1. Drugs for Coagulation Disorders Andrew N. Schmelz, PharmD Post-Doctoral Teaching Fellow Purdue University October 8, 2008 anschmel@purdue.edu

2. Objectives List important steps of hemostasis and fibrinolysis List important steps of hemostasis and fibrinolysis Describe thromboembolic disorders that are indications for coagulation modifiers Describe thromboembolic disorders that are indications for coagulation modifiers Identify the primary mechanism for each coagulation modifying-drug discussed Identify the primary mechanism for each coagulation modifying-drug discussed Match specific coagulation-modifying drugs to lab tests with which they are appropriately monitored Match specific coagulation-modifying drugs to lab tests with which they are appropriately monitored

3. Objectives (cont) Categorize coagulation-modifying drugs based on their classification and mechanism of action Categorize coagulation-modifying drugs based on their classification and mechanism of action List important adverse effects for each coagulation-modifying drug discussed List important adverse effects for each coagulation-modifying drug discussed

4. Process of Hemostasis Hemostasis: Protects the body from both external and internal injury Hemostasis: Protects the body from both external and internal injury Injury to blood vessels causes: Injury to blood vessels causes: –Vessel spasms (causing constriction) –Platelet adherence to injury site –Platelets aggregate and form plug –Insoluble fibrin strands form and coagulate

5. Process of Hemostasis

6. (Factor Xa) Intrinsic Pathway (In response to injury) Extrinsic Pathway (Blood enters tissue spaces)

7. Removal of Blood Clots Fibrinolysis: Removal of clot so that tissue can resume its normal activity Fibrinolysis: Removal of clot so that tissue can resume its normal activity

8. Diseases of Hemostasis Thromboembolic disorders (MI and CVA) Thromboembolic disorders (MI and CVA) –Stationary clot (thrombus) grows and deprives specific areas of oxygen Deep Vein Thrombosis (DVT) Deep Vein Thrombosis (DVT) –Formation of clots in large veins (usually legs) Embolus Embolus –Thrombus may break off and be carried by bloodstream to affect other areas

9. Diseases of Hemostasis (cont) Thrombocytopenia Thrombocytopenia –Low number of platelets, cannot properly form clots Hemophilias Hemophilias –Genetic deficiencies of clotting factors

10. Mechanisms of Action Anticoagulants Anticoagulants –Inhibition of clotting factors Antiplatelets Antiplatelets –Inhibition of platelet function Thrombolytics Thrombolytics –Lyse thrombi Hemostatics Hemostatics –Inhibition of fibrinolysis

11. Inhibition of Clotting Factors (Anticoagulants)

12. Heparin Example: Heparin (Heplock®) Example: Heparin (Heplock®) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa)

13. Heparin Enoxaparin (Factor Xa)

14. Heparin Example: Heparin (Heplock®) Example: Heparin (Heplock®) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa) Route: IV (continuous infusion), SC Route: IV (continuous infusion), SC Monitoring: aPTT (25-40 s), platelets, s/sxs of hemorrhage Monitoring: aPTT (25-40 s), platelets, s/sxs of hemorrhage Adverse Effects: Adverse Effects: –Hemorrhage –Anaphylaxis –Thrombocytopenia (HIT)

15. Low-Molecular-Weight Heparins Example: Enoxaparin (Lovenox®) Example: Enoxaparin (Lovenox®) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa) MOA: Enhances inhibitory effect of antithrombin III (inhibits factor Xa) Route: SC Route: SC Monitoring: Anti-factor Xa, SCr, platelets Monitoring: Anti-factor Xa, SCr, platelets Adverse Effects: Adverse Effects: –Hemorrhage –Thrombocytopenia –Hypersensitivity (anaphylaxis)

16. Vitamin K-Dependant Clotting Factor Inhibitors Example: Warfarin (Coumadin®) Example: Warfarin (Coumadin®) MOA: Inhibits enzymes responsible for cyclic conversion of Vitamin K MOA: Inhibits enzymes responsible for cyclic conversion of Vitamin K Route: PO Route: PO Monitoring: PT/INR (12-15 / 2-3.5), s/sxs of hemorrhage Monitoring: PT/INR (12-15 / 2-3.5), s/sxs of hemorrhage Adverse Effects: Adverse Effects: –Hemorrhage –Anemia –Bruising

17. Direct Thrombin Inhibitors Examples: Argatroban (Novastan®) Bivalirudin (Angiomax®) Examples: Argatroban (Novastan®) Bivalirudin (Angiomax®) MOA: Directly inhibit thrombin (preventing formation of fibrin clots) MOA: Directly inhibit thrombin (preventing formation of fibrin clots)

18. Argatroban Bivalirudin (Factor Xa)

19. Direct Thrombin Inhibitors Examples: Argatroban (Novastan®) Bivalirudin (Angiomax®) Examples: Argatroban (Novastan®) Bivalirudin (Angiomax®) MOA: Directly inhibit thrombin (preventing formation of fibrin clots) MOA: Directly inhibit thrombin (preventing formation of fibrin clots) Route: IV Route: IV Monitoring: aPTT (25-40 s) Monitoring: aPTT (25-40 s) Adverse Effects: Adverse Effects: –Serious internal hemorrhage –Back pain (bivalirudin)

20. Nursing Considerations Medication Safety Medication Safety Assess patients for signs of bleeding Assess patients for signs of bleeding –Bruising –Obvious signs of bleeding (nosebleeds, bleeding from rectum, blood in emesis) –“Coffee Ground” or black, tarry stools / emesis Patient education Patient education Toxicity: warfarin – vit K administration heparin – protamine sulfate Toxicity: warfarin – vit K administration heparin – protamine sulfate

21. Patient Case JR is 55 YOWM recently diagnosed with a DVT and is currently receiving enoxaparin (Lovenox). JR is 55 YOWM recently diagnosed with a DVT and is currently receiving enoxaparin (Lovenox). Before he can be d/c’ed from the hospital, his MD wants to starts him on chronic anticoagulation to prevent future DVTs Before he can be d/c’ed from the hospital, his MD wants to starts him on chronic anticoagulation to prevent future DVTs

22. Inhibition of Platelet Function (Antiplatelets)

23. GP IIb/IIIa Antagonists Example: Abciximab (ReoPro®) Example: Abciximab (ReoPro®) MOA: Inhibit GP IIb/IIIa, enzyme necessary for platelet aggregation MOA: Inhibit GP IIb/IIIa, enzyme necessary for platelet aggregation

25. GP IIb/IIIa Antagonists Example: Abciximab (ReoPro®) Example: Abciximab (ReoPro®) MOA: Inhibit GP IIb/IIIa, enzyme necessary for platelet aggregation MOA: Inhibit GP IIb/IIIa, enzyme necessary for platelet aggregation Route: IV Route: IV Monitoring: Platelets Monitoring: Platelets Adverse Effects: Adverse Effects: –Hemorrhage –Thrombocytopenia

26. Aspirin (Ecotrin®) Example: Aspirin (Ecotrin®) Example: Aspirin (Ecotrin®) MOA: Irreversibly binds to COX, inhibiting formation of thromboxane A2 MOA: Irreversibly binds to COX, inhibiting formation of thromboxane A2

28. Aspirin (Ecotrin®) Example: Aspirin (Ecotrin®) Example: Aspirin (Ecotrin®) MOA: Irreversibly binds to COX, inhibiting formation of thromboxane A2 MOA: Irreversibly binds to COX, inhibiting formation of thromboxane A2 Route: PO Route: PO Monitoring: S/sxs hemorrhage Monitoring: S/sxs hemorrhage Adverse Effects: Adverse Effects: –Increased clotting times –GI bleeding –Anaphylaxis

29. ADP Receptor Blockers Example: Clopidogrel (Plavix®) Example: Clopidogrel (Plavix®) MOA: ADP-receptor blockers MOA: ADP-receptor blockers

31. ADP Receptor Blockers Example: Clopidogrel (Plavix®) Example: Clopidogrel (Plavix®) MOA: ADP-receptor blockers MOA: ADP-receptor blockers Route: IV (loading dose), PO Route: IV (loading dose), PO Monitoring: S/sxs hemorrhage Monitoring: S/sxs hemorrhage Adverse Effects: Adverse Effects: –Increased clotting time –GI bleeding –Blood dyscrasias (TTP)

32. Agents for Intermittent Claudication Example: Cilostazole (Pletal®) Example: Cilostazole (Pletal®) MOA: PDE-3 inhibitor MOA: PDE-3 inhibitor Route: PO Route: PO Monitoring: S/sxs hemorrhage, heart Monitoring: S/sxs hemorrhage, heart Adverse Effects: Adverse Effects: –Palpitation, tachycardia, –Nausea, vomitting

33. Nursing Considerations Careful monitoring of patient condition (increased risk of bleeding) Careful monitoring of patient condition (increased risk of bleeding) Combination with anticoagulants – increased risk of bleeding Combination with anticoagulants – increased risk of bleeding Injection / venipuncture sites will require prolonged pressure to control bleeding Injection / venipuncture sites will require prolonged pressure to control bleeding Patient education Patient education

34. Pharmacotherapy with Thrombolytics

35. Thrombolytics Example: Alteplase (Activase®, TPA) Example: Alteplase (Activase®, TPA) MOA: Fibrin-enhanced conversion of plasminogen to plasmin MOA: Fibrin-enhanced conversion of plasminogen to plasmin

37. Thrombolytics Example: Alteplase (Activase®, TPA) Example: Alteplase (Activase®, TPA) MOA: Fibrin-enhanced conversion of plasminogen to plasmin MOA: Fibrin-enhanced conversion of plasminogen to plasmin Route: IV Route: IV Monitoring: S/sxs hemorrhage, coagulation tests, H/H, platelets, mental status, dysrhythmias (MI) Monitoring: S/sxs hemorrhage, coagulation tests, H/H, platelets, mental status, dysrhythmias (MI) Adverse Effects: Adverse Effects: –Serious internal bleeding –Intracranial hemorrhage

38. Nursing Considerations Identify underlying conditions that exclude patient from receiving thrombolytics Identify underlying conditions that exclude patient from receiving thrombolytics –Recent trauma, surgery, or biopsy –Arterial emboli –Recent cerebral embolism –Hemorrhage –Thrombocytopenia –Childbirth (within 10 days)

39. Pharmacotherapy with Hemostatics

40. Hemostatics Example: Aprotinin (Trasylol®) Example: Aprotinin (Trasylol®) MOA: Inhibits fibrinolysis (affects multiple mediators) MOA: Inhibits fibrinolysis (affects multiple mediators)

42. Hemostatics Example: Aprotinin (Trasylol®) Example: Aprotinin (Trasylol®) MOA: Inhibits fibrinolysis (affects multiple mediators) MOA: Inhibits fibrinolysis (affects multiple mediators) Route: IV Route: IV Monitoring: Clotting, peripheral pulses, paresthesias, (+) Homans’ sign Monitoring: Clotting, peripheral pulses, paresthesias, (+) Homans’ signHomans’ signHomans’ sign Adverse Effects: Adverse Effects: –Clotting –Extravasation

43. Questions

44. Summary Hemostasis protects the body from injury Hemostasis protects the body from injury Several pathologies may affect hemostasis Several pathologies may affect hemostasis Four main drug categories are used to treat coagulation disorders Four main drug categories are used to treat coagulation disorders Nurses play an important role Nurses play an important role –Monitoring drug efficacy –Monitoring patient for adverse effects

45. Drugs for Coagulation Disorders Andrew N. Schmelz, PharmD Post-Doctoral Teaching Fellow Purdue University October 8, 2008 anschmel@purdue.edu