Anticoagulant, Antithrombotic and Anti-Platelet Drugs

Department of Pharmacology

Robert Taylor, MD, Ph.D.

Clinical Thrombosis

• >2.5 million cases of deep venous thrombosis (DVT) per year

• >600,000 cases of pulmonary embolism (PE) per year

• >50,000 deaths per year from PE• PE contributes to another 150,000 deaths

per year• > 11,000 postsurgical PE deaths per year

Indications For Antithrombotic Therapy

• Venous thromboembolic disease– Deep venous thrombosis (DVT)– Pulmonary embolism (PE)– Primary prophylaxis of DVT or PE

• Arterial thromboembolic disease• Prosthetic heart valves• Mitral valve disease, especially with atrial fibrillation• Congestive cardiomyopathies, especially with atrial fibrillatio• Atrial fibrillation• Mural cardiac thrombi• Transient ischemic attacks• Stroke in evolution

• Disseminated intravascular coagulation• Maintenance of patency of vascular grafts, shunts, bypasses

Recombinant Human Activated Protein C

• Drotrecogin alfa (activated)- Xigris• Indicated for Severe Sepsis in Adults with

Acute Organ Dysfunction with High Risk of Death

• Reduction in Death as Primary End Point

• Antithrombotic, Antiinfammatory, Profibrinolytic Properties

• Serious Bleeding is Major Side Effect

Antithrombin III Inhibits the Following Serine Proteases

• Coagulation

• Factor XIIa• Factor XIa• Factor IXa• Factor Xa• Thrombin

• Fibrinolysis

• Plasmin

Inhibitory activity against all these enzymes is substantially accelerated by heparin

Heparin• Heterogeneous; 3,000-30,000 d

• Average=15,000 d (~45monosaccharide chains)

• About 1/3 of dose binds to AT III

• To form the AT III:Heparin:Clotting Factor Complex- requires at least 18 saccarides except

• Unique high affinity pentasaccaride heparin sequences catalyze inhibition of Xa by AT

Anticoagulant Properties of Heparin

1. Inhibits the thrombin-mediated conversion of fibrinogen to fibrin

2. Inhibits the aggregation of platelets by thrombin

3. Inhibits activation of fibrin stabilizing enzyme

4. Inhibits activated factors XII, XI, IX, X and II

Heparin

• Biologic Sources• Bioavailability• Metabolism• Elimination• Side Effects• Overdose• Contraindications• Pregnancy- YES

Unfractionated Heparin

• High Dose– Treatment of venous/arterial thrombi– Requires monitoring– IV- 5,000 Units bolus, then 30,000-35,000

units/24 hrs– 80 Units/kg bolus, then 18 Units/kg/hr to

maintain aPTT in therapeutic range

Monitoring of Anticoagulant Therapy

Heparin

s.q. – no monitoring required

i.v. - partial thromboplastin time (P.T.T.)

*daily or more frequent if PTT varies

mechanism – measures intrinsic pathway

therapeutic goal – 2-2.5 times normal control value (-30 sec)

Low Dose Unfractionated Heparin

• Surgical Prophylaxis– 5,000 Units SQ 2 hr preop– 5,000 Units SQ every 12 hours

• Medical Prophylaxis– 5,000 Units SQ every 12 hours

• No monitoring required

Indications for and Contraindications to Parenteral Anticoagulant Agents

Anticoagulant Agent Class Approved & Appropriate Indications

Contraindication

Unfractionated heparin

Enoxaparin

(Lovenox)

Dalteparin

(Fragmin)

Tinzaparin

(Innohep)

Antithrombin III inhibitor

Low-molecular-weight heparin

Low-molecular-weight heparin

Low-molecular-weight heparin

Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina

Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism

? Prophylactic treatment

Regional anesthesia

Pregnancy

Prosthetic Heart Valves

Regional anesthesia

Regional anesthesia

Indications for and Contraindications to Parenteral Anticoagulant Agents (cont’d)

Ardeparin

Lepirudin

Argatroban

Danaparoid

Bivalirudin

Fondaparinux

(Arixtra)

Low-molecular-weight heparin

Hirudin derivative

Direct thrombin inhibitor

Heparinoid

Hirudin derivative

Synthetic factor Xa inhibitor

Approved; not being marketed

Heparin-induced thrombocytopenia with thrombosis

Heparin-induced thrombocytopenia with thrombosis

Prophylaxis against thrombosis in heparin-induced thrombocytopenia

Unstable angina or angioplasty

Prophylaxis in high-risk patients?

Regional anesthesia

Thrombocytopenia other than heparin-induced thrombocytopenia

Thrombocytopenia other than heparin-induced thrombocytopenia

Thrombocytopenia other than heparin-induced thrombocytopenia

Unknown

Unknown

Heparin-Antibiotic Interactions

• The second-generation cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N-methylthiotetrazole (NMTT) side chain. This NMTT group can:

• - Dissociate from the parent antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding.

• - This side chain is also associated with a disulfiram-like reaction to alcohol.

• - Clinical bleeding has been less frequently reported with Cefotetan than with cefoperazone or cefamandole.

Mechanisms of HIT

• Type 1: In most of these cases, the fall in platelet count occurs within the first two days after heparin initiation, often returns to normal with continued heparin administration, and is of no clinical consequence. The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of heparin on platelet activation.

•    Type 2: Approximately 0.3 to 3 percent of patients receiving heparin develop an immune thrombocytopenia, mediated by antibodies to a heparin-platelet factor 4 complex. One study, for example, randomly assigned 665 patients to therapy with unfractionated heparin or LMW heparin. Type 2 HIT developed in 2.7 percent of patients treated with unfractionated heparin but in none of those receiving LMW heparin.

Therapy of HIT

• There are two recommended approaches: – Use of the heparinoid danaparoid – The direct thrombin inhibitor lepirudin (recombinant

hirudin)– Based upon the data published to date, either

danaparoid or lepirudin should be used to treat HIT that is complicated by thrombosis; these agents should also be considered for prophylactic therapy in patients with HIT without thrombosis until the platelet count has recovered

Warfarin• Bioavailability• Metabolism• Serum Protein Binding• Vitamin K Status• Protein C Effects• Elimination• Side Effects• Overdose• Contraindications• Pregnancy- NO

Contraindications to Antithrombotic Therapy

• General risk factors-Pre-existing coagulation or platelet defect,

thrombocytopenia, or other bleeding abnormality-Inaccessible ulcerative lesion (e.g., gastrointestinal tract

lesion)-Central nervous system lesion (e.g., caused by stroke,

surgery, trauma)-Spinal anesthesia or lumbar puncture-Malignant hypertension-Bacterial endocarditis-Advanced retinopathy-Old age (relative)-Aspirin or other antiplatelet drugs-Neoplastic disease

Contraindications to Antithrombotic Therapy

• Specific to warfarin (ambulatory patients)

-Early and late pregnancy

-Poor patient cooperation, understanding, reliability

-Unsatisfactory laboratory or patient follow-up

-Occupational risk to trauma

Contraindications to Antithrombotic Therapy

• Specific to thrombolytic agents-Recent thoracic, abdominal, or central

nervous system surgery-Recent cerebrovascular accident, trauma,

or neoplasm-Bleeding ulcer-Hypertension-Anticipated invasive procedures (arterial

punctures, biopsies, central lines)-Concurrent hemostatic dysfunction

Platelet Receptor Mediated Pathways: Drugs

Arachidonic Acid ASA

NSAIDs

ADP Ticlopidine

Clopidogrel

Thrombin

-Final Common Pathway

-Promotes Platelet Adhesion (Fibrinogen, vWF)

GP IIB/IIIA Inhibitors

Abciximab (ReoPro)

Eptifibatide (Integrilin)

Tirofiban

Anti Platelet DrugsDrug Mechanism Uses

Aspirin Permanently inhibits COX-1 and COX-2

CAD

Stroke-TIAs

NSAIDs Reversibly inhibits COX-1

Limited

Dipyridamole Inhibits PDE; increases cAMP

TIAs

Ticlopidine

Clopidrgrel

Inhibits ADP PlatAg;active metabolite

TIAs;Stroke

CAD;PVD