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Risk factors for VTE abound, but clinical utility is limited
From Factor V Leiden to D-dimer testing, painting a complete picture of risk is crucial to guiding treatment.
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More than 350,000 Americans have a deep vein thrombosis every year, according to the CDC. As many as 15% of those may result in a dangerous pulmonary embolism. However, in recent years, the understanding of some of the mechanisms underlying hypercoagulable states has improved, and this has resulted in an array of risk factors known to influence deep vein thrombosis occurrence.
These risk factors range from the well-known environmental factors such as pregnancy and oral contraceptive use to genetically inherited risks such as the presence of a Factor V Leiden or prothrombin gene mutation. There is also an increased focus on the strong connection between many cancers and thrombosis risk.
Despite this increase in knowledge, experts in the field are still examining the role that identifying these risk factors has in preventing or treating venous thromboembolism.
“We have been too enthusiastic about thrombophilia testing,” said Mark A. Crowther, MD, a professor of medicine and pathology at McMaster University in Ontario, Canada. “The message for thrombophilia testing should be that just because we can do the testing is not a reason that we should do it. The patients should be selected carefully and it should only be done in a setting where it is likely to influence outcomes.”
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Photo by Mike Lalich |
HemOnc Today spoke to several experts about some of the risk factors for thrombosis and how prevention and management may be changing in this arena.
Among the genetic thrombophilic disorders, Factor V Leiden mutation is among the most common. It was first described in 1994 by Bertina and colleagues. Later, research by Ridker and colleagues showed that about 5% of whites are heterozygous for Factor V Leiden, with lower percentages found in Hispanics, blacks and Asians. In those with the genetic variant, the coagulation cascade protein cannot be inactivated by activated protein C, resulting in the hypercoagulable state.
Those who have the heterozygous Factor V Leiden gene face an increased RR for DVT or pulmonary embolism by about five- to sevenfold. Although a significant relative increase, the background rate is only about one in 5,000 to 10,000 per year, making the absolute risk low, despite the presence of Factor V Leiden.
“The added risk is extremely modest, so it does not seem like there is a lot of low-hanging fruit,” said Kenneth A. Bauer, MD, a professor of medicine at Harvard Medical School.
Although Factor V Leiden appears to raise the risk for DVT, it has been shown to lower or have no effect on the risk for pulmonary embolism. In one recent family cohort study published in Haematologica, the RR for DVT in carriers of Factor V Leiden, after excluding other thrombophilic defects, was 7.0 (95% CI, 2.3-21.7). The RR for pulmonary embolism was 2.8 but did not reach statistical significance.
Another study, conducted by Van Stralen and colleagues, that included 3,574 DVT and pulmonary embolism patients found a similar result. Of 2,063 patients with isolated DVT, 20% were carriers of Factor V Leiden; only 8% of 885 patients with isolated pulmonary embolism were carriers. Thus, the risk for DVT among carriers was increased by 4.5-fold but only 1.7-fold for pulmonary embolism. Although the researchers explored five potential mechanisms for the contrast, including number of affected veins, thrombus location and thrombus density, none provided a definitive answer.
“We found an indication of a different clot lysis time, suggesting that the ‘Factor-V-Leiden-clot’ is different from other ones,” said Frits Rosendaal, MD, of Leiden University Medical Center in the Netherlands, one of the authors of that study and one of the authors of the paper originally describing Factor V Leiden. “I suppose that is the most likely explanation.”
The other relatively common thrombophilic genetic factor is the prothrombin G20210a gene mutation. The mutation occurs in 2% to 3% of individuals and is found in about 6% of patients with VTE, according to Rosendaal. Similar to Factor V Leiden, it is predominantly found among whites and appears to increase the risk for VTE by two- to threefold.
Other genetic risk factors for VTE exist, as well, but occur in a smaller percentage of the population. Many gene mutations may cause deficiencies in antithrombin, protein C and protein S. Although placing patients at higher risk of DVT than the Leiden or prothrombin mutation, these abnormalities are found in less than 1% of the general population, according to a 2009 review by Rosendaal and colleagues in the Journal of Thrombosis and Haemostasis.
Other factors may also contribute to thrombosis; individuals in the lowest 10% of levels of tissue factor pathway inhibitor appear to have twice the risk for VTE. About 6% of individuals carry a variant in the fibrinogen gene, which reduces the amount of gamma-fibrinogen in plasma, increasing VTE risk by about twofold.
The two primary genetic factors, as well as those less common factors, also have in common that their presence or absence does not appear to influence the management of patients
“There really is not much direct evidence that testing for these mutations improves clinical outcomes,” said Jodi Segal, MD, MPH, an associate professor of medicine at Johns Hopkins University in Baltimore. Segal led an analysis published in JAMA last year of the predictive value of Factor V Leiden and prothrombin G20210a. In the study, they found that although the presence of the mutations appears to predict recurrent VTE in those with a history of VTE, there was insufficient evidence to conclude if testing changed the outcomes.
“The evidence that exists is made up of looking at smaller pieces of the question: How much does testing actually detect the mutation, and how much is it associated with the outcomes of interest?” Segal said. “But that is not really demonstrating that testing improves outcomes.”
Crowther said the evidence does not suggest that knowledge of the mutations should affect duration or intensity of anticoagulant treatment. “Most of the time, if you have Leiden, they are going to tell you to watch for signs and symptoms of DVT and seek medical attention if they occur,” he said. “And if you don’t have Leiden, they are going to tell you the same thing. So as a screening test, it does not change the advice I am going to give you about the rest of your life.”
Cancer and thrombosis
For many years, the increased risk for clot was considered merely an inconvenient adverse effect of the presence of and treatment for various malignancies, according to Alok A. Khorana, MD, an associate professor of medicine at University of Rochester, New York.
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“What has changed in the last few years is this whole area that has developed in basic science looking at many of the factors involved in coagulation,” Khorana said. “It turns out that many of those are involved in angiogenesis as well.”
The primary protein responsible for this link is tissue factor, which acts in an early step in the coagulation cascade to initiate thrombin formation. “If you have high tissue factor levels, you also have high vascular endothelial growth factor expression, and you also have high microvessel density, which is a surrogate for angiogenesis,” Khorana said. “Many people in the field feel that this is intrinsically linked to tumor biology; it is not a side effect or complication, it is not the tumor pressing on blood vessels that causes the vessel to clot, it is the tumor that causes it to clot.”
The risk for VTE is increased by about sixfold in patients with cancer, and about 20% of all new VTE events occur in patients with active malignancies, according to a 2009 study by Khorana and colleagues. The risk for VTE varies widely depending on the type of malignancy; tumors of the pancreas, colon and prostate have higher risk. Hematological malignancies such as leukemia carry some increased risk, whereas the risk for VTE associated with breast cancer is not particularly high, according to Khorana.
Recent research also indicates that VTE has significant influence on outcome in cancer patients. In another study published in 2007, Khorana and colleagues examined the causes of death among 4,466 cancer patients undergoing chemotherapy. Although most of the 141 patients who died during the study died because of progression of underlying cancer, thrombosis and infection were the leading noncancer causes of death.
Rosendaal said the cancer setting may be the first arena in which some of the genetic risk factors might actually provide some clinical utility. Because the malignancy itself incurs elevated risk, adding the various genetic factors on top of that risk may guide treatment in ways that the genetic factors alone cannot.
“The first to benefit from a policy [of genetic testing] would be patients with cancer and those undergoing orthopedic surgery and those who had a prior event,” Rosendaal said.
The use of testing for Factor V Leiden and the prothrombin mutation among patients undergoing orthopedic surgery has also been investigated recently. In a 2009 study comparing 50 patients with symptomatic DVT within three weeks after total hip replacement and 85 asymptomatic control patients, no significant differences were seen for the presence of any single mutation.
The study, by Ringwald and colleagues, found trends of “borderline significance” for the presence of Factor V Leiden and another genetic risk factor, a homozygous methylenetetrahydrofolate reductase variant. There were also suggestions that combinations of some of the genetic mutations may increase risk, even though individual factors probably do not.
Future of risk assessment
Cancer may be the most important of acquired risk factors for VTE, and genetics have garnered a lot of attention in recent years, but there are numerous other factors that contribute to the occurrence of DVT and pulmonary embolism. Many other acquired factors exist, including immobilization, oral contraceptive or hormone replacement use and pregnancy.
Crowther said putting together the entire mosaic of risk factors for thrombosis is the only way to derive clinical utility from any individual test or factor. With regard to the use of genetic testing, for example, he said they could be used “when you are making decisions about the use of birth control pills or during subsequent pregnancies because those kind of things can be important. When patients are going to be in situations of particularly high risk, like prolonged immobilization, you might think about it.”
Bauer agreed. “If you look at the guidelines, it’s clear that clinical factors and clinical factors around the initial event — whether it is provoked or unprovoked — are the dominant driver of recurrence risk, of who may need long-term or shorter-term therapy,” he said. “It is clear that these tests are widely over-ordered. They have limited implications on management despite being risk factors.”
Currently, the use of testing for Factor V Leiden and prothrombin G21210a may help determine the reasons that a clot occurred but will not change the methods used to prevent its recurrence. “Hypercoagulable workups are still done a bit, but it is unclear if they are helpful with decisions concerning duration and/or intensity of therapy,” said Thomas Ortel, MD, PhD, a professor of medicine and pathology at Duke University Health System. He noted that another test used in patients who suffer a VTE, D-dimer testing, has more potential to actually tailor treatment regimens.
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The PROLONG trial showed that testing for levels of the fibrin degradation product D-dimer one month after the suspension of anticoagulant therapy in patients with a first unprovoked VTE improved the rate of recurrence by showing physicians who should receive extended prophylaxis. The results of a subsequent study, PROLONG II, published this year in Blood, further illustrated that testing for D-dimer levels every two months for one year can find more patients who may benefit from further treatment.
“The data with D-dimer, and maybe thrombin generation tests, look a little more promising to try and identify the people who may need longer-term therapy,” Bauer said.
As the understanding of the coagulation cascade and hypercoagulable states has improved, there is no shortage of factors to test for and monitor. The consensus for now, though, seems to be that only by examining the entire risk picture for a given patient can any particular factors play a role in their management. Segal said although it can be frustrating to continue to gain knowledge on the mechanisms involved in VTE with no clear change in how to manage patients, it is simply a result of the complicated nature of thrombosis physiology.
“There are so many other steps that go between identifying the risk factor and improving a health outcome,” she told HemOnc Today. “At this point, you just have to say that more information is needed.” – by Dave Levitan
For more information:
- Bertina RM. Nature. 1994;369:64-67.
- Cosmi B. Blood. 2010;115:481-488.
- Khorana AA. Thromb Res. 2010;doi:10.1016/j.thromres.2009.12.023
- Makelburg ABU. Heamtologica. 2009;doi:10.3324/haematol.2009.017061.
- Ridker PM. JAMA. 1997;277:1305-1307.
- Ringwald J. Clin Ortho Rel Res. 2009;467:1507-1515.
- Rosendaal FR. J Thromb Haemost. 2009;7:301-304.
- Segal JB. JAMA. 2009;301:2472-2485.
- Van Stralen KJ. Arterioscler Thromb Vasc Biol. 2008;28:1872-1877.