Activated Clotting Time [ACT]
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 bypass surgery, 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 with 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.
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.
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:
|Platelet count and platelet function||The ACT will be prolonged in cases of thrombocytopaenia when the platelet count is <30-50 x 109/L.
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 (<25% of normal), IX, X, XI, XII deficiency, in patients receiving oral anticoagulants or with liver disease.
Historically the ACT has been used to monitor factor replacement therapy in haemophilia and to monitor anticoagulation with heparin.
|Oral Anticoagulants||The ACT is sensitive to oral anticoagulants because of the fall in the vitamin K dependent clotting factors.|
|Hypothermia||Hypothermia prolongs the APTT even in the absence of heparin. When patients are rewarmed following bypass there is an increase in the clearance of UFH and more frequent ACTs to monitor the degree of anticoagulation may be necessary.
Heparin clearance is increased with the paediatric patient.
|Haemodilution||Haemodilution significantly prolongs the ACT by reducing the concentration of many of the clotting factors.|
|Aprotinin||Aprotinin prolongs the celite-based ACT but has a lesser effect upon kaolin-based ACTs. Therefore, a celite-based ACT may overestimate the concentration of heparin when aprotinin is present.|
|High Dose UFH||With high doses of UFH, the APTT cannot be used to monitor heparin therapy because the APTT becomes unclottable. The ACT or the measurement of anti-Xa levels are used instead of the APTT in such situations.|
|ACT v. APTT||A number of studies have compared the sensitivity of the ACT and APTT and have demonstrated a linear heparin/dose response curve for the ACT and a logarithmic response for the APTT. However, limited data comparing the ACT and APTT suggests that these two tests are not equivalent and may result in discordant clinical studies.|
|Heparinase||Heparinase can be used to neutralise UFH in the ACT allowing monitoring of the underlying coagulation and which would otherwise be masked by the heparin. By performing an ACT with/without heparinase when patients come off bypass - any remaining heparin that has not been neutralised with protamine can be established.|
Causes of a prolonged ACT include:
|Causes of a Prolonged ACT|
|Other clotting factor deficiencies|
|Qualitative platelet abnormalities|
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 goal is typically lower than it is for cardiopulmonary bypass.
Modifications of the ACT
A number of modifications of the ACT have been published and these are summarised below:
|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 well both in vitro and in vivo with plasma anti-Xa assays.|
|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|
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