Can Clopidogrel and Direct Oral Anticoagulants (DOACs) prolong Activated Partial Thromboplastin Time (APTT)?

From the Guidelines

Clopidogrel does not prolong Activated Partial Thromboplastin Time (APTT), while Direct Oral Anticoagulants (DOACs) may have variable effects on APTT depending on the specific agent.

Key Points to Consider

• Clopidogrel is an antiplatelet medication that inhibits platelet aggregation by irreversibly blocking the P2Y12 receptor, which affects platelet function rather than the coagulation cascade measured by APTT 1.
• Routine coagulation tests like APTT remain normal in patients taking clopidogrel.
• DOACs such as dabigatran (a direct thrombin inhibitor) can significantly prolong APTT, while factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban may cause mild to moderate APTT prolongation at therapeutic doses, though this effect is inconsistent and dose-dependent 1.
• The relationship between APTT prolongation and anticoagulant effect is not linear or predictable, making APTT not the recommended test for monitoring DOAC therapy 1.
• Specialized tests such as dilute thrombin time or anti-Xa assays are more appropriate for assessing DOAC activity when clinically necessary 1.

Clinical Implications

• In clinical practice, the effect of DOACs on APTT should be interpreted with caution, considering the specific DOAC used and its pharmacokinetic properties.
• Viscoelastic coagulation tests, such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), may provide useful information on coagulation status in patients taking DOACs, especially in trauma settings 1.
• A normal APTT does not rule out the presence of DOACs, and clinical judgment should be used to guide management decisions in patients taking these medications 1.

From the FDA Drug Label

As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel [see Warnings and Precautions (5. 2)].

APTT Prolongation:

• Apixaban (DOAC): Apixaban can prolong APTT, but the changes observed are small and not useful in monitoring the anticoagulation effect of apixaban.
• Clopidogrel: No pharmacodynamic interactions were observed with clopidogrel, which suggests that clopidogrel does not have a significant effect on APTT when coadministered with apixaban. However, this does not directly answer whether clopidogrel can prolong APTT on its own. The FDA drug label does not answer the question.

From the Research

Effect of Clopidogrel and DOACs on APTT

• Clopidogrel is known to affect platelet aggregation, and its impact on coagulation tests such as Activated Partial Thromboplastin Time (APTT) has been observed in some studies. For instance, a study 2 found that APTT was significantly higher in the clopidogrel/heparin group compared to the prasugrel/bivalirudin group 3 hours after drug administration.
• Direct Oral Anticoagulants (DOACs), on the other hand, have been shown to affect APTT, although the effect may vary depending on the specific DOAC and the assay used. A study 3 found that apixaban and rivaroxaban, two direct factor Xa inhibitors, prolonged APTT by less than 3-fold at antithrombotic doses.
• Another study 4 noted that DOACs can impact screening hemostasis assays, including APTT, but these tests are not suitable for quantifying drug levels. Instead, specific quantitative methods should be used to determine DOAC concentrations.
• The effect of DOACs on APTT can be influenced by the presence of other anticoagulants or antiplatelet agents. For example, a study 5 found that the use of DOAC-Stop, an agent that reverses the in vitro effects of DOACs, did not influence APTT measurements in patients taking rivaroxaban or apixaban.

Comparison of Clopidogrel and DOACs

• Clopidogrel and DOACs have different mechanisms of action, with clopidogrel inhibiting platelet aggregation and DOACs inhibiting specific coagulation factors (e.g., factor Xa or thrombin).
• The studies suggest that both clopidogrel and DOACs can affect coagulation tests, including APTT, although the extent and nature of the effect may vary depending on the specific drug and assay used.
• A study 6 found that clopidogrel efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time, while another study 3 found that apixaban and rivaroxaban exhibited lower bleeding times compared to dabigatran at equivalent antithrombotic doses.