The Activated Clotting Time (ACT) was first described by Hattersley in 1966 and is essentially a point of care test (POCT) of coagulation that is used to monitor the anticoagulant effect of unfractionated heparin (UFH) in patients on cardio-pulmonary bypass, on ECMO [extracorporeal membrane oxygenation], undergoing percutaneous transluminal coronary angioplasty, on haemofiltration or haemodialysis.
In the early days of cardio-pulmonary bypass (CPB) the dose of Heparin used to prevent clotting in the extra-corporeal circuit was established empirically – the dose being the minimum in which clotting in the extracorporeal circuit did not occur. The minimum safe ACT is in the region of 300 seconds based upon observations that above this level blood clots rarely occur in the extracorporeal circuit. In most cases of CPB – a dose of UFH in the region of 300-400 IU/kg is administered prior to CPB with additional boluses given as required to maintain the ACT >400s. The ACT is a useful monitor of unfractionated heparin when heparin is the ONLY variable, but when other variables are altered, it becomes non-specific to heparin.
This is covered in more detail in the 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery patients - see References.
The activated clotting time first came into clinical use in the mid-1970s to guide the administration and reversal of heparin during cardiopulmonary bypass procedures. Although originally proposal as a routine pre-operative screening test - it is now used almost exclusively for monitoring patients on CPB.
Fresh, whole blood is added to a tube containing a surface activator [– originally celite but other activators such as kaolin and glass balls are commonly used] - this results in the activation of coagulation via the Intrinsic [Factor XII] pathway. The test is dependent upon the presence of endogenous platelets as a source of Phospholipid.
Originally the tube was placed in a water bath at 37°C for 60s, removed and tilted slowly every 5s until a clot had formed. The time to clot formation was known as the ACT. The test is now more commonly performed using a fully automated technique in which the end point i.e. clot formation is recorded electronically – the principle, however, remains the same.
The test is performed immediately on whole blood and the samples cannot be stored.
Fresh whole blood is added to a tube containing a negatively charged 'activator' and this results in the formation of a clot. The type of activator affects the clotting time.
| Activator | Activated Clotting Time [ACT] |
|---|---|
| None | 190 - 300s |
| Celite | 100 - 170s |
| Glass | 110 - 190s |
| Kaolin | 90 - 150s |
Various machines have been developed which automate this process. In a non-anticoagulated patient, the ACT is in the region of 107s ± 13s. During cardiopulmonary bypass, heparin is titrated to maintain an ACT of between 400 and 600s. During ECMO, heparin is titrated to maintain the ACT between 220 and 260s.
The ACT is less precise than the APTT and lacks high correlation with the APTT or with heparin anti-Xa levels.
The ACT is influenced by a number of variables including:
| Variable | Comment |
|---|---|
| Platelet count and platelet function | The ACT will be prolonged in cases of thrombocytopaenia when the platelet count is Aspirin & Clopidogrel appear to have a variable effect upon the ACT with some studies reporting a prolongation of the ACT and others very little. GpIIb/IIIa inhibitors significantly prolong the ACT. |
| Lupus Anticoagulant | In some patients the presence of a Lupus Anticoagulant has been shown to interfere with and prolong the ACT but in other cases the ACT may be relatively unaffected. |
| Factor deficiencies | The ACT is sensitive to deficiencies in FVIII ( |
Historically the ACT has been used to monitor factor replacement therapy in Haemophilia and to monitor anticoagulation with Heparin.
Causes of a prolonged ACT include:
| Causes of a Prolonged ACT |
|---|
| Heparin |
| Hypothermia |
| Hypofibrinogenaemia |
| Clotting factor deficiencies [Except Factors VII and XIII] |
| Haemodilution |
| Aprotinin |
| Thrombocytopaenia |
| Qualitative platelet abnormalities |
| Oral anticoagulants |
The reference range for the ACT varies considerably depending on the method used for the test; it usually falls somewhere within 70-180 seconds.
With cardiopulmonary bypass heparinisation, the goal is to exceed 400-500 seconds (commonly >480 seconds), depending on the method, representing a mean heparin level of approximately 4-5 units/mL.
For other indications, the ACT target is typically lower than it is for cardiopulmonary bypass.
A number of modifications of the ACT have been published and these are summarised below:
| Test | Description |
|---|---|
| Xa-ACT | The Xa-ACT is a modification of the ACT in which the activator is replaced by bovine factor Xa. The Xa-ACT was designed for point-of-care testing (POCT) to monitor anticoagulation with Low Molecular Weight Heparin (LMWH) in patients undergoing haemodialysis. Whilst the ACT is prolonged in patients receiving LMWH the Xa-ACT is more sensitive and correlates with in vitro and in vivo plasma anti-Xa assays. However, it is not sensitive enough to act for routine monitoring of LMWHs. |
| MAX-ACT | The MAX-ACT uses a ‘cocktail’ of activators (celite, kaolin and glass) to maximally convert all the FXII to XIIa. If all the XII is converted to XIIa then any prolongation for the ACT above baseline will indicate heparin anticoagulation (there are other reasons why the MAX-ACT may be prolonged – see above). It is less sensitive than the standard ACT to the effects of hypothermia and haemodilution and shows a linear response to heparin with an upper limit of 6 IU/ml. |
| Plasma ACT | It is possible to undertake an ACT on anticoagulated plasma which is re-calcified to induce clotting. |
1. With high doses of heparin, the APTT cannot be used to monitor heparin therapy because the APTT is unclottable. The ACT or heparin anti-Xa levels are used instead of the APTT in such situations.
2. The ACT is used almost exclusively to monitor patients on cardio-pulmonary bypass.
3. In individuals with a prolonged APTT prior to anticoagulation e.g. Factor XII deficiency - the ACT may/will be prolonged and in such cases cannot be used to monitor, for example UFH in a patient on CPB. In such cases the use of an Anti-Xa assay may be used to monitor the degree of anticoagulation and to guide reversal following bypass.
4. ACT devices should not be used interchangeably and cut-off values for anticoagulation during cardio-pulmonary bypass should be determined for each device.
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2. Hattersley PG. Activated coagulation time as screening test. JAMA. 1972 30;222(5):583-4.
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12. Leyvi G, Shore-Lesserson L, Harrington D, Vela-Cantos F, Hossain S. An investigation of a new activated clotting time "MAX-ACT" in patients undergoing extracorporeal circulation. Anesth Analg. 2001; 92(3):578-83.
13. Marmur JD, Anand SX, Bagga RS, Fareed J, Pan CM, Sharma SK, et al. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration. J Am Coll Cardiol. 2003; 41(3):394-402.
14. Paniccia R, Fedi S, Carbonetto F, Noferi D, Conti P, Bandinelli B, et al. Evaluation of a new point-of-care celite-activated clotting time analyzer in different clinical settings. The i-STAT celite-activated clotting time test. Anesthesiology. 2003; 99(1):54-9.
15. Lawrence M, Mixon TA, Cross D, Gantt DS, Dehmer GJ. Assessment of anticoagulation using activated clotting times in patients receiving intravenous enoxaparin during percutaneous coronary intervention. Catheter Cardiovasc Interv. 2004; 61(1):52-5.
16. Dincq AS, Lessire S, et al. Impact of the Direct Oral Anticoagulants on Activated Clotting Time. Journal of Cardiothoracic and Vascular Anesthesia. 2017; 31: e24-e7.
17. Frank RD, Brandenburg VM, et al. Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis. Nephrol Dial Transplant. 2004; 19: 1552-8.
18. Terai C, Saitoh D, et al. Plasma activated clotting time as an indicator of dangerous hypocoagulability in warfarin-treated trauma patients: a preliminary study. Surgery Today. 1998; 28: 834-8.
19.Click HERE for information on the MAX-ACT.
20. Click HERE to access the 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery .
21. Delmas C, Jacquemin A, Vardon-Bounes F, et al. Anticoagulation Monitoring Under ECMO Support: A Comparative Study Between the Activated Coagulation Time and the Anti-Xa Activity Assay. J Intensive Care Med. 2020;35(7):679-86.
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