Severe Post Thrombotic Syndrome Is Associated to Lower Echogenicity of the Residual Venous Thrombosis
Authors: Mazetto Bruna M , Orsi Fernanda Loureiro de Andrade , Silveira Sandra A.F , Flores-Nascimento Mariane Cristina , Bittar Luis Fernando , Custódio Isadora , Annichino-Bizzacchi Joyce M 
Published: October 2019

Abstract
Introduction: The post-thrombotic syndrome (PTS) is a common chronic complication of deep venous thrombosis (DVT) of the lower limbs and may occur even after an appropriate anticoagulant treatment. PTS may develop in the first two years after DVT in about 20-50% of patients; 5–10% of those may present severe manifestations of the disease. PTS is associated to an increased risk for DVT recurrence, morbidity, poor quality of life and significant cost to public health. The diagnosis of PTS is performed by clinical evaluation; particularly, the Villalta scale is recommended by the ISTH for PTS diagnosis and severity evaluation. The PTS-associated medical conditions are poorly understood, and it seems that hypercoagulability and inflammation, after the first episode of DVT, may play an important role in the disease development. Therefore, we performed a comprehensive analysis of clinical parameters, inflammation and ultrasound (US) examination of the affected limb in patients with history of previous DVT and PTS.
Objective: The aim of this study was to evaluate possible medical conditions associated to PTS and its severity.
Material and Methods: Between February 2013 and October 2013, consecutive patients with history of previous unprovoked DVT of lower limbs (> 6 months from the diagnosis), attended at the Hematology Center of the University of Campinas, Brasil, were included. Patients were submitted to physical evaluation for body mass index (BMI) determination and PTS diagnosis, by Villalta scale. Levels of the IL-8, IL-6 and TNF-α were performed by ELISA, D-dimer by turbidimetry and CRP by nephelometry. US examination was performed by duplex. In patients with residual venous thrombosis (RVT), the thrombus echogenicity was determined by grayscale median (GSM) evaluation, as described for atherosclerotic plaques. The GSM analysis was performed by a computer based US using specific software. Only the region containing the thrombus was analyzed, the image was depicted manually point by point to trace the line surrounding the thrombus, the final GSM values were automatic calculated and translated the thrombus echogenicity. A low GSM value (<25) suggests acute thrombosis and a high GSM vlaue (> 25) suggest subacute thrombosis.. Continuous variables were analyzed by Kruskal-Wallis test and categorical variables were compared using the Fisher´ s exact test.
Results: From the 56 patients included, 15 did not present PTS, 23 were classified as mild, 11 as moderate and 7 as severe PTS. Serum levels of CRP was significantly higher in patients with severe PTS when compared to patients with mild+moderate PTS and to those without PTS (respectivelly 0.64mg/dL, 0.31mg/dL and 0.13mg/dL; P=0.02).Serum levels of IL-6 and TNF-α were higher in patients with severe PTS compared to patients with mild/moderate PTS and without PTS (IL-6= 2.81pg/mL vs. 1.48pg/mL vs. 0.80pg/mL respectively, and TNF 1.68pg/mL vs. 1.33pg/mL vs 1.17pg/mL respectively), however the differences did not reach statistical significance. Levels of IL-8 and DD were similar between severe PTS and the other two groups. The presence of RVT was similar between groups, however US-generated GSM was significantly lower in patients with severe PTS compared to patients with mild+moderate PTS and patients without PTS (GSM= 22, 31 and 28.5, respectively; P=0.04). As predicted, the BMI was also higher in patients with severe PTS when compared to mild+moderate PTS and no PTS group (BMI= 34,8 vs. 29,3 vs. 25,9, respectively P=0.007).
Conclusion: Our results suggest that severe PTS may be associated with a chronic inflammatory response, characterized by obesity and higher levels of CRP. Besides, we could also observe that severe PTS may be associated with the persistence of a hypoechoic residual thrombus, determined by lower US-generated GSM values. The finding about the persistence of a hypoechoic thrombus in patients with severe PTS, even long time after the acute thrombosis event, is new and may possibly suggest that an adequate thrombus organization process is required to avoid the development of PTS.

Disclosures
No relevant conflicts of interest to declare.