Objectives:

At the end of the lecture, the student should know the :

Principles of AnticoagulantTherapy
Yeoh Peng Nam Professor
Read: Rang, Dale. Ritter & Flower 6th ed, 2007, ch21, pg 331-346

1. Principles of antithrombotic & thrombolytic drug therapy in thromboembolic disorders 2. Clinical pharmacology of drugs used in prevention and treatment of thromboembolic disorders

Terminology
Haemostasis :
arrest of blood loss from damaged blood vessels

Antithrombotic drugs - prevent clotting

Anticoagulants
1. Oral anticoagulants: Warfarin 2. Heparin, Low Molecular Weight Heparin (LMWH) 3. Hirudin

Thrombosis:
pathological formation of a haemostatic plug within the blood vessels in the absence of bleeding

Arterial thrombus:
white thrombus with platelets and leucocytes (associated with atherosclerosis)

Antiplatelet Drugs
-

Aspirin, Clopidogrel,

Dipyridamole, Ticlopidine

Venous thrombus:
red thrombus with small white head and a large jelly-like red tail (associated with e.g., deep vein thrombosis)

Thrombolytic drugs - dissolve clot

Fibrinolytic drugs

HEMOSTASIS
Has 4 phases
1 1. Vascular Phase 2. Platelet Phase

HEMOSTASIS
3. Coagulation Phase 4. Blood Clot

3. THE COAGULATION PHASE

2 PLATELET PHASE

4. A BLOOD CLOT

EXTRINSIC PATHWAY

INTRINSIC PATHWAY

THE COAGULATION CASCADE Oral Anticoagulants Interfer with post-translational -carboxylation of factors II, VII, IX, X Heparin [A] antithrombin III Hirudin [I] thrombin III

Blood Coagulation
Main Events:
Thrombin: fibrinogen (soluble) Blood factors: e.g., fibrin (insoluble)

II, VII, IX, X present as inactive precursors of proteolytic enzymes & cofactors Activated by proteolysis IIa, VIIa, IXa, Xa [A] of one factor starts the coagulation cascade

Coagulation cascade inhibited by: Antithrombin III, by neutralizing serine proteases in the cascade fibrinolysis

Principles of Antithrombotic & Thrombolytic Drug Therapy in Thromboembolic Disorders

AIM: [-] morbidity & mortality Thrombolytic drugs *(TLD): if given early enough can lyse formed thrombi good for myocardial infarction; massive pulmonary embolism Antithrombotic drugs (ATD): prevention of thrombosis , embolism (arterial , venous circulation) 1. Anticoagulants: prophylactic Prevents deposition of thrombus or Limit extension of thrombus or its fragmentation 2. Antiplatelet: prevent thrombus formation (artery & vein)

Principles . (2)
1.

Anticoagulants (heparin, warfarin):

effective prophylaxis for venous thrombosis, important to recognise thrombus-prone patients (those prone to deep vein thrombosis)

2.

Oral anticoagulants have narrow therapeutic window:

margin between the minimum therapeutic dose and the minimun dose producing haemorrhage is very narrow

3.

Dosage have to be individualised:

individual variation , difference in elimination rate, factors affecting vitamin K , clotting factor synthesis

4.

Certain drugs / herbs / foods can increase risk of haematological complications in patients with blood disorders
Aspirin, oral anticoagulants causing bleeding Ginkgo / gingseng / Morinda citrifolia / black cloud fungus

5.

Patient cooperation: compliance to medication

Oral Anticoagulants
Active in vivo only (inside the
body)

MECHANISM OF ACTION OF WARFARIN

Warfarin
Prevent normal formation of clotting factors II,VII, IX & X Prevent enzyme reduction of vitamin K (co-factor of carboxylase) to its active hydroquinone form By [I] translational carboxylation of glutamic acid residues in Factor II, VII, IX & X Onset : 2-3 days (factors present in the body have to be depleted first)

Clinical uses of Anticoagulants

To prevent thombosis / & embolisation) In patients with:
Deep vein thrombosis Extension of established deep vein thrombosis Pulmonary embolism Unstable angina (myocardial infarction) Atrial fibrillation Prosthatic heart valves Clotting in extracorporeal circulation (haemodialysis) Associated with fibrin rich thrombus

Warfarin (2)
Main side effect:
Haemorrhage / bleeding Monitor by measuring prothrombin time International normalized ratio (INR) : PTd/PTc
prophylaxis [+] 2-2.5 treatment: 3.5

Antidote for bleeding

phytomenadione or prothrombin complex (contain clotting factors)

Is highly bound to plasma proteins

Drug interactions with other highly bound drug e.g. aspirin [++] coagulation time (> likely to bleed)

Intravenous Anticoagulants: Heparin

Family of sulphated glycosaminoglycans Strongly acidic Present on endothelial & mast cells Commercial Source : lungs, intestines of cattle & pigs Inhibit coagulation in vivo and in vitro [++] Antithombin III (ATIII) action 1,000X: -ATIII inhibit coagulation proteases inhibits activation of IIa, IXa, Xa, XIa XIIa Heparin Antagonist (intrinsic and common pathways) Protamine Sulphate Strongly basic , forms Prolonged use : depletion ATIII inactive complex with LMWH do not catalyse ATIII inhibition of the acidic heparin factor II

EXTRINSIC PATHWAY

INTRINSIC PATHWAY

THE COAGULATION CASCADE Oral Anticoagulants Interfer with post-translational -carboxylation of factors II, VII, IX, X Heparin [A] antithrombin III Hirudin [I] thrombin III

Heparin
Mechanism of action
Heparin binds to plasma antithrombin III [++] its action 1000X: 1. Antihrombin III binds to and inhibit the activated thrombin, XIIa, XIa, Xa & IXa prolonging clotting time 2. [A] lipoprotein lipase which HOH plasma TG 3. Not effective orally; given iv, sc but NOT im (haematomas) 4. When given iv : onset is immediate, peaks 5-10 min, clotting time becomes normal within 2-4 hr 5. [M] by heparinase in the liver 6. Normally given by a bolus of 5000 units followed by maintenance dose of 1000 units / hr as infusion Adverse effects: 1. Bleeding / haemorrhage, 2. hypersensitivity reactions, thrombocytopenia, 3. alopecia, osteoporosis, 4. hypoaldosteronism hyperkaelemia

Low Molecular Weight Heparins (LMWH)

Heparin fragments: Enoxaparin Increase action of AT III on factor Xa but NOT on thrombin Benefits compared to Heparin: LMWH are: < protein bound, better bioavailability, longer elimination t1/2 ; longer duration; Lower risk of bleeding, Lower risk of osteoporosis Lower incidence of thrombocytopenia and thrombosis Dosing once a day; effects are more predictable Given sc Use: (rapid onset) initiate treatment of venous thrombosis & pulmonary embolism; prevention in those with recurrent thromboembolism despite adequate oral anticoagulation (Trousseaus syndrome) Initiate management of unstable angina Maintain the patency of tubes in dialysis patients

Other Intravenous Anticoagulants

Hirudin (salivary gland of leeches)
Binds directly to thrombin (both catalytic & fibrinogen recognition sites Powerful thrombin inhibitor Danaparoid: (porcine intestinal mucosa) (+) ATIII inhibition of Xa; sc, iv Heparan sulphate (found in some tissues) Lepirudin : recombinant hirudin Used in patients who cannot tolerate heparin Fondaparinux Synthetic pentasaccharide [I] activated Factor X

Antiplatelet Drugs
ASPIRIN: Inhibitor of Thromboxane A2
Thromboxane A2 (TxA2) cause platelet to change
shape, release their granules and aggregate

Low dose aspirin (75-150 mg/day) [microaspirin]

Selectively [I] cyclooxygenase [-] thromboxane A2 production [-] platelet aggregation [++] clotting time NO BLOCK of production of prostacyclin PG I2 which prevents platelet aggregation

High Dose Aspirin BLOCK formation of:

Prostacyclin (PGI2) & thromboxane A2 (TxA2) Does not have anti-platelet action

Low Dose Aspirin : Uses

1.

Inhibitors of Platelet Glycoprotein IIb/IIIa receptor

GP IIb/IIIa receptor on platelets mediates its binding to fibrin; a key step in formation of mature thrombus Activation of platelets (ATP, thrombin) changes the glycoprotein IIb/IIIa receptor into a ligand competent form Inhibitors to platelet GPIIb/IIIa receptor : 1. monoclonal antibodies: abciximab 2. clinically useful synthetic inhibitors: epifibatide, tirofiban (iv for short term) Inhibit diverse agonists like ADP, TXA2 Used in high risk conditions: Unstable angina Patients waiting for percutaneous angioplasty

2.
1.

Secondary prevention of ischaemic episode in patients who had myocardial infarction (MI) or stroke Primary prevention in Patients :
2. 3. 4. 5.

with high CV risk following coronary bypass surgery with atrial fibrillation with stable angina with Intermittent claudication [FDA: 325 mg/d primary prophylaxis of myocardial infarction]

3.

Low dose aspirin + thrombolytic agent better therapy than either drug alone for patients in first few weeks after MI

Drugs which Increase Platelet cAMP

cAMP [I] platelet function
Drugs which [+] platelet cAMP will [-] platelet activation 1. [S] platelet adenylcyclases Prostacyclin (PGI2) , iloprost (longer duration) PGI2 cause vasodilatation [-] BP (side effect) 2. Inhibitors of platelet phosphodiesterase (-) Metabolism of cAMP [+] cAMP Dipyridamole Effective antithrombotic agent experimentally , but not so effective in patients with coronary thrombosis 3. Inhibitors of ADP induced aggregation : ADP antagonists Ticlopidine Clopidogrel

3. ADP antagonists
Ticlopidine [T] & Clopidogrel [C] : prodrug prevent ADP induced platelet aggregation Potentiates GP IIb/IIIa inhibitors [I] thrombin induced binding of fibrin [I] expression of P-selectin
Used as alternative to aspirin

Ticlopidine : slow onset of action (7-11 days) and slow to

wear off (a disadvantage)
Adverse effects: dyspepsia, diarrhoea, bleeding leukopenia

Clopidogrel [C] very similar to ticlopidine, Toxicity is milder , less incidence of leukopenia, thrombocytopenia

Dietary Omega-3 fatty acids (Fish Oil)

Have CVS protective effect
[+] incorporation of omega-3 polyunsatrated fatty acids into platelet membrane in place of arachidonic acid Drives platelet-Tx synthetase to form TxA3 instead of TxA2 TxA3 is inactive as platelet agonist

Fibrinolysis
Removal of blood clot by fibrinolytic system
Enzyme plasmin cleaves fibrin into small soluble products

Plasminogen [inactive form of plasmin] circulates freely in plasma & accumulates on fibrin strands within a thrombus
is [A] by tissue plasminogen activator (t-PA) from endothelium Is also [A] by activator derived from action of factor XII on plasma and tissue proactivators

FIBRINOLYTIC SYSTEM

Fibrinolytic Agents / Thrombolytic Agents

Streptokinase: Bacterial product : + circulating plasminogen [A] plasminogen complex This cleaves other plasminogen molecules to form plasmin Is antigenic & immunogenic Combined with low molecular wt polyethylene glycols to [-] binding to immunoglobulins [A] all circulating plasminogen undesirable systemic anticoagulant effect Tissue plasminogen activators (tPAs) : alteplase, duteplase , reteplase Engineered product Binds to fibrin before [A] plasminogen ; acts only where there is a fibrin clot (clot selective)

Read: Rang, Dale. Ritter & Flower 6th ed, 2007, ch21, pg 331-346