• Anuclear
• Discoid (disc shape)
• Contain RNA, mitochondria, lysosomes
• Dense Granules (ADP, ATP, 5-HT, histamine, Ca2+)
• Alpha Granules (fibrinogen, von Willebrand Factor, coagulation factors V and XIII)
• Source of phospholipids, cofactor for coagulation factors (II, VII, IX, X)

1. Collagen
2. Thrombin

1. ADP/ATP - released from damaged cells and platelets (blocked by clopidogrel and ticlopidine)
2. PGH2/TXA2 - from platelets (blocked by aspirin)
3. PAF - from platelets
4. 5-HT - from platelets
5. Epinephrine/NE - circulating hormones (potentiates platelet aggregation)

1. PGI2 (prostacyclin) - from endothelium
2. PGD2 - from platelets
3. Adenosine - released by hypoxic cells formed during ADP/ATP degradation (facilitated by dipyridamole)
4. NO - from platelets and endothelium

• Low dose of Aspirin selectively inhibits the synthesis of TXA2 w/o having as much effect on prostacyclin
• Aspirin irreversibly inhibits COX, the enzyme that catalyzes an early step in TXA2 synthesis
• Aspirin inhibits platelet aggregation for the life of the platelet (5-7 days) and effectively reduces platelet aggregation when administered once a day or every other day

• low doses of Aspirin (80-160 mg) have minimal adverse effects
• therapeutic doses of Aspirin (650-975 mg) can cause gastric irritation and contribute to GI bleeding and peptic ulcer
• effective doses of Aspirin produce toxic effects including hyperventilation, fever, dehydration, and severe metabolic acidosis
• Aspirin hypersensitivity

1. Acute myocardial infarction
2. Angina
3. Arterial thromboembolism prophylaxis
4. Postmyocardial Infarction
5. Stroke prophylaxis

• Acts primarily by inhibiting platelet aggregation
• Increases [cAMP] in platelets by inhibiting PDE3
• Increases extracellular adenosine by inhibiting platelet reuptake, and by inhibiting adenosine break down
• Adenosine binds to GPCR (increases [cAMP] in platelets)
• Reduces activation and expression of surface GPIIb/IIIa receptors
• Dipyridamole is also a coronary vasodilator by increasing [cGMP]i via inhibiting PDE5

1. GI effects
2. Myalgia
3. Dizziness, headache
4. Flushing, hypotension, tachycardia
5. Hypersensitivity reactions

• A prodrug that requires conversion to the active thiol metabolite
• Inhibits platelet aggregation by irreversible blockade of the ADP receptors on the platelet membrane

• A prodrug that requires conversion to the active thiol metabolite
• Inhibits platelet aggregation by irreversible blockade of the ADP receptors on the platelet membrane

• Neutropenia
• Thrombocytopenia
• Thrombotic Thrombocytopenic Purpura (TTP)
• Less adverse effects with clopidogrel
• The GI effects of clopidogrel are similar to those of aspirin

• Neutropenia
• Thrombocytopenia
• Thrombotic Thrombocytopenic Purpura (TTP)
• Less adverse effects with clopidogrel
• The GI effects of clopidogrel are similar to those of aspirin

GPCR

Coupled with Gi --> results in decrease in cAMP and subsequent platelet activation

GPCR

Gq coupled --> results in increase in Ca2+ and subsequent platelet activation

1. Acute Myocardial Infarction
2. Angina
3. Arterial thromboembolism prophylaxis
4. Postmyocardial Infarction
5. Stroke prophylaxis

1. Acute Myocardial Infarction
2. Angina
3. Arterial thromboembolism prophylaxis
4. Postmyocardial Infarction
5. Stroke prophylaxis

GPIIb/IIIa Antagonist

• A murine monoclonal antibody with Fc fragment removed to prevent immunogenicity
• The Fab fragment is then joined to a human Fc region to form a chimeric molecule
• Abciximab binds irreversibly to the GPIIb/IIIa receptors and blocks the binding of fibrinogen
• Abciximab can reduce platelet aggregation by more than 90%
• Administered via IV infusion

• Bleeding
• Thrombocytopenia
• Nausea, vomiting, hypotension, bradycardia, headache
• Hypersensitivity occasionally

GPIIb/IIIa Antagonist

• competitive, reversible inhibitor of fibrinogen binding to GPIIb/IIIa receptors
• Non-peptide inhibitor
• Has a short half-life --> given as an IV loading dose followed by maintenance infusion

GPIIb/IIIa Antagonist

• competitive, reversible inhibitor of fibrinogen binding to GPIIb/IIIa receptors
• A cyclic heptapeptide from rattlesnake venom
• Has a short half-life --> given as an IV loading dose followed by maintenance infusion

1. Calcium and Phospholipids: Enhance activation of clotting factors (VIIa, Xa)
2. Vitamin K: essential for post-translational modification facotors (II, VII, IX, X)

Protein C: degrades Va and VIIIa

Antithrombin: a serine protease inhibitor that inhibits the activity of IIa (thrombin), VIIa, IXa, Xa, XIa, XIIa

• Warfarin is structurally similar to Vitamin K
• Blocks the reduction of oxidized Vitamin K and thereby prevents the post-translational carboxylation of clotting factors II, VII, IX, X
• Blocks epoxide reductase that is responsible for reducing oxidized Vitamin K

1. Bleeding which can range in severity from mild nosebleed to life-threatening hemorrhage (antidote - phytonadione AKA vitamin K₁)
2. Contraindicated in pregnancy - potential to cause fetal hemorrhage and various structural malformation

1. Broad-spectrum antibacterial agents which suppress the production of Vitamin K by gut bacteria; increase anticoagulant effects of warfarin
2. NSAIDs displace warfarin from its binding site on plasma proteins; increase its effects
3. Amiodarone and Cimetidine inhibit the cytochrome P450-mediated metabolism of warfarin; increase its effect
4. Phenytoin, phenobarbitol, and alcohol reduce the effect of warfarin by increasing its metabolism

It is a measure of extrinsic (tissue factor) pathway of coagulation

It determines the clotting tendency of blood

For most indications, an INR of 2 - 3 is recommended

Usage:

1. Monitor warfarin dosage
2. Liver damage
3. Vitamin K status

It is a measure of the intrinsic pathway of coagulation

Determines the clotting tendency of blood

Usage:

1. Detect abnormalities in blood clotting
2. Monitor the treatment effects of heparin

1. Deep Venous Thrombosis
2. Cardiomyopathy
3. Coronary Artery Thrombosis Prophylaxis
4. Ischemic Stroke
5. Myocardial Infarction Prophylaxis
6. Angina

• Heparin inactivates clotting factors  by potentiating the activity of an endogenous anticoagulant, antithrombin III
• Antithrombin III inhibits II (thrombin), VIIa, IXa, Xa, XIa, XIIa

• Bleeding caused by excessive anticoagulation (heparin can be neutralized by protamine)
• Heparin can cause heparin-induced thrombocytopenia (Heparin/PF-4 Complex; antigenic)
• Heparin occasionally causes hyperkalemia b/c of suppression of aldosterone secretion

• An additive risk of bleeding in patients receiving platelet inhibitors, thrombolytic agents, or other anticoagulants
• When mifepristone (RU486) is used in the termination of pregnancy, concurrent use of anticoagulants is contraindicated
• Upon contact with heparin, protamine forms a salt, neutralizing the anticoagulant effect of both drugs

• Heparin therapy is routinely monitored by the aPPT
• A clotting time of 1.8-2.5 times the normal mean aPPT value generally is assumed to be therapeutic

1. Acute myocardial infarction
2. Coronary artery thombosis prophylaxis
3. Deep venous thrombosis
4. Cerebral thromboembolism
5. Pulmonary embolism

• Hirudin is a polypeptide produced by the salivary gland of the medicinal leech
• Hirudin and its analogues are direct thrombin inhibitors that do not require antithrombin III as a cofactor

Direct Thrombin Inhibitor

• Does not require antithrombin III as a cofactor
• Used to prevent thrombosis in patients with unstable angina and acute myocardial infarction

Fibrinolytic Drug

• It is an enzyme that converts plasminogen to plasmin
• Plasmin degrades fibrin to fibrinogen and thereby causes clot dissolution
• Alteplase is a recombinant plasminogen activator of the naturally occurring tPA

Fibrinolytic Drug

• It is an enzyme that converts plasminogen to plasmin
• Plasmin degrades fibrin to fibrinogen and thereby causes clot dissolution
• Reteplase is a recombinant plasminogen activator containing 355 of the 527 aa tPA

Fibrinolytic Drug

• It is an enzyme that converts plasminogen to plasmin
• Plasmin degrades fibrin to fibrinogen and thereby causes clot dissolution
• Streptokinase must first combine with the plasminogen to form an activator complex that converts inactive plasminogen to plasmin

1. Most common is hemorrhage
2. Arrhythmias (bradycardia and tachycardia) due to free radicals generated during reperfusion
3. Streptokinase can cause hypersensitivity reaction
4. Hypotension due to the release of the vasodilator bradykinin from its circulating precursor

1. Most common is hemorrhage
2. Arrhythmias (bradycardia and tachycardia) due to free radicals generated during reperfusion
3. Streptokinase can cause hypersensitivity reaction
4. Hypotension due to the release of the vasodilator bradykinin from its circulating precursor

1. Acute myocardial infarction
2. Pulmonary embolism
3. Deep venous thrombosis
4. Peripheral arterial thromboembolism

1. Acute myocardial infarction
2. Pulmonary embolism
3. Deep venous thrombosis
4. Peripheral arterial thromboembolism

Antifibrinolytic Agent

• Used to treat bleeding disorders; hemophilia, patients who are recovering from GI or prostate surgery, etc.
• Inhibits fibrinolysis by competitively blocking plasminogen activation to plasmin and by blocking the binding of plasmin to fibrin
• Administered orally or IV
• Adverse Effects include thrombosis, hypotension, and arrhythmias

Antifibrinolytic Agent

• Prescribed for excessive bleeding; hemophilia, excessive menstrual bleeding
• Competitively inhibits the activation of plasminogen to plasmin
• Adverse Effects: nausea, vomiting, diarrhea, hypotension