (Hemochron Jr) ACTs. METHODS: Hemotec and Hemochron Jr ACT monitors were compared by simultaneous measurement of paired arterial blood samples (n = 114) with respect to precision and bias during clinical conditions of cardiopulmonary bypass (CPB). The influence of haemodilution on the ACT was tested in an ex-vivo model. RESULTS: The precision of Hemotec and Hemochron Jr ACT measurements attained 21 +/- 2.6 s versus 27.0 +/- 2.6 s (p = 0.126) during CPB and 2.5 +/- 2.2 s versus 9.4 +/- 6.9 s (p = 0.000) after protamine administration, respectively. The Hemochron Jr monitor was associated with a bias of -102 +/- 13.7 s compared to the Hemotec ACT monitor (p = 0.000) during CPB and -6.9 +/- 2.9 s after protamine (p = 0.025). Linear regression analysis of ACT readings between monitors reached r = 0.526 (p = 0.000). Hemochron Jr ACT values correlated with the erythrocyte volume fraction r = 0.379 (p = 0.000). Ex-vivo data indicated that the Hemotec ACT monitor was associated with relatively higher ACT readings after haemodilution. CONCLUSION: The ACT is not a standardized measure. Test results are strongly associated with the specific compounds used to initiate the coagulation process.     

Monitoring of the heparin therapy during acute haemodialysis

Anticoagulation during renal replacement therapy is recommended to avoid thrombosis of the filter devices and to maintain the blood flow. However, in the case of multiorgan failure and sepsis, an imminent bleeding complication in patients with acute renal failure may cause the need for an extracorporeal circulation without anticoagulation. The most common drug used in renal replacement therapy is the unfractionated heparin (UFH). With low molecular weight heparin (LMWH) good experiences are reported, too. Based on the level of evidence from clinical studies plasma measurement of heparin is indispensable for patients with renal insufficiency. The activated whole blood clotting time (ACT), the activated partial thromboplastin time (aPTT), and the determination of the anti-factor Xa activity (anti Xa) with chromogenic substrates are available as routine as well as as point-of-care tests. To monitor plasma levels of LMWH the anti Xa assay serves exclusively as a suitable monitoring. The anti Xa assay using chromogenic substrates is the most specific and valid one for monitoring heparin therapy. In lack of large controlled studies for the anticoagulation therapy and its monitoring with the anti Xa test in acute renal failure, the current experiences are based on the results of chronic renal replacement therapy.     

Evaluation of CoaguChek Pro ACT in cardiac catheterization laboratory

The objective of this study was to assess the analytical performance of CoaguChek Pro ACT assay versus Hemochron Celite ACT assay concerning activated clotting time (ACT) values and the correlations versus heparin. Enrolled were 158 patients and 101 normal subjects from five cardiac catheterization laboratories (cathlabs). Two different CoaguChek Pro ACT lots were compared to different lots of Hemochron Celite ACT. All sites used arterial blood and one site also used venous blood. Determinations were carried out before and directly after heparinization, and 1-4 h later. Besides the ACT values, hematocrit, platelet counts and factor Xa levels were also determined. The correlations between the Hemochron Celite lots and the two different CoaguChek Pro lots for arterial and venous blood for all sites were good (r=0.88 and 0.84). The agreement between both CoaguChek Pro ACT lots was excellent (r=0.99). The correlations between heparin and CoaguChek Pro ACT were similar to those for the Hemochron Celite lots. There was no influence of the hematocrit and the platelets. The imprecision of the method was very good (CV<6%). This demonstrates that the CoaguChek Pro ACT assay is especially useful for monitoring heparin in cathlabs.     

Effects of inhaled nitric oxide on hemostasis in healthy adults treated with heparin: a randomized, controlled, blinded crossover study

Background

Effects of nitric oxide (NO) on hemostasis have been studied in various investigational settings, but data regarding inhaled NO on bleeding and platelet function are conflicting. It is not known if inhaled NO has an effect when administered with drugs that influence hemostasis. This trial evaluated effects of inhaled NO on hemostasis in the presence of heparin using aspirin as a positive control.

Patients/Methods

Twelve healthy adult males were enrolled in a single-center, randomized, single-blind, four-way crossover trial. Subjects received 80 ppm NO or medical air (placebo) inhalation for 30 min with simultaneous injection of placebo or heparin. Aspirin capsules were used as a positive control. Parameters of hemostasis were measured before treatment and at post-treatment intervals.

Results

Activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased only in groups that received heparin. Areas under the curve for ACT in heparin groups receiving inhaled NO were judged to be equivalent to those receiving medical air for both 0- to 4-h (ratio: 1.00; 90% CI, 0.90-1.11) and 0- to 24-h time intervals (ratio: 1.01; 90% CI, 0.92-1.12). Changes in bleeding time and platelet aggregation were observed only in aspirin groups. No clinically significant changes in hemoglobin, red blood cell counts or haematocrit were observed in any group.

Conclusions

Inhaled NO, when administered with heparin, exhibited no significant additive effects on ACT, PT, aPTT, bleeding time or platelet aggregation.     

Comparison of three prothrombin time and activated partial thromboplastin time reagent systems on the MLA 700 coagulation analyzer.

OBJECTIVE: To determine the difference in prothrombin time (PT) and activated partial thromboplastin time (aPTT) results among three reagent systems using a single analyzer instrument. DESIGN: Convenience sample of 100 patient specimens tested in duplicate with three reagent systems: Baxter-Dade, Pacific Hemostasis, and Organon Teknika. SETTING: A tertiary hospital that services other institutions within a three-state area. PATIENTS: Patients were divided into four groups: (1) normal preoperative patients who received no anticoagulants, (2) patients who received warfarin for at least the week immediately before the study, (3) patients who received heparin on the day of the testing, and (4) patients with severe liver disease accompanied by abnormal liver function tests. MAIN OUTCOME MEASURE: Coefficients of correlation of Baxter-Dade results versus the other two systems. RESULTS: PT values were significantly different in normal samples and in warfarin-treated patients. aPTT values were significantly different for normal patients and, for the Organon system only, for heparin-treated patients. When expressed as international normalized ratio (INR) values, taking reagent sensitivity into consideration, the results correlated well. Problems with precipitation when using Organon's system limited its practical utility. CONCLUSION: Compatibility between a reagent system and analyzer instrument should be verified by the manufacturer of the instrument. Use of the INR format produced more accurate and comparable results, allowing safer and more effective dosage adjustments. Laboratories should convert PT and aPTT results to the INR format routinely.     

Therapeutic Concentrations of Heparin Augment Platelet Activation at the Time of Coronary Angiography

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess the platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 +/- 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 +/- 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 +/- 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 +/- 86 seconds (8 +/- 9 v -1 +/- 4% change in resulting PLTs, P =.01, and 11 +/- 12 v 1 +/- 6% increase in adenosine diphosphate (ADP) [5 μM]-stimulated PLTs, P =.02). Heparin produced a slight increase in PA in group 1 patients (1.4 +/- 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 +/- 5.3 ohms, P.05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients (r = -.5, P =.05, -ADP; r = -.65, P =.006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients (r = -0.4, P =.2, -ADP; r =.11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (<0.7 U/mL). These findings may have implications for optimal dosing strategy for heparin as an antithrombotic agent in clinical situations characterized by platelet-dependent thrombotic events.     

The uncalibrated prothrombinase-induced clotting time test. Equally convenient but more precise than the aPTT for monitoring of unfractionated heparin

The activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT's dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT?) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit?PiCT?, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.     

Frequency and timing of activated clotting time levels for sheath removal

Guidelines currently exist that describe the medical management of patients undergoing percutaneous coronary interventions (PCI), but these guidelines do not include nursing management of the patient post procedure. The nursing staff on an intermediate care unit believed there were numerous and unnecessary activated clotting time (ACT) levels obtained on post PCI patients. The purpose of this study was to identify the most appropriate time to begin analyzing ACT levels. Results from a retrospective chart audit of 44 patients indicated that 3 hours after the last dose of heparin, only 7% of the patients met the criteria of ACT < 150 seconds in order to have their femoral sheaths removed, and 21% of patients had an ACT of < 160 seconds. It is recommended that current standard orders be changed to begin drawing ACT levels at 3 hours post last heparin dose and removing sheaths when ACT is < 160 seconds. This change would save the hospital nearly dollars 5000 in nursing time alone.     

Inflammo-coagulatory response, extrinsic pathway thrombin generation and a new theory of activated clotting time interpretation

When blood is subjected to contact with foreign surfaces, as during cardiopulmonary bypass (CPB), the whole body inflammatory response is initiated, resulting in the expression of procoagulant molecules on the vascular endothelium and white blood cells. These surface bound procoagulants participate in the extrinsic coagulation pathway. It appears that the primary source of thrombin generation during CPB is due to extrinsic pathway activation. Thrombin not only converts fibrinogen to fibrin, it also acts as a proinflammatory agent resulting in a positive feedback loop or the inflammo-coagulatory response. Extrinsic pathway thrombin generation occurs as a membrane bound event. Membrane bound factors are resistant to heparin/ATIII inhibition. Therefore, the anticoagulant effect of heparin/ATIII is due to thrombin inhibition, not the inhibition of thrombin generation. Interpretation of the activated clotting time (ACT) must take into account the thrombin concentration [T]; this results in the coagulatory ratio, ACT is proportional to ([Hep -ATIII]/[T]). Considering this proportionality, it can be seen that the ACT cannot be used to quantitate heparin concentration. Changes in the ACT can reflect changes in [Hep - ATIII], changes in [T], or changes in both concentrations. Anti-inflammatory agents which suppress or inhibit the extrinsic pathway, such as aprotinin, result in decreased thrombin generation. As thrombin generation decreases, the ACT-heparin dose response curve is warped, resulting in a dose response curve resembling a PTT-heparin dose response curve. We can no longer assume that the disproportionate rise in the ACT relative to the [HEP - ATIII] when aprotinin is used as indicative of failure of the ACT to provide a credible indication of anticoagulation.     

Comparing direct thrombin inhibitors using aPTT, ecarin clotting times, and thrombin inhibitor management testing

BACKGROUND: Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with direct thrombin inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). OBJECTIVE: To compare 14 methods for measuring aPTT, as well as ECT and thrombin inhibitor management test (TIM), in samples containing DTIs. METHODS: DTIs were added to pooled normal plasma to achieve low (0.1-1.2 microg/mL) and high (1.5-8.0 microg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM. RESULTS: All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 microg/mL of drug concentration. The TAS-aPTT and Pathromtin were the most sensitive aPTT reagents to bivalirudin, with aPTTs of 87.4 seconds and 101.5 seconds, respectively, at 1.2 microg/mL of drug. Pathromtin was the most sensitive aPTT reagent to lepirudin, with a maximum aPTT of 108.9 seconds at 1.2 microg/mL of drug. There was no statistically significant difference between the TIM and ECT clotting times for each DTI. Lepirudin and bivalirudin ECT and TIM clotting times were equivalent. CONCLUSIONS: There are unique differences between reagent manufacturers in the monitoring of DTIs. Acceptable alternatives to aPTT monitoring of DTI anticoagulation include the ECT and TIM.