New discovery sparks hope of safer dosage of Warfarin

May 17 2005

The blood-thinning drug Warfarin tops the list of drug side-effects in Sweden. Patient sensitivity to Warfarin varies, which can lead to over-dosage and in certain cases to death.

A study led by Mia Wadelius at Uppsala University in Sweden, together with researchers in Cambridge, indicates that two genes may be the explanation. The findings are being published in the latest issue of The Pharmacogenomics Journal.

Warfarin is used to prevent blood clots, but a side-effect can be severe, even fatal, bleeding. In Sweden since the 1960s more fatal side-effects have been reported from Warfarin than for any other drug. Of the 118 deaths reported in connection with drug treatment in Sweden last year, nearly half involved bleeding from Warfarin.

There is still no good alternative to Warfarin in cases of blood clots or heart or valve diseases. Every year 70,000 patients in Sweden are treated with Warfarin. All patients receive the same dose the first few days, then the dosage is determined by a test of the capacity of the blood to coagulate. The differences are great in how much Warfarin patients need to attain an effect. One patient can require 20 times the dose needed by another patient.

The Uppsala University Section for Clinical Pharmacology is carrying out a pharmacogenetic study in collaboration with the Sanger Institute in Cambridge, England. The findings show that hereditary variations in two genes, together with the patient’s age, weight, disease, and other medicines, explain nearly 60 percent of the variations in dosage. One of the genes is called the vitamin-K-reductase gene and was discovered by two U.S. research teams last year. The other gene is the gene for the enzyme cytochrome P450 2C9, which governs the degradation of Warfarin and has long been known. Now Mia Wadelius and her associates will be analyzing a further score of genes that affect the uptake, transport, degradation, or effect of Warfarin.

“We want to develop clinical analyses that can predict what dosage of Warfarin a patient should have from the moment the drug is prescribed. If we can create such analyses, then we can reduce the risk of early bleeding. With the newly discovered gene and our findings, we are one step closer to a solution,” says Mia Wadelius.