1. Anticoagulant, Antiplatelet, and Thrombolytic Drugs
Chapter 52
Anticoagulant, Antiplatelet, and Thrombolytic Drugs 1

2. Physiology and Pathophysiology of Coagulation
Hemostasis
Stage 1: formation of platelet plug
Platelet aggregation
Stage 2: coagulation
Intrinsic coagulation pathway
Extrinsic coagulation pathway
Keeping hemostasis under control
Physiologic removal of clots
Thrombosis
Arterial thrombosis
Venous thrombosis 2

3. Overview of Drugs for Thromboembolic Disorders
Three major groups
Anticoagulants
Antiplatelets
Thrombolytics
See Table 52-1 3

4. Anticoagulants Reduce the formation of fibrin Two mechanisms of action
Inhibit the synthesis of clotting factors
Inhibit the activity of clotting factors 4

5. Heparin and Heparin Derivatives
Heparin (unfractionated)
Enhances antithrombin
Sources
Lungs of cattle
Intestines of pigs
Rapid-acting anticoagulant
Administered by injection only IV
Continuous and intermittent
Deep subQ 5

6. Heparin (Unfractionated)
Therapeutic uses
Preferred anticoagulant during pregnancy and when rapid anticoagulation is required
Pulmonary embolism (PE)
Stroke evolving
Massive deep venous thrombosis (DVT)
Open heart surgery
Renal dialysis
Low-dose therapy postoperatively
Disseminated intravascular coagulation (DIC)
Adjunct to thrombolytic therapy 6

7. Heparin (Unfractionated)
Adverse effects
Hemorrhage
Heparin-induced thrombocytopenia
Hypersensitivity reactions
Contraindicated
Thrombocytopenia
Uncontrollable bleeding
During and immediately after surgery of the eye, brain, or spinal cord
Antidote for OD: protamine sulfate
Activated partial thromboplastin time (aPTT) 7

8. Low-Molecular-Weight Heparins
Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin
Therapeutic uses
Prevention of DVT following surgery
Including replacement of hip, knee
Treatment of established DVT
Prevention of ischemic complications
Patients with unstable angina, non–Q-wave MI, and STEMI 8

9. Low-Molecular-Weight Heparins
Administered subQ
Dosage based on body weight
Antidote for toxicity: protamine sulfate
Costs more than unfractionated heparin
Does not require monitoring; can be given at home
Adverse effects and interactions
Bleeding (but less than with unfractionated heparin)
Immune-mediated thrombocytopenia
Severe neurologic injury for patients undergoing spinal puncture or spinal epidural anesthesia 9

10. Other LMW Heparin
In the United States, three LMW heparins are available:
Enoxaparin
Dalteparin
Tinzaparin

11. Warfarin, an Oral Anticoagulant
Originally discovered while cattle were observed ingesting spoiled clover silage
Used as rat poison
Failed suicide attempt with large dose brought renewed clinical interest
Clinical use
Oral anticoagulant with delayed onset
Vitamin K antagonist
Blocks biosynthesis of factors VII, IX, and X and prothrombin 11

12. Warfarin, an Oral Anticoagulant
Therapeutic uses
Not useful in emergencies
Long-term prophylaxis of thrombosis
Prevention of venous thrombosis and associated pulmonary embolism
Prevention of thromboembolism (in patients with prosthetic heart valves)
Prevention of thrombosis during atrial fibrillation 12

13. Warfarin, an Oral Anticoagulant
Monitoring treatment
Prothrombin time (PT)
International normalized ratio (INR)
Adverse effects
Hemorrhage (vitamin K for toxicity)
Fetal hemorrhage and teratogenesis from use during pregnancy
Use during lactation
Other adverse effects 13

14. Warfarin, an Oral Anticoagulant
Drug interactions
Drugs that increase anticoagulant effects
Drugs that promote bleeding
Drugs that decrease anticoagulant effects
Heparin
Aspirin
Acetaminophen 14

15. Warfarin, an Oral Anticoagulant
Warfarin overdose
Vitamin K
Dietary vitamin K
Contrasts between warfarin and heparin 15

16. Direct Thrombin Inhibitors
Direct inhibition of thrombin (unlike heparin, which enhances the activity of antithrombin)
Dabigatran Etexilate
Approved in 2010
Oral prodrug undergoes conversion to dabigatran
Advantages of dabigatran: doesn’t require monitoring of anticoagulation, little risk of adverse interactions, same dose can be used for all patients regardless of age or weight

17. Direct Thrombin Inhibitors
Hiruden Analog: Bivalirudin (Angiomax)
Prevents clot formation (combined with aspirin) in patients with unstable angina who are undergoing coronary angioplasty
Mechanism of action
Facilitates the actions of antithrombin
Prevents conversion of fibrinogen to fibrin
Prevents activation of factor XIII
Adverse effects
Bleeding
Back pain
Nausea, headache 17

18. Other Direct Thrombin Inhibitors
Lepirudin (Refludan)
Argatroban (formerly known as Acova)
Desirudin (Ipravask)
Dabigatran (Pradaxa) 18

19. Selective Factor Xa Inhibitors
Produce selective inhibition of factor Xa
Fondaparinux
Activation of antithrombin
Injection
Rivaroxaban
Binds directly with factor Xa to cause inactivation
Oral 19

20. Fondaparinux (Arixtra)
Synthetic anticoagulant
Selective inhibition
Therapeutic uses
Prevention of DVT following surgery
Treatment of acute PE (in conjunction with warfarin)
Treatment of acute DVT (in conjunction with warfarin)
Adverse effects
Bleeding
Avoid in patients weighing less than 50 kg
Thrombocytopenia
Spinal or epidural hematoma 20

21. Rivaroxaban (Xarelto)
Oral anticoagulant approved in 2011
Does not require laboratory monitoring
Patients who received rivaroxaban were found to be much less likely to experience DVT, VTE, PE, or death 21

22. Antithrombin (AT)
Endogenous compound that suppresses coagulation, primarily by inhibiting thrombin and factor Xa
Used to prevent thrombosis in patients with inherited AT deficiency
Two preparations, marketed as Atryn and Thrombate III

23. Antiplatelet Drugs Aspirin (ASA) Ticlopidine (Ticlid)
Inhibition of cyclooxygenase
Adverse effect
Increases risk for GI bleeding
Ticlopidine (Ticlid)
Inhibits ADP-mediated aggregation
Adverse effects
Hematologic effects
Clopidogrel (Plavix)
ADP receptor antagonist 23

24. Aspirin (ASA) Therapeutic uses Ischemic stroke
Transient ischemic attack (TIA)
Chronic stable angina
Unstable angina
Coronary stenting
Acute MI
Previous MI
Primary prevention of MI 24

25. Aspirin (ASA) Adverse effects Bleeding
GI bleeding and hemorrhagic stroke
Enteric-coated tablets may not reduce the risk for GI bleeding 25

26. Clopidogrel (Plavix) Therapeutic uses
Prevents blockage of coronary artery stents
Reduces thrombotic events in patients with acute coronary syndromes
MI, ischemic stroke, and vascular death
Similar adverse effects to those of aspirin
Use with caution in combination with other drugs that promote bleeding 26

27. Antiplatelet Drugs Glycoprotein (GP) IIb/IIIa receptor antagonists
Most effective antiplatelet drugs
“Super aspirins”
Reversible blockade of platelet GP IIb/IIIa receptors 27

28. Other Antiplatelet Drugs
Dipyridamole
Dipyrindamole + aspirin
Aggrenox
Cilostazol

29. Thrombolytic Drugs Streptokinase (Streptase); Alteplase (tPa)
Major adverse effect – bleeding (minor oozing to life-threatening amount)
Likely sites of bleeding
Recent wounds, needle puncture sites, invasive procedure sites
Anticoagulants increase the risk for hemorrhage
Blood replacement may need to be considered

30. Minimizing the Risk of Bleeding
Minimizing physical manipulation of the patient
Avoiding subQ and IM injections
Minimizing invasive procedures
Minimizing concurrent use of anticoagulants (eg, heparin, warfarin, dabigatran)
Minimizing concurrent use of antiplatelet drugs (eg, aspirin, clopidogrel)

31. Streptokinase (Streptase)
Binds to plasminogen to form active complex
Therapeutic uses
Acute coronary thrombosis (acute MI)
Deep venous thrombosis (DVT)
Massive pulmonary emboli
Adverse effects
Bleeding – excessive fibrinolysis can be reversed with IV aminocaproic acid (Amicar)
Antibody production
Hypotension
Fever

32. Alteplase (tPa) Converts plasminogen to plasmin
Given in accelerated schedule
Therapeutic uses
Myocardial infarction
Ischemic stroke
Massive pulmonary emboli 32

33. Alteplase (tPa) Adverse effects Advantages Bleeding Fever
Risk for intracranial bleeding higher than with streptokinase
Fever
Advantages
Does not cause allergic reactions
Does not induce hypotension 33

34. Other Thrombolytic Drugs
Tenecteplase
Reteplase 34