Strengths of Warfarin Available and the colour of their tablets (Marevan)
- 1mg (Brown)
- 3mg (Blue)
- 5mg (Pink)
Mechanism of action of Warfarin
Vitamin K antagonist
- Active vitamin K is use to convert factors VII, IX, X, II and protein C and S (SNOT-CS), from their inactive form to their active form. In this process, vitamin K is converted to its inactive form
- An enzyme, vitamin K epoxide reductase complex 1, recycles the used vitamin K, converting the inactive form of vitamin K to the active form of vitamin K
- This active form of vitamin K can activate the factors and proteins again
- Warfarin Vitamin K epoxide reductase complex 1, halting the conversion of inactive vitamin K to the active vitamin K
- Once vitamin K runs out, the active factors and proteins are slowly depleted as there are no new factors and proteins to replenish the used factors
What are the factors that affect the onset of warfarin?
- The inhibition of the PRODUCTION of vK clotting factors
AND - Depletion of previously synthesised clotting factors
What is the order of depleting factors and proteins in increasing half-life?
S-C-NOTS
What is the onset of the full effect of Warfarin?
5-7d
What is the most important parameter used to monitor Warfarin?
INR
Describe Prothrombin time. State the factors in the coagulation cascade that is involved in Prothrombin time. Which pathways do the Prothrombin time measures?
Time taken for plasma to clot when exposed to tissue factors.
- Factors: VII, X, V, II, (I and XIII does not prolong PT)
- Pathways: Extrinsic and Common pathways
Formula for INR. Define the variables in the formula
INR = (PT of patient / PT of control)^ISI
- INR = International Normalised Ratio
- PT of patient = Prothrombin time of the patient
- PT of control = normal range of PT, depending on lab reagents and instruments
- ISI = International Sensitivity Index, differing between countries, labs and reagents used
Indications of Warfarin
- MI, prevent recurrence
- Thromboembolic complications
- AF
- Valve replacements
- TKR
- etc.
In Warfarin, the target INR for most of the indications is 2-3. What are the THREE exception and what is the usual target INR? State the duration of anticoagulant therapy
- MECHANICAL MITRAL valve replacement: 2.5 - 3.5, lifelong
- RECURRENT VT, 2.5 - 3.5, lifelong
- RECURRENT PE, 2.5 - 3.5, lifelong
Patients with liver impairment are more sensitive to Warfarin dose changes. Why is this so?
- Decreased albumin production in the liver causes an increase in free warfarin in the blood as warfarin is strongly bound to albumin
- Warfarin is metabolised primarily in the liver. With liver impairment, the rate of warfarin metabolism is lowered hence reaching higher peak concentrations at lower doses compared to patients with normal liver functions
What are the lab test to be carried out before Warfarin is initiated?
- PT/INR
- CBC (complete blood count)
- Stools for occult blood
- Chemistry panel (i.e. chem-7, or basic metabolic panel)
Before initiating Warfarin, what are the factors that affect the patient’s sensitivity to Warfarin hence affecting the risk of over-anticoagulation and the initial dose of warfarin?
- Age > 70
- Body Weight < 50
- CHF (severe)
- Drug Interactions (E.g. Amiodarone, Rifampin)
- Falls history
- GI bleeding
- HAS-BLED score > 2 (at least 3)
- INR at baseline > 1.4 (or low platelet count)
- Liver disease (severe)
- Malnutrition
- Major Surgery within 10-14d
- Malignancy
(ABCD, FGHI, LMMM)
Components of HAS-BLED score before initiation of Warfarin
- HTN > 160
- Abnormal Renal or liver disease (1 pt each)
- Stroke
- Bleeding tendency
- Labile INR, if on warfarin
- Elderly > 65yo
- Drug or Alc (1 pt each)
- Unless stated, each factor contributes one point
Factors that could affect Warfarin Therapy
- Alcohol Ingestion: Acute increase INR, Chronic reduces INR
- Underlying diseases (E.g. Hyper/Hypothyroidism)
- Smoking
- Non-adherence
- Diet, especially vitamin K rich food
- Traditional medicines and supplements
What are the enzymes involved in the metabolism of Warfarin, and which is more significant?
CYPs: 1A2, 2C9, 3A4
Significant: 2C9
Common herbs that may increase the risk of bleeding?
Garlic, Ginger, Ginkgo (3Gs)
A common herb that can reduce INR
Ginseng
Most common AE of Warfarin
Bleeding
Manifestations of subtherapeutic in AF, in which patient should be counselled for?
- Stroke: One side numbness/ weakness, mental retardation
- DVT: Unilateral swelling and pain at the calves. May be red
- PE: SoB
