The Relationship Between D-Dimer Level, Venous Valvular Reflux and Development of the Post-Thrombotic Syndrome after Deep Venous Thrombosis.

Background: The pathophysiology of the post-thrombotic syndrome (PTS) is postulated to involve persistent venous thrombosis and valvular reflux. We prospectively studied if d-dimer levels or valvular reflux were associated with subsequent development of the PTS after objectively confirmed deep venous thrombosis (DVT).

Methods: Consecutive patients with objectively diagnosed acute symptomatic DVT were recruited at 8 hospital centres in Quebec and Ontario, Canada. Patients attended study visits at Baseline, 1, 4, 8, 12, and 24 months. Blood was taken to measure d-dimer (VIDAS d-dimer; cut off <500 ug/L) at the 4 month visit. A standardized ultrasound assessment for popliteal venous valvular reflux was performed at the 12 month visit. Standardized assessments for PTS (using Villalta scale) were performed at each follow-up visit. Subjects were classified as having developed PTS if the ipsilateral Villalta score was >5 on at least 2 visits starting at the 4 month visit or later or was >5 at the final follow-up visit. Statistical analyses assessed associations between d-dimer level, ipsilateral reflux and PTS.

Results: 387 patients were recruited and followed. Mean age was 56 years and 51% were male. PTS developed in 45% of patients. Mean d-dimer was significantly higher in patients who developed PTS compared with those who did not (712.0 vs. 444.0 ug/L; p= 0.02). In logistic regression analyses adjusted for age and warfarin use at the time of d-dimer determination, d-dimer levels significantly predicted PTS (p=0.03). Ipsilateral venous valvular reflux was more frequent in patients with moderate/severe PTS than in patients with no PTS or mild PTS (65% vs. 40% vs. 43%, respectively; p=0.013). Finally, mean d-dimer was higher in patients who developed recurrent VTE during follow-up (n=31) than in those who did not (1126.8 vs. 514.9 ug/L; p=0.05), and d-dimer was an independent predictor of recurrent VTE (p=0.04) after adjustment for other known predictors of recurrence.

Conclusion: D-dimer levels measured 4 months after DVT are associated with subsequent development of PTS and are predictive of VTE recurrence. Venous valvular reflux was associated with moderate/severe PTS. Further studies are required to assess whether d-dimer or valvular reflux may be useful in determining which patients are most at risk of developing PTS or severe PTS and who may thus benefit from preventive strategies.