Activated coagulation time

The activated coagulation time (ACT) was devised by Hattersley in 1966 for the care of patients with severe haemophilia requiring heparin monitoring. The ACT records the time between exposure in a tube of whole blood to glass (contact activation) and the formation of a visible thrombus.

The ACT is sensitive to heparin and measures the heparin effect rather than the level. Factors beyond the plasma coagulation affect the absolute result, as it is a whole-blood assay.

There is no universally agreed therapeutic range. It is a near-patient assay. Most hospitals have not validated their in-house ACT cartridges and do not know how this value correlates with their coagulation tests (which are highly variable from institution to institution). Each hospital should validate the ACT measurements to either their laboratory activated prothrombin time (aPTT) or anti-Xa measures to ensure that the adopted ACT range is at least comparable to the laboratory coagulation tests range. An example is shown in Figure 7.2. The ACT tests will vary in their sensitivity to heparin, and different systems should be used to monitor various clinical settings (e.g. an ACT system designed to be used during cardiac surgery will monitor much higher doses of heparin than systems used during ECMO).

Figure 7.2

Relationship between anti-Xa and ACT, as well as the interrelationship between anti-thrombin, unfractionated heparin and thrombin. APR, activated prothrombin time ratio; UFH, unfractionated heparin.

Activated prothrombin time

The aPTT is triggered by exposing platelet-poor plasma to phospholipids and sand. Centrifugation from whole blood to platelet-poor plasma introduces a delay of 10 min in obtaining a result. Using platelet-poor plasma introduces a bias that is dependent on the composition of the patient’s whole blood when trying to compare it directly with the ACT. The aPTT is relatively inexpensive.

The aPTT measures the heparin effect rather than the heparin level. It can be validated against heparin protamine titration by performing the test repeatedly with increasing doses of protamine added to neutralize the heparin effect in the sample.

The activated prothrombin time ratio (APR) is a modification of the aPTT result: the patient’s aPTT (measured in seconds) is divided by the mean of the normal range (in seconds). The APR is a dimensionless ratio (e.g. 1.5) but must not be confused with the INR. The aPTT range and APR must be standardized to heparin protamine titration in each laboratory, as it is dependent on the reagent providers or analysers.

The sensitivity of the test varies between different reagent manufacturers. Care must be taken when adopting the aPTT ranges validated in another centre, as this may use a different aPTT/analyser combination.

The aPTT will also be affected by the presence of lupus anticoagulant, or by changes in factor VIII, IX, XI and XII levels.

Anti-Xa levels

The anti-Xa level has replaced heparin protamine titration as the ‘gold standard’ test for some of the fractionated heparins.

The anti-Xa level can measure heparin effect (if patient endogenous antithrombin is used in the assay) or heparin level (if exogenous antithrombin is added to the assay). The ECMO physician should establish whether the assay uses exogenous antithrombin or not, as this will affect interpretation of the results.

The anti-Xa level measurement is performed in platelet-poor plasma and therefore is not comparable to the whole-blood ACT. The anti-Xa level does not measure the inhibition of factors XIa, IXa and IIa, and will only reflect part of the unfractionated heparin activity.

The anti-XA level will only be slightly affected by global changes in coagulability, such as that observed in disseminated intravascular coagulation.

The anti-Xa level requires initial calibration by the laboratory but can then be compared between different centres. In ECMO support, a multicentre consensus appears to be obtaining anti-Xa levels of 0.3–0.5 IU/mL. These are lower than the levels required when treating venous thrombosis (0.5–1.0 IU/mL).

Thromboelastography

Thromboelastography is a functional test that measures the viscoelastic properties of blood and evaluates the whole clotting system, including platelet function, clotting factors and fibrinolysis.

The use of thromboelastography during ECMO can sometimes be useful in bleeding patients, but it will not detect some antiplatelet effects (it will usually be normal in patients on aspirin). The addition of various reagents such as heparinase facilitates the interpretation of thromboelastography.

How important are all these tests?

Specialist input will save lives, but this is not always obvious to the bedside clinician.

This can be shown in the example of a patient admitted with acute heart failure following CPR and established on ECMO. A first dose of heparin was administered on cannulation and an aPTT obtained several hours later showed an APR of 4.8. The heparin dose was progressively decreased and the APR levelled at 1.9. Despite what was thought adequate anticoagulation, multiple thrombi developed in the cardiac chambers. Anti-Xa levels were found to be disproportionally low in relation to APR, and further testing revealed a deficiency in factor XI. Multimodal monitoring would have detected this anomaly earlier.

Standard decision trees should be developed to support staff at the bedside. This should include when to call the haematology department (see example in Figure 7.3).

Figure 7.3

Example of a decision tree to support staff at the bedside. VA, veno-arterial; VV, veno-venous; PT, prothrombin time.