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NICHD Looking to Outlicense Thrombosis-Risk Microarray Panel; Clinical Demand is Uncertain


The use of tests for estimating patients' risk of deep-vein thrombosis appears to be rising — or at least it was recently — and a microarray-based diagnostic from the National Institutes of Health for assessing risk of the condition may put a cheaper, broader test on the market.

Developed as a research tool, the assay could be useful in situations where a clinician suspects the influence of inherited mutations in coagulation genes based on familial evidence. "This would be a reasonably inexpensive, rapid way to assess who's at risk within a family in which this is known to be a problem," Owen Rennert, scientific director of the National Institute of Child Health and Human Development and one of the microarray's developers, said in an interview this week with Pharmacogenomics Reporter.

"Conceivably, it could increase the use of a variety of agents [such as warfarin and aspirin] that are used to treat people who have potential thrombophila," such as warfarin and aspirin, said Rennert. But he cautioned that the array, which is at least as useful as a laboratory assay as it is a diagnostic, could reduce the use of anticoagulating agents by demonstrating that some conditions are not related to defects in coagulation-related genes.

With the US Food and Drug Administration's relabeling of the popular anticoagulant warfarin expected to happen soon the test could have an indirect impact on companies selling molecular diagnostics for properly dosing patients for that drug. An increase in risk prediction could lead to increased use of warfarin as a prophylactic, and molecular diagnostic shops with assays for predicting adverse events may benefit.

"The question is, 'Will a panel for eight markers help?' I certainly think yes. However, will it be successful commercially? I'm not too sure."

In a notice last week, the National Institutes of Health said that the microarray, which interrogates 143 total polymorphisms in eight genes — antithrombin III; protein C; protein S; fibrinogen; factor V; prothrombin; MTHFR; and ACE — is available for licensing. So far, no companies have expressed interest in licensing the array, said Rennert. However, there is probably a market for it, he added.

The main advantage of incorporating eight risk-related genes into the test is an approximately 20-fold increase in predictive power over single-gene analysis in several ethnic groups, according to an NIH statement.

Although a great deal of research supports risk assessment using factor V and factor II — and doctors have heavily requested testing for both — the use of all eight genes for risk assessment is thinly supported, said Jorge León, head of the molecular diagnostics consulting firm Leomics, this week in an interview. "The question is, 'Will a panel for eight markers help?' I certainly think yes," he said. "However, will it be successful commercially? I'm not too sure."

Generally, clinicians test only certain groups of patients for venous thrombosis — pregnant women or women who plan to become pregnant; and patients who also have other risk factors, such as advanced age or hormone replacement therapy. While genomic risk assessment promises more informed decision-making, some question the clinical benefit of this knowledge. "Does this mean that if you have other high-risk conditions … that we would be earlier to treat you prophylacticly? Does it mean a long flight or other issues or trauma would maybe make you more likely to clot, and so you should be treated earlier and more aggressively?" Richard Stein, a spokesperson for the American Heart Association and director of preventive cardiology at Beth Israel Hospital in New York, asked rhetorically. "I don't know yet what it means clinically — we'll probably need a clinical study to understand how much of a risk you represent."

But when it comes to specific cases of higher risk types of patients, clinicians often err on the side of safety, said Stein. "If knew somebody with these genes was pregnant, I would probably prophylactically put them on aspirin during their pregnancy … or if they were operated on, I might consider putting them on warfarin after surgery or a big surgical orthopedic operation more than I would be tempted to with the average patient," he said. "But other than that, if you just gave me a healthy person with no episodes [who carries some risk genes], so far we have no clear evidence — unless they were very abnormal — that prophylactic coagulation would make sense," he added.

"If you have what we consider genes for thrombosis … then if you have any evidence for thrombosis or an occlusion, anticoagulation with warfarin" is the long-term prophylactic treatment of choice, said Stein.

León, whose group introduced factor V leiden testing when he worked for Quest Diagnostics, said that testing for deep-vein thrombosis "has been growing dramatically" since its introduction in 1997. León estimated that Quest performs "close to half a million tests every year for factor V mutation, and about half of those for factor II mutation. Clearly these two assays are joining the mainstream in management of deep-vein thrombosis," he said.

But it is possible the market need for these genetic tests has been fulfilled. "I would say [factor V and factor II] have been routine now for several years at least — they're some of the highest-volume molecular genetic tests that we have," said Wayne Grody, a professor at the University of California, Los Angeles, School of Medicine and director of the UCLA Medical Center's molecular diagnostics laboratory. "It may have plateaued out, but in my lab, it's probably the highest volume genetic test," and possibly equal to cystic fibrosis carrier screening, he said.

Cost is a major factor discouraging doctors from ordering genetic tests for thrombophilia, and one of the NICHD assay's advertised strong points. According to Rennert, the assay will probably cost about the same as other microarray chips, depending on the manufacturer, and "clearly will be less expensive than doing all the tests that are presently available."

Prices for factor V and factor II testing "probably range from about $150 to $300" each, said Grody. DNA testing for protein C, protein S, and fibrinogen are generally done by functional coagulation, in part "because there are so many mutations" in those genes, he said.

Grody estimated that a reasonable price for an eight-gene array might be around $600. "I'm not aware of a huge demand to do the complete panel, so I don't know if physicians are going to go for it if it costs much more than the common ones that we already do — which are going to pick up most of the cases," he said.

A full battery of coagulation tests can cost more than $1,000, and a panel might be competitive "if you can do it quickly and inexpensively," Stein said.

The most common risk factors for thrombosis include taking oral contraceptives or hormone replacement therapy, trauma, bone fractures, prolonged immobilization, age, and malignancy. In pregnant women, thrombophilia increases the chance of miscarriage, intrauterine growth restriction, preeclampsia, placental abruption, stillbirth, and post-partum thrombotic events, the NICHD statement said.

— Chris Womack ([email protected])

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