In this multicenter prospective study conducted mainly in Italy, investigators studied ~600 patients with a first episode of well documented, unprovoked venous thromboembolism (DVT and/or PE). After completing at least three months of oral anticoagulation (OAC) therapy with vitamin K antagonists, all subjects stopped therapy and ~30d later underwent qualitative testing for d-dimer and a limited thrombophilia panel. After excluding subjects with AT3 deficiency, anti-phospholipid antibodies, liver or kidney disease, or serious life-threatening illnesses, those with positive d-dimer were randomized to either resume OAC or not, while those with negative d-dimer remained off therapy. Subjects were then followed for at least nine months. Bleeding events were rare during the relatively short period of follow-up, but interesting differences were seen with regard to recurrent VTE. Those with detectable d-dimer who remained off OAC had a 2.5-fold increased risk of recurrence (11 events per 100 patient years) compared to those with negative d-dimer. More importantly, they had a 5.4-fold increased risk compared to those with positive d-dimer who were placed back on OAC. Thus a positive d-dimer test identified a high risk group for preventable recurrence.
In Brief
One of the most vexing problems managing patients with VTE is balancing the bleeding risk, expense, and inconvenience associated with prolonged OAC with the threat of recurrent thrombosis once therapy is stopped. Thrombosis risk is highest in the first year after a VTE, but it never returns to population baseline, presumably reflecting the presence of an underlying thrombophilia in many patients. Although major advances have been made in understanding genetic, biochemical, and immunologic factors related to primary thrombotic risk, screening patients for these risk factors has contributed little to our ability to predict secondary risk in an individual patient, with the possible exception of detecting antiphospholipid antibody syndrome or the rare patient with AT3 deficiency or homozygous Factor V Leiden. The PROLONG study begins to help refine therapeutic decision-making for a subset of patients. Their data suggests strongly that a simple diagnostic test (d-dimer) performed one month after stopping OAC defines a subgroup that clearly benefits from prolonged anticoagulation. Unfortunately the data do not help in deciding what to do with the 60 percent whose d-dimer is negative and who still have a substantial event rate (4.4 percent per year in this study)! It is also important to remember that this study included only subjects with first episode unprovoked VTE, representing less than half of all VTE patients seen in the ambulatory setting.
What is the pathophysiologic meaning of a persistent positive d-dimer months after a VTE? The observation that more than 50 percent of the recurrent events were contralateral suggests that circulating d-dimer might be a marker of systemic thrombophilia (i.e., an ongoing imbalance of thrombin generation) rather than of an unresolved primary thrombus. This is consistent with studies showing that residual vein thrombosis detected by sonography months after a VTE also correlates with contralateral recurrence. Recent studies have suggested that d-dimer levels tend to increase with age (and in this study those with positive d-dimer were on average 10 years older than those negative), and d-dimer is known to increase in the setting of chronic inflammatory disorders, so this test is likely to be less useful in decision making for these patient groups. Nevertheless, the PROLONG study indicates that segregating risk in VTE patients is an attainable goal, but that there is still a need to develop more sensitive and specific biomarkers to detect persistent underlying thrombophilia in subjects who have suffered VTE.
Competing Interests
Dr. Silverstein indicated no relevant conflicts of interest.
