Sequelae of Venous Thromboembolic Disease: Postthrombotic Syndrome and Chronic Thromboembolic Pulmonary Hypertension

Vittorio Pengo

Susan R. Kahn

POSTTHROMBOTIC SYNDROME

The postthrombotic syndrome (PTS) is an important, underrecognized, chronic sequela of deep vein thrombosis (DVT). PTS develops in 20% to 50% of patients with DVT,¹^,² even when appropriate anticoagulant therapy is used to treat DVT (see Chapter 87). Clinical manifestations of PTS range from mild symptoms or signs to more severe manifestations such as intractable leg pain, severe edema, and leg ulcers that limit daily activity and ability to work.³ PTS reduces quality of life and productivity,⁴^,⁵^,⁶ and is costly as measured by health resource utilization, direct costs, and indirect costs.⁷^,⁸

DIAGNOSIS OF THE POSTTHROMBOTIC SYNDROME

PTS is a Clinical Diagnosis

PTS is diagnosed on clinical grounds based on the development of characteristic symptoms and signs in a patient with prior DVT (Table 85.1). Symptoms include pain, aching, heaviness, swelling, cramps, itching, or tingling in the affected limb. These may be present in varying combinations and can be persistent or intermittent. Typically, symptoms are made worse by standing or walking and improve with rest and leg elevation. Signs noted on physical examination of the limb include edema, perimalleolar or more extensive telangiectasiae, brown pigmentation, and venous eczema (FIGURE 85.1). Secondary varicose veins may become manifest, and tender thickening of the subcutaneous tissues of the medial lower limb known as lipodermatosclerosis may occur. Venous leg ulcers may develop, which require careful medical attention and often recur. Leg ulcers can be precipitated by minor trauma and are typically chronic, painful, and slow to heal.³^,⁹

The clinical picture of PTS can be nonspecific, as conditions other than DVT (e.g., primary venous insufficiency, chronic congestive heart failure) may produce similar symptoms or signs in the lower extremities. However, PTS is usually the correct diagnosis in a patient with objectively confirmed prior DVT who has typical PTS symptoms and signs in that limb. In some patients, it may take up to 3 to 6 months for the initial symptoms of acute DVT to resolve, hence a diagnosis of established PTS should be deferred until after the acute phase has passed.¹⁰

In the absence of clinical features of PTS in a patient with previous DVT, demonstrating the presence of venous abnormalities such as valvular reflux, persistent venous obstruction, or venous hypertension on invasive or noninvasive imaging or testing does not indicate a diagnosis of PTS. This is because while many patients with symptomatic PTS have detectable venous abnormalities, many DVT patients who do not have symptoms of PTS can also be shown to have such abnormalities.¹¹^,¹²^,¹³^,¹⁴ Therefore, there is no indication to routinely perform invasive or noninvasive venous testing in patients with a clear clinical diagnosis of PTS.

Objective confirmation can be useful in patients who have a characteristic presentation of PTS but who do not have a history of previous DVT. Compression ultrasonography can assess for lack of compressibility of the popliteal or common femoral veins, along with continuous-wave Doppler to assess for reflux of their venous valves. In one study, the combination of a standardized clinical evaluation, compression ultrasonography, and continuous-wave Doppler analysis reliably diagnosed or excluded previous proximal vein thrombosis in almost 90% of patients.¹⁵

Clinical Tools to Diagnose PTS

Three clinical tools to measure PTS are the Villalta PTS scale,¹⁶ Ginsberg PTS measure,¹⁷ and the CEAP (Clinical, Etiological, Anatomical, Pathophysiological) classification for chronic venous disease.¹⁸ The Villalta scale is a clinical scoring system that is based on the severity ratings of PTS symptoms and signs. The Ginsberg measure diagnoses PTS if both pain and swelling of the limb of more than 1 month’s duration are present, are of typical character (worse at the end of the day or with prolonged sitting or standing, better after a night’s rest or with leg elevation), and occur at least 6 months after acute DVT. As well, objective evidence of valvular incompetence is required. The CEAP measure combines clinical and objective findings into seven classes of chronic venous disease with subcategories to denote etiologic, anatomic, and pathophysiologic attributes. Other, less frequently used scales have been proposed as well.¹⁹

In a step toward harmonizing the definition and measurement of PTS in clinical studies and with a view to encouraging PTS research, a subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis has recently recommended that the Villalta scale be adopted as a standardized measure to diagnose and grade the severity of PTS.²⁰ This scale is a reliable and valid measure of PTS and shows responsiveness to clinical change.²¹
The individual components of the Villalta scale and its scoring algorithm are shown in Table 85.2.

Table 85.1 Clinical manifestations of the PTS

Limb Symptoms	Signs on Physical Examination
Heaviness	Edema
Pain	Telangiectasiae
Swelling	Venous ectasia, secondary varicose veins
Itching	Hyperpigmentation, venous eczema
Cramping	Redness
Tingling	Dependent cyanosis
Bursting sensation	Lipodermatosclerosis Healed ulcer, open ulcer

Distinguishing Postthrombotic Syndrome from Recurrent Acute Deep Vein Thrombosis

It is not uncommon for PTS symptoms to wax and wane over time. If new symptoms in the affected leg develop or chronic symptoms in the leg become worse and there are no associated
symptoms that could suggest acute pulmonary embolism (PE), patients can be advised to rest their leg and wait a day, as in most cases the symptoms are likely to be due to PTS and will settle down. However, patients with PTS are at increased risk of recurrent venous thromboembolism.²² Hence, if leg symptoms persist or progress, especially if new clinical risk factors for DVT are present, investigation is warranted to rule out recurrent DVT. The general approach to diagnosing recurrent DVT is the same as in patients without PTS (see Chapter 83). However, diagnosis of recurrent ipsilateral DVT can be challenging, as finding a noncompressible venous segment in the same area as the initial DVT can represent new or residual thrombus. Compared with the previous ultrasonogram, an unambiguous change in the extent of thrombosis or an increase in clot diameter of 4 mm or more on the current ultrasonogram indicates new ipsilateral DVT.²³^,²⁴^,²⁵ Studies suggest that strategies that use d-dimer testing alone²⁶ or in combination with clinical probability testing²⁷ can reduce the need to perform ultrasonography in patients with suspected recurrent DVT.

FIGURE 85.1 The postthrombotic syndrome.

Table 85.2 Components of Villalta PTS scale

Symptoms	None	Mild	Moderate	Severe
	0 Point	1 Point	2 Points	3 Points
Pain	□	□	□	□
Cramps	□	□	□	□
Heaviness	□	□	□	□
Paresthesiae	□	□	□	□
Pruritis	□	□	□	□
Clinical Signs	None	Mild	Moderate	Severe
	0 Point	1 Point	2 Points	3 Points
Pretibial edema	□	□	□	□
Skin induration	□	□	□	□
Hyperpigmentation	□	□	□	□
Redness	□	□	□	□
Venous ectasia	□	□	□	□
Pain on calf compression	□	□	□	□
Venous ulcer	Absent □	Present □
Each symptom is self-rated by the patient and each clinical sign is rated by the clinician as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe), except ulcer, which is marked as present or absent. All numeric points are summed to yield a total score: a score of 0-4 indicates the absence of PTS and a score of ≥5 indicates PTS (5-9, mild PTS, 10-14, moderate PTS and ≥15 or the presence of an ulcer, severe PTS).
Modified from Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the postthrombotic syndrome. Haemostasis 1994;24:158a.

PATHOPHYSIOLOGY OF THE POSTTHROMBOTIC SYNDROME

PTS occurs primarily as a consequence of venous hypertension, which in turn leads to reduced venous return, diminished calf muscle perfusion, impaired microvasculature function, and clinical manifestations of PTS.⁹^,²⁸

DVT leads to chronic venous hypertension by two principal mechanisms, persistent venous obstruction, and venous valvular reflux. Follow-up studies of patients with DVT who were treated with standard anticoagulants have shown that in many cases, there is only partial clearance of the thrombus.²⁹^,³⁰^,³¹^,³² Damage to venous valves with consequent valvular reflux is frequent after DVT, and is likely caused by thrombus-induced activation of inflammation, fibrous scarring associated with acute and resolving thrombosis, or venous dilation distal to the obstructed venous segment.³³^,³⁴^,³⁵^,³⁶^,³⁷ Residual venous obstruction 6 months after DVT, alone or in combination with valvular reflux, predicts the development of PTS, whereas reflux alone does not.³¹^,³⁸

Elevated levels of markers of inflammation (e.g., ICAM-1, interleukin-6, and C-reactive protein),³⁷^,³⁹ D-dimer,⁴⁰^,⁴¹ and vein wall response to acute thrombosis⁴² early after diagnosis or within a few months of DVT were associated with the development of PTS. A large, multicenter study is underway to prospectively assess the relationship between markers of inflammation and vessel injury and the development of PTS.⁴³

EPIDEMIOLOGY OF POSTTHROMBOTIC SYNDROME: INCIDENCE, RISK FACTORS AND PROGNOSIS

Data from contemporary prospective studies with 1 year or longer follow-up demonstrate that 20% to 50% of DVT patients will develop PTS and 5% to 10% will develop severe PTS, which may include venous ulcers.¹^,²^,¹⁴^,⁴¹^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ In most cases, PTS develops within the first 1 to 2 years after DVT.¹^,²

It is difficult to predict which DVT patients will develop PTS. A key finding from a recent prospective cohort study of 387 patients with acute symptomatic DVT was that incomplete resolution of leg symptoms and signs by 1 month after DVT strongly predicted the development of PTS during the subsequent 2 years.² In addition, venous thrombosis of the common femoral or iliac vein (compared with distal or popliteal vein DVT),²^,⁴¹^,⁴⁷^,⁴⁸ previous or recurrent ipsilateral venous thrombosis,¹^,²^,⁴¹^,⁴⁵^,⁴⁹^,⁵⁰^,⁵¹ higher body mass index,²^,⁴⁶^,⁴⁷^,⁵²^,⁵³ and older age²^,⁴⁵^,⁴⁶ are associated with a greater risk of developing PTS. One study reported that DVT patients who had subtherapeutic International Normalized Ratios (INRs) more than half of the time during the initial 3 months treatment with vitamin K antagonists had a threefold higher risk of developing PTS,⁴⁶ thereby reinforcing the importance of close monitoring of the intensity of oral anticoagulant therapy following the initial thrombotic episode. The risk of PTS is not influenced by the patient’s sex,² presence of the factor V Leiden, or the prothrombin mutation²^,⁴⁷ or by the context of the initial DVT (i.e., unprovoked, secondary, or cancer related).²^,⁴¹^,⁴⁵^,⁴⁶

In summary, extensive DVT, prior ipsilateral DVT, persistent venous symptoms 1 month after DVT, obesity, and older age appear to be robust clinical predictors of PTS. However, DVT patients without these features can also develop PTS.

Despite the common belief that patients with PTS have a uniformly poor prognosis, outcomes might be better than previously reported, with more than half of patients remaining stable or improving during long-term follow-up.²^,⁵⁴^,⁵⁵^,⁵⁶ Currently, it is not possible to predict the course of PTS in individual patients.

PREVENTION OF THE POSTTHROMBOTIC SYNDROME

Preventing First and Recurrent Deep Vein Thrombosis

Preventing DVT with the systematic use of thromboprophylaxis in high-risk hospitalized patients as recommended in evidence-based consensus guidelines⁵⁷^,⁵⁸ will prevent cases of PTS. Furthermore, as recurrent ipsilateral DVT is an important risk factor for PTS, providing anticoagulation of appropriate intensity and duration to treat the initial DVT so as to reduce the risk of recurrent DVT is a key means of preventing cases of PTS.⁵⁹^,⁶⁰

Elastic Compression Stockings to Prevent the Postthrombotic Syndrome

Graduated elastic compression stockings (ECS) decrease venous hypertension, reduce edema, and improve tissue perfusion.⁶¹ Two trials have evaluated the effectiveness of long-term use of ECS for the prevention of PTS, started within days of diagnosis of symptomatic proximal DVT. Among 194 patients who were randomly assigned a made-to-measure 30 to 40 mm Hg knee-length ECS to be worn daily for at least 2 years or no stockings, ECS led to a decrease from 47% to 20% of mild PTS and from 23% to 11% of severe PTS.⁶² A subsequent study evaluated the effectiveness of the “off the rack” knee length 30 to 40 mm Hg ECS, worn for 2 years, versus no stockings in 180 proximal DVT patients. Use of ECS reduced the risk of PTS from 49% to 26% (adjusted hazard ratio 0.5 [95% confidence interval [CI] 0.3 to 0.8] in favor of ECS).⁴⁵ Conversely, in a randomized trial of patients with proximal DVT who had not developed PTS by 1 year after the initial DVT, there was no benefit of daily use of 20 to 30 mm Hg ECS for up to 4 years, compared with use of sham stockings (1 or 2 sizes too large); PTS developed in 0/24 patients in the ECS group versus 1/23 patients in the sham
stockings group (P = 0.49).¹³ A meta-analysis that pooled the three studies concluded that use of ECS after DVT significantly reduces the risk of any PTS (odds ratio [OR] 0.3; 95% CI 0.20 to 0.48) and of severe PTS (OR 0.39; 95% CI 0.20 to 0.76).⁶³ Notwithstanding these results, questions remain regarding the effectiveness, optimal duration, and feasibility of use of ECS to prevent PTS.

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