Antiplatelet and anticoagulants

Edson Mutandwa mbbs v

What are they• Antiplatelet agents prevent platelets from clumping and also prevent

clots from forming and growing. (primary hemostasis)• Anticoagulants slow down clotting, thereby reducing fibrin formation

and preventing clots from forming and growing. (secondary hemostasis)

Clotting mechanism

Medical uses of antiplatelet1.Transient cerebral ischemic attacks.

2.Following coronary artery bypass grafting.

3.Prevention of myocardial infarction.

4.Following coronary artery angioplasty.

5.Prosthetic heart valves.

6.Chronic disseminated intravascular coagulation

Antiplatelet classification 1. COX inhibitors2. ADP antagonist3. Phosphodiesterase inhibitors4. GPIIb/IIIa inhibitors5. Others

COX inhibitors Examples : Aspirin Mechanism of action

• Aspirin produces the irreversible inhibition of the enzyme cyclooxygenase• This effect inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect. • Low doses (typically 75 to 81 mg/day) are sufficient to irreversibly acetylate serine 530 of cyclooxygenase (COX)-1

USES OF ASPIRIN • Prevention of AMI in patients of unstable angina • Acute coronary syndrome; 160-325mg PO within minutes of presentation• Prevention of reinfarction in patients of AMI(secondary prevention); 75-81 mg PO QID indefinitely• Prevention of stroke in patients of cerebrovascular accidents and h/o TIA; 50-325 mg/day PO within 48 hrs then 75-

100 mg/day PO• For improving prognosis in patients with atherosclerotic peripheral vascular diseases • Percutaneous angioplasty for coronary thrombosis; • Primary prophylaxis of thromboembolism in patients with prosthetic heart valves

Unwanted effect of COX inhibitors• Angioedema• Bronchospasm dermatological problems• GI pai, ulceration, bleeding• Hepatotoxicity• Hearing loss• Nausea and vomiting• Renal damage• etc

ADP antagonist Examples; clopidogrel, ticlodipine Mechanism of action

• inhibit adenosine diphosphate (ADP)-dependent platelet function by irreversible modification of the platelet P2Y12 receptor through short-lived active metabolites, generated by liver cytochrome P-450 (CYP) isozymes,

Clinical use• Acute coronary syndrome 300 mg loading dose, then 75mg/day for up to 12 months,

indefinitely if used in combination with aspirin• Recent MI, Stroke or established peripheral arterial disease; 75 mg/day• Coronary artery disease; 75 mg PO QID• Cardio embolic stroke; if not candidate for oral anticoagulant• Carotid artery stenting

Unwanted effects include• Upper respiratory tract infection• Chest pains• headache• flulike syndrome• Arthralgia• Dizziness, rash,• TTP, acute liver failure hypotension eczema <1%

Phosphodiesterase inhibitors Examples; Dipyridamole, Cilostazol Mechanism of action• It has been suggested that it inhibits types 3 and 5 PDEs, leading to the

intraplatelet accumulation of cAMP• reduces cellular adenosine uptake

Clinical use• Thromboembilic prophylaxis post cardiac valve replacement; 75-100

mg PO QID as adjunct to warfarin• Prevention of MI recurrence in combination with aspirin

Unwanted effects• Chest pains• Angina exacerbation• Abnormal ECG• Headache• Dizziness, abdominal discomfort• Nausea• Hypotension• Peripheral oedema etc

GPIIb/IIIa inhibitors Examples; abciximab, eptifibatide and tirofiban Mechanism of action• The platelet integrin receptor αIIbβ3 (GPIIb/IIIa) plays a critical role in thrombosis

and hemostasis by mediating interactions between platelets and several ligands, primarily fibrinogen. Inhibition of these receptors prevents the aggregation of platelets hence their antiplatelet function

Clinical use• Adjunct to PCI• Unstable angina with planned PCI within 24 hours (abciximab)• Acute coronary syndrome (eptifibatide and tirofiban)

Side effects• Bleeding• Pelvic pain• Bradycardia• Thrombocytopenia• Edema• Dizziness• Injection site pain• Anemia• etc

Other groups include• Reversible P2Y12 Antagonists (ticagrelor, cangrelor, elinogrel)• Thrombin Receptor Antagonists (disappointing results in clinical trials)• Thromboxane Receptor Antagonists (under clinical trials)

Recommended antiplatelet medications for selected clinical indications

AnticoagulantsAn anticoagulant is a substance that prevents coagulation; that is, which stops blood from clottingThis in turn prevents • Deep vein thrombosis, • Pulmonary embolism, • Myocardial infarction • Stroke.

Indications for anticoagulantsoDeep Vein ThrombosisoPulmonary EmbolismoMyocardial InfarctionoUnstable AnginaoRheumatic Heart Diseases; Atrial FibrillationoCerebrovascular DiseasesoDefibrination SyndromeoVascular Surgery, Prosthetic Heart Valves, Retinal Vessel Thrombosis, oExtracorporeal Circulation, Haemodialysis

Anticoagulants• Heparin and derivative substances• Coumarins (vitamin K antagonists)• Synthetic pentasaccharide inhibitors of factor Xa• Direct thrombin inhibitors• Antithrombin protein therapeutics

Heparin and derivative substances• Examples; UH, LMWH• Mechanism of action• low dose inactivates Factor Xa and inhibit nof prothrombin to thrombin• High dose inactivates Factor iX, X, XI and XII and thrombin and inhibits

conversion of fibrinogen to fibrin

Medical use• Acute coronary syndrome• Catheter patency• DVT and PE both prophylaxis and treatment

Side effects• Heparin induced thrombocytopenia• Hematoma• Hemorrhage• Erythema• Injection site ulcer• Anaphylaxis• Osteoporosis• etc

Coumarins (vitamin K antagonists) Examples; warfarin mechanism of action• Depletes functional vitamin K reserves, which in turn reduces synthesis of active clotting factors,

by competitively inhibiting subunit 1 of the multi-unit vitamin k epoxide reductase complex

Clinical use• Venous thrombosis; both prophylaxis and treatment; initial dose 2-5 mg PO/iv QID for 2 days..

Initiate on day 1 or 2 of LMWH or UH and overlap until desired INR (2-3), then discontinue heparin

• Stroke and thromboembolism• Cardiac valve replacement• Post myocardial infaction

Undesirable effects • Cholesterol embolus syndrome• Intraocular hemorrhage• Abdominal pain• Flatulence• Alopecia• Pruritus• Hematuria• Respiratory track bleeding• Hypersensitivity reaction• etc

Synthetic pentasaccharide inhibitors of factor Xa Examples; Fondaparinux, Idraparinux Mecahnism of action• Inhibits factor Xa which interrupts blood coagulation cascade and

inhibits thrombin formation and thrombus development. It generally does not increase PT or PTT

Clinical use• Deep vein thrombosis• Acute pulmonary embolism

Unwanted effects• Anemia• Fever• Nausea• Rash• Constipation • hypokalemia• Insomnia• Urinary retention/ UTI• etc

Direct factor Xa inhibitors Examples; rivaroxaban, apixaban and edoxaban Mechanism of action• factor Xa inhibitor that inhibits platelet activation by selectively blocking the

site of factor Xa without requiring a cofactor (eg antithrombim) for activity

clinical use• DVT prophylaxis (orthopedic surgery) eg, rivaroxaban 10 mg PO• Nonvalvular atrial fibrillation; eg rivaroxaban 20 mg/day PO• DVT or PE treatment eg rivaroxaban 15 mg PO BD for 21 days then 20mg PO

QID for 6 months

Side effects• Bleeding; GI, intracranial, intraocular• Hypersensitivity reaction• syncope

Antithrombin protein therapeutics Examples; Atryn Mechanism of action• Serine protease inhibitor; important natural inhibitor of blood

coagulation; inhibits thrombin and factor VIIa/tissue factor complex

Clinical use• Prophylaxis of venous thromboembolism in surgery of patients with

congenital antithrombim deficiency

Side effects• Application site pruritus• Chest pain; non cardiac• Dizziness• dyspnea• Headache• Hemorrhage• Postprocedural hemorrhage• Hepatic enzyme changes

Contraindications to anticoagulants and antiplateletsAbsolute Contraindications• Known large esophageal varices.• Significant thrombocytopenia (platelet count < 50 • Within 72 hours of major surgery with risk of severe bleeding • Previously documented hypersensitivity to either the drug• Acute clinically significant bleed• Decompensated liver disease or deranged baseline clotting screen (INR>1.5) (Contraindication

applies to oral anticoagulants only)• Severe renal impairment GFR < 30 mL/min/1.73 m2 or on dialysis).Contraindication applies to

dabigatran only.

Contraindications cont……Relative Contraindications• Previous history intracranial haemorrhage • Recent major extracranial bleed within the last 6 months where the

cause has not been identified or treated• Recent documented peptic ulcer (PU) within last 3 months• Recent history recurrent iatrogenic falls in patient at higher bleeding

risk• Pregnancy or within 48 hours post-partum (Contraindication applies

to oral anticoagulants only.

References American heart association; cardiovascular drugshttp://circ.ahajournals.org/content/101/10/1206.fullAntiplatelet Agents for the Treatment and Prevention of

Atherothrombosishttp://www.medscape.com/viewarticle/755091_3Uptodateaccessmedicine

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