**3. Pathophysiology of PTS development**

It is generally believed that the PTS develops as a result of the combination of venous hypertension, due to persistent outflow obstruction and/or valvular incompetence, with abnormal microvasculature or lymphatic function. Long-standing venous hypertension in the deep-vein system ultimately leads to the onset of valve incompetence at the level of a constant series of perforating veins located in the medial ankle area. This allows the direct transmission of the high deep-venous pressures (especially during walking) to the venous end of subcutaneous capillaries, resulting in increased endothelial permeability. The escape of large molecules into the interstitial tissue may, in turn, explain the typical pattern of edema, hyperpigmentation and even ulcer formation (42,44,45). A few authors speculate that increased venous pressure with standing or walking causes a reduction in capillary flow rate, resulting in trapping of white blood cells in the leg and the subsequent release of free radical and proteolytic enzymes ultimately responsible for the venous ulceration (54,55).

The presence of reflux in the proximal veins is reputed to be crucial for the development of the PTS, and so is the persistence of venous obstruction, alone or in combination with venous reflux (15,35,56-61). However, this is an area of considerable uncertainty. Recently, we assessed the role of residual vein thrombosis and popliteal valve incompetence for the development of the PTS, as measured with the Villalta scale, in 180 consecutive patients who were followed for at least three years after an episode of acute proximal DVT (62). In the first six months following the thrombotic episode, venous abnormalities were detected in 104 patients (60%). The PTS developed in 18 of the 76 patients (24%) without vein abnormalities, and in 49 of the 104 (47%) with at least one abnormality: in 25 of the 52 (48%) with residual vein thrombosis alone, in 9 of the 24 (37.5%) with popliteal valve incompetence alone, and in 15 of the 28 (54%) with both abnormalities. The relative risk of the PTS was 1.0 (95% CI, 0.5 to 2.2) in patients with popliteal valve incompetence alone; 1.4 (0.9 to 2.3) in patients with transpopliteal reflux alone or combined with persistent venous obstruction; 1.6 (1.0 to 2.4) in patients with residual vein thrombosis alone; and 1.7 (1.2 to 2.3) in patients with persistent venous obstruction alone or combined with popliteal valve incompetence.

Roumen-Klappe and coworkers assessed the role of residual thrombosis, reflux and venous outflow resistance in 93 patients with proximal and distal DVT, followed for 6 years; the incidence of the PTS was 49% after 1 year, 55% after 2 years, without further increase up to 6 years. While the presence of reflux had only moderate predictive value, a strong increase in the predictive value was achieved by combining measures of residual thrombus, assessed by a thrombosis score, and venous outflow resistance, at three months (32). On the basis of these findings, a lack of recanalization within the first six months after the thrombotic episode appears to be an important predictor of PTS, while the development of transpopliteal venous reflux is not. However, incompetence of the popliteal valve increases the risk of the PTS when combined with residual vein thrombosis (32,62).

In a recent report, increased levels of inflammatory cytokines or adhesion molecules such as IL-6 and ICAM-1 were linked with the subsequent development of PTS (63). This suggests

Besides the demonstration of previous episodes of DVT, either invasive or non-invasive methods can be employed to document and quantify the presence of obstruction, reflux, or

It is generally believed that the PTS develops as a result of the combination of venous hypertension, due to persistent outflow obstruction and/or valvular incompetence, with abnormal microvasculature or lymphatic function. Long-standing venous hypertension in the deep-vein system ultimately leads to the onset of valve incompetence at the level of a constant series of perforating veins located in the medial ankle area. This allows the direct transmission of the high deep-venous pressures (especially during walking) to the venous end of subcutaneous capillaries, resulting in increased endothelial permeability. The escape of large molecules into the interstitial tissue may, in turn, explain the typical pattern of edema, hyperpigmentation and even ulcer formation (42,44,45). A few authors speculate that increased venous pressure with standing or walking causes a reduction in capillary flow rate, resulting in trapping of white blood cells in the leg and the subsequent release of free radical

The presence of reflux in the proximal veins is reputed to be crucial for the development of the PTS, and so is the persistence of venous obstruction, alone or in combination with venous reflux (15,35,56-61). However, this is an area of considerable uncertainty. Recently, we assessed the role of residual vein thrombosis and popliteal valve incompetence for the development of the PTS, as measured with the Villalta scale, in 180 consecutive patients who were followed for at least three years after an episode of acute proximal DVT (62). In the first six months following the thrombotic episode, venous abnormalities were detected in 104 patients (60%). The PTS developed in 18 of the 76 patients (24%) without vein abnormalities, and in 49 of the 104 (47%) with at least one abnormality: in 25 of the 52 (48%) with residual vein thrombosis alone, in 9 of the 24 (37.5%) with popliteal valve incompetence alone, and in 15 of the 28 (54%) with both abnormalities. The relative risk of the PTS was 1.0 (95% CI, 0.5 to 2.2) in patients with popliteal valve incompetence alone; 1.4 (0.9 to 2.3) in patients with transpopliteal reflux alone or combined with persistent venous obstruction; 1.6 (1.0 to 2.4) in patients with residual vein thrombosis alone; and 1.7 (1.2 to 2.3) in patients with persistent venous obstruction alone or combined with popliteal valve

Roumen-Klappe and coworkers assessed the role of residual thrombosis, reflux and venous outflow resistance in 93 patients with proximal and distal DVT, followed for 6 years; the incidence of the PTS was 49% after 1 year, 55% after 2 years, without further increase up to 6 years. While the presence of reflux had only moderate predictive value, a strong increase in the predictive value was achieved by combining measures of residual thrombus, assessed by a thrombosis score, and venous outflow resistance, at three months (32). On the basis of these findings, a lack of recanalization within the first six months after the thrombotic episode appears to be an important predictor of PTS, while the development of transpopliteal venous reflux is not. However, incompetence of the popliteal valve increases

In a recent report, increased levels of inflammatory cytokines or adhesion molecules such as IL-6 and ICAM-1 were linked with the subsequent development of PTS (63). This suggests

the risk of the PTS when combined with residual vein thrombosis (32,62).

and proteolytic enzymes ultimately responsible for the venous ulceration (54,55).

both, that are considered the major determinants of the PTS.

**3. Pathophysiology of PTS development** 

incompetence.

that inflammation at the time of, or consequent to the episode of acute DVT may play a role in the pathophysiology of PTS, a hypothesis that is being further explored in a large prospective study (64).
