A. Introduction
[Figure] "The Clotting Pathways"

1. Warfarin (Coumadin®) is the most prevalent oral anti-coagulant in use
2. Major roles in prevention of arterial and venous thromboemboli
3. Mechanism of Action
   1. Key pharmacologic target is vitamin K epoxide reductase (VKORC1) enzyme
   2. VKORC1 catalyzes steps in synthesis of vitamin K-dependent proteins involved in clotting
   3. These proteins are normally produced in the liver
   4. They require attachment of a second carboxyl group to the gamma carbon of glutamate
   5. By blocking VKORC1, Vitamin K inhibits gamma-carboxylation with first order kinetics
   6. Synthesis of coagulation factors II, VII, IX, and X is inhibited
   7. Synthesis of anticoagulation factors C, S and Z are also inhibited
   8. Net effect, however, is blocking coagulation and increasing prothrombin time (PT)
   9. Variant polymorphisms of VKORC1 associated variability in initial warfarin effects [2,10]
4. Metabolism
   1. Absorbed from the gut; only 3-5% of drug circulates in active (inhibitory) form
   2. Metabolized by hepatic cytochrome P450 system (see below)
   3. Many drugs affect these P450 levels and alter warfarin metabolism
   4. The half-life of warfarin is 40-200 hours
   5. Acute ethanol intake can induce P450s and thereby reduce warfarin levels
   6. Chronic alcoholism destroys hepatic metabolic pathways, reduces Vitamin K, and therefore can increase warfarin activity
   7. Acetaminophen is a competitive inhibitor of P450, and increases warfarin efficacy [15]
   8. CYP2C9 and VKORC1 polymorphisms may be responsible for >50% of variability [30]
   9. Mutation testing for these polymorphisms (SNPs) are available from several commercial labs [30]
5. Vitamin K ingestion competes out warfarin and affects level of anticoagulation
6. In most settings, moderate to high anticoagulation with warfarin is superior to aspirin (ASA), but increases bleeding risk [22]

B. Risks of Thromboembolism in Various Settings [4]

1. Deep Vein Thrombosis
   1. Main risk for recurrent thromboembolism is within 3-6 months of initial embolism
   2. Risk is ~30% within 3 month period after proximal DVT [1]
   3. Warfarin reduces risk to: ~10% with 1 month therapy, 5% with 3 months, <5% 6 months
   4. Overall risk reduction with anticoagulation is ~80%
2. Atrial Fibrillation (AFib)
   1. Non-valvular AFib: risk is ~4.5% per year (range 1-20%)
   2. Recurrence risk with non-valvular AFib and one cerebral emoblism is ~12% per year
   3. Anticoagulation reduces overall risk by ~66%
   4. For valvular AFib, risk reduction is much higher, because incidence of emboli is higher
3. Mitral Stenosis (MS) [16]
   1. MS alone has little risk of thromboembolism
   2. MS with left atrial thrombus has 37X increased risk
   3. MS with moderate or severe aortic regurgitation has 22X increased risk
4. Mechanical Heart Valves
   1. Average rate of major thromboembolism with metal heart valves is ~8% per year
   2. Anticoagulation reduces this rate by ~75%; addition of ASA reduces further
   3. Addition of low dose aspirin reduces this rate even further
   4. Bioprosthetic heart valves have risk of 5-6% in first 3 months only
   5. Unclear benefit of anticoagulation with bioprosthetic heart valves [1]
5. Myocardial Infarction (MI) [1]
   1. Risk of thromboembolism ~6% per year
   2. Overall risk reduction with anticoagulation is ~65%
   3. ASA added to anticoagulation leads to even further risk reduction
6. In most cases, warfarin should not be stopped for dental surgery [17]

C. Recommended Levels of Anti-Coagulation [22]

1. Depends on particular disease being treated
2. INR=International Normalization Ratio, is most common measure of antigocatulation
3. Atrial Fibrillation (AFib) [7]
   1. Non-Rheumatic high or moderate risk: INR 2.0-3.0X (2.0-2.5X may be sufficient)
   2. Rheumatic Atrial Fibrillation: INR 2.5-3
   3. Lone Atrial Fibrillation (in young persons): INR 1.5-1.8 or ASA 160-325mg qd
   4. Duration indefinitely while in AFib
4. Ventricular Clot
   1. INR 2.0-2.5
   2. Duration until resolution of clot on echocardiography
5. Pulmonary Embolism/Deep Vein Thrombosis
   1. INR 2-3.0
   2. Duration >3 months, probably <12 months if not associated with underlying condition
   3. After 3 months, INR should be maintained 2.0-3.0 [11]
   4. After 6 monhts, the INR may be reduced to 1.5-2.0 [12]
   5. Indefinite duration with malignancy or other underlying condition
6. Myocardial Infarction
   1. INR 2-3.5
   2. High risk or Recurrent MI
   3. Failed with ASA or allergic to aspirin
   4. May be used in addition to ASA
7. Metal Heart Valve
   1. INR 3.0-3.5X
   2. May add low dose aspirin (eg. 81mg po qd) to improve efficacy
8. Use after cardiac stenting not generally recommended
9. In men at high risk for cardiovascular disease, addition of low dose warfarin (INR ~1.5X) to aspirin appears to improve overall mortality [14]
10. Warfarin provides benefit but increased complications compared with ASA for secondary stroke prevention [9]
11. Stopping anticoagulation during dental surgery is a risk for thromboembolism [17]

D. Warfarin Dosage and Monitoring [24]

1. Generally loading doses 5-10mg x 1-2 days at night (2-4mg in very elderly) [5]
   1. 5mg dose leads to less over-anti-coagulation than 10mg initial dose
   2. However, 10mg initial dose achieves more rapid achievement of therapeutic INR [5]
   3. 5mg dose also has less effect on Protein C (anticoagulant) levels
   4. No benefit but increased risk of loading with 10mg versus 5mg doses [20]
   5. Revised nomogram with 10mg initial dose is probably most efficient [5]
2. Requires ~36 hours to obtain effect of given dose
   1. 5mg loading dose very rarely increases INR in first 24 hours
   2. However, monitor INR in 24 hours to detect rare patients with high warfarin sensitivity
   3. Normally expect PT/INR elevation in 36-60 hours
3. 3-4 days usually required for attainment of desired goal [4]
   1. Maintenance dose usually 2-5mg qhs
   2. Adjustments in warfarin dose should be 5-20% per week
   3. Do NOT adjust warfarin dose based on single INR; repeat the test first
4. Monitoring Warfarin
   1. After initiating therapy, monitor INR 2-4 times per week until stable
   2. Gradually lengthen time between tests to maximum of 4-6 weeks
   3. Patients with elevated INRs should be monitored more closely
   4. Self-monitoring of coagulation level with protable coagulometer weekly (or as needed) is probably safer and as effective as monitoring in the clinic in selected patients [28]
5. After stopping warfarin, ~4 days are required for INR to go below 1.5X
   1. Surgery can safely be performed when INR < 1.5
   2. Restarting warfarin requires about 3 days to reach INR ~2.0
   3. Vitamin K or fresh-frozen plasma may be used to reverse overcoagulation (see below)
6. Warfarin in very high doses can strongly block protein C and precipitate thromboses [13]

E. Contraindications for Chronic Anticoagulation

1. Patient at high risk of falling including elderly, alcoholics, patients with syncopy
2. Previous hypertensive stroke or uncontrolled hypertension
3. CNS metastases or other unstable lesions
4. Dental surgery is not an absolute indication for stopping anticoagulation [17]

F. Risk Factors for Bleeding on Anti-Coagulation [8,15]

1. Serious Premorbid Conditions (1 point for each , <4 points)
   1. Cardiovascular (Acute MI, Hypotension SBP <90mm)
   2. Liver dysfunction (hyperbilirubinemia or macrocytosis)
   3. Renal Insufficiency (Creatinine >1.5mg/dL)
   4. Cancer
   5. Hematocrit <30%
   6. Use of thrombolytics increases bleeding risk considerably
2. Age
   1. 60-74 years old (2 points)
   2. Age 75 years old or higher (4 points)
   3. In other studies, age 80 or less was NOT a predictor of serious bleeding [8]
   4. Age >85 years and INR >3 was associated with increased bleeding risk [8]
3. Maximal Prothrombin Time (PT)
   1. 2.0-2.9X control (1 point)
   2. >2.9X control (2 points)
   3. This is consistently the most important factor for bleeding risk [8,18]
4. Liver Dysfunction - worsening during therapy
5. Total Points: 11
   1. Low Risk: 0-2 points
   2. Moderate Risk: 3-4 points
   3. High Risk 5 points or more
6. Actions based on risk assessment
   1. High risk patients were closely monitored
   2. Alternate therapy was attempted if possible
7. Cytochrome P450 Variants [21,27]
   1. Warfarin is metabolized (hydroxylated) by Cytochrome P450 2C9 (CYP2C9)
   2. Variant alleles of CYP2C9 (2C9*2 and 2C9*3) associated with impaired metabolism
   3. These variant alleles are associated with high risk for over-anticoagulation
   4. Persons with these variants should receive much lower doses of warfarin
   5. Variants in VKORC1 affect initial INR response to warfarin more than 2C9 variants [2]
   6. Genotyping CYP 2C9 should reduce bleeding complications [21]
8. Concommitant nonselective non-steroidal anti-inflammatory drugs increases risk [18]
9. Overall risk of bleedingis ~6.5% per year [18]
10. Brodifacoum is a "super-warfarin" which can cause broad coagulopathy and hemorrhage [29]

G. Drugs which Increase the Efficacy of Warfarin [1]

1. Destruction of bowel flora leads to decreased Vitamin K production
   1. Usually by broad spectrum antibiotics
   2. Includes many cephalosporins (particulary 3rd and 4th generation)
   3. Imipenam
   4. Combination antibiotics
2. Other Antibiotics block hepatic metabolism
   1. Erythromycin
   2. Fluconazole
   3. Miconazole
   4. Isoniazide
   5. Metronidazole
   6. Trimethoprim-sulfamethoxazole
3. Cardiac medications - amiodarone, propafenone, propranolol, sulfinpyrazone
4. Other Agents
   1. Anti-ulcer: omeprazole, cimetidine
   2. Chronic alcohol
   3. NSAIDs: phenylbutazone, piroxicam, oxyphenbutazone, sulfinpyrazone
   4. Theophylline
   5. Acetaminophen - chronic high doses; intermittent use no effect [15,31]
   6. 17-alkyl Androgens
   7. Disulfiram
   8. High dose Salicylates
   9. Tamoxifen
   10. Thyroid hormone
   11. High dose intravenous methylprednisolone (glucocorticoids) [23]
   12. Most of these drugs block or compete with hepatic P450 Metabolism
5. Additional agents will affect warfarin metabolism (this list is incomplete)
6. Caution and careful study should be exercised in all patients on warfarin

H. Drugs which Reduce the Efficacy of Warfarin

1. Antibiotics - griseofulvin, nafcillin, rifampin
2. Central Nervous System Agents - barbiturates, carbamazepine, chlordiazapoxide
3. Antithyroid Drugs
4. Other - high vitamin K foods (such as cruciferous vegetables), cholestyramine, sucralfate
5. Vitamin K (phytonadione) and derivatives can reverse effects of warfarin
6. Warfarin completely inactivates cyclosporin but warfarin is not affected
7. This list is not complete
8. Caution and careful study should be exercised in all patients on warfarin

I. Reversal of Anticoagulation in Warfarin Overdose

1. In general, patients with INR > 4.5-5.0 should have anticoagulation reversed
2. Warfarin should be withheld for 1-2 doses
3. Vitamin K or fresh frozen plasma (FFP) may be given
4. Vitamin K
   1. Giving 1.0-2.5mg oral vitamin K x 1 dose can rapidly and safely correct INR [3]
   2. Single dose vitamin K 1.0mg po reverses anticoagulation and prevents bleeding episodes [25]
   3. These doses of oral vitamin K (as phytonadione) can reverse INRs up to 9
   4. Oral vitamin K reverses warfarin overdose more rapidly than subcutaneously [6]
   5. Intravenous phytonadione can also be given, but no real benefit over oral [19]
   6. Vitamin K given subcutaneously is least reliable method for correction [19]
   7. Oral dose of phytonadione of 2.5mg or 5.0mg is also effective for reversal
5. Fresh Frozen Plasma [1,24]
   1. Can be used to reverse anticoagulation in bleeding patients
   2. Equations for calculating volume of plasma or dose of prothrombin complex for reversal are available [1]

J. Warfarin Pro-Coagulant Effects

1. Females 3:1 Males but very few cases
2. Overall very uncommon with ~1:10,000 new warfarin prescriptions per year
3. Associated with various Hypercoagulable States
   1. Protein C or S deficiency implicated in many cases
   2. Associated also with Antithrombin III deficiency
   3. Warfarin, particularly high doses, can exacerbate heparin induced thrombocytopenia [13]
   4. Low doses may exacerbate or have no effect on Antiphospholipid Antibody syndrome
4. Thrombosis may occur in any vessel
5. High Dose Warfarin [13]
   1. very high doses can strongly block protein C and precipitate thromboses
   2. Most serious condition is warfarin induced skin necrosis
   3. Limb gangrene due to rapid depletion of protein C by warfarin has been reported [26]
   4. May be avoided in some patients by initial use of heparin with low dose warfarin overlap

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