1. Clinical Use of Coagulation Inhibitors
PHM Fall 2015
Instructor: Dr. Jeffrey Henderson
Clinical Use of Coagulation Inhibitors
Presenters:
Jacqueline Cheung, Olivia Hoang, Sylvia Kong, and Shirley Seto
September 15, 2015

2. BLEEDING
COAGULATION ☺

3. Bleeding
Good
Coagulation 1

4. Coagulation Cascade2
-Picture fill whole slide

5. ☹ BLEEDING COAGULATION Examples of Clinical Diseases
・Deep Vein Thrombosis
・Pulmonary Embolism
・Heart Attack
・Stroke ☹

6. Examples of Clinical Diseases3,4
・Deep Vein Thrombosis
・Pulmonary Embolism
・Heart Attack
・Stroke
treat venous thromboembolism (deep vein thrombosis and pulmonary embolism) during surgery [2]
deep vein thrombosis: blood clot in deep vein, usually leg [3]
pulmonary embolism: blood clot in pulmonary arteries that traveled from other part of body, usually from leg[4]
deep vein thrombosis and pulmonary embolism usually occur together [4]
used in cardiac surgery to prevent blood clot [2]

7. Coagulation Inhibitors
Also known as anticoagulants
Clinical Use:
Prevent blood clots
Reduce risk of getting aforementioned clinical diseases
Drugs examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)
Many people refer to these medicines as "blood thinners," although they do not actually cause the blood to become less thick, only less likely to clot.

8. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)

9. Warfarin (Vitamin K Antagonist)2,5
Inhibits the synthesis of vitamin K-dependent clotting factors in the liver (Factors II, VII, IX, and X) (Shirley’s image, JC1)

10. Warfarin Mechanism
Warfarin interferes with vitamin K epoxide reductase enzyme complex, which hinders the completion of the vitamin K cycle6,7
· Mechanism: interferes with vitamin K epoxide reductase enzyme complex, which hinders the completion of the vitamin K cycle (2) [The VKOR reduces Vitamin K epoxide to Vit K quinone (K) to Vitamin K hydroquinone.]

11. Warfarin - Clinical Use 8-10
Brand name: Coumadin
Oral Tablet
Therapeutic Monitoring by blood tests
Side Effects: bleeding, and skin necrosis
Contraindication in pregnant women:
Warfarin passes the placenta from mother to baby, which can interfere with normal blood clotting in the baby.
Brand name is Coumadin
Prescription Medication
Oral Tablet
prescribed for patients who are at increased risk for developing harmful blood clots, and also used in people who have already developed a harmful blood clot
Indicated for:
[prevention and treatment of] Deep Vein Thrombosis and Pulmonary Embolism
[prevention and treatment of thromboembolic complications associated with] atrial fibrillation (AF) and/or cardiac valve replacement.
[Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as] stroke or systemic embolization after myocardial infarction.
Need therapeutic monitoring by blood test: The dosage and administration of Warfarin sodium must be individualized for each patient according to the patient's international normalized ratio response (clotting tendancy) to the drug
A woman who becomes pregnant or plans to become pregnant while on warfarin therapy should notify her healthcare provider immediately, usually heparin is used during pregancy.

12. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)

13. What is Heparin Large, highly sulfated, anionic molecule11
Mucopolysaccharide (Glycosaminoglycans): long unbranched polysaccharide composed of repeating disaccharide unit 11

14. Mechanism of Heparin12 Antithrombin III: Antithrombin III activator 13
Endogenous thrombin inhibitor14
Inhibits activated Factor Xa14
Antithrombin III
Heparin
Thrombin
Factor Xa

15. Heparin
include diagram
Antithrombin III
Heparin2

16. Heparin Details Administration
Low bioavailability; not absorbed through gastrointestinal mucosa15
Intravenous or deep subcutaneous15
Adverse Effects
Bleeding15
Thrombocytopenia (deficiency of platelet)14
Dyspnea (difficulty in breathing)15
Hypotension15
Heparin Resistance
Some individuals have anti-thrombin III deficiency16

17. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)

18. LMWH
include diagram
Antithrombin III
LMWH2

19. Low Molecular Weight Heparin (LMWH)
Smaller fragments of heparin13
High affinity for antithrombin III13
Inactivates factor Xa13
High anti-Xa activity and low anti-thrombin activity; ratio 4: 113
LMWH lack length to bridge between thrombin and antithrombin III thus LMWH has low anti-thrombin activity 13
More predictable pharmacokinetics than heparin13
Not used if patient has renal failure because LMWH mainly eliminated by renal clearance13

20. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)

21. Direct Thrombin Inhibitor
Inhibits the enzymatic activity of thrombin by binding to active site18
2 types19
Bivalent→ Bivalirudin
Univalent→ Dabigatran

22. Dabigatran2

23. Dabigatran (Pradaxa) Small peptidomimetic19
Orally administered as a prodrug called Dabigatran etexilate18
Reversibly inhibits free floating and bounded thrombin19
Lack of interaction with cytochrome p450 and foods19
No monitoring18
Adjustments needed for patients with renal impairment20
no bioavilabilty when it is orally absorbed on its own

24. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)
Factor Xa Inhibitors

25. Eliquis (Apixaban)
Xarelto (Edoxaban)
Factor Xa Inhibitors2

26. Factor Xa Inhibitors Drug Examples Eliquis (Apixaban) Xarelto (Edoxaban)
Biochem
Both intrinsic and extrinsic complexes activate fX to fXa21
1 molecule of fXa → ~ 1000 molecules of Thrombin21
Clinical Advantages
Orally administered at fixed doses21
Reduced variability in therapeutic response21
Less drug-drug interaction21
Dual mechanism of excretion (renal and fecal)21
✓ Inhibit critical thrombin amplification step
✓Easier to administer
✓ No routine monitoring
✓ Safer for patients with renal impairment

27. Coagulation Inhibitors Examples:
Warfarin (Coumadin)
Heparin
Low Molecular Weight Heparin
Dabigatran (Pradaxa)
Apixaban (Eliquis)
Rivaroxaban (Xarelto)

28. include diagram Summary Page LMWH Heparin Antithrombin III
Eliquis (Apixaban)
Xarelo (Edoxaban)
include diagram
Antithrombin III

29. Summary Page Coagulation Inhibitors - prevent blood clots
Drug Examples
Warfarin (Coumadin) - Vitamin K Antagonist
Heparin - Antithrombin III activator
Low Molecular Weight Heparin - Antithrombin III activator
Dabigatran (Pradaxa) - Direct Thrombin Inhibitor
Apixaban (Eliquis) - FXa Inhibitor
Rivaroxaban (Xarelto) - FXa Inhibitor

30. References
HyperVibe. How Blood Clots Form [Internet] [cited 13 September 2015]. Available from:
Nature Reviews Cardiology. Oral Anticoagulants for Asian patients with atrial fibrillation [Internet] [cited 13 September 2015]. Available from:
Society of Interventional Radiology. [Internet] [cited 13 September 2015]. Available from:
Idaho Artery and Vein. Deep Vein Thrombosis [Internet] [cited 10 September 2015]. Available from:
Thrombosis Adviser. Vitamin K Antagonist, Warfarin, Warfarin Therapy [Internet] [cited 10 September 2015]. Available from:
Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood. 2015;125(3):
Pubchem.ncbi.nlm.nih.gov. Warfarin [Internet] [cited 10 September 2015]. Available from:
Drugs. Warfarin [Internet] [cited 10 September 2015]. Available from:
Hull R, Garcia D. Warfarin (Coumadin) [Internet]. Uptodate.com [cited 10 September 2015]. Available from:
Cutting the red tape: Is the FDA a threat to patient health? [Internet] [cited 10 September 2015]. Available from:
Heparin Science. History of Heparin [Internet] [cited 10 September 2015]. Available from:
Jairajpuri M, Rashid Q, Abid M. (2010). Elucidating the specificity of non-heparin-based conformational activators of antithrombin for factor Xa inhibition. Journal of Natural Science, Biology and Medicine [Internet] [cited 10 September ]; 5(1): Available from:
OH1. Heparin Science. History of Heparin [Internet] [cited 10 September 2015]. Available from:
OH2. Drugs.com. Heparin [Internet] [cited 10 September ]. Available from:
OH3. Hirsh J, Anand S, Halperin J, Fuster V. Mechanism of Action and Pharmacology of Unfractionated Heparin. Arteriosclerosis, Thrombosis, and Vascular Biology [Internet] [cited 10 September ]; 21: Retrieved September 10, 2015, Available from:
OH4. Idaho Artery and Vein. Deep Vein Thrombosis [Internet] [cited 10 September 2015]. Available from:
OH5. Harper J. Antithrombin III Deficiency [Internet] Jul [cited 10 September 2015] Available from:
OH6. Jairajpuri M, Rashid Q, Abid M. (2010). Elucidating the specificity of non-heparin-based conformational activators of antithrombin for factor Xa inhibition. Journal of Natural Science, Biology and Medicine [Internet] [cited 10 September ]; 5(1): Available from:
OH7. Sancar, E. Heparin-Induced Thrombocytopenia [Internet].2014 Aug [cited 10 September 2015] Available from:

31. References Continued
Hirsh J, Anand S, Halperin J, Fuster V. Mechanism of Action and Pharmacology of Unfractionated Heparin. Arteriosclerosis, Thrombosis, and Vascular Biology [Internet] [cited 10 September ]; 21: Retrieved September 10, 2015, Available from:
Sancar, E. Heparin-Induced Thrombocytopenia [Internet].2014 Aug [cited 10 September 2015] Available from:
Drugs.com. Heparin [Internet] [cited 10 September ]. Available from:
Harper J. Antithrombin III Deficiency [Internet] Jul [cited 10 September 2015] Available from:
Rhea J, Molinaro R. Direct thrombin inhibitors: Clinical uses, mechanism of action, and laboratory measurement >> Medical Laboratory Observer [Internet]. Mlo-online.com [cited 13 September 2015]. Available from:
Lee C, Ansell J. Direct thrombin inhibitors. British Journal of Clinical Pharmacology. 2011;72(4):
McAuley D. Direct Thrombin Inhibitors [Internet]. Globalrph.com. [cited 13 September 2015]. Available from:
Oral Direct Factor Xa Inhibitors. Circulation Research [Internet] [cited 13 September 2015];111: Available from: