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Learning Center
Coagulation Corner
Tuesday, October 7, 2008
Oral Anticoagulation: Positives, Pitfalls and Polymorphisms
Do you know how frequently patients are in a therapeutic range on warfarin?
How does your reagent affect their results?
How does this drug work?
Are there alternatives for oral anticoagulants?
In 1936 cattle grazing in a field developed a bleeding disorder from eating spoiled sweet clover hay. The hay contained a chemical agent (dicumarol). Warfarin was discovered by the Wisconsin Alumni Research Foundation or WARF and was found to inhibit vitamin K synthesis.
We know that we measure oral anticoagulation in the laboratory with the Prothrombin time (PT). This renders the Vitamin K dependent factors (II, VII, IX, and X, Protein C, S ) non-functional, so it works to prevent clotting. Warfarin works by enabling the liver to
inhibit the y-carboxylation step of clotting and the Vitamin K dependent factors, rendering them non-functional. This will, as a result, impair fibrin formation. Sounds like a great system!
However, there are issues- first and foremost this is an oral anticoagulant (OAC) drug, therefore you might deal with non-compliance- when the patient takes the drug, the amount that they take, and when they decide to adjust the dose on their own. People are placed on warfarin for extensive periods of time, even lifetime. Warfarin has a half life of between 20-60 hours, this varies in individuals. Dosing must be individualized and the patient must be considered for hepatic and cardiac function, age, nutrition, concurrent therapy and the clinical situation. Patients are started on 2-10mg daily for 2 days, doses are adjusted according to INR results with maintenance doses from 2-10mg daily.
There are several inherent variables with warfarin use including the addition or discontinuation of other medication or changes in diet. The response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis and cirrhosis due to reduced vitamin K absorption. Foods high in vitamin K such as beef and pork liver, green tea and leafy green vegetables will decrease the efficacy of warfarin. Many drugs can decrease the risk of anticoagulation (anti-thyroid drugs, barbiturates, estrogens, aluminum hydroxide), while others can increase the risk of hemorrhage (quinidine, indomethacin, adrenal corticosteroids). There are also over 80 drugs that interfere with OAC.
We also then have our reagents which are phospholipid based with inherent variabilities. In the 1940 and 50 the initial thrombolplastin was made with human brain, yes that is human brain where tissue factor was extracted and formulated into reagents. In the 1960's commercial reagents came into play using rabbit brain etc. The outcome was a reagent that was not as responsive to oral anticoagulation.
The combined rate of a major hemorrhage or recurrent thromboembolism is 15 percent per patient year of therapy. This presents with a risk of being either excessive or sub therapeutic They wanted to come up with a mechanism for standardizing the monitoring of the drug, so people could be monitored anywhere, and end up with the same result regardless of the instrument reagent combination. This mechanism was called the International Normalized Ratio (INR), that is, sort of a correction factor to harmonize PT results, so that regardless of the result in seconds, the INR should be the same. The way the correction factor is derived is compare a manufactures reagent against the "Manchester reagent", or one made with human brain thromboplastin, which is very sensitive, with an International Sensitivity Index of 1!
In 1995, it was published that "Oral anticoagulant therapy should only be monitored with thromboplastin reagents with an ISI of 1.2 or lower" In addition , the imprecision of the PT that occurs with a higher ISI will be magnified. The lower the ISI, the less the variability resulting in a lower CV of about 6-8%, while a higher ISI will result in inter-laboratory variations of 15-26%. The lower the ISI the better able you are to assess bleeding potentials, and is more sensitive to factor deficiencies as well as liver disease and vitamin K factors. Since the PT will have a longer range, these entities will demonstrate a wider range of clotting times, which will allow for finer adjustments in dosages of warfarin.
The PT's are performed by a manual tilt tube method ( how many people remember how to do that!!! Raise there hand- mine is up) versus the PT on the manufacturer's analyzer with their reagent, hence they come up with a "corrected" sensitivity the ISI of the manufacture's reagent. Sounds pretty good, don't get too excited yet!
ISI
The formula is: INR = Patient PT
Geometric mean of PT
Normal range
.
First, you must make sure you collect a good normal range, normal controls should be used, no ED or pre-op patients, too many acute phase reactants. Remember, coagulation is inversely proportional- when factors are increased, clotting times will be shortened. Second, make sure you use the geometric mean. Your greatest variable is the ISI, if there is a miscalculation of the ISI, it is exponential, and will cause the greatest error. That in itself is a different article- The question I am asking is: How frequently are patients in a therapeutic range while on OAC-
The answer about 50-80%- average about 64% of the time, not so hot-
This brings me to the focus of this - which would be pharmacogenetics of warafin.
This area is becoming more and more prevalent in medicine to determine how people metabolize drugs.
There have been several components that affect warfarin dosing variability identifying clinical, demographic and genetic components. Three common single nucleotide polymorphisms (SNPs) account for between 40-55% of dosing variability. Two SNPs in the cytochrome P-450 (CYP2CP gene are associated with impaired metabolism. A glutamine to arginine SNP in the promoter region VKORC1 results in decreased messenger RNA transcription and increased sensitivity to warfarin. Other factors influencing dose include body mass index, age, interacting drugs, and indication for therapy. In August of 2007 the FDA changed the labeling of warfarin to include a description of the use of lower doses for patients with certain CYP2C9 and VCORC 1 SNPs.
Allelic frequencies for these variants differ considerably among different ethnic groups: Caucasians carry the 2C9*2 and 2C9*3 variants (8% to 20% and 6% to 10%, respectively) more frequently than Asians do (0% and 2% to 5%) while polymorphisms of cytochrome P450 CYP2C9 do not seem to play an important role in sensitivity to dicoumarol in the Spanish population.
There is a growing interest in the variation of genetic populations and how they respond to OAC. It is believed there are several mutations that contribute to this occurrence. I will keep you posted!
What about alternatives to warfarin?
To date there has not been any other oral anticoagulant FDA approved.
Ximelagatran: (EXANTA) is an oral agent that acts as a competitive inhibitor of thrombin. It is converted to the active form of meletagran which inhibits clot-bound thrombin. It was being evaluated for use in acute venous thrombosis and prophylaxis, but there were problems with liver enzymes, so the drug was not approved. There is no interaction with drugs, food or alcohol, or Vitamin K, therefore it can be administered without coagulation monitoring. This drug has a half life of 3 hours, excreted by the kidney, is dosed twice/day. Pharmacokinetics differs due to differences in renal function.
Warfarin is one of the most commonly given drugs with many inherent problems. Defining pharmacogenetics may be a wonderful option to help patients minimize bleeding events and maximize dosing capabilities without forming a clot.
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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