Antiplatelets and Anticoagulants Overview

Antiplatelets and Anticoagulants

• Drugs are used to prevent or reverse thrombus formation
• Classified into 3 groups:
  • Anticoagulants:
    • Factor Xa inhibitors
    • Anti-thrombins
    • Heparin
    • Vitamin K antagonists
  • Anti-platelet drugs:
    • Aspirin: Inhibits COX-1 activity, inhibiting platelet aggregation
  • Fibrinolytic agents:
    • Alteplase: Breaks down fibrin

Classes of Anticoagulants

• Selective factor Xa inhibitors:
  • Apixaban
• Direct thrombin inhibitors:
  • Dabigatran
• Heparin and low molecular weight heparins
• Vitamin K antagonists:
  • Warfarin

Venous Thromboembolism

• For confirmed proximal DVT or PE, use apixaban/rivaroxaban
• If the above are contraindicated, use LMWHs, followed by dabigatran or edoxaban, or LMWHs with vitamin K antagonists (Warfarin) until INR is achieved or with vitamin K antagonist alone.
• Use in patients undergoing surgery with thrombosis risk (thromboprophylaxis - NICE guidelines)

Anti-coagulant cascade

• Apixaban inhibits factor Xa
• Dabigatran inhibits factor 2a (thrombin)
• Heparin inhibits XIIa, Xla, IXa, Xa, and thrombin
• LMWH inhibits Xa
• Warfarin inhibits VIIa, Xa, IXa, and thrombin

Direct-acting oral anticoagulants (DOACs)

• Dabigatran etexilate: Reversible thrombin inhibitor (Idarucizumab is a reversal agent)
• Apixaban, edoxaban, and rivaroxaban: Reversible activated factor X (Xa) inhibitors (Andexanet alfa reversal agent prevents thrombin generation)
• Used to prevent strokes and secondary prevention of DVT or PE, and venous thromboembolism following surgery
• Other use for Apixaban/Rivaroxaban to prevent arterial thrombosis, stroke and myocardial infarction.

Contraindications and side-effects of Apixaban

• Side effects: Anaemia and haemorrhage
• Contraindicated in conditions with significant risk of bleeding (gastrointestinal ulceration, malignant neoplasms with high bleeding risk, oesophageal varices)
• Not appropriate for elderly patients (STOPP criteria, significant risk of bleeding e.g. severe hypertension)

What is the pharmacodynamics of Heparin?

• Heparin is a family of sulphated mucopolysaccharides (long sugar chains) found in mast cell secretory granules
• Can range in molecular weight from 3,000 to 30,000 Daltons
• Mechanism of action: Activates antithrombin 3 (ATIII), inhibiting the coagulation cascade
• ATIII is a natural inhibitor of thrombin and clotting factors IX, Xa, XI

Low Molecular Weight Heparin (LMWH's)

• Dalteparin sodium, Enoxaparin sodium, and Tinzaparin sodium
• Fragments of synthetic heparin with consistent activity.
• Inactivate factor Xa, thrombin, and activate antithrombin III.
• Immediate onset, given intravenously or subcutaneously. Heparin has shorter half-life (low/high doses) than LMWHs.
• Heparin-induced thrombocytopenia is less common with LMWHs.

Warfarin

• Vitamin K antagonist; inhibits activation of vitamin K-dependent clotting factors (II, VII, IX, X)
• Requires administration with INR monitoring due to its narrow therapeutic window.
• Absorbed rapidly from the GI tract, peaks in 0.5-4 hours.
• Metabolic termination by CYP450 enzymes (CYP2C9, 2C19, 3A4)
• Excreted in urine and faeces.
• Side Effects: Haemorrhage or skin necrosis.

Antiplatelet drugs

• Platelets form the initial haemostatic plug for vascular injury, and their inhibition is essential
• Aspirin irreversibly binds to COX-1, inhibiting TXA2 synthesis; lasts for the entire platelet lifecycle.
• Used to prevent arterial thrombosis like transient ischemic attack (TIA), stroke, and myocardial infarction.
• Other antiplatelet drugs include: Ticlopidine, Clopidogrel, and Prasugrel to inhibit ADP-mediated aggregation.

Fibrinolytic/Thrombolytic drugs

• Streptokinase and alteplase are thrombolytic and fibrinolytic drugs; potentiate fibrinolytic system by converting plasminogen to plasmin.
• Plasmin breaks down fibrin, dissolving clots. 
• Given intravenously, immediate effect, short half-lives (<10-90 minutes); major hazard is bleeding (dissolving normal clots).
• Used for clot-related issues like restoring catheter function/shunts, and occlusion of blood vessels/hollow organs.