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 • Fibrinolysis

• Factor XIIa • Plasmin

• Factor XIa
• Factor IXa
• Factor Xa
• Thrombin
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 Contraindication
Indications

Unfractionated heparin Antithrombin III Treatment of venous ? Prophylactic treatment

inhibitor thromboembolism or unstable angina;
used when rapid reversal is important

Prophylaxis in moderate-risk or high-

risk patients, treatment of venous
Enoxaparin Low-molecular-
thromboembolism or unstable angina Regional anesthesia
weight heparin
(Lovenox) Pregnancy
Prophylaxis in moderate-risk or high- Prosthetic Heart Valves
risk patients, treatment of venous
Low-molecular- thromboembolism or unstable angina Regional anesthesia
Dalteparin
weight heparin
(Fragmin)
Prophylaxis in moderate-risk or high-
risk patients, treatment of venous
thromboembolism
Regional anesthesia
Low-molecular-
Tinzaparin weight heparin
(Innohep)
 Indications for and Contraindications to
Parenteral Anticoagulant Agents (cont’d)
Ardeparin Low-molecular-weight Approved; not being Regional anesthesia
heparin marketed

Lepirudin Hirudin derivative Heparin-induced Thrombocytopenia other than

thrombocytopenia with heparin-induced
thrombosis thrombocytopenia

Heparin-induced Thrombocytopenia other than

Argatroban Direct thrombin inhibitor
thrombocytopenia with heparin-induced
thrombosis thrombocytopenia

Danaparoid Heparinoid Prophylaxis against Thrombocytopenia other than

thrombosis in heparin- heparin-induced
induced thrombocytopenia
thrombocytopenia

Hirudin derivative Unstable angina or

Bivalirudin Unknown
angioplasty

Prophylaxis in high-risk
Fondaparinux Synthetic factor Xa patients? Unknown
inhibitor
(Arixtra)
 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 GP IIB/IIIA Inhibitors
-Final Common Pathway Abciximab (ReoPro)
-Promotes Platelet Eptifibatide (Integrilin)
Adhesion (Fibrinogen, Tirofiban
vWF)
 Anti Platelet Drugs
Drug Mechanism Uses
Aspirin Permanently CAD
inhibits COX-1 Stroke-TIAs
and COX-2

NSAIDs Reversibly Limited

inhibits COX-1
Dipyridamole Inhibits PDE; TIAs
increases cAMP
Ticlopidine Inhibits ADP TIAs;Stroke
Clopidrgrel PlatAg;active CAD;PVD
metabolite