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Blood Coagulation, Fibrinolysis and Cellular Haemostasis

The predictive value of markers of fibrinolysis and endothelial dysfunction in the post thrombotic syndrome A systematic review Anat Rabinovich1; Jacqueline M. Cohen1,2; Susan R. Kahn1–3 for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; 3Division of Internal Medicine and Department of Medicine, McGill University, Montreal, Canada

Summary The post thrombotic syndrome (PTS) develops in 20–40% of deep venous thrombosis (DVT) patients. Risk factors for PTS have not been well elucidated. Identification of risk factors would facilitate individualised risk assessment for PTS. We conducted a systematic review to determine whether biomarkers of fibrinolysis or endothelial dysfunction can predict the risk for PTS among DVT patients. Studies were identified by searching the electronic databases PubMed, EMBASE, Scopus and Web of science. We included studies published between 1990 and 2013, measured biomarker levels in adult DVT patients, and reported rates of PTS development. Fourteen studies were included: 11 investigated the association between D-dimer and PTS; three examined fibrinogen; two measured von Willebrand factor; one measured plasminogen activator Correspondence to: Susan R. Kahn, MD MSc FRCPC Division of Internal Medicine & Center for Clinical Epidemiology Jewish General Hospital, 3755 Cote Ste. Catherine Room H420.1 Montreal QC, H3T 1E2, Canada Tel.: +1 514 340 8222 X 4667 E-mail: [email protected]

Introduction The post thrombotic syndrome (PTS) is a chronic condition that develops in 20–40% of patients within 1–2 years after deep venous thrombosis (DVT) (1). Patients with PTS experience pain, heaviness and swelling in the affected limb, aggravated by standing or walking and improved with rest and recumbency. Oedema, hyperpigmentation, eczema and varicose collateral veins may be apparent. In severe cases, ulceration can occur (2). Factors that influence the development of PTS after DVT have not been well elucidated. As a result, physicians are unable to provide their DVT patients with reliable, individualised prognostic information. The fact that a substantial fraction of DVT patients do not go on to develop PTS suggests that alterations or derangements in the process of thrombus resolution may be critical in the pathogenesis of PTS (3), which is thought to relate to a combination of persistent venous obstruction and valvular reflux (4–6). D-dimer is a degradation product of cross-linked fibrin. Elevated D-dimer measured off oral anticoagulants has been found to be predictive of recurrent venous thromboembolism (VTE) (7, 8), perhaps because D-dimer levels reflect chronic thrombus or on© Schattauer 2014

inhibitor-1; one assessed ADAMTS-13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats) and one measured factor XIII activity. Studies varied with regards to inclusion criteria, definition of PTS, time point and method of biomarker measurement. We were unable to meta-analyse results due to marked clinical heterogeneity. Descriptively, a significant association with PTS was found for D-dimer in four studies and factor XIII in one study. Further prospective research is needed to elucidate whether these markers might be useful to predict PTS development.

Keywords Post thrombotic syndrome, deep vein thrombosis, D-dimer, risk factors, fibrinolysis Received: November 13, 2013 Accepted after minor revision: January 5, 2014 Prepublished online: February 6, 2014 doi:10.1160/TH13-11-0931 Thromb Haemost 2014; 111: 1031–1040

going activation of coagulation. Whether D-dimer might be a useful marker to predict the development of PTS after DVT is not known. Activated factor XIII (FXIII) stabilises and crosslinks overlapping fibrin stands in the forming thrombus. Once the thrombus forms in the vein, endogenous fibrinolysis results in recanalisation and reabsorption of the mass. Plasmin lyses clot by breaking down fibrinogen and fibrin within the clot. Plasmin activity is regulated by vascular endothelial cells that secrete both serine protease plasminogen activators and plasminogen activator inhibitors (PAI-1 and PAI-2). The overall progression of the initial DVT towards propagation or resolution depends on the balance between these two processes (3), hence, the above mentioned fibrinolysis markers might be of interest. The endothelium is critical for normal vessel homeostasis, primarily maintaining an anticoagulant state (9). DVT induces a paracrine-like scarring process in the adjacent vein wall and subsequent fibrosis (10). The resultant fibrosis can cause valve damage, which leads to reflux and subsequent localised venous hypertension. A driving force for fibrosis is endothelial loss, with thrombotic injury likely related to the mechanical effects of the distendThrombosis and Haemostasis 111.6/2014

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ing thrombus (11). Markers of endothelial function include ADAMTS (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats)-13 and von Willebrand factor (VWF). Hence, fibrinolysis and endothelial dysfunction are components of the pathophysiological pathway to PTS, and alterations in levels of their related biomarkers might be of interest when assessing a patient’s risk of developing PTS. We conducted a systematic review aimed at answering the question: among patients diagnosed with DVT, can D-dimer, markers of fibrinolysis and of endothelial dysfunction predict the risk of developing PTS?

Methods We conducted this study as part of a comprehensive literature search to identify studies where biomarkers of inflammation, D-dimer levels, markers of fibrinolysis and of endothelial dysfunction and/or markers of inherited or acquired thrombophilia (reported separately [12]) were measured at least once after DVT diagnosis and assessed for their association with the development of PTS. Study objectives, study selection criteria, definition of outcome, search strategy, data extraction process, statistical analyses and methods for assessment of study quality were all pre-specified in a protocol. Case-control, prospective and retrospective cohort studies published between January 1990 and March 2013 and written in English, French, German or Spanish (languages for which we had translators available) were included. Review articles, case reports, conference abstracts, book chapters and duplicate publications were excluded. Studies of interest enrolled adult patients (defined as age ≥18 years) objectively diagnosed with DVT, who had biomarker levels measured during study participation. Outcome of interest was PTS, as defined using Villalta scale (13, 14), clinical, aetiological, anatomical and pathological (CEAP) classification (15), or other criteria described by the study authors. Studies were identified by searching the electronic databases PubMed, EMBASE via Ovid, Scopus and Web of Science. We also scanned reference lists of review articles, reference lists of retrieved papers, and studies that have cited these papers. Additional information on study methods or results was retrieved by contacting the authors. The following represents a selection of search terms, relevant to the subject of this review, that were used to search all databases: • Search terms for markers: fibrinolysis; factor XIII; thrombin activable fibrinolysis inhibitor; plasminogen activator inhibitor 1; D-dimer. • Search terms for outcome: postphlebitic syndrome; postthrombotic syndrome; venous stasis syndrome; chronic venous ulcers. An example for the complete search strategy (including search terms for markers of thrombophilia and inflammation not included in this report) used for the PubMed search is presented in Suppl. Table 1 (available online at www.thrombosis-online.com). Thrombosis and Haemostasis 111.6/2014

Two reviewers (AR, SK) independently screened the titles and abstracts of records retrieved through database searches and recommended studies for full text review. The secondary screen of full text articles recommended by at least one reviewer was done independently by two reviewers (AR, SK) and assessed for inclusion in the systematic review based on the inclusion and exclusion criteria described above. Disagreements between reviewers were resolved by consensus. For the studies recommended for inclusion in the secondary screen, data were extracted using a data extraction form that was tailored for the review and improved via several pilot extractions. Relevant data was independently extracted by two investigators (AR, JC). Collected data included: 1. Study characteristics; 2. Inclusion and exclusion criteria; 3. Characteristics of study participants (including malignant and inflammatory diseases that could influence the result of measured markers and use of anticoagulants); 4. Biomarker measured, time point(s) of measurement, measurement method; 5. Measure of association and adjustment variables, when used; 6. Outcome, including criteria by which PTS was diagnosed. Extracted data were compared and disagreements were resolved by consensus. To elucidate the information that is important for judging risk of bias in individual studies, we used the Newcastle-Ottawa Scale (16). Some additional quality items specific to this literature were added, including techniques used to measure biomarkers, adequacy of the statistical analyses and handling of confounders. These items were selected in the design stage of this review as they were considered pertinent for quality assessment of this literature by all authors. All quality items used are presented in ▶ Table 2. Although different study designs were included, our goal was to use cohorts in our analyses. Therefore, in controlled cohort studies, we used only the cohort of VTE patients and excluded the healthy controls. We planned to perform a meta-analysis using the random effects model only if three or more papers were available.

Results

▶Figure 1 depicts the flow diagram for the process of study selec-

tion. The electronic database search provided 3,397 citations. Scanning the reference lists of narrative reviews and of located relevant papers and searching for studies that have cited these papers yielded an additional 43 citations. After adjusting for duplicates, a total of 2,376 remained. Of these, we excluded 2,292 studies that did not meet the above inclusion criteria after title and abstract screening. The full text of the remaining 84 citations was examined in more detail. After full text assessment we excluded an additional 47 papers for the following reasons: four papers excluded because we were unable to translate them (1 Polish, 1 Korean, 1 Portuguese, 1 Italian); one case report; one book chapter; five conference abstracts; one paper used the same cohort as another publication; 15 papers did not provide data separately for PTS patients; seven studies gave no clear definition of PTS; in six studies, analysis on the association between biomarker and PTS was not reported/not done; five papers had no subgroup of PTS, and fin© Schattauer 2014

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Figure 1: Process of study selection. A comprehensive literature search was performed to identify studies where biomarkers of inflammation, D-dimer, markers of fibrinolysis and endothelial function and/or markers of inherited or acquired thrombophilia were measured after DVT diagnosis and

assessed for their association with the development of PTS. This figure depicts the process of study selection. After exclusions, 37 studies remained. In this paper, we report the results of the 14 studies that measured D-dimer, markers of fibrinolysis and endothelial function.

ally, in two studies, no relevant biomarkers of inflammation and/ or thrombophilia were measured. A total of 37 studies met the inclusion criteria. In this report we describe only the results that pertain to the association between D-dimer, markers of fibrinolysis and endothelial function and PTS, hence, 14 of the 37 studies will be discussed. Eleven studies investigated the association between D-Dimer and PTS, three examined Fibrinogen level, two measured VWF antigen and activity, one study measured PAI-1, one assessed ADAMTS-13 antigen and activity, and one study measured FXIII activity. We contacted authors of three of the included studies (17–19) and received data from two of them (17, 19). ▶Table 1 summarises the included studies. Studies varied with regards to inclusion and exclusion criteria, definition of PTS and timing of PTS assessment. ▶ Table 2 presents our methodological quality assessment of included studies. Only half of the studies used a validated scale (CEAP, recommended by the International Consensus Committee on Chronic Venous Disease for evaluation of PTS [15], or Villalta scale, recommended by the International Society on Thrombosis

and Haemostasis [31]) to diagnose PTS. In most studies there was no account for confounders in the design or analysis stages. Six studies assessed for PTS at or beyond two years post DVT. The other eight assessed this outcome one year post DVT or earlier, which raises the concern that some of the PTS cases might have been missed.

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D-dimer Eleven studies investigated the association between D-Dimer and PTS (▶ Table 3). There was significant heterogeneity between studies regarding time point of biomarker measurement after DVT, measurement method, and analysis of association between marker and outcome. Studies are grouped according to time point of D-dimer measurement after DVT. Five studies (20–24) measured D-dimer in the acute phase (up to one month post-DVT). In all of them blood was drawn before commencement of anticoagulation. Only two of these studies used the validated Villalta scale to diagnose PTS (21, 24) (▶ Table 1), and three included only patients with first DVT (20–22). Studies Thrombosis and Haemostasis 111.6/2014

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Table 1: Characteristics of included studies.

Author /year Study (ref.) design

Inclusion criteria

Exclusion criteria

Gabriel 2004 (20)

Prospective cohort

First, idiopathic DVT

COPD; on AC, OC, HRT; cancer; 135 hepatic/renal failure; CHF, MI, endocarditis, stroke; pregnancy/ puerperium; surgery (4 weeks); hospitalisation (6 months); trauma (60 days); myeloproliferative disorders, intestinal inflammatory illness, connectivopathies.

Venographic criteria: total occlusion in 56.3% the affected venous segment/ narrowing > 50% of ≥ half of the segment Assessed 12 months post DVT

Roberts 2012 (21)

Prospective cohort

First DVT

Cancer, IVDU

122

Villalta >5 assessed six months after AC stopped

BellmuntMontoya 2006 (22)

Retrospective First DVT cohort

None

118

Clinical signs/ symptoms: venous 48.3% claudication, pain, swelling, heaviness, cramps, itching, each scored on a visual analogue scale of 0–100, PTS diagnosed if result ≥30%. Doppler-Duplex ultrasound. Assessed a median of 3.1 years post DVT

MarcheaYglesias 2006 (23)

Prospective cohort

DVT

None

100

Clinical signs /symptoms: tenderness/ oedema/local heat/ pigmentation/collateral veins. Assessed at 12 months post DVT

43%

Lopez-Azkarreta Prospective 2005 (24) cohort

Symptomatic proximal DVT

Hepatic/renal failure

103

Villalta ≥3 assessed at 12 months post DVT

54%

Latella 2010 (25)

Prospective cohort

Symptomatic DVT

None

387

Villalta ≥5 during 2 years follow-up

45.1%

Bouman 2012 (26)

Prospective cohort

Proximal DVT

None

228

Villalta ≥ 5 assessed at 24 months post DVT

19%

Stain 2005 (27)

Prospective cohort

First DVT

LAC, cancer, on AC

406

CEAP ≥1 assessed a mean of 44 ± 23 months post DVT

43.3%

Galanaud 2013 (17)

Prospective cohort

First, unprovoked proximal DVT

Surgery (3 months); cancer, on AC

328

Villalta≥5 assessed 5–7 months post DVT

27.1%

Krieger 2004 (28)

Controlled cohort

DVT

Acute illness, recent surgery

43

VCSS and VSDS analysed as a continuous variable. Assessed a median of 28 months post DVT

Wik 2012 (29)

Controlled cohort

Pregnancy-related DVT

None

204

Self-reported Villalta ≥5 assessed 3–16 years post DVT

42%

Mazetto 2012 (18)

Controlled cohort

At least one episode of VTE

Cancer, liver/ renal failure, inflammatory, autoimmune and infectious diseases

77

Villalta ≥5 assessed a median of 32 months (range 7.1 – 76.6) after VTE

53% (n=51)

Vanscheidt 1991 Cross (30) sectional

CVU not responding to treatment

Liver/kidney diseases, inflammatory diseases, cancer, surgery (6 months), on AC

92

Venographic criteria: post-phlebitic vein damage (no other diagnostic criteria provided)

63%

Schulman 2006 (19)

DVT

Recurrent DVT

545

CEAP ≥3 assessed 10 years after DVT

56.3%

Prospective cohort

No. of patients

Criteria for PTS diagnosis/ time of assessment

% PTS

51.6%

DVT, deep venous thrombosis; PTS, post thrombotic syndrome; COPD, chronic obstructive pulmonary disease; AC, anticoagulants; OC, oral contraceptives; HRT, hormone replacement therapy; CHF, congestive heart failure; MI, myocardial infarction; IVDU, recreational intravenous drug use; LAC, lupus anticoagulant; CEAP, clinical, aetiological, anatomical and pathological classification; VCSS, Venous Clinical Severity Score; VSDS, Venous Segmental Disease Score; VTE, venous thromboembolism; CVU, chronic venous ulcer.

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Gabriel Ro2004 berts (20) 2012 (21)

Legend: white = yes; black = no; grey = unclear.

Confounding accounted for in the design and/or analysis

Confounders pre-defined and adequately measured

Study report free of the suggestion of selective outcome reporting

Authors’ conclusions supported by the results of the analysis

Statistical analyses described adequately, analyses appropriate, analysis provide sufficient presentation of data

Missing data adequately addressed

Degree of completeness of follow-up described, completeness of follow-up adequate, loss to follow-up addressed

Follow-up long enough for outcomes to occur

Outcome defined and diagnosed appropriately

Techniques used to measure biomarkers accurate and valid

Study population represent source population or population of interest

Study population well-described (setting, location, relevant dates)

Source population clearly defined

Author/year (ref.)

Marchena-Yglesias 2006 (23)

LopezLatella Bouman Stain Azkarreta 2010 2012 2005 2005 (25) (26) (27) (24)

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BellmuntMontoya 2006 (22)

Table 2: Methodological quality assessment of included studies.

Galanaud Krieger Wik 2013 2004 2012 (17) (28) (29)

Mazetto VanSchulman 2012 scheidt 2006 (18) 1991 (19) (30)

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Table 3: The association between D-dimer and PTS.

Author/ year (ref.)

Measurement method

Association between D-dimer and PTS

Comments

ACUTE PHASE (UP TO 1 MONTH AFTER DVT) Gabriel 2004 (20)

DG-D dimer

D-dimer > 260 ng/ml in 54/64 (84.3%) PTS+ versus 32/42 (76.1%) PTS-, P=0.061.

D-dimer measured before starting AC.

Roberts 2012 (21)

latex photometric Immunoassay

Median (IQR) 3260 ng/ml (820–8000) in PTS+ versus 1540 (810–2520) in PTS-, P < 0.001. D-dimer >1910 ng/ml; *Adjusted OR 2.71, 95% CI 1.05–7.03.

D-dimer measured before starting AC. *Adjusted for age, BMI, common femoral vein involvement and daily use of stockings.

Bellmunt-Montoya 2006 (22)

ELISA

D-dimer ≥ 3780 µg/l (median for all patients) in 36/57(63.2%) PTS+ versus 9/61(14.8%) PTS-.

D-dimer measured before starting AC. In 20% of patients, cancer diagnosed before DVT diagnosis or during follow up.

Marchea-Yglesias 2006 (23)

HemosIL

Mean (SD) 1540.6 (961) ng/ml in PTS+ versus 1681.2 (1304) in PTS-, P =0.57. D-dimer >500 ng/ml in 35/43 (81.4%) PTS+ versus 40/57 (70.2%) PTS-.

D-dimer measured before starting AC. Patient comorbidities: 16 cancer, 6 CHF, 4 collagen-vascular disease, 2 sepsis and 1 inflammatory bowel disease

Lopez-Azkarreta 2005 (24)

Not described

D-dimer ≥4.5 mg/ml: OR 1.00, 95% CI 0.7–1.6.

D-dimer measured before starting AC.

Mean (SD) 712.0 (550.9) µg/l in PTS+ versus 444.0 (1263.4) in PTS-, mean difference 268.0 (95% CI 53.9– 482.1) Per 100 µg/l difference in D-dimer, *adjusted OR 1.05, 95% CI 1.00– 1.09. D-dimer >500 µg/l: OR 1.13, 95% CI .68– 1.88; restricted to subjects not on AC, OR 3.79, 95% CI 1.46– 9.85.

At blood draw, 213 patients taking AC. *Adjusted for AC use, age, gender, BMI, previous DVT, type of DVT (idiopathic, cancer related, transient risk factor), extent of DVT, use of stockings and recurrent VTE.

EARLY SUBACUTE PHASE (1–4 MONTHS POST DVT) Latella 2010 (25)

VIDAS D-dimer

LATE-SUBACUTE PHASE (5–12 MONTHS AFTER DVT) Bouman 2012 (26)

VIDAS D-dimer until May 2008. From June 2008 Innovance D-dimer

4–7 months: median (IQR) 495 ng/ml (330–838) in PTS+ versus 360 (222–607) in PTS-; P=0.11.

Patients on AC excluded from analysis

12 months: 725 (400–1400) in PTS+ versus 378 (251–652) in PTS-; P=0.004. D-dimer >1000 ng/ml (90th percentile of controls), OR 3.1, 95% CI 0.92–10.3. 24 months: 550 (330–1137) in PTS+ versus 457 (286–750) in PTS-; P=0.20.

Stain 2005 (27)

Asserchrom D-dimer

D-dimer >500 ng/ml in 36/176 (20.5%) PTS+ versus Blood draw 3 weeks after AC withdrawal. *Adjusted 20/230 (8.7%) PTS-; *Adjusted OR 1.9, 95% CI for older age, male gender, proximal DVT, BMI > 25 1.0–3.9. kg/m2.

Galanaud 2013 (17)

VIDAS D-dimer

D-dimer ≥250 µg/l in 31/88 (35.2%) PTS+ versus 80/232 (34.5%) PTS-; OR 1.0, 95% CI 0.999–1.001.

Measured while patients on AC.

REMOTE PHASE (> 12 MONTHS AFTER DVT) Krieger 2004 (28)

Not described.

D-dimer as a continuous variable, a tendency for D-dimer to increase with increasing VCSS score, r=0.28; P=0.07. No correlation between increasing VSDS score and d-dimer.

Number of patients on AC at time of measurement not provided.

Wik 2012 (29)

Not described.

D-dimer ≥ 0.4 µg/l in 33/85 (38.8%) PTS+ versus 37/118 (31.4%) PTS-; OR 1.4, 95% CI 0.8–2.5.

No information on type and duration of AC.

DVT, deep venous thrombosis; PTS, post thrombotic syndrome; ELISA, enzyme linked immunosorbent assay; AC, anticoagulants; IQR interquartile range; OR, odds ratio; CI, confidence interval; SD, standard deviation; BMI, body mass index; CHF, congestive heart failure; VTE, venous thromboembolism. Note: Units of measurement are as presented in the original papers.

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population, crude ORs may already reflect a certain degree of control for confounding. In general, adjusted ORs (where available) tended to attenuate the association. Even after subgrouping, we were still unable to combine the results due to clinical heterogeneity discussed above. Generally speaking, as the cut-off was set higher, the association to PTS became stronger.

Fibrinogen Three studies (20, 23, 28) assessed the association between fibrinogen level and PTS development (▶ Table 4). Two of them (20, 23) measured fibrinogen level on presentation of DVT, and one (28) measured fibrinogen a median of 28 months after DVT. None demonstrated a significant association between fibrinogen level and PTS.

Other markers Two studies (18, 19) assessed VWF antigen, and one of them (18) also assessed VWF collagen binding activity (▶ Table 5). No significant association to PTS was found. PAI-1 was measured in one study (19) and ADAMTS-13 in another study (18) with no significant predictive value of these markers. One study measured FXIII activity (30) and found it to be lower both in patients with post-thrombotic ulcers and in PTS without

Figure 2: The association between D-dimer and PTS. This figure presents results from 10 studies that analysed the association between D-dimer and PTS. Studies are grouped according to time point of D-dimer measurement. Point estimates represent crude OR for PTS according to the D-dimer cut-off chosen by the studies’ authors for analysis.

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used different cut-off values for analysis, and some also presented mean or median D-dimer for PTS-positive and PTS-negative patients. Two studies (21, 22) found a statistically significant association between D-dimer at presentation and PTS. Only the study by Roberts et al. (21) presented an adjusted odds ratio (OR). One study (25) measured D-dimer level four months after DVT (early subacute phase), and found a significant difference in means between PTS-positive and PTS-negative patients (▶ Table 3). The association was stronger when analysis was restricted to patients not taking anticoagulants at the time of blood draw. Using a cutoff of D-dimer of more than 500 µg/l, the association was significant only in patients off anticoagulants. Three studies (17, 26, 27) measured D-dimer level in late subacute phase (5–12 months after DVT). Using different cut-off levels for D-dimer, one of them (27) found a significant association to PTS. In the remote phase (more than 12 months post DVT), the two available studies (28, 29) did not demonstrate a significant association between D-dimer and PTS. ▶Figure 2 summarises results from 10 studies that used cutoffs for analysis of the association to PTS (one study [28] is not included in this figure because correlation analysis was performed using D-dimer and outcome measure as continuous variables). We used crude ORs as the summary measure, as adjusted ORs were available for only a few studies, and adjustment variables differed between studies. Furthermore, as some studies restricted their

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Table 4: The association between fibrinogen and PTS.

Author/ year (ref.)

Measurement Time method

Association with PTS

Gabriel 2004 (20)

Not described

Day 0

Mean (SD) 4.6 (1.54) g/l in PTS+ versus 4.74 (1.49) in PTS-, P=0.617.

Marchena-Yglesias ACL 2006 (23)

Day 0

Mean (SD) 462.5 (139) in PTS+ versus 514.6 (171.2) in PTS-; P=0.11. Fibrinogen > 460 mg/dl (upper limit of normal) 21/43 (48.8%) in PTS+ versus 31/57 (54.4%) in PTS-

Krieger 2004 (28)

Median Fibrinogen as a continuous variable. No significant 28 months correlation to VCSS or VSDS.

Clauss method

PTS, post-thrombotic syndrome; SD, standard deviation; ACL, Automated Coagulation Laboratory; VCSS, Venous Clinical Severity Score; VSDS, Venous Segmental Disease Score.

ulcer, as compared to patients with non PTS related venous ulcers. However, definition of a venous ulcer as PTS related was based solely on venographic findings.

Discussion Defining risk factors for PTS is important in order to identify DVT patients at high risk of developing this condition, and to target appropriate prophylactic measures in those patients. To date, data that allows stratification of DVT patients according to their risk of PTS are limited. The only well-established risk factors for PTS are proximal (versus distal) DVT (27, 32-36) and recurrent ipsilateral DVT (37–41). We systematically reviewed available literature on the association between D-dimer, markers of fibrinolysis and of endothelial dysfunction and PTS. Fourteen studies were included, most with methodological limitations. Populations included were heterogen-

eous (e.g. first or recurrent DVT, inclusion of patients with malignancy or inflammatory diseases). Patients with recurrent DVT have an increased risk for development of PTS; hence, study populations may differ in their baseline risk for PTS development. Malignancy and inflammatory diseases are known to influence D-dimer and fibrinogen measured results (42–45), and not all studies accounted for this confounder in their design or analysis. Time point of biomarker measurement after DVT as well as method of measurement also varied between studies. Measurement of these markers in the acute phase of DVT might reflect acute phase reaction and thrombus load, while measuring the same marker at later time points might be more indicative of ongoing activation of the coagulation and fibrinolytic pathways. Therefore, combining results from different time points after DVT would not be informative. We grouped studies according to similar time point of biomarker measurement. Eight out of 14 studies used accepted criteria for outcome assessment. PTS rates, therefore, varied between studies, and indi-

Table 5: Other markers in association with PTS.

Author /year (ref.)

Marker

Measurement method

Time

Association with PTS

Mazetto 2012 (18)

ADAMTS13-Ag

Imubind®ADAMTS13 ELISA

ADAMTS13–CBA

collagen binding assay

median 32 months (range 7.1 – 76.6 months)

Levels of ADAMTS 13 (Ag, CBA, activity) similar, regardless of the presence of PTS. No numerical data provided. Levels of VWF (Ag, CBA) similar, regardless of the presence of PTS. No numerical data provided.

ADAMTS13 activity Technozym ADAMTS13 Activity VWF-Ag

ELlSA

VWF-CBA

collagen binding assay

Vanscheidt 1991 (30)

FXIII

coagulation FXIII rapid reagent

Not described

FXIII activity ≤50% in 20/39 (51.3%) post-thrombotic ulcer versus 11/19 (57.9%) in PTS without ulcer versus 3/23 (13%) in primary varicosis ulcer versus 1/11 (9.1%) in non-venous ulcers.

Schulman 2006 (19)

PAI-1

Not described

6 months

PAI-1 ≥30 U/ml (twice the upper limit of normal) 18/128 (14.1%) PTS+ versus 48/400 (12%) PTS-. (n=528)

VWF-Ag

VWF-Ag ≥1.5 IU/ml (upper limit of normal) in 7/12 (58.3%) PTS+ versus 33/77 (42.9%) PTS-. (n=89)

PTS, post-thrombotic syndrome; ADAMTS-13, A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats; ELISA, enzyme-linked immunosorbent assay; Ag, antigen; CBA, collagen binding activity; VWF, Von-Willebrand factor; FXIII, Factor XIII; PAI-1, Plasminogen Activator Inhibitor-1.

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© Schattauer 2014

What is known about this topic?

• • •

Post-thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT), affecting 20–50% of DVT patients despite adequate anticoagulation. Established clinical risk factors for PTS are proximal DVT and recurrent DVT. Other risk factors have not been well elucidated.

What does this paper add?

• • •

This systematic review aimed to identify biomarker risk factors for PTS. For D-dimer, the majority of studies suggested an increased risk of PTS; if confirmed in future research, D-dimer might prove to be a relevant marker for PTS. Markers of fibrinolysis and markers of endothelial dysfunction could not be clearly associated to PTS.

each subgroup. While we cannot exclude publication bias, its assessment in this type of literature is difficult. In conclusion, the available literature does not provide sufficient good quality evidence for an association between any of the markers in question and the development of PTS. Future clinical studies should enroll larger numbers of patients, use more rigorous, prospective designs, use validated criteria to diagnose PTS and account for confounding in the design and/or analysis, thereby increasing the strength of evidence. In our opinion, based on our results, D-dimer might be a relevant marker to measure. We suggest restricting study population to patients with first DVT, measuring D-dimer off anticoagulants, and finally, assessing for PTS two years after diagnosis of DVT. Acknowledgements

We thank the authors we contacted who provided additional data for this systematic review. Dr. Rabinovich is supported by The Richard and Edith Strauss Clinical Fellowship in Medicine award from the Faculty of Medicine, McGill University. Ms Cohen is supported by an award from the McGill Faculty of Medicine. Dr. Kahn is supported by a National Research Scientist award from FRQ-S. Conflicts of interest

None declared.

References 1. Kahn SR. The post-thrombotic syndrome: progress and pitfalls. Br J Haematol 2006; 134: 357–365. 2. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management – Summary of an evidencebased report of the VEINES task force. Int Angiol 1999; 18: 83–102. 3. Phillips LJ II, Sarkar R. Molecular characterization of post-thrombotic syndrome. J Vasc Surg 2007; 45: 116A-122A. 4. Johnson BF, Manzo RA, Bergelin RO, et al. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after

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vidual effect estimates may be difficult to compare. Furthermore, assessment for PTS was performed at different time points post DVT, with eight studies assessing for PTS one year or less after DVT. As most cases of PTS occur up to two years after DVT (38, 46), some of the cases might have been missed by an earlier assessment. Methods for data summary and analysis were different between studies, with some using cut-off points and some using means or medians. Finally, some studies accounted for confounders in the design phase, while others provided an adjusted measure of association. In most studies, only crude estimates were provided. When provided, adjustment variables differed. Due to this marked heterogeneity, we felt a meta-analysis would not give a meaningful combined estimate. Descriptively, a statistically significant association to PTS was found only in four studies measuring D-Dimer at different phases after DVT. We also summarised studies that used a cut-off D-dimer value in their analysis. As the cut-off for analysis was set higher, the association became stronger. Based on these data we cannot come to a clear conclusion as to whether such an association exists. Studies using D-dimer as a marker of risk for recurrent VTE have shown that there are additional limitations that need to be taken into account. Ideally, D-dimer should be expressed as a continuous variable, but a cut-off that dichotomises patients’ risk might be more useful in clinical practice. The drawback of this approach is the potential need for assay-specific D-dimer cut-off. In addition, even if the prognostic value of D-dimer is independent of patient age and comorbidity, D-dimer levels are higher, on average, in the elderly and age-specific D-dimer cut-offs may increase its specificity (47). Another important issue is whether D-Dimer should be measured on or off anticoagulants. Patients taking anticoagulants have lower D-dimer levels, thus limiting the usefulness of a qualitative D-dimer value as a predictor of PTS in this population. D-dimer levels off anticoagulants may be a more useful predictor of PTS. Overall, additional research is needed to identify the optimal manner in which D-dimer might be used as a predictor of PTS. The few studies available for markers of fibrinolysis and endothelial function did not show any association between these markers and PTS, and the only available study for FXIII found it to be lower in PTS patients. Clearly, more studies are needed before the association to PTS can be fully assessed. Our systematic review has several strengths. Our comprehensive search strategy allowed us a wide search of available biomarker literature. Two reviewers independently completed screening, study selection, and data extraction. Finally, we attempted to analyse data within specific subgroups to lessen the effect of heterogeneity and highlight the impact of different thresholds for D-dimer on the risk of PTS. This review also had limitations. Apart from the limitations imposed by the available literature and discussed above, we could not translate four of the available papers. We also decided not to include conference abstracts, as they contained insufficient information for extraction. Finally, a formal assessment of publication bias was not possible because of the small number of studies within

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The predictive value of markers of fibrinolysis and endothelial dysfunction in the post thrombotic syndrome. A systematic review.

The post thrombotic syndrome (PTS) develops in 20-40% of deep venous thrombosis (DVT) patients. Risk factors for PTS have not been well elucidated. Id...
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