_D-Dimer Testing a Flawed Predictor of VTE in Elderly

ATLANTA -- The relationship between increasing venous thromboembolism rates in the elderly and rising _D-dimer levels presents a diagnostic dilemma. "Older age reduces the clinical usefulness of _D-dimer testing. ... We probably need age-adjusted cutoffs in older people," Dr. Kenneth A. Bauer of Harvard Medical School, Boston, said at the annual meeting of the American Society of Hematology.

Incidence of venous thromboembolism rises exponentially starting at age 45 years, said Dr. Mary Cushman of the University of Vermont, Burlington. VTE is three times more common in people aged 65 years and older, compared with those aged 45-64 years. When VTE patients are stratified by age, 70% are 60 years and older.

Just why VTE incidence increases with age is not clear, but she offered several hypotheses: increased comorbidities and frailties, impaired mobility, inflammation, alteration of vein health, sarcopenia, and increased coagulation potential.

Despite limited data, she said, the evidence to date makes clear that the impact is also worse in the elderly, with rates of death, recurrence, post-thrombotic syndrome, and treatment complications rising with each decade of life. The elderly "are more likely to fail treatment than those under age 65," she said.

In healthy elderly individuals, however, researchers have found high levels of many coagulation activation markers, including _D-dimer, a fibrin degradation product released when blood clots. The fact that _D-dimer is heterogeneous has led to issues in using and standardizing _D-dimer assays, contrasting it with other coagulation markers that are discrete polypeptides with defined molecular weights.

"_D-Dimer is a physiological variable and can vary over time," Dr. Bauer said, discussing a study of centenarians conducted in Italy (Blood 1995;85:3144-9). Investigators compared healthy centenarians with two control groups of healthy people aged 18-50 years and 51-69 years. Each group was made up of 25 people.

The healthy centenarians showed laboratory signs of coagulation activation, including high levels of proteins that can predict cardiovascular disease in middle-aged people. Notably, the _D-dimer concentrations were highly elevated in the centenarians: 323 ng/mL, compared with 29 ng/mL in the younger control group and 50 ng/mL in the middle group. That healthy centenarians have significantly higher levels of _D-dimer suggests it "is not necessarily a bad thing. It is consistent with long life," Dr. Bauer commented.

While many coagulation activation markers increase with age, he focused on _D-dimer because it has the potential to stratify recurrence risk in patients after treatment for their first idiopathic VTE and thereby identify who would benefit from extended anticoagulation. Among several studies showing higher recurrence risk in patients with elevated _D-dimer levels, he highlighted an investigation conducted in Italy (N. Engl. J. Med. 2006;355:1780-9).

_D-Dimer levels were tested 1 month after anticoagulation was stopped if there was a first unprovoked deep vein thrombosis or pulmonary embolism. Patients with normal levels did not resume therapy. Those with "abnormal" _D-dimer levels were randomly assigned to resuming or ending treatment; 74% of those with elevated _D-dimer levels were age 65 and older.

At a median follow-up of 1.4 years, 10.7% of untreated patients with abnormal _D-dimer levels had a recurrence, compared with 4.4% of those with normal levels (hazard ratio 2.27). When untreated patients were stratified by age, Dr. Bauer said the risk of recurrence was less in the elderly; they had a hazard ratio of 1.63, compared with 4.40 for those younger than age 65. Among patients with normal _D-dimer levels, recurrence was higher in the elderly.

When asked to comment on this story, Dr. Russell H. Samson, clinical associate professor of surgery (vascular) at Florida State University Medical School, Sarasota, Fla. stated: "Elevation of the _D-dimer in the elderly can also result in a diagnostic dilemma. For example, _D-dimer is often utilized to help determine whether a DVT diagnosed by duplex scan is acute or chronic. If the _D-dimer is elevated simply because of the patient's age, this may be misinterpreted as evidence for acute DVT resulting in potentially unnecessary anticoagulation. Therefore, it would seem appropriate that in the future clinical laboratories identify a spectrum of normal values based on age rather than reporting a single upper limit of normal for their _D-dimer analysis." Dr. Samson is an associate medical editor of VASCULAR SPECIALIST