Incidence and Risk Factors of the Post-thrombotic Syndrome

Abstract

Annually 1–2 in every 1000 adults will develop a deep venous thrombosis of the lower extremity. A third to half of these patients will develop the post-thrombotic syndrome (PTS). However, predicting which patients will develop the PTS remains elusive. Ipsilateral thrombosis recurrence seems to be the most important risk factor. Moreover, residual venous occlusion and valvular reflux seem to predict PTS incidence to some degree. Laboratory parameters, including D-dimers and inflammatory markers, have shown promise in predicting development of the PTS in patients and are currently under investigation. Creating a model based on all combined risk factors and patient characteristics might aid in risk stratification in individual patients.

Keywords

post-thrombotic syndrome deep venous thrombosis risk factors incidence

Introduction

Annually, approximately 1–2 in every 1000 adults will develop a deep venous thrombosis (DVT) of the leg, slightly more than half of these are hospital-acquired.¹ Apart from the acute symptoms, consisting of a painful, swollen, red and warm extremity, at least one-third of these patients will develop the post-thrombotic syndrome (PTS). PTS encompasses a great range of symptoms varying from relatively mild signs (slight swelling, venous eczema, pigmentation and minor complaints) to the gravest of venous symptoms: i.e. severe oedema, venous claudication, chronic pain and recurrent ulcers. PTS incidence in the DVT population is generally accepted to be between 20% and 50%. Reported percentages depend mostly on patient characteristics, follow-up duration and treatments used (Table 1).^{2

35} In 5–10% of DVT patients, severe PTS, characterized by chronic debilitating symptoms, will develop.^6,10,25 Symptoms of PTS normally arise within the first year post-DVT, thereafter only PTS severity rises.²⁷ Quality of life (QoL) is dramatically decreased in these most severe cases, with QoL scores comparable with patients with congestive cardiac failure or chronic obstructive pulmonary disease.^18,36,37 Furthermore, enormous socioeconomic costs are associated with PTS, especially when patients develop chronic venous ulcers.^{38

40}

Table 1

Incidence of the post-thrombotic syndrome^{2

35}

Author	Year	No. patients	Mean FU time (years)	PTS (%)	Severe PTS (%)	Ulcers (%)	Recurrent DVT (%)	Comments
O'Donnell et al.	1977	21	>10	100	NR	86.0	42.9	Strong selection bias
Strandness et al.	1983	61	3.25	67	23	4.9	NR	Abstract only
Widmer et al.	1985	278	5	16	NR	8.0	14	Abstract only
Lindner et al.	1986	47	7	79	NR	4.3	NR	Abstract only
Monreal et al.	1993	79	3	56	20	NR	NR	Abstract only
Heldal et al.	1993	76	7.4	42	21	NR	NR	Abstract only
Eichlisberger	1994	223	13	39	NR	9.8	NR	Abstract only
Beyth et al.	1995	124	6–8	42	NR	NR	15.0	Abstract only
Johnson et al.	1995	78	3	41	32	2.6	NR
Prandoni et al.	1996	355	8	29	9	NR	30.0
Franzeck et al.	1996	39	12	36	8	3.0	24.0
Brandjes et al.	1997	194	6	31/70	11/23	1/3	15/13	ECS versus no ECS
Prandoni et al.	1997	528	8	30	5	NR	19.0
AbuRahma et al.	1998	105	5	44	NR	6.7	21.8
Biguzzi et al.	1998	51	3.9	59	4	NR	NR	Abstract only
Masuda et al.	1998	54	3	57	0	0.0	9.0
McLafferty et al.	1998	37	3.4	38	3	2.7	0.0
Haenen et al.	1999	82	10	73	34	5.0	12.0
Holmström et al.	1999	265	5–14	76	NR	4.2	27.5
Ginsberg et al.	2000	91	5	5	NR	NR	NR
Saarinen et al.	2000	26	2	73	NR	NR	NR	Abstract only
Mohr et al.	2000	1527	7.3	27	NR	3.7	NR
Ginsberg et al.	2001	202	1	17	NR	0.0	NR
Ziegler et al.	2001	162	6.6	82	7	7.0	30.0
Gabriel et al.	2004	135	1	62	NR	0.0	7.4
Stain et al.	2005	406	5	43	1	1.4	6.4
Roumen-Klappe et al.	2005	93	6	56	33	0.0	22.6
Kahn et al.	2005	145	2.2	37	4	1.4	1.4
Schulman et al.	2006	897	10	56	6	NR	29.0
Tick et al.	2008	1668	1	25	7	3.0	NR
González-Fajardo et al.	2008	165	5	65	24	NR	26.1
Aschwanden et al.	2008	169	3.2	17	1	0.0	NR
Roumen-Klappe et al.	2008	69	1	88	NR	0	NR
Kahn et al.	2008	387	2	43	3	1.3	9.9

NR, not reported; FU, follow-up; ECS, elastic compression stockings; Abstract only, only the abstract of the paper was available to the authors; PTS, post-thrombotic syndrome; DVT, deep venous thrombosis

Pathophysiology

The PTS can be seen as a special form of chronic venous insufficiency, with a clearly definable starting point at the moment of the first DVT and a generally rapid progression towards venous complaints and symptoms, i.e. high CEAP (clinical, aetiological, anatomical and pathological elements) (Table 2), VCSS (Venous Clinical Severity Score) and Villalta (Table 3) scores. The basis of PTS pathophysiology is formed by a triad of venous obstruction by residual thrombus or scarification of venous tracts, venous insufficiency due to valve destruction and reduced mobility leading to impairment of calf muscle pump function. Recent and current studies are clarifying the role of the inflammatory system and the manner of thrombus fibrin degradation in post-DVT vein tracts.^{41

44} Ultimately these changes in the venous system of the lower extremity might all lead to impaired venous outflow, venous hypertension and finally abnormal capillary perfusion.

Table 2

CEAP Classification, adapted from Eklöf et al.⁹⁷

Clinical manifestations of the revised 2004 CEAP classification	Attributed signs and symptoms
CEAP C0	No visible or palpable signs of venous disease
CEAP C1	Telangiectases or reticular veins
CEAP C2	Varicose veins; distinguished from reticular veins by a diameter of 3 mm or more
CEAP C3	Oedema
CEAP C4a	Pigmentation or eczema
CEAP C4b	Lipodermatosclerosis or atrophie blanche
CEAP C5	Healed venous ulcer
CEAP C6	Active venous ulcer

CEAP, clinical, aetiological, anatomical and pathological elements

Table 3

Villalta score, adapted from Kahn et al.⁹⁸

Symptoms and clinical signs	None	Mild	Moderate	Severe
Symptoms
Pain	0 points	1 point	2 points	3 points
Cramps	0 points	1 point	2 points	3 points
Heaviness	0 points	1 point	2 points	3 points
Paraesthesia	0 points	1 point	2 points	3 points
Pruritus	0 points	1 point	2 points	3 points
Clinical signs
Pretibial oedema	0 points	1 point	2 points	3 points
Skin induration	0 points	1 point	2 points	3 points
Hyperpigmentation	0 points	1 point	2 points	3 points
Redness	0 points	1 point	2 points	3 points
Venous ectasia	0 points	1 point	2 points	3 points
Pain on calf compression	0 points	1 point	2 points	3 points
Venous ulcer	Absent	Present

PTS, post-thrombotic syndrome

Points are summed into a total score (range 0–33). PTS is defined by a total score of ≥5 or the presence of a venous ulcer. PTS is classified as mild if the Villalta score is 5–9, moderate if the Villalta score is 10–14 and severe if the Villalta score is ≥15 or a venous ulcer is present. To use the Villalta score as a continuous measure, it is recommended that patients who meet criteria for severe PTS based solely on the presence of an ulcer (i.e. total Villalta score is <15) be assigned a score of 15

Current treatment options

The cornerstone of PTS prevention remains the use of elastic compression stockings (ECS) after a symptomatic DVT event. Studies on long-term use of ECS after a proximal DVT have shown a highly significant reduction in both mild/moderate PTS and severe PTS.⁴⁵ Therefore, it is generally recommended to prescribe below-knee ECS with a pressure gradient of 30–40 mmHg to patients with symptomatic proximal DVT.⁴⁶ Use of lower-pressure gradient stockings might increase patient satisfaction and therapy compliance; however, evidence on the lowest amount of pressure needed to prevent PTS is currently unavailable. Also, ECS treatment duration is controversial. Current guidelines advocate the use of ECS for two years or longer after an initial thrombotic event; however, Aschwanden et al.³ recently showed no added effect of prolonging ECS treatment after six months for prevention of skin changes and PTS symptoms, suggesting that a decrease in treatment duration is feasible. Moreover, Roumen-Klappe et al.²⁸ suggest multilayer compression bandaging in the acute phase of DVT to have no effect on the development of the PTS compared with delayed compression therapy with stockings. Starting treatment solely with elastic stockings within two weeks post-DVT thus seems feasible.

Prevention of PTS is now the major focus of trials researching catheter-directed thrombolysis to treat proximal DVT (e.g. the Scandinavian CAVENT trial, the American ATTRACT trial and the Dutch CAVA trial).^{47

49} Thrombolysis in the acute phase of DVT has been proposed to reduce long-term venous occlusion. Furthermore, rapid recanalization of venous tracts may reduce valve damage and avert deep venous insufficiency. Short-term studies have shown the safety and feasibility of this treatment modality; however, the long-term effects on PTS development are currently unknown.^{50

53}

During the last two decades a number of invasive treatments have been proposed to treat both deep venous insufficiency and persistent occlusion after a thrombotic event. A number of surgical procedures to treat venous valve insufficiency currently exist: internal and external valvuloplasty,⁵⁴ external banding,⁵⁵ the Maleti neovalve⁵⁶ and axial vein transfer.⁵⁷ Valvuloplasty is preferred by most authors. However, in a great number of patients valvuloplasty is not a viable option, due to destruction of the valve leaflets during the recanalization process in post-thrombotic legs. Persistent post-DVT occlusions are now being recognized as being of importance and treated in a number of specialized centres by angioplasty and stenting. Mid- and long-term follow-up show good results with primary patency rates of approximately 80% two years post-stenting and a clinically significant decrease in PTS symptoms;^{58

60} however, randomized controlled trials of these treatments are lacking. In general, interventional treatment is only offered at select centres with expertise in these techniques to patients with severe persistent symptoms after the initial DVT.

In light of the limitations of the current treatment options, identification of risk factors for the development of PTS remains of greatest importance. Likewise, identification of high-risk patients will be needed in selecting patients for treatment with catheter-directed thrombolysis in the future.

Risk factors

Age

Differences between young and old patients might underlie differences in PTS incidence, though no clear mechanism has been postulated yet. Changes in the vein wall, hormonal factors, innate thrombus lysis, inflammatory response to thrombosis and mobility/calf muscle pump function might all differ by age. Advancing age has been clearly shown to be a risk factor for DVT, with incidence being very low in children (ranging from 34 to 58 cases of venous thromboembolism per 10,000 hospital admissions in children of <18 years of age) and increasing steadily to 3.1 per 1000 by the age of 85–89 years.^61,62 However, the relation between age and incidence of PTS remains controversial. Conflicting reports in the literature have been put forward; some authors have described a positive correlation,^{17,30,31,63-65} some reported no correlation¹⁷ and some even a lower incidence of PTS in older patients.³³ An increase of 0.3 points in the Villalta score per 10-year age increase was found by Kahn et al.,⁶⁵ whereas Stain et al.³¹ reported an odds ratio (OR) for PTS development of 1.2 for every 10-year age increase. Moreover, Schulman et al.³⁰ showed age above 60 years to be associated with a higher proportion of proximal DVT (58% versus 42%, P = 0.001) and a higher DVT recurrence rate (31% versus 25%, P = 0.049), compared with younger patients, both of which are independent risk factors for the development of PTS. A relationship between severity of PTS and age, however, has not been noted.¹⁷

Obesity

Increased body weight has been proposed to lead to poor calf muscle function via lack of physical exercise, increased venous pressure and promotion of venous reflux. Obesity has indeed been associated with an increased risk of PTS.^{5,17,31,33,64,66} A 1.5-fold increase in PTS incidence in patients with a body mass index (BMI) ≥30 kg/m² has been described.³³ An increase in Villalta score of 0.14 and 0.16 per 1 kg/m² increase in BMI has been described by Kahn et al.^17,65 in two studies. Furthermore, a higher BMI has been associated with less favourable QoL scores in PTS patients.¹⁸

Gender

Sex differences have historically been of great interest within the whole spectrum of venous pathology. However, underlying causes of such differences have been poorly understood. These might include hormonal, mechanical or anatomical dissimilarities. Increased incidence of PTS has been described in both males and females.³³ Stain et al. found male gender to be a weak predictor of PTS occurrence (OR 1.6) and also found an increased incidence of DVT recurrence in men, which is an independent risk factor for PTS development.³¹ However, a greater number of studies found PTS to be more prevalent in women.^33,65 Female sex had no effect on two-year QoL changes in post-DVT patients, including PTS patients.¹⁸

Table 4

Summary of risk factors for PTS

Risk factor	Correlation with PTS incidence	Comment
Age	+	Also correlates with DVT recurrence risk
Obesity	+
Female gender	+	Conflicting evidence
Provoked (vs. unprovoked) deep venous thrombosis	±	Strong risk factor for venous thromboembolism recurrence
Ipsilateral recurrence	+ +	Also correlates with severity of PTS
Thrombus location (proximal versus distal)	+	Also correlates with severity of PTS
Residual occlusion	+ +
Residual reflux	+ +	Deep and superficial reflux
Insufficient quality of anticoagulant therapy	+	Conflicting evidence
Thrombophilia	±	Factor V Leiden or the G20210A prothrombin gene mutations
D-Dimer	+
Inflammatory markers	±	Currently being evaluated

PTS, post-thrombotic syndrome; DVT, deep venous thrombosis Risk factor's relation with PTS incidence: + + strong correlation, + moderate correlation, ± mostly unclear or no correlation

Unprovoked vs. provoked DVT

While surgery and trauma are associated with a high incidence of provoked DVT (ORs as high as 21.7 and 12.7, respectively⁶⁷), unprovoked DVT on the other hand might be an indication of an underlying hypercoagulable state that could lead to a higher incidence of recurrent thromboembolic events and PTS. However, a difference in the incidence of PTS after unprovoked versus provoked DVT has not been noted.^{5,11,31,68,69}

Ipsilateral DVT recurrence

Ipsilateral recurrent thrombosis is common in DVT patients (Table 1). Two or more thrombotic events in the same extremity have been shown to increase the incidence of PTS,^{4,12,25,26,31,35,63} and previous ipsilateral thrombosis was associated with a 1.78-point increase in Villalta score.^18,65 Conversely, presence of PTS was associated with a 6- to 11-fold increased incidence of recurrent DVT in patients treated with anticoagulants.¹² This might be explained by the findings of Young et al.⁷⁰ who showed an increased risk (hazard ratio 2.2) of DVT recurrence in limbs with residual thrombosis, as residual thrombus is also a known predictor of PTS. The mechanism by which DVT recurrence increases PTS incidence and/or severity most likely relates to aggravation of local venous damage and worsening of venous reflux via valvular destruction and extension of residual occlusion of affected vein segments. Kahn et al.⁶⁵ showed a 9.9% incidence of recurrent thrombosis during two years after treatment of DVT with anticoagulants; predictors of recurrence were cancer-associated venous thrombosis, unprovoked venous thrombosis, proximal (versus distal) thrombosis, symptomatic pulmonary embolism at study enrolment and male gender. Higher incidences of recurrence in patients with proximal DVT and in males have also been noted after longer patient follow-up.^26,30,65 Increased contralateral recurrence has also been noted in a number of studies, probably via systemic vein wall defects, blood hypercoagulability or body habitus.^12,35 A lower incidence of recurrence was seen after DVT provoked by surgery or trauma, conceivably because no underlying systemic venous aberrations were present.²⁶

Thrombus location

In many studies, proximal thrombi in the deep venous system (popliteal, femoral, common femoral and iliac veins) have been associated with a worse clinical and haemodynamic outcome and lower QoL scores than distal thrombi (peroneal, tibial, gastrocnemial, and soleus veins).^{9,15,18,23,31,33,65,71,72} Controversy remains, however, as some studies did not find this correlation.^25,63 Kahn et al. found a PTS incidence of 52% in patients with proximal DVT versus 41 % in distal DVT, and a 2.23-point increase in Villalta score with proximal versus distal DVT.^18,65 Similar findings were shown by Holmström et al.¹⁵ QoL scores were also lower in patients with proximal versus distal DVT.¹⁸ Van Ramshorst et al.⁷³ showed thrombus extent to correlate well with the number of refluxing vein segments at follow-up, but no association was shown for clinical severity. Eichlisberger et al.⁷ showed a greatly increased incidence of PTS in patients with four-level thrombosis compared with those with popliteal vein thrombosis only (55% versus 4%, respectively) at 13 years after the initial DVT, and Tick et al. showed a 1.3-fold increase in PTS incidence with iliofemoral as compared with popliteal thrombosis.³³

Residual occlusion

Incomplete recanalization of thrombosed venous tracts is thought to impair the outflow of post-DVT extremities, thereby promoting venous hypertension. Johnson et al.¹⁶ showed residual occlusion to be present in 80% of post-thrombotic limbs and reflux to be present in 83% (in 65% of limbs both occlusion and reflux were present). It takes a mean of 3.4 + 5.9 months to achieve 50% recanalization after DVT.⁷² Prandoni et al.⁷⁴ found a relative risk for PTS development of 1.56 with the presence of residual vein thrombosis, and 1.69 if both residual vein thrombosis and popliteal vein reflux were present. In another study, they found a hazard ratio of 2.4 for recurrent thromboembolism in patients with residual thrombosis compared with those with complete recanalization.⁷⁵ This was confirmed in another study that showed the risk of DVT recurrence and mortality was increased in patients with residual occlusion after DVT (hazard ratios 2.2 and 3.9, respectively).⁷⁰ However, controversy remains as Haenen et al.¹³ found no relation between non-compressibility or the combination of reflux and non-compressibility and PTS. Kahn et al.¹⁷ found comparable results. Furthermore, the proportion of venous occlusion was reported to be the same in patients with CEAP scores of C0–3 and C4–6.⁷⁶

Residual reflux

Loss of venous valve function due to thrombosis has been proposed as one of the main pathological pathways by which PTS develops. Indeed, it has long been shown that reflux in the deep veins of the affected limb correlates well with incidence and severity of PTS.^13,76,77 Yamaki et al.⁷⁶ showed peak reflux velocity in the popliteal and femoral vein on duplex to correlate highly (OR 60.32 for popliteal vein and 25.77 for femoral vein) with severity of chronic venous insufficiency. Haenen et al.¹³ showed reflux in the proximal deep veins to be associated with worse CEAP scores (Table 2), but no such relation was shown for reflux in superficial veins and distal deep veins. In a second study, the same group showed superficial venous reflux to be the most important risk factor for onset of PTS symptoms and 64% of patients with severe PTS were shown to have a combination of superficial and deep reflux.⁷⁸ A combination of deep and superficial reflux therefore seems to underlie PTS pathogenesis.

Insufficient quality of anticoagulant therapy

Vitamin K antagonist treatment is still one of the cornerstones of DVT treatment.⁴⁶ Insufficient quality of anticoagulation might inhibit the recanalization process and worsen clinical outcome in the affected limb. Ziegler et al.³⁵ indeed showed this relation. They described insufficient anticoagulation measurements in half of the patients suffering from venous ulcers. More recently an increased incidence of PTS (OR 2.71) was described in patients whose international normalized ratio (INR) level was below 2.0 for >50% of the time.⁶⁴ Moreover, longer treatment duration with oral anticoagulants significantly reduces the risk of recurrent thrombosis, which is an important risk factor for PTS.¹⁵

Thrombophilia

The presence of factor V Leiden or the G20210A prothrombin gene mutation has been shown to increase the risk of a first venous thrombosis.^79,80 Moreover, in family members of patients with one of these mutations, an OR of 1.68 was found for DVT incidence.⁸¹ There is conflicting evidence on the role of these thrombophilia markers on PTS incidence. Kahn et al.¹⁷ showed factor V Leiden or the prothrombin gene mutation to be independently associated with a decreased incidence of PTS (OR 0.33) and a 1.6 decrease in Villalta score. However, in another study by the same group, these results could not be replicated and the same is true for a number of other recent studies.^31,33,63-65

D-dimer

Elevated plasma D-dimer concentration predicts both first and recurrent DVT events.^{82

88} Stain et al³¹ showed D-dimer levels to be positively associated (OR 1.9) with PTS incidence. The recent finding that D-dimer was strongly reducible by vitamin K antagonists supports this assumption and reflects the fact that increased INR seems to protect against PTS development.⁸⁹ Latella et al.⁹⁰ showed that increased D-dimer levels were associated with occurrence of PTS in both DVT patients treated with and without vitamin K antagonists, and the association was strongest in those not currently treated (OR 3.79).

Inflammatory markers

Recently, a number of studies have focused on the role of inflammatory cytokines and adhesion molecules in the development of PTS. These include interleukin 6, 8 and 10 (IL-6, IL-8 and IL-10), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Studies were based on the hypothesis that the inflammatory response to DVT leads to vein wall abnormalities. PTS patients were shown to have a 1.6-fold increase in mean IL-6 level and a trend towards higher median levels of IL-6 four months after DVT diagnosis.⁴⁴ Roumen-Klappe et al. showed that IL-6 and CRP levels measured on the day of DVT diagnosis did not correlate with Villalta score one year post-DVT and only weakly correlated with CEAP classification one year post-DVT, but strong associations were seen between these markers and venous outflow resistance 90 days post-DVT (which in itself correlates with PTS incidence after 1 year), and in the case of IL-6, Porter's thrombosis score (based on thrombus extent and site involvement).^43,91 ICAM-1 levels are also associated with PTS ^44,92 No correlations between PTS and IL-8, IL-10, MCP-1 and VCAM-1 were shown.^43,44 An association between inflammatory markers and reflux was not seen, supporting the notion that the inflammatory response may act on vein wall characteristics rather than venous valves.^43,44,92 However, studies in animal models strongly suggest a role of inflammatory pathways in the development of venous valve degradation in chronic venous insufficiency, which indicates that secondary damage due to pathological haemodynamics post-DVT might contribute to PTS progression rather than initiation.^93,94 Moreover, increased plasma levels of IL-6, IL-8 and MCP-1 have been shown to be increased in patients with recurrent DVT, which is an independent risk factor for PTS development.⁹⁵ The value of inflammatory markers in the prediction of PTS is currently being evaluated in a large prospective study.⁹⁶

Conclusion

General interest and awareness of the PTS have recently been stimulated by improved standardization of PTS measurement and the emergence of new potential treatment modalities such as new oral anticoagulants, catheter-directed thrombolysis and deep venous stenting procedures. However, effective stratification of the risk for progression to PTS in patients presenting with a first or recurrent DVT remains elusive. Recurrence of thrombosis in the same extremity as the index DVT, with resultant increased venous damage, seems to be one of the most important risk factors for PTS development. Residual venous occlusion and valvular reflux, signifying venous damage, also seem to predict PTS incidence to some degree. Based on promising preliminary work, the value of D-dimer and inflammatory marker levels as a means to predict PTS is currently being investigated. Work to develop a future model that combines the above factors together with patient characteristics could provide a useful tool for stratifying risk of PTS development in individual patients with DVT.

Conflicts of interest: MAFW, CHAW and SRK declare no conflicts of interest.

Footnotes

Acknowledgements

SRK is a recipient of a National Research Scientist Award from the Fonds de la Recherche en Santé du Québec.

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