Postthrombotic Syndrome

Historical Background

Postthrombotic syndrome (PTS) remains an important health care problem in United States. A population-based study showed that the incidence of venous ulcers currently approaches 18 per 100,000 habitants per year. The same study identified that PTS is responsible for economic expenses estimated at least $200 million.

Diagnosis of PTS is based on history and clinical presentation. The syndrome consists of signs and symptoms of heaviness, intolerance to exercises, pain, leg edema, paresthesia, cramps, and pruritus that may evolve to skin damage, such as hyperpigmentation, lipodermatosclerosis, and ulcers ( Fig. 17.1 ). The severity of PTS is measured by different scales and scores assigning points for the presence of each sign and symptom. Although there is a good association with PTS severity, further refinement and validation are necessary.

Attention to differential diagnosis should be outlined. Trauma, congenital venous disease (i.e., venous malformations, valve aplasia), and other causes of ulcerative disease, such as rheumatologic (lupus, scleroderma, rheumatoid arthritis), oncologic (squamous and basal cell carcinoma), or infectious disorders (syphilis, lymphangitis) are potential causes of misdiagnosis and inappropriate treatment. Table 17.1 shows the location and cause of nonvenous-related ulcers.

TABLE 17.1

Characteristics of the Ulcers Found on 21 Patients

(Adapted from Labropoulous N, Manalo D, Patel NP, et al. Uncommon leg ulcers in the lower extremity. J Vasc Surg. 2007;45:568–573.)

Sex	Age (Years)	Limb	Location on Calf	Duration (Years)	Duplex	ABI	Medication	Pathology
M	63	L	u-1/med	3	nl	nl	abx	Undetermined
		R	u-1/med	3	nl	nl	abx	Undetermined
F	72	L	1/med	5	nl	nl		Vasculitis
		R	1/med	5	nl	nl		Vasculitis
F	52	L	m-l/med	4	nl	nl	abx	Chronic inflammation
M	73	R	1/med	8	nl	nl	abx	Chronic inflammation
M	54	R	1/ant-lt	2	nl	nl	abx	Chronic inflammation
M	68	L	m/post	1	nl	nl		Kaposi sarcoma
M	79	L	1/med	16		nl		Carcinoma
F	76	R	1/med	18	Venous reflux	nl		Squamous cell carcinoma
F	73	R	1/med	15	Venous reflux	nl		Squamous cell carcinoma
F	64	L	m-1/med	3	nl	nl		Undetermined
		R	m-1/med	3	nl	nl		Undetermined
M	71	L	1/med	4	nl	nl		No histology
F	82	R	m-1/med	7	nl	nl	abx	No histology
F	73	R	1/med	14	nl	nl		Basal cell carcinoma
M	78	L	m/med	2	nl	nl		Pyoderma gangrenosum
	59	L	1/med	0.17	nl	nl		Hydroxyurea
M	17	R	1/med	0.33	nl	nl		Sickle cell
M		L	1/med	0.25	nl	nl		Sickle cell
F	62	R	1/med	0.75	Mild reflux	0.7		Rheumatoid arthritis

ABI, Ankle-brachial index; abx, antibiotics; ant-lt, anterior lateral; m, midcalf; nl, normal; post, posterior; u, upper calf.

Not all patients who have had a documented episode of deep venous thrombosis (DVT) sustain PTS. Recovery with no signs or symptoms of PTS occurs in two-thirds of the patients, and only the rest will eventually develop PTS with variable spectrum and severity. It appears that other factors are involved in the disease process, rendering some patients more vulnerable than others to PTS changes. A list of important clinical predictors of PTS is shown in Table 17.2 . Among those predisposing factors, the strongest one for PTS remains ipsilateral recurrent DVT because several prospective studies have shown high odds for skin damage ( Fig. 17.2 ). Patients who had unprovoked DVT and are older than 65 years have a higher risk of recurrent DVT and therefore PTS. Residual thrombus was also reported as a cause of recurrent DVT ( Fig. 17.3 ). In addition, patients who had DVT in more than one site, popliteal valve insufficiency, or a calf DVT associated with a proximal DVT also have an increased risk of recurrent DVT ( Fig. 17.4 ). Notably, the recurrence of DVT is likely to affect the proximal veins and is related to inadequate duration of anticoagulation. In a recent review, the limitations of studies on recurrent DVT are discussed. Most of the studies used a nonstandardized ultrasound analysis, giving limited or inaccurate information on the incidence of fatal pulmonary embolism (PE) as well as having poor documentation of anticoagulation and its monitoring. The effects of thrombolytic therapy and its socioeconomic and quality-of-life impact are also questions that remain unanswered. These are important because ipsilateral recurrent DVT has a significant impact on the development of PTS.

TABLE 17.2

Important Clinical Predictors of Postthrombotic Syndrome

Clinical Predictors of PTS

1. Recurrent ipsilateral DVT 2. Iliofemoral DVT 3. Higher 1-month Villalta score 4. Nonoptimal anticoagulation 5. Higher BMI

BMI, Body mass index; DVT, deep venous thrombosis; PTS, postthrombotic syndrome.

Biomarkers have been used to estimate the odds of developing PTS. In a study of 305 patients with PTS, persistent elevated levels of D-dimer in the course of DVT were investigated. Patients with elevated levels of D-dimer at 4 months following DVT, after stopping anticoagulation, showed a 4-fold risk of PTS. The molecular aspects of chronic postthrombotic changes following an episode of DVT were recently reported by Comerota and colleagues. Their recent study of 16 patients undergoing endovenectomy of common femoral and femoral veins to treat chronic obstruction showed dystrophic calcification and a collagen-rich tissue material on the analyzed specimens. Interestingly, no thrombus or smooth cells were found in the material analyzed ( Fig. 17.5 ). These findings suggest the term chronic deep vein thrombosis is likely a misnomer.

Patients with asymptomatic DVT are also at risk of developing PTS. A systematic review including 364 patients with asymptomatic DVT showed that abdominal and orthopedic surgeries are major predictors for PTS. The drawbacks in the former study were different definitions of PTS according to each author's criteria, random use of anticoagulation upon diagnosis, and different diagnostic methods including venography, duplex ultrasound (DUS), and ¹²⁵ I-fibrinogen uptake test. Regardless of distinct methodology found in the literature, if a poor DVT history is associated with marked PTS findings, it must prompt careful investigation with DUS first, especially following major abdominal or orthopedic surgery.

Progression of secondary cardiovascular disease (CVD) evolving to PTS has been demonstrated. A study of 73 limbs with secondary CVD showed overall progression in clinical CEAP (clinical, etiologic, anatomic, and pathophysiologic) classes in 31% of the limbs. Skin damage (C4–C6) rate strikingly rose from 4% at the first year to 25% in the 5-year follow-up. Other studies also investigated secondary CVD and clinical course of PTS. In an Italian cohort of 355 patients, the incidence of PTS increased from 17% after the first year to 29% at 8 years of follow-up. Development of reflux alone has been associated with PTS. However, a combination of reflux and obstruction is associated with more severe PTS than reflux or obstruction alone.

Patients with a hypercoagulable state, such as carriers of factor V Lieden (FVL), prothrombin gene mutation, or proteins C and S have been investigated for occurrence of PTS. A study comprising 667 patients with DVT, who sustained hypercoagulable state, demonstrated no association with increased risk of PTS. Furthermore, heterozygosis for FVL was even less associated with PTS than in noncarriers. Another study of 387 patients tested for thrombophilia found no increased risk of PTS in carriers of FVL or prothrombin gene mutation. The same study also showed that the intensity of persistent signs and symptoms in the first month after the episode of acute DVT predicted the incidence of PTS in a dose-dependent manner in the first 2 years.

Nonoperative Treatment

PTS generates high expenses for government and insurance companies because of disability premiums, loss of labor force, and need for rehabilitation and wound care. Thus prevention should always be contemplated to minimize the socioeconomic impact of the disease. DVT prophylaxis is mandatory in different settings such as major surgeries, critically ill patients, and those with significant risk factors for DVT.

Multiple reports have shown that elastic compression applied in patients with acute DVT may decrease the incidence of PTS by 50% at long term. This was evident in two review papers that analyzed all the relevant prospective studies before the release of the SOX trial results. In patients with established PTS, a few treatments are available. Initial treatment for all patients with PTS is nonoperative, with compression to the legs in different levels and intensity. The use of compression stockings in 387 patients could not predict the progression or lack of PTS. However, 20% of patients who did use compression stockings had a risk of developing PTS compared with 47% who did not use compression stockings. The Cochrane collaboration review of 39 randomized control trials concluded that compression was more effective than no compression on ulcer healing. It was also shown that multicomponent systems were more effective in ulcer healing compared with single-component systems. The shortcoming of compression therapy is that up to 20% of patients are noncompliant, and compliance with stockings does not change regardless of the symptoms of PTS. Further discussion of compression and its role on preventing PTS is provided later under Pearls and Pitfalls.

Complementary to the compression therapy, wound care is important to improve ulcer healing rates and patients' quality of life. Many techniques have been applied in different settings varying from local care to more extensive surgical debridement.

More recently, in a small prospective randomized study of patients with PTS, exercise training for 6 months was associated with improvement in quality of life and improvement in scores on the Villalta scale. The authors concluded that these results should be confirmed in a large, prospective randomized trial.