At which level of the hemostatic cascade do ticagrelor and aspirin act?

Mechanism of Action: Ticagrelor and Aspirin in Hemostasis

Both ticagrelor and aspirin act at the level of primary hemostasis by inhibiting platelet activation and aggregation through distinct molecular pathways. 1

Aspirin's Mechanism

Aspirin prevents thromboxane A2 (TxA2) formation by irreversibly acetylating platelet cyclooxygenase-1 (COX-1), thereby blocking one pathway of platelet activation for the entire 7-10 day lifespan of the platelet. 1

• This irreversible inhibition means that aspirin's antiplatelet effect persists until new platelets are produced by the bone marrow 2
• Low-dose aspirin (75-100 mg daily) is sufficient to achieve complete inhibition of platelet TxA2 synthesis 1
• The effect is permanent on individual platelets, requiring platelet turnover (approximately 10% per day) for recovery of hemostatic function 2

Ticagrelor's Mechanism

Ticagrelor reversibly blocks the platelet P2Y12 receptor, preventing adenosine diphosphate (ADP)-mediated platelet activation and aggregation. 1

• Unlike thienopyridines (clopidogrel, prasugrel), ticagrelor does not require metabolic activation and binds directly and reversibly to the P2Y12 receptor 3, 4
• The reversible binding allows for faster recovery of platelet function after discontinuation compared to irreversible P2Y12 inhibitors 5
• Ticagrelor has a plasma half-life of approximately 7 hours, with its active metabolite AR-C124910XX having a half-life of 8.5 hours, necessitating twice-daily dosing 1, 5
• Peak platelet inhibition occurs approximately 2 hours after administration of either a 180 mg loading dose or 90 mg maintenance dose 1, 5

Combined Effect on Primary Hemostasis

When used together, ticagrelor and aspirin provide dual inhibition of platelet activation by blocking two independent pathways: the TxA2 pathway (aspirin) and the ADP pathway (ticagrelor). 1

• This dual blockade occurs at the platelet activation stage of primary hemostasis, before platelet aggregation and fibrin formation 1
• Both drugs affect platelet function without directly impacting the coagulation cascade (secondary hemostasis), though reduced platelet activation may indirectly decrease thrombin generation 6
• The combination produces more potent inhibition of platelet aggregation than either agent alone, as demonstrated by multiple aggregometry studies 1, 7

Clinical Implications for Hemostatic Recovery

The different binding mechanisms result in distinct recovery profiles: aspirin requires 5-7 days for adequate platelet function recovery through new platelet production, while ticagrelor requires only 5 days due to its reversible binding. 1, 5, 2

• Platelet transfusion can partially overcome aspirin's effect by providing non-inhibited platelets, but is largely ineffective against ticagrelor because the drug remains in plasma at high concentrations for up to 24 hours after the last dose and can inhibit transfused platelets 1
• This distinction is critical for perioperative management and bleeding complications 1