[Frontiers in Bioscience E2, 771-778, January 1, 2010]
Clinical biomarkers and management of post thrombotic syndrome
Antonio Biondi1, Giuseppe Strano1, Luca Ruggeri1, Salvatore Vadala1, Alessandro Tropea1, Francesco Basile1
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TABLE CONTENTS
1. ABSTRACT
The post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterized by chronic, persistent pain, swelling and other signs in the affected limb. PTS is common, burdensome and costly. It is likely to increase in prevalence, since despite widespread use of and improvements in the efficacy of thromboprophylaxis, the incidence of DVT has not decreased over time. Preventing ipsilateral recurrence of DVT, by ensuring an adequate duration and intensity of anticoagulation for the initial DVT and by prescribing situational thromboprophylaxis after discontinuation of oral anticoagulants, is likely to reduce the risk of developing PTS. Pending the results of ongoing studies, stockings are recommended in patients with persistent symptoms or swelling after DVT. Future research should focus on standardizing criteria for PTS diagnosis, identification of DVT patients at high risk for PTS, and rigorously evaluating the effectiveness of stockings, thrombolysis, and venoactive drugs in preventing or treating PTS.
2. INTRODUCTION
Morbidity of patients with deep venous thrombosis (DVT) is high even years after the initial event (1,2). Besides the risk of acute pulmonary embolism (PE), DVT is associated with a variety of symptoms, generally referred to as ``post-thrombotic syndrome'' (PTS), which restrict the quality of life (2,3) ultimately leading to ulceration of the affected extremity (2-4-5).
The PTS is still not clearly defined, in fact there are several means of measuring and classifying chronic venous disease, based on clinical signs and symptoms. The most consented definition concerning this pathology says that is a long-term local complication after episode of DVT prevalently due by venous hypertension which results from valvular incompetence, outflow obstruction, calf muscle dysfunction.
To the best of our knowledge, only one study in Europe (10) and another study in the United States (11) have attempted to determine the costs associated with the entire range of long-term complications of DVT.
Results from an European study reported that after 15 years of follow-up, 35% of the patients with thrombosis and 57% of the controls were alive. Two hundred forty-two complications were reported among the patients with thrombosis, and 25 similar events were reported among the controls. The average expected present value of the health care cost of treating complications of thrombosis was estimated to be about $4659 in the patients with thrombosis and $375 in the controls. In controls, primary deep venous thrombosis cost about $6000; thus, the additional long-term health care cost of post-thrombotic complications is about 75% of the cost of primary deep venous thrombosis (10). Results from an American study was too old (1977) in order to be taken in consideration with a new prospect about cost (11).
Although the clinical manifestations of PTS are well known, the quality-of-life and socioeconomic impacts of PTS have not been extensively documented, except for the most severe forms of the syndrome, such as venous leg ulcer (12,13).
PTS is burdensome and costly to patients and society. At present, effective, evidence-based treatments for PTS are lacking, which is a source of difficulty and frustration for patients with PTS. Until effective treatments are found, prevention of PTS is the key to reducing its overall impact on patients and society. Preventing DVT recurrence is likely to reduce the risk and costs of PTS. Daily use of graduated ECS after DVT may reduce the risk of PTS. As of yet, there is no established role for thrombolysis in preventing PTS (14,15).
The present review aims to analyze the large amount of informations on this issue trying to find some conclusions on a topic that is often unclear and confused.
2.1. Incidence of venous thromboembolism (VTE)
Since PTS is a direct consequence of DVT, its prevalence is influenced by the incidence of DVT. Despite advances in the prevention and treatment of VTE, population-based studies from Europe and North America performed in each of the last three decades consistently show that the overall annual incidence of VTE is 1.0-1.6 per 1000 persons per year, with a per-person lifetime incidence of 2-5%.(18-19).
The apparent lack of decrease in VTE incidence over time could be the result of more complete case ascertainment in recent compared to older studies, but might also be due to aging of the population, exposure to more or new risk factors, and persistent under-utilization of appropriate thromboprophylaxis. There are approximately 200,000-250,000 new cases of VTE in the US per year (20). Thus, it is convincing that VTE represent a major global health problem.
2.2. Frequency of the PTS after DVT
Population-based studies demonstrate that reliable estimates of the incidence and prevalence of PTS are difficult to obtain. A recent retrospective cohort study evaluating cases of objectively diagnosed DVT or PE in which venous stasis syndrome subsequently developed (as diagnosed by a physician, or by objective evidence of venous valvular incompetence, or venous ulcer) reported that 16% of patients developed venous stasis syndrome after a mean follow-up of 7.3 years (20).
The cumulative rates were 7.3% at 1 year, 14.3% at 5 years, 19.7% at 10 years, and 26.8% at 20 years. The cumulative risk of ulcer by 20 years was 3.7%.Using this same population base, it was shown that about one quarter of patients with venous stasis syndrome, or 170,000 new cases per year in the US, are attributable to prior VTE, i.e. represent bona fide PTS (21).
3. METHODS
To perform a systematic review of clinical studies that have examined the incidence, clinical features, risk factors and management of post-thrombotic syndrome.
Using combinations of keywords venous thrombosis, postphlebitic syndrome, thrombophlebitis, biomarkers, post-thrombotic syndrome, the MEDLINE database was searched for English language articles published. Retrieval and review of articles were restricted to clinical studies in humans that described long-term outcomes after objectively confirmed PTS.
4. CLINICAL SIGNS AND PATHOPHYSIOLOGY
The fundamental pathophysiological disturbance found in patients with severe leg symptoms or signs after deep vein thrombosis is sustained venous hypertension, which results from valvular incompetence, outflow obstruction, calf muscle dysfunction, or a combination of these (16). Even in patients who do achieve clot lysis, permanent damage to venous valves occurs frequently, conceivably via thrombus-induced activation of inflammation (17) or scarring associated with acute and resolving thrombosis, leading to valve incompetence (reflux). On physical examination, edema, telangiectasiae, hyperpigmentation, eczema, and varicose superficial (collateral) veins may be present (Table 1). In severe cases, there may be thickening and induration of the subcutaneous tissue around the ankle (lipodermatosclerosis) and evidence of healed or open ulceration (13,22,23).
Valvular incompetence results from damage to venous valves at the time of the acute DVT, or during the process of vein recanalization after DVT. If recanalization is incomplete, venous outflow obstruction occurs and leads to the development of collateral circulation via the superficial and perforator veins, which may gradually become incompetent and varicose due to progressive dilation. Venous hypertension, the end result of these processes, leads to the appearance of telangiectasiae and venous ectasia, and causes capillary leakage of plasma proteins, erythrocytes and leukocytes, with resultant edema, tissue hypoxia and damage, and ultimately, in some cases, skin ulceration.
Reflux in the proximal veins, particularly the popliteal vein, appears to be important for the development of the clinical manifestations of PTS (26, 27). However, patients with objectively documented reflux after DVT may have no clinical evidence of PTS (28). Furthermore, the correlation between the severity of PTS and the site or severity of previous DVT or DVT-related hemodynamic or anatomic changes is unclear.
Pathophysiology of this syndrome involves the interplay of two processes: damage to delicate venous valves by the thrombus itself or by associated inflammatory mediators, which causes valvular reflux and residual venous obstruction because of incomplete thrombus clearance, which leads to impaired venous return. Both processes lead to increased venous pressure (venous hypertension), which results in reduced calf muscle perfusion, increased tissue permeability and the associated clinical manifestations of PTS (e.g. pain, effort intolerance, swelling) (14,23,24).
5. DIAGNOSIS OF PTS AND CLINICAL SCORE SYSTEM
At baseline visit the physician examined the patient's legs and classified the clinical categories and severity of PTS using the different scoring systems.
Three clinical scales for the diagnosis of PTS have been developed (29-31) and are summarised in Table 2. These have been used to assess the presence and grade the severity of PTS in a number of clinical studies, including trials of therapies to prevent or treat PTS. However, none has undergone full evaluation of reliability, validity or responsiveness to change and their use for the routine clinical monitoring of DVT patients has not been assessed. Moreover, differences in the test characteristics of these measures could help to explain the differing rates of PTS that have been reported in long-term follow-up studies of patients with DVT.
The best known is the CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic) classification, which categorises patients into one of seven classes based on clinical signs, with modifiers that reflect the underlying cause (congenital, primary, or secondary to DVT), anatomic distribution (superficial, deep, or perforating veins), and pathophysiologic condition (reflux, obstruction, or both).(30,32)(Tab.3).
In patients with objectively confirmed DVT and a typical clinical presentation, PTS is usually the correct diagnosis. Documenting venous reflux by Doppler ultrasound or by photo or air plethysmography can help to confirm the diagnosis.(27,34,36,37). However, patients who have venous reflux on objective testing but who are asymptomatic do not have PTS.
Documenting prior DVT is important to confirm the diagnosis of PTS and to help guide patient management (e.g. appropriate thromboprophylaxis).Evidence of deep vein reflux on Doppler ultrasound (38,39) persistent obstruction, recanalized veins or collateral channels on venography, or outflow obstruction on plethysmography (40) reliably confirm previous proximal DVT. In one study, the combination of normal photoplethysmography and ultrasound reliably excluded prior proximal DVT.
6. RISK FACTORS
6.1. Age and sex
Two studies found that increasing age was associated with a higher risk of developing PTS (40,41), but other studies did not In one study, male sex was a weak risk factor for PTS . Overall, there do not appear to be consistent relationships between age or sex and the development of PTS.
6.2. Body mass index (BMI)
Results of prospective studies suggest that higher BMI is associated with a greater risk of PTS. Similarly found that BMI >25 was a significant independent predictor of PTS after proximal DVT. As obesity is a potentially modifiable risk factor, the role of weight reduction in the prevention or management of PTS merits evaluation as some type of cancer (41).
6.3. Thrombophilia
Inherited and acquired thrombophilic disorders increase the risk of developing a first episode of VTE (42) and in some studies, increased the risk of recurrent VTE (43). Some established risk factors for VT in general, such as older age, obesity, cancer in general, and stroke were not associated with VT in this study of medical inpatients (44).
6.4. Elevated D-dimer
This is a risk factor for first and recurrent DVT (45,46). Elevated levels of D-dimer (defined as cut-off of >500 ng/ml on an enzyme-linked immunosorbent assay), measured 3 weeks after withdrawal of oral anticoagulant therapy, were found to be a modest risk factor (OR 1.9, 95% CI 1.0-3.9) for PTS in a recent study (7). These results require confirmation in large prospective studies.
7. PREVENTION OF PTS
Thromboprophylaxis is an effective means of preventing DVT, it is highly likely, by extrapolation, that use of thromboprophylaxis in high risk patients and settings as recommended in evidence-based consensus guidelines (47) will prevent cases of PTS. Further, while thromboprophylaxis is effective, its use does not eliminate the risk of VTE. Moreover, nearly 50% of VTE events occur unpredictably and are therefore not preventable with thromboprophylaxis. (14).
Catheter-directed thrombolysis, which involves direct delivery of a fibrinolytic drug into the clot via a catheter introduced within the thrombosed vein, may be safer and more effective than systemic Thrombolytic therapy and could hold promise as a means of preventing PTS (50).
The routine use of thrombolysis to prevent PTS in patients with acute DVT cannot be recommended at present. Large, adequately powered, randomized controlled trials of standard anticoagulation vs. catheter-directed thrombolysis (which may be safer and more effective than systemic therapy (52) are required to determine whether this form of thrombolysis is effective in preventing PTS and safe.
7.1. Elastic compression stockings
Graduated elastic compression stockings (ECS) decrease oedema and improve tissue microcirculation (49). Knee-length and thigh-length ECS appear to have equal physiological effects, but the former are easier to apply and more comfortable (51). A recent meta-analysis that pooled these three studies reported an overall 54% relative risk reduction in PTS with use of ECS (53).
8. TREATMENT OF PTS
Clinicians often prescribe physical compression methods to counteract increased venous pressure. ECS on an as-needed basis may reduce swelling in some patients with PTS (54) and should be tried. However, their treatment benefit has not been definitively shown in the setting of PTS and is primarily extrapolated from studies of patients with chronic venous disease (55).Indeed, a recent Cochrane review (53) concluded that there is no evidence to support the use of ECS to treat PTS, and while intermittent pneumatic compression units may be of benefit for the management of severe, intractable PTS symptoms or severe oedema, they are cumbersome, expensive and there are no data on their long term effects. Finally, surgical treatments for PTS, such as venous valve repair or venous bypass have been evaluated primarily in small patient series at single, specialised centres and appear to be of limited value (56).
The recommendations about the duration and type of long term treatment in patients with a first episode of VTE are summarized in. Although VKA is mostly used for long-term treatment, LMWH is preferred in patients with cancer (57).The endovenous 980-nm diode laser surgery is a safe and effective, cosmetically preferential procedure while a long-term follow-up is being awaited (58).
9. CONCLUSION
PTS leads to chronic and severe morbidity. It's best treatment remains prevention and early identification of risk factors, prevention of DVT, and aggressive management of DVT. In established DVT patients, anticoagulation, compression, exercise, and skin care measures are needed in order to prevent DVT recurrence and long-term sequellae such as PTS. Post-thrombotic syndrome is burdensome and costly to patients and society. Until effective treatments are found, prevention of PTS is the key to reducing its overall impact on patients and society.
Most physicians believe that ECS are useful for preventing PTS and for managing venous symptoms, many do not routinely prescribe them, and there is considerable variation in practice regarding the timing of initiation of ECS, duration of therapy, and compression strength. On the other hand, DVT patients appear to be willing to purchase ECS despite their cost, tolerate them well, and most are willing to wear them daily. As of yet, there is no established role for thrombolysis in preventing PTS.
With evalution of new anticoagulants there is no doubt that in the near future the treatment of patients with VTE will become more patient friendly, effective, safe and evidence based.
10. ACKNOWLEDGMENTS
Author A. Biondi and G. Strano equaly contributed to this article. Sources of financial support: 1) Departed of General Surgery - University of Catania; 2) Postgraduate Research Degrees on "Physiopathology pre and post-operative surgery for election and the emergency" - University of Catania.
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Key Words: Deep venous thrombosis, Upper extremity, Post-thrombotic syndrome, Biomarkers, Review
Send correspondence to: Antonio Biondi, Section of General Surgery and Oncology, Department of General Surgery, University Medical School of Catania, Italy, Ospedale Vittorio Emanuele Via Plebiscito, 628,95100 Catania, Italy, Tel.: 390957435151, Fax: 39095457345, E-mail:biondian@tin.it