Clinical Use of Coagulation Inhibitors PHM142 Fall 2015 Instructor: Dr. Jeffrey Henderson Clinical Use of Coagulation Inhibitors Presenters: Jacqueline Cheung, Olivia Hoang, Sylvia Kong, and Shirley Seto September 15, 2015

BLEEDING COAGULATION ☺

Bleeding Good Coagulation 1

Coagulation Cascade2 -Picture fill whole slide

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

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]

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. http://www.nhs.uk/conditions/Anticoagulant-medicines/Pages/Introduction.aspx

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

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)

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.]

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.

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

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

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

Heparin include diagram Antithrombin III Heparin2

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

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

LMWH include diagram Antithrombin III LMWH2

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

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

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

Dabigatran2

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

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

Eliquis (Apixaban) Xarelto (Edoxaban) Factor Xa Inhibitors2

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

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

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

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

References HyperVibe. How Blood Clots Form [Internet]. 2014 [cited 13 September 2015]. Available from: https://www.hypervibe.com/us/blog/blood-clots-%E2%80%93-how-threatening-are-they-and-how-can-i-prevent-them/ Nature Reviews Cardiology. Oral Anticoagulants for Asian patients with atrial fibrillation [Internet]. 2014 [cited 13 September 2015]. Available from: http://www.nature.com/nrcardio/journal/v11/n5/fig_tab/nrcardio.2014.22_F1.html Society of Interventional Radiology. [Internet]. 2003 [cited 13 September 2015]. Available from: http://www.idahoarteryandvein.com/conditions/deep-vein-thrombosis.php Idaho Artery and Vein. Deep Vein Thrombosis [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.idahoarteryandvein.com/conditions/deep-vein-thrombosis.php Thrombosis Adviser. Vitamin K Antagonist, Warfarin, Warfarin Therapy [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.thrombosisadviser.com/en/_thrombosis/warfarin/ Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood. 2015;125(3):438-442. Pubchem.ncbi.nlm.nih.gov. Warfarin [Internet]. 2015 [cited 10 September 2015]. Available from: http://pubchem.ncbi.nlm.nih.gov/compound/warfarin#section=Top Drugs. Warfarin [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.drugs.com/pro/warfarin.html Hull R, Garcia D. Warfarin (Coumadin) [Internet]. Uptodate.com. 2015 [cited 10 September 2015]. Available from: http://www.uptodate.com/contents/warfarin-coumadin-beyond-the-basics Cutting the red tape: Is the FDA a threat to patient health? [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.pharmaceutical-technology.com/features/featurefda-drug-development-patient-health/featurefda-drug-development-patient-health-6.html Heparin Science. History of Heparin [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.heparinscience.com/history_heparin.html 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]. 2010 [cited 10 September 10 2015]; 5(1): 36-42. Available from: http://www.jnsbm.org/article.asp?issn=0976-9668;year=2014;volume=5;issue=1;spage=36;epage=42;aulast=Rashid OH1. Heparin Science. History of Heparin [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.heparinscience.com/history_heparin.html OH2. Drugs.com. Heparin [Internet]. 2015 [cited 10 September 10 2015]. Available from: http://www.drugs.com/heparin.html OH3. Hirsh J, Anand S, Halperin J, Fuster V. Mechanism of Action and Pharmacology of Unfractionated Heparin. Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. 2001 [cited 10 September 10 2015]; 21: 1094-1096. Retrieved September 10, 2015, Available from: http://atvb.ahajournals.org/content/21/7/1094.long OH4. Idaho Artery and Vein. Deep Vein Thrombosis [Internet]. 2015 [cited 10 September 2015]. Available from: http://www.idahoarteryandvein.com/conditions/deep-vein-thrombosis.php OH5. Harper J. Antithrombin III Deficiency [Internet]. 2015 Jul [cited 10 September 2015] Available from: http://emedicine.medscape.com/article/954688-overview 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]. 2010 [cited 10 September 10 2015]; 5(1): 36-42. Available from: http://www.jnsbm.org/article.asp?issn=0976-9668;year=2014;volume=5;issue=1;spage=36;epage=42;aulast=Rashid OH7. Sancar, E. Heparin-Induced Thrombocytopenia [Internet].2014 Aug [cited 10 September 2015] Available from: http://emedicine.medscape.com/article/1357846-overview

References Continued Hirsh J, Anand S, Halperin J, Fuster V. Mechanism of Action and Pharmacology of Unfractionated Heparin. Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. 2001 [cited 10 September 10 2015]; 21: 1094-1096. Retrieved September 10, 2015, Available from: http://atvb.ahajournals.org/content/21/7/1094.long Sancar, E. Heparin-Induced Thrombocytopenia [Internet].2014 Aug [cited 10 September 2015] Available from: http://emedicine.medscape.com/article/1357846-overview Drugs.com. Heparin [Internet]. 2015 [cited 10 September 10 2015]. Available from: http://www.drugs.com/heparin.html Harper J. Antithrombin III Deficiency [Internet]. 2015 Jul [cited 10 September 2015] Available from: http://emedicine.medscape.com/article/954688-overview Rhea J, Molinaro R. Direct thrombin inhibitors: Clinical uses, mechanism of action, and laboratory measurement >> Medical Laboratory Observer [Internet]. Mlo-online.com. 2011 [cited 13 September 2015]. Available from: http://www.mlo-online.com/articles/201108/direct-thrombin-inhibitors-clinical-uses-mechanism-of-action-and-laboratory-measurement.php Lee C, Ansell J. Direct thrombin inhibitors. British Journal of Clinical Pharmacology. 2011;72(4):581-592. McAuley D. Direct Thrombin Inhibitors [Internet]. Globalrph.com. [cited 13 September 2015]. Available from: http://www.globalrph.com/direct_thrombin_inh.htm Oral Direct Factor Xa Inhibitors. Circulation Research [Internet]. 2012 [cited 13 September 2015];111:1069-1078. Available from: http://circres.ahajournals.org/content/111/8/1069.full