The first response to a vascular insult is the contraction of the smooth muscles of the vessel wall itself and platelet adhesion to the wall. Antiplatelet therapy, which inhibits platelet activation, adhesion and aggregation, is used to prevent vessel occlusion.

The active metabolites of thienopyridines (ticlopidine, clopidogrel and prasugrel), produced by cytochrome P450 metabolism, bind to receptor P₂Y₁₂ with a covalent, irreversible bond during the platelets’ whole life. The new receptor P₂Y₁₂ inhibitors (cangrelor and ticagrelor) change receptor conformation, inducing an irreversible block. All P₂Y₁₂ receptor blockers act by stopping the platelet activation induced by adenosine diphosphate (ADP).

The event triggering the initiation of the coagulation cascade is exposure of tissue factor (TF, thromboplastin) from the microvascular bed. The TF-factor VII complex generates activated factor VII (extrinsic pathway), favouring the initiation, amplification and propagation of subsequent coagulation phases [8, 9]. Activation of coagulation factors II, VII, IX and X requires γ-carboxylation in the liver in the presence of the reduced form of vitamin K. Vitamin K antagonists (VKA) inhibit the enzyme vitamin K epoxide reductase, thus blocking the formation of reduced vitamin K and limiting the activity of coagulation factors [10]. The response to VKA is influenced by several factors such as polymorphisms altering the metabolism of the cytochrome P450 system, other medications, diet and other conditions.

Both UFH and LMWH are administered to reduce the risk of thromboembolism. Binding to heparin accelerates the effects of the inhibitor antithrombin; the heparin-antithrombin complex inactivates thrombin (factor IIa) and other proteases involved in clotting, especially factor Xa, but also factors IXa, XIa and XIIIa. Owing to their low molecular weight, LMWH have modest anti-factor IIa activity, and their anticoagulant activity is mostly exerted as anti-factor Xa activity, whereas UFH acts on both targets.

Direct thrombin inhibitors inactivate thrombin by binding it directly; bivalent inhibitors (bivalirudin, hirulog) bind thrombin both on the active site and on exosite1; monovalent inhibitors (argatroban, melagatran and dabigatran) bind only to the active site. (Dabigatran is a prodrug for oral administration).

The new factor X-antagonists (rivaroxaban, apixaban, endoxaban) are also administered orally.

No efficient inhibition strategies have yet been developed for the new oral anticoagulants [11].

Fibrinolysis is an enzymatic process that involves dissolution of fibrin clots by plasmin. Plasmin is generated from plasminogen by the action of an activator (tissue plasminogen activator, TPA) synthesised by endothelial cells and secreted locally following stimulation of the endothelium. Recombinant TPA (rTPA) is so powerful that it can reduce the concentration of fibrinogen in vitro (Fig. 8.1).