pathtalk.org is a weblog about pathology.

Testing-testing: You want fries with that INR?

This is a superficial post on point-of-care (POC) testing touching on general background info. This topic and especially “Lab On A Chip (LOC)” has been addressed several times by Dr. Friedman in LabSoftNews (see links tab to the right).

Over a dinner of delicious home-cooked food, my mother, in a perpetual exercise to understand the scope of exactly what it is a pathologist does, asked me on my last visit home about laboratory testing. She wondered how her cousin, who is a high school graduate, could be involved with medical laboratory testing–including DNA test handling–without additional training. As I am not a laboratory manager and still consider myself a somewhat green resident (Will this feeling ever go away?), my first response was “?”.

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Kling on Heath Care Economics

If you have an hour to kill, and an interest in health care policy, you could do worse than listen to Arnold Kling, author of Crisis of Abundance, in a recent podcast.

Pathology. The Movie.

There’s not a lot to be said here, except that you’ve GOT to watch the trailer for this movie. It’s a must-see. Could we buy better publicity?

Testing-testing: do we give verbiage a bad name?

Like many people, I dislike the word “verbiage” , but just testing the waters for catchy blog titles. Directly influenced by my PGY year (4) I have been interested in report construction and the use of language to convey diagnostic findings, diagnostic uncertainty, and the interpretation of newer tests such as new molecular tests which look for genetic variations as discussed with PathDoc15 in this post.

Construction of pathology reports using diagnostically accurate and meaningful language has been a focus of the major pathology organizations, especially the CAP, undoubtedly influenced by the IOM 1999 report and fueled by the relatively frequently cited article “Clinicians are from Mars and Pathologists are from Venus” published in the Archives in 2000¹. This article reported that surgical pathology reports were “misunderstood” 30% of the time.¹ The CAP, the Association of Directors of Anatomic and Surgical Pathology, and other organizations such as the Association for Molecular Pathology publish recommendations for pathology reporting, including the minimal requirements for specific body sites, tumor types and testing modalities. Some institutions have implemented synoptic templates for cancer reporting to ensure that all of the required elements and important features of a patient’s tumor are present in the report and to display these elements in a list-type manner so that features such as tumor size or vascular invasion are readily identifiable.

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Testing-testing: drug dosing based on SNPs?

Warfarin is one of the most commonly prescribed anticoagulants for prophylaxis and treatment of venous and arterial thromboembolic disorders or those at high risk for such disorders. Warfarin also has an FDA-issued “Black Box” warning for a high risk of fatal bleeding, most commonly from the gastrointestinal tract and in the brain. It acts by inhibiting the synthesis of the vitamin K dependant clotting factors (II, VII, IX, X) and the anticoagulants proteins C and S. Vitamin K promotes the synthesis of gamma-carboxyglutamic acid residues in these vitamin K-dependant proteins. Warfarin acts to reduce the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of vitamin K reductase.¹

The molecular target of warfarin is the protein product of the Vitamin K epoxide Reductase Complex, subunit 1 gene (VKORC1). This gene product is inhibited by warfarin. Polymorphisms of this gene product have been extensively studied over the past several years, and variant genotypes are associated with variable response to warfarin.¹ Compared to patients with a wild-type genotype, patients with at least one variant allele had an increased risk for elevated INR (HR = 1.4) and required more time to achieve a stable dosing (median = 95 days).¹

Warfarin is eliminated via metabolism in the liver. It is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450).⁴ The warfarin breakdown products have minimal anticoagulant activity.⁴ The metabolites are principally excreted into the urine, and to a lesser extent into the bile.⁴ The drug is comprised of a mix of the R and S stereoisomers. The S isomer is 3 to 5 times more potent than the R isomer, and is metabolized by the cytochrome P450 family. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4.⁴

CYP2C9 is reported to be the main liver P-450 which modulates the in vivo anticoagulant activity of warfarin.⁴ Two variants of CYP2CP have been identified.¹ These variants ( the *2 allele -R144C and the *3 allele – I359L) are reportedly associated with a decrease in enzymatic activity of 30% and 80%.¹

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