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  Advanced coag, deep in the heart of Texas

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March 2007
Feature Story

Karen Titus

When the New England Journal of Medicine reported last fall that it might be smart to measure D-dimer to determine the duration of anticoagulation therapy, William E. Luper, MD, agreed.

He was, in fact, several steps ahead of the publication, having begun offering the test for this purpose several years before the article appeared (Palareti G, et al. 2006;355:1780–1789).

Dr. Luper is no prophet, but he appears to comprehend the future of hemostasis and coagulation testing with notable quickness. That includes developing a working knowledge of new tests and applications that for many might still be only a glimmer on the horizon: antiannexin V autoantibodies, for example; aspirin and clopidogrel (Plavix) resistance; low factor XIII levels as a possible link to miscarriages as well as the etiology of patients with unexplained bleeding problems; the new indication for D-dimer to determine the duration of anticoagulation therapy.

As the medical director of the private reference laboratory HTL Ltd., Houston, Dr. Luper makes it his business to know as much as possible about hemostasis testing. He has carved out a successful niche, filling the gaps for clinicians and pathologists who can’t keep up with the latest developments and taking advantage of the fact that, in his words, “Most doctors don’t understand hemostasis.” There’s plenty of information to absorb, and physicians need help taking it all in, he says. “They’re not always sure what to order, and then when they get numbers back, they’re not always sure what they mean.”

“That’s the crux of what I do—service and interpretation. Otherwise, technically, it’s not all that complicated,” he says.

It is, and it isn’t. It can be a study in contradictions, not unlike Dr. Luper, who blends cutting-edge hemostasis testing with old-fashioned doctoring.

He got his start as an internist, practicing general medicine in a small west Texas town, “making house calls, you know, like the Old West, Doc Adams type stuff,” he recalls.

He later did a pathology residency. His interest in clinical matters led him to St. Luke’s Episcopal Hospital, Houston, where Denton A. Cooley, MD, founded the Texas Heart Institute. Naturally, that meant plenty of cardiac surgeries, and Dr. Luper and his laboratory and blood bank colleagues were called on to treat postoperative bleeding problems. Before long, they were asked to see patients preoperatively as well, to deal with those who had a history of bleeding. “We actually acted as internist hematologists,” Dr. Luper says. Working with Dr. Cooley, he says, “you get patients from all over the world. We’d see a lot of different things in the lab, instead of just doing platelets and PTs and PTTs.”

In 1988 he moved to Spring Branch Medical Center, Houston, lured by the institution’s bone marrow transplant program and the need to set up a sophisticated coagulation laboratory. Since Houston lacked a private reference laboratory for services such as apheresis, bone marrow transplants, and stem cell transplants, HTL (for Hemostasis Thrombosis Laboratory) was born. “Why not?” said Dr. Luper.

Acting on that question proved to be a smart move. HTL serves more than 30 Houston-area hospitals, including MD Anderson, as well as acting as a reference lab for physicians elsewhere in the country. The lab, which is located within the main laboratory at Spring Branch, bills about 31,000 tests annually, says HTL administrative director Ziad Dejani—or, as Dr. Luper says, looking at the lab’s billables for 2005, “It’s as thick as four Houston phone books.” Either way, the volume is sufficient to cover the costs of running esoteric tests, which may be the biggest hurdle in offering them. As Dejani points out, the tests in and of themselves are not difficult to do, though they can be labor-intensive. “Anybody can set them up, but it’s not cost-effective if the volume isn’t there.”

Adds Dr. Luper, “You have to have techs who understand them quite well.” (He employs four at his lab.) “And then you need a pathologist or somebody who has special interest or training who wants to do this. Most pathologists are busy with their anatomic work and frozen sections and everything else, and in most hospitals it just wouldn’t work out.”

“It’s not that I’m doing anything super unusual,” Dr. Luper says, and it’s tempting to believe him. It would be easy to be lulled by his deep Texas voice, which sounds as if it’s been rolled in gravel. Ask him if it’s convenient to talk, and he answers affably, “It ain’t gonna be better any other time.” Wait for him to hook up his speakerphone, or to put you on hold, and you might find yourself on the receiving end of a dial tone more than once before he reconnects and says, “I think I’ll just stay away from that.”

That may be the only thing he steers clear of in his lab, however. “We keep up with just about everything,” he says. In addition to attending meetings and talking to physicians from around the country, Dr. Luper says he’s a regular reader of research-heavy, relatively obscure hemostasis journals, which is how he first learned about a possible new use for D-dimer. It soon became obvious to Dr. Luper that a groundswell might be in the offing, as he read one article after another hinting at a new use for the test. “But they didn’t hit the ‘mainstream’ medical media—it wasn’t in American Journal of Clinical Pathology, it wasn’t in New England Journal, it wasn’t in JAMA.”

Dr. Luper doesn’t wait for their endorsement to broach matters with his clinical colleagues. “I tell them what the literature says. If I read enough articles, and I think it looks significant, then I start doing it. I try to stay ahead of the curve—that’s my job.”

Among his areas of interest:

Aspirin/Plavix resistance

This is a more recent offering at HTL. Dr. Luper notes that some 20 percent of the population is, to some degree, resistant to aspirin or Plavix, which is a concern for patients with cerebrovascular insufficiency or those who’ve had bypass surgery and received coronary stents, and who are taking aspirin or Plavix prophylactically. Aspirin resistance can be measured on a metabolic product in urine; Plavix requires a whole blood assay. Both assays, in Dr. Luper’s opinion, are underutilized. “Patients are having recurrent TIAs, or strokes, or MIs,” he says. “This is very, very important. But I would bet you, if you went down the street and picked out 10 doctors, or go into the doctors’ dining room at the hospital, and asked them about this, at least nine of them wouldn’t know what you were talking about.” HTL uses the Verify/Now aspirin whole blood assay (Accumetrics); for Plavix resistance, it uses the Verify/Now P2Y12 whole blood assay. In his June 2006 newsletter to clients, he cites multiple studies to support his use of both tests, including those published in American Journal of Cardiology (Gum P, et al. 2001; 88: 230– 235), Journal of the American College of Cardiology (Gum, et al. 2003;41:961–965), British Medical Journal (Antithrombotic Trialists’ Collaboration. 2002; 324: 71– 86), Thrombosis Research (Anderson K, et al. 2002;108:37–42), Circulation (Eikelboom JW, et al. 2002; 105: 1650– 1655), and Lancet (Mehta SR, et al. 2001; 358: 527– 533).

Fetal loss

Most obstetricians know that women who have spontaneous abortions need to be evaluated, says Dr. Luper. The first time it happens, it’s likely due to a genetic defect in the fetus; the second or third time, unless there’s an underlying anatomic abnormality in the mother, the cause is likely to be tied to a thrombophilic abnormality, he says, which can be difficult to pinpoint.

In addition to his lab’s antiphospholipid panel (which includes lupus anticoagulant, anticardiolipin antibodies, antiphosphatidylserine antibodies, and anti-β2 glycoprotein antibodies), Dr. Luper offers the antiannexin V test, which at this point is familiar to researchers but not most physicians. “But I think it’s important,” he says. Oftentimes this or prothrombin antibodies, which he also runs (IgG and IgM), will be the only tests with positive results. Though the international consensus statement on antiphospholipid syndrome (Miyakis S, et al. J Thromb Haemost. 2006; 4: 295– 306) focuses on anticardiolipin, anti-β2GPI, and lupus anticoagulant, he says, the other two antibodies have been associated with the syndrome. “So when you’re looking for antiphospholipid problems, or lupus anticoagulant, since it’s such a heterogeneous complex, I think you need to cast a pretty wide net, to look for a lot more than most people do.” He points to an Archives of Pathology & Laboratory Medicine article (Bizzaro N, et al. 2005; 129: 61– 68) as one good article on the topic; another, a prospective study of 1,038 pregnancies on the predictive value of antiannexin V antibodies for fetal loss, comes from the Annals of the New York Academy of Sciences (Bizzaro N, et al. 2005; 1050: 348– 356).

He’s also looking at factor XIII. “I’ll have to think about this a little more,” he muses. “If you look at any textbook, they talk about how it’s needed to maintain pregnancy, but they don’t say much more about it.” Dr. Luper suspects it may play a crucial role in fetal loss. “Most of the time we’re looking at thrombophilia, but low XIII might be another reason they’re having miscarriages.”

D-dimer

The NEJM article reported that patients with an abnormal D-dimer level one month after halting anticoagulation have a significant incidence of recurrent venous thromboembolism. The discussion noted a clear benefit of prolonged treatment with vitamin K antagonists in those whose D-dimer levels were abnormal. The D-dimer assay, the authors write, correlates with individual risk of recurrence after a first episode of venous thromboembolism and may be useful in guiding duration of anticoagulation.

Occasionally a test doesn’t work as well as he had hoped. ACE polymorphisms, which looked to be associated with atherosclerosis and cardiovascular disease, for one, burned brightly but quickly, and he stopped doing the test. “But I haven’t dropped too many,” he says.

He’s not asking physicians to receive his recommendations as Delphic visions. “I don’t do things unless I’ve got pretty good evidence for it. If they ask me why I’m suggesting a test, I give them the articles. I say, ‘Make up your own mind.’ I don’t say, ‘Do it.’ I say, ‘This may be of value—put it together with your clinical findings. This is something that has come out, and I would suggest you consider it.’ ”

The testing menu isn’t the full picture. Some labs offer more tests than HTL; some offer fewer. The way Dr. Luper describes it, he’s built his business by talking about—not just providing—test results. What sets him apart, he says, is that he offers information, and plenty of it. He educates.

That’s why Quest and LabCorp view him as their primary competition in the Houston area, which Dr. Luper finds amusing. “I’m one-millionth of a percent of their revenue,” he says, laughing.

Quest and LabCorp turn out tests, he continues, but primarily “they turn out numbers.” His own reports are quite different.

Take, for example, what Dr. Luper terms a typical thrombophilia report from his lab—it discusses the evaluation of a 42-year-old male for arterial thrombophilia. The 12-page document includes test data and notes; a list of impressions (“No evidence for prothrombin gene [20210] mutation,” “Factor V Leiden—heterozygous mutation [see comment],” “No evidence for elevated levels of anticardiolipin, antiprothrombin, antiphosphatidylserine or antibeta-2 glycoprotein antibodies”); comments dictated by Dr. Luper; and a list of references.

The two pages of comments are thorough yet simple, discussing each test and possible implications of the results. (Related article: Hemostasis Thrombosis Lab Ltd.) The comments are followed by references for fibrinogen, lupus, factor V, factor VIII, von Willebrand, PAI-1, lipoprotein (a), hsCRP, D-dimer, and treatment of deep vein thrombosis.

Dr. Luper considers this to be part of his job—part of the job of any clinical pathologist. It’s easy for him to take aim at LabCorp and Quest, everyone’s favorite bad guys. But he looks sidelong at anyone tempted to skimp on his or her answers.

“Of course, I’ve carried it maybe to the other extreme,” he cheerfully acknowledges.

He doesn’t see how he could do otherwise. In part, he says, it’s because he enjoys talking with patients and his colleagues and tackling unusual cases. But hemostasis testing is nothing if not fraught. “Every lupus, I look at it kind of with a jaundiced eye, to be sure we’re not dealing with something else,” he says. “Or, with our hexagonal phospholipid test, if the ratio is high—over 15—I automatically do a factor VIII. I don’t charge for it, I just call it part of QC. I do a lot of factor VIIIs and IXs, when I’m not real sure of what’s going on, just not to miss anything.

“All of this is like walking through a field of land mines,” he says. “And you can get blown up real fast.”


Karen Titus is CAP TODAY contributing editor and co-managing editor.
 

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