Postthrombotic Syndrome: Natural History, Pathophysiology, and Etiology

Introduction

Chronic venous disorders (CVD) are a spectrum of venous diseases that affect the lower limb. The manifestations include varicose veins, pain, edema, skin changes, and venous ulcerations. The pathophysiology involves reflux within the deep, superficial, and perforating vein valves and/or venous obstruction, usually postthrombotic in etiology. Both reflux and residual obstruction can produce venous hypertension and the manifestations of CVD. Compared with nonthrombotic etiologies, lower extremity deep venous thrombosis (DVT) often leads to higher rates of the advanced forms of CVD, with skin changes and ulcerations. DVT often begin in the legs (calf) near valve cusps and may propagate proximally. About 50% of leg thrombi resolve spontaneously; however, nearly 20% will extend more proximally into the popliteal, femoral, and iliac veins. The consequences can range from minor leg swelling at the end of the day to severe complications such as chronic debilitating lower-limb pain, intractable edema, and venous leg ulceration. Other symptoms associated with postthrombotic syndrome (PTS) include leg cramping, pruritus, fatigue, heaviness, venous claudication, paresthesias, and bursting thigh pain with exercise, termed venous claudication . It is estimated that PTS occurs in 20% to 50% of patients from a few months to 1 to 2 years, following a lower extremity DVT. The importance of PTS is the significant morbidity and reduction of quality of life, and the economic costs associated with treatment of this disease. Early recognition and intervention may reduce the sequela of PTS.

Etiology And Epidemiology

DVT affects up to three individuals per 1000 annually in the general population. DVT is the major cause of secondary CVD, and is strongly associated with PTS. Although primary CVD (CVD in which no etiologic factor can be identified; see Chapters 154 , Varicose Veins: Surgical Treatment 155 , Varicose Veins: Endovenous Ablation and Sclerotherapy and 157 , Treatment of Chronic Venous Disorders) is much more common than secondary CVD, DVT is responsible for CVD in 18% to 28% of limbs. In a study of 64 patients with 73 limbs affected by DVT, 4% of limbs had skin changes at 1 year, increasing to 25% at 5 years.

Recurrent ipsilateral DVT is the most important risk factor for developing PTS, with a sixfold increased risk in one study. Numerous other studies have found significant associations between ipsilateral recurrent DVT and the risk of developing PTS, with increases of up to 630% ( Table 156.1 ). ^, Recurrent ipsilateral DVT is also the most important clinical factor for progression of CVD (relative risk [RR] 4.4; 95% CI, 1.4 to 13.3, P = 0.0049). ^,

The incidence of recurrent DVT is 17% at 2 years, 24% at 5 years, and 30% at 8 years. ^, It is estimated that 5% to 10% of patients with recurrent DVT develop severe PTS (lipodermatosclerosis, ulceration) after a proximal DVT. Ulceration as a consequence of PTS has a cumulative incidence of approximately 5% over 10 years. However, some studies have reported that the cumulative incidence of PTS continues to increase, even up to 20 years after DVT diagnosis.

The postthrombotic syndrome has been shown to occur in 20%–50% of patients within 1–2 years following a DVT. Features of venous thrombosis including extensive DVT, ipsilateral recurrent DVT, and insufficient anticoagulation increase the risk of developing clinically significant CVD. Factors found to affect the onset of secondary CVD were the event type and site of venous thromboembolism. Several studies have found that the persistence of obstruction following a DVT, and not the presence of reflux, imparts the greater risk of developing PTS and progression of the disease. ^, Another cross-sectional study of patients with previous DVT determined that the combination of reflux in the superficial and deep venous systems, and involving the entire limb, resulted in significant symptoms and signs of skin changes including ulcerations. It appears that the combination of obstruction and reflux together are more detrimental than each factor alone in the development of PTS.

In one study, 355 patients (55% male) with a first time symptomatic DVT were followed at 6-month intervals for 8 years. A total of 245 patients (69%) completed 5 years of follow-up, and 148 patients (42%) completed 8 years of follow-up. The mean age was 63 years old (range 29 to 83). The cumulative incidence of recurrent venous thromboembolism was 4.9% after 3 months, 8.6% after 6 months, 17.5% after 2 years, 24.6% after 5 years, and 30.3% after 8 years. Eighty-four patients developed PTS, with a cumulative incidence of 22.8% after 2 years and 28.0% after 5 years. The incidence did not change substantially thereafter. Of the 84 patients with PTS, 30.2% had severe PTS. Of note, the development of ipsilateral recurrent DVT was associated with an increased risk for PTS (hazard ratio 6.4; 95% CI, 3.1 to 13.3) and more predictive of skin damage (odds ratio 5.3; 95% CI, 1.2 to 24.2) compared with nonrecurrence ( P = 0.001).

Other features of venous thrombosis, including location and extent of DVT and insufficient anticoagulation, also increase the risk of developing clinically significant CVD.

In one study, patients with DVT were followed for a mean of 3.4 years with duplex ultrasound, to determine the effects of location and extent of DVT on the development of CVD. Patients were divided into a group which presented with multisegment DVT and a group which presented with single-segment DVT. More patients with multisegment disease were found to be symptomatic, and the prevalence of skin damage and ulceration was higher in this group compared with that in the group with single segment DVT (61 of 79 vs. 26 of 41, P < 0.001; 29 of 79 vs. 6 of 41, P = 0.019, respectively).

The most severe forms of PTS, such as venous leg ulcers, produce adverse social and economic outcomes, and significant decreases in quality of life. The economic burden of PTS is significant; costs increase by roughly 50% compared with those associated with DVT without PTS. The high cost of treating venous leg ulcers is due largely to the need for surgery, lost workdays, and loss of employment. It is estimated that 2 million workdays are lost annually in the United States as a result of venous leg ulcers.

Further examination of all causes (primary CVD and secondary PTS) of venous leg ulcers shows that the annual US expenditure for treating venous leg ulcers is approximately $14.9 billion (quantification of the incremental resource use and costs of treating these patients [$6391 per Medicare patient, and $7086 per privately insured patient]). In addition, PTS has a significant impact on quality of life, which worsens with advanced forms of PTS compared with patients with DVT but no PTS. One study demonstrated that patients with venous ulceration missed more workdays than those without ulceration, which resulted in increased work-related costs of 29% in the ulceration group ( P < 0.0001). It has been shown that patients with PTS have a generic physical quality of life that is worse than for patients with osteoarthritis, angina, and chronic lung disease.