Anticoagulation Overview: Vitamin-K Antagonists (Warfarin)

January 4, 2021

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Warfarin  (Coumadin®) tablets: (approved by FDA June 8, 1954)             
Mechanism: Vitamin K antagonist: produces its pharmacological effect by interfering with the interconversion of Vitamin-K and its 2,3 epoxide.  Leads to depletion of Factors: II, VII, IX and X (produced in liver) and anticoagulant proteins C & S. 

Dosage: at least 4 to 5 days are necessary before a patient is anti-coagulated.
Initial dose: 5mg / day in normal patients.  The INR should be 2 in four to five days. 

  • 2.5 to 4mg for elderly or patients with liver disease 
  • 7.5 to 10mg for young, healthy or obese patients 
  • Most clinicians titrate warfarin doses by trial and error 
  • Now the FDA is suggesting lower doses for patients with certain genetic variations. 

Genetic Variations in Warfarin 

  • CYP2C9 activity indicates a slow or fast metabolizer. A slow metabolizer may need a lower maintenance dose and take longer for their INR to get to steady state 
  • Vitamin K epoxide reductase activity (VKORC1) tells whether a patient is sensitive or resistant to warfarin’s effects. 

Adverse effects: bleeding
Treatment: stop the drug 

  • If minor bleeding progresses to major bleeding: Administer Vitamin-K 5 to 25mg parenterally. May cause prolonged resistance to warfarin. 
  • If INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given 
  • Greater than 9: give 5 mg orally.  Will reduce the INR within 12 to 24 hours. 

Contraindications: pregnancy Category X

Drug interactions: Warfarin is metabolized by the P450 enzyme system.  Lots of drug interactions.  

  • P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc. 
  • P450 inducers: carbamazepine, barbiturates, phenytoin 
  • Can be displaced from binding sites: loop diuretics, valproate 
  • Platelet aggregation: NSAIDS can enhance warfarin’s effect. 

Drug monitoring:  

  • Initial: INR should be done daily while in the hospital. 
  • Every 2 or 3 days if not hospitalized 
  • Once stabilized, monitor every 4 to 6 weeks 
  • TARGET INR is between 2 and 3 for most conditions requiring anticoagulation therapy 


  1. Consult pharmacist or practitioner for recommendations for OTC medications 
  1. Bleeding:  have lots of Band-Aids; use electric razors 
  1. FOODdrug interactions:  Be careful with diets and Vitamin K rich foods.   Patients are often told to avoid foods high in vitamin K because of warfarin antagonism. A diet too low in vitamin K makes it MORE difficult to manage INR, because any change in dietary vitamin K can cause large fluctuations in INR. Encourage patients to eat a well-balanced consistent diet. 
  1. Note: Warfarin patients are at the goal INR only 55% of the time (yikes!) 
  1. –BEFAST: teach your patients signs and symptoms of a stroke, pulmonary embolism, deep vein thrombosis and heart attack: 

Signs and symptoms of a Stroke—BE FAST!  

  • -Balance: sudden loss of balance, headache, or dizziness 
  • -Eyes: trouble seeing out of one or both eyes 
  • F -Face: Uneven smile or expression, facial droop or numbness in the face 
  • A -Arms: weakness, numbness, one arm drifts down 
  • S -Speech: slurred, mute, inappropriate words or strange speech 
  • T– Time: seek help immediately. Immediately call 9-1-1. 

Signs and Symptoms of Pulmonary Embolism (PE)  

  • Dyspnea: Difficulty breathing or shortness of breath. Usually sudden and severe 
  • Hemoptysis: Coughing up blood 
  • Diaphoresis: Abnormal sweating 
  • Cyanosis: Nails or lips turning blue 
  • Tachycardia: Rapid heartbeat 
  • Pain: Unexplained sharp, severe pain in the chest and/or back 
  • Syncope: Loss of consciousness 

Signs and Symptom of Deep Vein Thrombus (DVT)  

  • throbbing or cramping pain in 1 leg (rarely both legs), usually in the calf or thigh. 
  • swelling in 1 leg (rarely both legs) 
  • warm skin around the painful area. 
  • red or darkened skin around the painful area. 
  • swollen veins that are hard or sore to the touch 

Signs and symptoms of Heart Attack in WOMEN
Usually in female patients multiple symptoms may occur:  

  • Chest pain: or fullness in the chest (an elephant sitting on my chest!) 
  • Nausea or stomach pain: feeling like the need to vomit. More commonly seen in women 
  • Anxiety: feeling like something is wrong, but cannot put your finger on it 
  • Arm pain: pain in the arm, leg, or jaw. A woman may feel numbness radiating down the left arm, and this pain or sensation can pread elsewhere in the body, especially the shoulders 
  • Dyspnea: shortness of breath or difficulty with breathing 
  • Cold sweats: resulting in cold clammy skin  
  • Dizziness: sudden onset of lightheadedness, room spinning is usually combined with other symptoms on this list 
  • Extreme fatigue: unexpected sluggishness or exhaustion 
  • Heart palpitations: heart skips a beat or fluttering sensation 

Signs and symptoms of Heart Attack in Men
Usually in male patients the following symptoms occur:  

  • Pain or tingling in back, neck, shoulder, or jaw 
  • Chest pain 
  • Sweating 
  • Shortness of breath 
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The history of the discovery and marketing of warfarin (Coumadin®) is a most fascinating story that begins in the pastures of the northeast:
Numerous cows in the 1920’s died after routine minor surgical procedures such as castration or dehorning. A Canadian veterinarian named Frank Shofield astutely reasoned that this hemorrhaging could be attributed to animals that ate silage that had rotten sweet clover.  This hemorrhaging became known as “sweet clover disease.”
Dr Karl Paul Link, a chemist from Wisconsin, started his own investigation into the curious problem in 1933. He published an article in Circulation describing the effects of the rotted sweet clover. Dr Link’s work was supported by the Wisconsin Alumni Research Foundation (WARF), which is the root name for warfarin.  Dr Link’s student Harold Campbell isolated the anticoagulant dicoumarol in 1939. 
At first this compound was sold as a rat poison, and it wasn’t until the 1950’s that Endo Pharmaceutical began marketing warfarin for human use.
While on vacation in 1955, President Eisenhower was given warfarin after a heart attack, which vaulted this drug to national prominence.  Warfarin poisoning was also postulated to have caused the cerebral hemorrhage and gastrointestinal bleed that lead to the demise of Russian dictator Josef Stalin.
My daughter Gretchen gave me a 1959 drug handbook, which listed the available strengths of Coumadin as 1mg, 5mg and 25mg!
Have a great day on the bench!