**1. Introduction**

142 Deep Vein Thrombosis

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Despite appropriate anticoagulant therapy, at least 1 of every 2-3 patients with deep-vein thrombosis (DVT) of the lower extremities will develop post-thrombotic sequelae. These vary from minor signs (i.e., stasis pigmentation, venous ectasia, slight pain and swelling) to severe manifestations such as chronic pain, intractable edema and leg ulcers (1). The established postthrombotic syndrome (PTS) remains a significant cause of chronic illness, with considerable socio-economic consequences for both the patient and the health care services (2,3).

The precise incidence of the PTS following confirmed venous thrombosis is still controversial, as the rate of post-thrombotic sequelae reported in published studies has varied between 20% and 100%. In earlier studies, a surprisingly high rate of severe PTS complications was reported (50 to 100% of the patients within 4 to 10 years after the qualifying thrombotic episode) (4-6). This rate sharply decreased in studies performed in the last 25 years (7-39), which could be due to improved diagnostic and therapeutic approaches to patients with DVT. However, owing to large differences among studies in terms of study design, definition of PTS, sample size, length of follow-up, and use of compression elastic stockings, the reported incidence of both overall and severe PTS still shows considerable variability. In the absence of elastic stockings, PTS is expected to develop in approximately 50% of patients suffering an episode of DVT, and is severe in one fifth of patients (1). Of interest, PTS can develop, although to a lower extent, also after an asymptomatic episode of postoperative DVT (40,41).

According to the results of the most recent studies, most patients who develop postthrombotic manifestations become symptomatic within two years from the acute episode of DVT (1,18-20,29-32,35-37,39). These findings challenge the general view that the PTS requires many years to become manifest.

#### **2. Clinical diagnosis and objective diagnostic testing**

#### **2.1 Clinical diagnosis and scoring systems**

The post-thrombotic syndrome is characterized by aching pain on standing, dependent edema, and the frequent development of brawny, tender induration of the subcutaneous

The Post Thrombotic Syndrome 145

Class 2 Varicose veins Class 3 Edema

disease

above

**Anatomic distribution** Superficial, deep, or perforator, alone or in combination

Table 2. CEAP (clinical, etiologic, anatomic, pathophysiologic) classification of the PTS

If a patient with a history of a previous (documented or highly suspected) DVT develops symptoms and signs compatible with PTS there is no need for further investigation. As the clinical picture may be non-specific (43-45), the need for objective confirmation arises in patients with leg complaints but without a likely or objectively proven previous DVT. Ascending phlebography is potentially useful to detect a previous DVT. Suggestive findings include narrowing or occlusion of the deep veins, contrast dye opacification of fewer veins (than normal) or perfusion of superficial or deep collateral veins. Recanalized veins show irregular margins, bizarre-appearing or multi-channeled lumen with webs, and usually have reduced caliber due to fibrotic thickening of their walls. Such veins may subsequently become dilated, probably because of loss of their elastic tissue (52). Despite the predictive value of these venographic patterns in patients with possible PTS, the invasive nature and cost of plebography makes such an approach inapplicable to most patients with a history of

We have shown that the combination of standardized clinical evaluation with compression ultrasonography and continuous-wave Doppler analysis can reliably diagnose or exclude a prior proximal-vein thrombosis in almost 90% of patients with a suggestive history (53). Compression ultrasonography should be performed first, checking the popliteal and the common femoral vein for compressibility. If either or both veins are incompressible, then a definite diagnosis of previous (proximal) DVT is made. Patients with normal ultrasound test results are interviewed and examined according to a standardized form (Table 1), and subsequently undergo continuous-wave Doppler analysis to test valve function, both in the common femoral and in the popliteal vein. The finding of both a popliteal reflux and/or of a clinical score > 8 is highly specific for the adjudication of a prior DVT in patients with a normal ultrasound test result. If ultrasound testing is normal, deep venous reflux is absent, and the clinical score is < 8, then previous proximal DVT is virtually excluded (53). The widespread availability of Duplex scanning renders our approach even more rapid and

precise, as it permits venous flow sampling during direct visualization of the vessels.

Class 1 Telangiectasia or reticular veins

Reflux or obstruction, alone or in combination

Class 4 Skin changes ascribed to venous disease Class 5 Skin changes as described above with healed ulceration Class 6 Leg ulceration, skin changes as defined

**Clinical signs** Class 0 No visible or palpable signs of venous

**Etiologic classificatio** Congenital, primary, secondary

**Pathophysiologic dysfunction** 

**2.2 Objective diagnostic testing** 

clinically suspected DVT.

tissues of the medial lower limb, a condition that has been termed "lipodermatosclerosis". Pruritus and eczematous skin changes are frequently present, and a proportion of patients develops secondary superficial varicose veins as the syndrome evolves. Ulceration, often precipitated by minor trauma, arises in a considerable number of patients and is characteristically chronic and indolent with a high recurrence rate, once healing has been achieved. Uncommonly, patients with persistent obstruction may experience venous claudication, a bursting pain in the leg during exercise, which, in some respects, mimics arterial claudication (42).

The clinical picture of the PTS is non-specific, as clinical conditions other than DVT may result in a similar set of symptoms and signs in the lower extremity, including superficial venous insufficiency, increased body mass index, and trauma (43-45).

The diagnosis of the PTS is made based on the development of the above mentioned clinical manifestations in patients with a history of DVT, irrespective of the presence of venous abnormalities as shown by invasive or non-invasive diagnostic procedures. In the absence of characteristic signs and symptoms, the demonstration of venous abnormalities (such as venous reflux, persistent venous obstruction, or both) does not, in itself, allow a patient with a history of DVT to be defined as having PTS.


\*Each sign or symptom is graded with a score between 0 and 3. The presence of ulcer is only noted. PTS is classified as mild if the score is 5-9, moderate if the score is 10-14, and severe if the score is ≥ 15 or a venous ulcer is present.

Table 1. Villalta scale for the assessment of the PTS

Although the clinical picture of the PTS is classical, there is large variation among published studies as to its clinical classification. Among the suggested scoring systems, the Villalta scale and the CEAP classification are the most widely adopted (46). The former, based on clinical findings alone (Table 1), has high interobserver agreement (47,48), and good ability to discriminate patients with versus those without PTS and patients with mild versus those with severe PTS (1,47,49). In addition, this scale correlates well with the patient's perception of the interference of leg complaints with daily life (31,47,49). The Villalta scale has recently been recommended as a standard to define PTS for use in clinical investigations by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (50). The latter, known as CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic) classification, was developed as a result of the cooperative work of a panel of experts in the field of vascular disease, and combines clinical and objective findings into a sophisticated scoring system (Table 2) (51).

tissues of the medial lower limb, a condition that has been termed "lipodermatosclerosis". Pruritus and eczematous skin changes are frequently present, and a proportion of patients develops secondary superficial varicose veins as the syndrome evolves. Ulceration, often precipitated by minor trauma, arises in a considerable number of patients and is characteristically chronic and indolent with a high recurrence rate, once healing has been achieved. Uncommonly, patients with persistent obstruction may experience venous claudication, a bursting pain in the leg during exercise, which, in some respects, mimics

The clinical picture of the PTS is non-specific, as clinical conditions other than DVT may result in a similar set of symptoms and signs in the lower extremity, including superficial

The diagnosis of the PTS is made based on the development of the above mentioned clinical manifestations in patients with a history of DVT, irrespective of the presence of venous abnormalities as shown by invasive or non-invasive diagnostic procedures. In the absence of characteristic signs and symptoms, the demonstration of venous abnormalities (such as venous reflux, persistent venous obstruction, or both) does not, in itself, allow a patient with

Redness

\*Each sign or symptom is graded with a score between 0 and 3. The presence of ulcer is only noted. PTS is classified as mild if the score is 5-9, moderate if the score is 10-14, and severe if the score is ≥ 15 or

Although the clinical picture of the PTS is classical, there is large variation among published studies as to its clinical classification. Among the suggested scoring systems, the Villalta scale and the CEAP classification are the most widely adopted (46). The former, based on clinical findings alone (Table 1), has high interobserver agreement (47,48), and good ability to discriminate patients with versus those without PTS and patients with mild versus those with severe PTS (1,47,49). In addition, this scale correlates well with the patient's perception of the interference of leg complaints with daily life (31,47,49). The Villalta scale has recently been recommended as a standard to define PTS for use in clinical investigations by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (50). The latter, known as CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic) classification, was developed as a result of the cooperative work of a panel of experts in the field of vascular disease, and combines clinical and objective findings

Pain during calf compression

Ulceration of the skin

venous insufficiency, increased body mass index, and trauma (43-45).

**Subjective Symptoms Objective Signs**  Heaviness Pretibial edema Pain nduration of the skin Cramps Hyperpigmentation Pruritus New venous ectasia

a history of DVT to be defined as having PTS.

Table 1. Villalta scale for the assessment of the PTS

into a sophisticated scoring system (Table 2) (51).

arterial claudication (42).

Paresthesia

a venous ulcer is present.


Table 2. CEAP (clinical, etiologic, anatomic, pathophysiologic) classification of the PTS

#### **2.2 Objective diagnostic testing**

If a patient with a history of a previous (documented or highly suspected) DVT develops symptoms and signs compatible with PTS there is no need for further investigation. As the clinical picture may be non-specific (43-45), the need for objective confirmation arises in patients with leg complaints but without a likely or objectively proven previous DVT. Ascending phlebography is potentially useful to detect a previous DVT. Suggestive findings include narrowing or occlusion of the deep veins, contrast dye opacification of fewer veins (than normal) or perfusion of superficial or deep collateral veins. Recanalized veins show irregular margins, bizarre-appearing or multi-channeled lumen with webs, and usually have reduced caliber due to fibrotic thickening of their walls. Such veins may subsequently become dilated, probably because of loss of their elastic tissue (52). Despite the predictive value of these venographic patterns in patients with possible PTS, the invasive nature and cost of plebography makes such an approach inapplicable to most patients with a history of clinically suspected DVT.

We have shown that the combination of standardized clinical evaluation with compression ultrasonography and continuous-wave Doppler analysis can reliably diagnose or exclude a prior proximal-vein thrombosis in almost 90% of patients with a suggestive history (53). Compression ultrasonography should be performed first, checking the popliteal and the common femoral vein for compressibility. If either or both veins are incompressible, then a definite diagnosis of previous (proximal) DVT is made. Patients with normal ultrasound test results are interviewed and examined according to a standardized form (Table 1), and subsequently undergo continuous-wave Doppler analysis to test valve function, both in the common femoral and in the popliteal vein. The finding of both a popliteal reflux and/or of a clinical score > 8 is highly specific for the adjudication of a prior DVT in patients with a normal ultrasound test result. If ultrasound testing is normal, deep venous reflux is absent, and the clinical score is < 8, then previous proximal DVT is virtually excluded (53). The widespread availability of Duplex scanning renders our approach even more rapid and precise, as it permits venous flow sampling during direct visualization of the vessels.

The Post Thrombotic Syndrome 147

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

Among parameters that have been found to be associated with an increased risk of the PTS are proximal DVT (33,38,39,60), previous ipsilateral DVT (14,16,18,28,29,33,39), older age (29,65), obesity (38,39,65-67), and varicose veins (38). In one investigation the male gender was a predictor of the PTS (33), while in others the opposite was seen (38,39). Finally, whether the carriage of factor V Leiden or the prothrombin mutation are predictors of a lower risk or reduced severity of the PTS is controversial, as there are data in favor (31) and

In order to determine the frequency, time course, and predictors of the PTS after acute DVT, we followed 387 patients for up to two years after an episode of acute symptomatic DVT (39). With the use of the Villalta score, greater postthrombotic severity category at the 1 month visit strongly predicted higher mean postthrombotic scores throughout 24 months of follow-up (1.97, 5.03, and 7.00 increase in Villalta score for mild, moderate, and severe 1 month severity categories, respectively, vs. none). Additional predictors of higher scores over time were venous thrombosis of the common femoral or iliac vein (2.23 increase in score vs. distal venous thrombosis), higher body mass index (0.14 increase in score per kg/m2), previous ipsilateral venous thrombosis (1.78 increase in score), older age (0.30 increase in score per 10-year age increase), and female sex (0.79 increase in score). Accordingly, appropriate strategies aimed at reducing the risk of recurrent DVT, and reducing the body weight in obese patients have the potential to help prevent late post-

Proximal DVT is associated with a higher frequency and more severe PTS than distal DVT. In the abovementioned study, patients with more extensive proximal (femoral or iliac vein) DVT had significantly worse PTS scores at all visits (adjusted average increase of > 2 points on the Villalta scale) than those with distal or popliteal vein DVT (39). Similarly, in another recent prospective study, proximal DVT was found to be associated with a 2-fold increased risk of PTS compared with distal DVT (33). As the rates of PTS in the control arms of trials of compression stockings to prevent PTS in patients with proximal DVT ranged from 40-50%, the rate of PTS after distal DVT is likely to be in the range of 20-25%, however in one study,

Finally, an insufficient quality of oral anticoagulant therapy following the acute thrombotic episode has been found to be associated with an increased risk of the PTS (28,65). Accordingly, appropriate attention to the monitoring of oral anticoagulant therapy following the initial thrombotic episode, in terms of both adequate intensity and duration,

Once established, PTS, especially when complicated by leg ulceration, is a significant cause of disability with a considerable economic burden for both patients and the health care

symptoms of PTS after distal DVT were relatively mild (23).

has the potential to help prevent late post-thrombotic sequelae.

prospective study (64).

**4. Predictors of PTS development** 

against (38,39) this association.

thrombotic sequelae.

**5. Treatment of the PTS** 

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