Anticoagulation: Drugs For Treatment And Prevention Of Thrombosis

5.1.07

Haemostasis and thrombosis
• Haemostasis: complex normal and physiological responses and control mechanisms that ensure limited blood loss following tissue damage and maintain circulating blood in fluid state.
• Thrombosis: abnormal and pathological responses which occur as a consequence of disorders/imbalance of control mechanisms.

Structure of thrombus
• Venous/arterial.
• Endothelial damage.
• Platelet aggregation.
• Activation of clotting cascade.
• Deposition of fibrin.
• Formation of thrombus.


• Subsequent degradation of formed clot.

Diseases caused by thrombus
• MI and unstable angina.
• Arterial thrombosis.
• Thrombotic strokes.
• Venous thrombosis.
• PE.

Coagulation factors
• Factors I - XIII.
• Protein C.
• Protein S.
• Factor IV = Ca2+ ions.
• Factor VI = activated factor V.

Drugs
• Heparins.
• Oral anticoagulants e.g. warfarin.
• Thrombolytics.
• Anti-platelet agents.
• Other drugs.

Heparins
• Naturally occurring mucopolysaccharide.
• Binds and enhances antithrombin III.
• Inhibits clotting factors (IXa, Xa, XIa) and thrombin.
• Dosed parenterally (IV, SC) - adjusted according to APTT.
• Short half-life.
• Low-molecular weight heparins (e.g. dalteparin, enoxaparin) dosed according to body weight and have longer half-life.
• Side effects: bleeding, thrombocytopenia, osteoporosis, hair loss.
• Reversal: protamine (binds to heparin).

Oral anticoagulants
• Warfarin (others, e.g. phenindione, rarely used).
• Inhibits vitamin K-dependent clotting factors (prothrombin II, VII, IX, X, protein C, protein S) - produced in liver.
• Onset of action 48-72 hours (needs to clear factors already formed and circulating).
• Monitored using INR - target value depends on type of clot.

Warfarin
• Metabolised by cytochrome p450 enzymes.
• Protein binding 99%.
• Numerous interactions:
-Potentiate - antibiotics, cimetidine, fluconazole etc. (inhibit p450 or protein displacement).
-Antagonise - anti-TB drugs, anti-epileptics etc.
• Side effects: bleeding, teratogenic.
• Reversal: FFP (rapid), vitamin K.

Thrombolytics
• Streptokinase, Alteplase.
• Activate plasminogen to plasmin.
• Break down established clot.
• Major uses:
-Early MI where reperfusion beneficial.
-Life-threatening PE.
• Contraindications:
-Active peptic ulcer.
-Bleeding disorders.
-Severe hypertension.
-Recent CVA.
-Recent surgery/trauma.
• Side effects: bleeding, allergy (streptokinase).
• Reversal: short half-life, tranexamic acid (inhibits fibrin breakdown).

Anti-platelet drugs
• Oral: aspirin, dipyridamole, clopidogrel.
• Parenteral: prostacyclin.
• Thromboxane A2 and ADP released by activated platelets.
• Thromboxane A2 triggers further platelet aggregation.
• Aspirin inhibits cyclo-oxygenase, which decreases thromboxane A2.
• Clopidogrel inhibits ADP-induced platelet aggregation.
• Side effects: gastric ulceration, hypersensitivity.

Other drugs
• Glycoprotein IIb/IIIa inhibitors:
• Glycoprotein IIb/IIIa:
-Binds VWF (platelet adhesion, carrier for factor VIII).
-Binds fibrin.
• Glycoprotein IIb/IIIa inhibitors block fibrinogen binding to platelets.
• Administered parenterally.
• Expensive! E.g. Abciximab.

Clinical uses
Indication Criteria Treatment Notes
MI Clinical history and ECG Aspirin, fibrinolytics (<6hours) Bleeding, allergy, reperfusion arrhythmias, short door→needle time
Unstable angina, non-STEMI Chest pain
Refractory chest pain Aspirin and heparins ? + GP IIb/IIIa inhibitors
PEs Proven/suspected Heparin followed by warfarin Heparin in pregnancy
DVT Proven/suspected Heparin followed by warfarin Heparin in pregnancy
DVT prophylaxis At risk (dehydration, pre-/post-op, immobility) Low-dose heparin
Prevention of stroke Recurrent TIAs
AF
Valve replacement Aspirin
Warfarin
Warfarin
INR 2-3
INR 3-4