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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica, Inc.

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INTRODUCTION

The Activated Clotting Time (ACT) was a POCT described in 1966 by Hattersley. It was used to monitor the anticoagulant effect of UFH in patients on cardio-pulmonary bypass (CPB), ECMO, percutaneous transluminal coronary angioplasty, on hemofiltration, or hemodialysis.¹

The principle of the ACT used fresh whole blood added to a tube containing a surface activator (celite, kaolin, glass balls) resulting in the activation of the intrinsic pathway (FXII) and dependent on the presence of endogenous platelets as a source of phospholipids. The time to clot formation was known as the ACT. The therapeutic range for the ACT is between 180-220 seconds to demonstrate the effectiveness of anticoagulation. ¹

ACT is prolonged by thrombocytopenia (<30-50 x 109/L), GpIIb/IIIa inhibitors, factor deficiencies (except VII and XIII) or liver disease, OACs, pediatric patients, aprotinin (in particular in celit-based ACT), and hemodilution. The presence of a lupus anticoagulant may prolong the ACT but in other cases may have no effect.¹

ACT AND HEPARIN

UFH was discovered in 1916 and one of the most common anticoagulants used in the prevention of thrombosis. It is used in ACS, AF, DVT, PE and other high risk conditions including cardiac procedures such as PCI, CPB and ECMO. Some clinicians believe using the ACT represents clotting of the whole blood, not just UFH and gives an overall status of coagulation. Using the ACT to monitor and adjust UFH dose can be a disadvantage since there is a lack of correlation. The ACT is a nonspecific measurement of whole blood and anything that affects coagulation will affect the results. This also includes genetic factors that may have an undefined role in ACT and coagulation. Different lots of UFH may also impact correlation due to stoichiometric differences since UFH requires a specific pentasaccharide sequence to bind AT.²

The correlation between ACT and UFH was looked at in 19 studies. In 15 studies there was a weak correlation, 3 found a moderate correlation however no strong correlation was found and the ACT was not found to be superior to other types of measurement. The ACT is widely used in ECMO to monitor UFH, but there is a weak correlation with UFH infusion. Its accuracy at lower concentrations of anticoagulants have prompted the use of other tests. In pediatric patients, there is higher heterogeneity possible due to the difference in pharmacokinetics in this population, as well as a lower concentration of AT.³

ACT is also used to monitor UFH during noncardiac arterial procedures (NCAP) to prevent under and overdosing. Blood samples from 196 samples on 34 patients were tested for ACT and anti-Xa assay. In this cohort a strong correlation was observed. Bleeding complications were observed in 29% of patients, however they underwent vascular surgery, which may have contributed to bleeding. Having an accurate heparin test can help to prevent over and underdosing. An anti-Xa is not a POC assay, aPTT is measured in a laboratory setting, POC thromboelastometry takes a long time and has not been studied in NCAP. ACT is the preferred test in this situation; however results could be impacted by things that interfere with the performance of the ACT (responsiveness to coagulation factor deficiencies, low thrombocyte count, anemia, haemodilution, and GPIIb/IIIa inhibitors).⁴

EXTRACORPOREAL MEMBRANE OXYGENATION

A study looked at the correlation between activated clotting time (ACT) and UFH infusion during Extracorporeal membrane oxygenation (ECMO). Patients undergoing ECMO require anticoagulation to maintain flow and risk reduction of circuit component failure. This comes with the risk of hemorrhage, so monitoring is crucial to avoid adverse events. Recommendations for monitoring advocate the use of the ACT, aPTT, viscoelastic testing or anti-Xa assays. The aPTT and anti-Xa assays are being utilized more, but ACT is still used up to 30% of centers to monitor ECMO, aPTT in 42% and anti-Xa in 23%, however there is no evidence of the correlation of the ACT with UFH.³

Recommendations from the International Society on Thrombosis and Haemostasis favoring anti-Xa monitoring over ACT or aPTT. Given the data from analyzed studies, this work advocates the use of alternative methods when feasible.³ Results are from ACT, aPTT, and viscoelastometric tests are often discordant. Other factors such as altered platelet function, acquired coagulation factor deficiencies (including decreased factor XI and AT), increased levels of acute phase proteins (including factor VIII, fibrinogen, and alpha-2-macroglobulin), lupus anticoagulants, and hemodilution, might affect these tests. Anti-Xa could improve outcomes by reducing bleeding. Dose should be an anti-Xa level of 0.3-0.5 U/mL. Other tests ranges aPTT 50-70 seconds, or ACT of 180-220 seconds.⁵

A prospective cohort controlledcohort-controlled study which included 40 patients showed that anti-Xa activity was better correlated to UFH than aPTT, aPTT ratio and ACT, and may better predict the anticoagulant effect of UFH. The anti-Xa had a 55% correlation, 31% aPTT ratio, 26% with the ACT and 23% with the aPTT.⁵

CARDIOPULMONARY BYPASS

Up to 60% of patients undergoing CPB require blood transfusions due to perioperative bleeding. This comes with an increased risk of morbidity and short-term mortality. Massive blood loss occurs in 10% of cardiac surgery. Having the ability to control hemostasis reduces the use of transfusions and complications.⁶ The ACT was used clinically in the mid 1970s to guide the administration and reversal of heparin during CPB to prevent clotting in the extracorporeal circuit. The minimum safe ACT is 300 seconds, a dose of UFH 300-400 IU/kg is administered prior to CPB with additional boluses given as required to maintain the ACT >400s.¹ The ACT in CPB should be greater than 480 seconds.⁶

ACT RESULTS AND BLEEDING

A study was conducted to determine if there was a specific ACT value that correlated to a lower risk of bleeding to reduce transfusion which may improve surgical outcomes and can decrease hospital associated costs. Preoperative HCT is a predictor of bleeding, and 25-30% of cardiac surgery patients have preoperative anemia. Men also have a higher risk (2.8) than females, but females are more likely (27%) to receive a postoperative transfusion.⁶

The ACT is useful in evaluating the degree of anticoagulation, however there is no data supporting the ideal ACT value post protamine, but rather matching the values pre and post heparin administration. Some data suggest that a final ACT lower than initial ACT may result in less bleeding and transfusions.⁶

The study showed that there was a statistically significant difference in bleeding in patients with ACT. ACT values ≥140 s and those who had final ACT values <140 s, with the former experiencing a higher bleeding rate in the first 12 h after surgery. But the final ACT value is not a strong predictor for significant bleeding regardless of its value. However, it is a predictor for transfusion with the risk of transfusion use increasing 1.021 times with each second in the final ACT. Furthermore, patients with a final ACT ≥ 140 s have a 1.81 times higher risk of requiring transfusion compared to those with a final ACT < 140 s. This leads to the observation that a final ACT result of <140 s may be a safer value leading to less bleeding and transfusion.⁶

CONCLUSION

The ACT is a tool in determination of the risk of bleeding and clotting in certain cohorts of patients. It does have several limitations. When trying to compare ACT performance among devices, results are close at clinically significant values (100-700s) whereas values closer to 1000 were less precise. The other issue with the ACT is that optimal ranges for specific conditions is a matter of debate and controversy among clinicians. ACT also measures the end of the clotting cascade and doesn't represent the entire UFH effect.

Using the POC test such as the ACT is associated with improved patient outcomes. Advantages include it only requires a small sample, results are available quickly, no issues with sample mislabeling since tested on fresh whole blood and can be performed by a trained person. The ACT can also be used to monitor the reversal of heparin which may be helpful in reducing bleeding and transfusion use.

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REFERENCES

1. Practical Hemostasis, SANG Medicine https://www.practicalhaemostasis.com/Miscellaneous/act.html
2. A Heidi Dalton, Michael Martin.Pamela Garcia Filion Sean Beinart, Andrew Israel, Nichole Korpi Steiner, Activated clotting time in inpatient diagnostic and interventional settings, Journal of Thrombosis and Thrombolysis (2022) 54:660–668, https://doi.org/10.1007/s11239-022-02672-y
3. Rajsic, Sasa et al., Anticoagulation Monitoring Using Activated Clotting Time in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis of Correlation Coefficients, Journal of Cardiothoracic and Vascular Anesthesia, Volume 38, Issue 11, 2651 – 2660, November 2024 https://www.jcvaonline.com/article/S1053-0770(24)00510-X/fulltext
4. Max Hoebink, Thomas A.H. Steunenberg, Liliane C. Roosendaal, Arno M. Wiersema, Henrike M. Hamer, Kak Khee Yeung, Vincent Jongkind, Ability of Activated Clotting Time Measurements to Monitor Unfractionated Heparin Activity During NonCardiac Arterial Procedures, Annals of Vascular Surgery, Volume 110, Part B, 2025,
5. Helms, Julie et al., Anticoagulation in adult patients supported with extracorporeal membrane oxygenation: guidance from the Scientific and Standardization Committees on Perioperative and Critical Care Haemostasis and Thrombosis of the International Society on Thrombosis and Haemostasis Journal of Thrombosis and Haemostasis, Volume 21, Issue 2, 373 – 396, 2023.
6. Rafael Maniés Pereira, Diogo Magueijo, Nuno Carvalho Guerra, Catarina Jacinto Correia, Anabela Rodrigues, Ângelo Nobre, Dulce Brito, Luís Ferreira Moita, Tiago R Velho, Activated clotting time value as an independent predictor of postoperative bleeding and transfusion, Interdisciplinary CardioVascular and Thoracic Surgery, Volume 38, Issue 5, May 2024, ivae092, https://doi.org/10.1093/icvts/ivae092, 08 May 2024

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