Inflammation Markers and The Risk Of Post Thrombotic Syndrome: Results From The Bio-Sox Study
Authors: Rabinovich Anat , Cohen Jacqueline M , Cushman Mary , Houweling Adrielle H , Shapiro Stan , Wells Philip S , Rodger Marc A , Kovacs Michael J , Anderson David , Tagalakis Vicky , Lazo-Langner Alejandro , Solymoss Susan , Miron Marie-José , Yeo Erik , Smith Reginald , Schulman Sam , Kassis Jeannine , Kearon Clive , Changon Isabelle , Wong Turnly , Demers Christine , Hanmiah Rajendar , Kaatz Scott , Selby Rita , Rathbun Suman , Desmarais Sylvie , Opatrny Lucie , Ortel Thomas L. , Ginsberg Jeffrey S , Kahn Susan R. 
Published: October 2019

Abstract

Introduction
The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is not understood why up to 50% of DVT patients develop PTS despite optimal anticoagulation. In the Bio-SOX Study, we investigated whether markers of inflammation, one of the putative pathophysiologic processes leading to PTS, are of value in predicting the development of PTS in DVT patients.

Objective
To assess whether markers of inflammation measured at three time points after DVT diagnosis are predictors of risk of PTS.

Methods
The Bio-SOX is a sub-study of the SOX Trial, a multicenter, randomized controlled trial of elastic compression stockings for the prevention of PTS. Eight hundred and three patients with a first, symptomatic, proximal DVT were randomly allocated to receive active or placebo stockings to be worn daily, starting within 2 weeks of DVT diagnosis. During the SOX trial we prospectively collected blood samples from participants at baseline, one and six months. We measured plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. Differences between median biomarker levels in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed using the Wilcoxon rank-sum test. Multivariable logistic regression models were used to calculate crude and adjusted odds ratios (OR) of PTS by biomarker levels.

Results
Among study patients, 60.1% were male and mean age was 55.1 years. There were 334 cases of Villalta-defined PTS during follow up, with no significant difference in incidence between the active and placebo stockings groups. Median values of biomarkers between cases and noncases of PTS showed statistically significant differences in CRP and IL-6 at one and six months, ICAM-1 at all time points, and IL-10 at six months post DVT (Figure 1). Table 2 summarizes crude and adjusted ORs for PTS, using the median as a cut-off value. ICAM-1 was associated with PTS at all time points, IL-10 at six months, and CRP at 1 month post DVT, though this association was attenuated after adjustment.

Conclusion
The Bio-SOX Study is the first large scale prospective study we are aware of that evaluated the predictive role of biomarkers measured at baseline and relevant time points after acute DVT in the development of PTS. Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein important in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Its expression and secretion by activated endothelial cells is induced by thrombin. Future therapeutic trials should be aimed at targeting this pathway.

Disclosures:
No relevant conflicts of interest to declare.