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Supporting InformationContents: Table S1. Complete search strategy used for PubMedTable S2. Studies analyzing the association between CRP and PTSTable S3. Studies analyzing the association between IL-6 and PTSTable S4. Studies analyzing the association between other cytokines and PTSTable S5. Other Markers in association with PTSTable S1. Complete search strategy used for PubMedSearch numberSearch nameSearch terms1Post thrombotic syndrome"postthrombotic syndrome"[MeSH Terms] OR ("postthrombotic"[All Fields] AND "syndrome"[All Fields]) OR "postthrombotic syndrome"[All Fields] OR ("post"[All Fields] AND "thrombotic"[All Fields] AND "syndrome"[All Fields]) OR "post thrombotic syndrome"[All Fields]2Post phlebitic syndrome"postphlebitic syndrome"[MeSH Terms] OR ("postphlebitic"[All Fields] AND "syndrome"[All Fields]) OR "postphlebitic syndrome"[All Fields] OR ("post"[All Fields] AND "phlebitic"[All Fields] AND "syndrome"[All Fields]) OR "post phlebitic syndrome"[All Fields]3Venous stasis syndrome"postthrombotic syndrome"[MeSH Terms] OR ("postthrombotic"[All Fields] AND "syndrome"[All Fields]) OR "postthrombotic syndrome"[All Fields] OR ("venous"[All Fields] AND "stasis"[All Fields] AND "syndrome"[All Fields]) OR "venous stasis syndrome"[All Fields]4Outcome1 OR 2 OR 3 5C reactive protein"c-reactive protein"[MeSH Terms] OR ("c-reactive"[All Fields] AND "protein"[All Fields]) OR "c-reactive protein"[All Fields] OR "c reactive protein"[All Fields]6Transforming growth factor beta"transforming growth factor beta"[MeSH Terms] OR ("transforming"[All Fields] AND "growth"[All Fields] AND "factor"[All Fields] AND "beta"[All Fields]) OR "transforming growth factor beta"[All Fields] OR ("tgf"[All Fields] AND "beta"[All Fields]) OR "tgf beta"[All Fields]7E selectin"e-selectin"[MeSH Terms] OR "e-selectin"[All Fields] OR "e selectin"[All Fields]8P selectin"p-selectin"[MeSH Terms] OR "p-selectin"[All Fields] OR "p selectin"[All Fields]9Matrix metalloproteinases"matrix metalloproteinases"[MeSH Terms] OR ("matrix"[All Fields] AND "metalloproteinases"[All Fields]) OR "matrix metalloproteinases"[All Fields]10Interleukin-10"interleukin-10"[MeSH Terms] OR "interleukin-10"[All Fields] OR "interleukin 10"[All Fields]11Interleukin-8"interleukin-8"[MeSH Terms] OR "interleukin-8"[All Fields] OR "interleukin 8"[All Fields]12Interleukin-6"interleukin-6"[MeSH Terms] OR "interleukin-6"[All Fields] OR "interleukin 6"[All Fields]13Intercellular adhesion molecule-1"intercellular adhesion molecule-1"[MeSH Terms] OR ("intercellular"[All Fields] AND "adhesion"[All Fields] AND "molecule-1"[All Fields]) OR "intercellular adhesion molecule-1"[All Fields] OR "icam 1"[All Fields]14Tumor necrosis factor"tumor necrosis factor"[All Fields]15Monocyte chemotactic protein-1"monocyte chemotactic protein 1"[All Fields]16Cytokines"cytokines"[MeSH Terms] OR "cytokines"[All Fields] OR "cytokine"[All Fields]17Acute phase reactants"acute-phase proteins"[MeSH Terms] OR ("acute-phase"[All Fields] AND "proteins"[All Fields]) OR "acute-phase proteins"[All Fields] OR ("acute"[All Fields] AND "phase"[All Fields] AND "reactants"[All Fields]) OR "acute phase reactants"[All Fields]18Inflammation"inflammation"[MeSH Terms] OR "inflammation"[All Fields]19Biomarker"biological markers"[MeSH Terms] OR ("biological"[All Fields] AND "markers"[All Fields]) OR "biological markers"[All Fields] OR "biomarker"[All Fields]20Biomarkers of inflammation combined5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 21Final20 AND 4Table S2. Studies analyzing the association between CRP and PTSRefAuthor /yearAssociation between CRP and PTScomments25Krieger 2004CRP as a continuous variable was positively correlated with VCSS (r= 0.42 and P< .01)26Marchena-Yglesias 2006Mean ± SD 41.3 ± 55.8 mg/dl in PTS+ vs. 46.8 ± 58.3 mg/dl in PTS- , p=0.orbid conditions: 16 had cancer, 6 had CHF, 4 had collagen-vascular disease, 2 had sepsis and 1 had inflammatory bowel disease27Roumen-Klappe2009CRP?54 mg/L (80th percentile of day 0 concentration):*adjusted RR 1.2, 95% CI 0.6–2.5.*Adjusted for age, sex, BMI, IL-6, D-dimerCRP measured on day 0, 7, 30, 90. Analysis presented for day 0. CRP below detection limit at day 30 and 90 after DVT for all patients.28Bouman 20124–7 months after DVT, median 3.7mg/l, IQR 2.2–8.2 in PTS+ vs. 2.7mg/l, IQR 1.4–5.8 in PTS-; p=0.06. 12 months after DVT, median 3.9 mg/l, IQR 1.6–8.5 in PTS+ vs. 2.4 mg/l, IQR 1.0–4.3 in PTS-; p = 0.018. CRP ? 5 mg/l (75th percentile of PTS-), *adjusted OR 3.0, 95% CI 1.3–7.3; p = 0.011. 24 months after DVT, median 2.8mg/l ,IQR 1.8–6.6 in PTS+ vs. 2.3mg/l, IQR 1.2–4.9 in PTS-; p= 0.31.16.7% of the cohort had background of “inflammatory disease” (no details provided).*Adjusted for varicosities, previous ipsilateral DVT.29Bittar 2013Median 0.197 mg/dL (range 0.017-0.5) in PTS+ vs. 0.109 mg/dL (range 0.017-0.381) in PTS-; p=0.48.22Galanaud 2013CRP?5.48 mg/l in 20/89 (22.5%) PTS+ vs. 65/239 (27.2%) PTS-; OR 0.978, 95% CI 0.936 – 1.022.23Bouman 2014Median 2.2 μg/mL, IQR 1.1-4.4 in PTS+ vs. 1.4 μg/mL, IQR 0.7-3.3 in PTS-; p=0.244.24Bittar 2015Median 0.21 mg/dL, IQR 0.07 - 0.44 vs. 0.21 mg/dL, IQR 0.05 - 0.38 in PTS-; p=0.90.30Rabinovich2015Day 0, median 8.35 mg/L, IQR 3.24-27.3 in PTS+ vs. 8.36 mg/L, IQR 3.19-26 in PTS-; P=0.78. CRP? 8.5 mg/L (median for all patients) *adjusted RR 0.95 (95% CI 0.81-1.11). *Adjusted RR (95% CI) Q2 vs. Q1 0.96 (0.77-1.95), Q3 vs. Q1 0.91 (0.72-1.13), Q4 vs. Q1 0.95 (0.75-1.19); ?P=0.60. 1 month, median 3.20 mg/L, IQR 1.37-6.02 in PTS+ vs. 2.47 mg/L, IQR 1.03-5.14 in PTS-; P=0.03. CRP? 3.0 mg/L (median for all patients) *adjusted RR 1.10 (95% CI 0.93-1.30). *Adjusted RR (95% CI) Q2 vs. Q1 0.98 (0.77-1.26), Q3 vs. Q1 1.19 (0.94-1.49), Q4 vs. Q1 0.98 (0.76-1.27); ?P=0.64.6 months, median 2.31 mg/L, IQR 1.06-4.87 in PTS+ vs. 1.92 mg/L, IQR 0.81-4.21 in PTS-; P=0.07. CRP?2.1mg/L (median for all patients) *adjusted RR 1.06 (95% CI 0.89-1.26). *Adjusted RR (95% CI) Q2 vs. Q1 1.03 (0.80-1.32), Q3 vs. Q1 1.08 (0.84-1.39), Q4 vs. Q1 1.07 (0.83-1.38); ?P=0.54.*Adjusted for treatment arm (active or placebo stockings), age, sex, BMI, infectious or inflammatory conditions, CHF, stroke or MI within 1 month, smoking, type of DVT (unprovoked, vs. secondary), extent of DVT (popliteal, femoral, common femoral or iliac vein), use of anti-platelet agents, non-steroidal anti-inflammatory drugs, steroids, and statins within 30 days before DVT diagnosis.? P value for trendCHF- congestive heart failure, BMI- body mass index, MI-myocardial infarction ELISA- enzyme linked immunosorbent assay, OR- odds ratio, RR- relative risk, CI- confidence interval, IQR- inter quartile range, Q1 (0-<25th percentile), Q2 (25th-<50th), Q3 (50th-<75th), Q4 (75th-100th), VCSS- Venous Clinical Severity Score.Table S3. Studies analyzing the association between IL-6 and PTSRefAuthor /yearAssociation with PTScomments26Marchena-Yglesias 2006IL-6 ?10pg/ml (cut off for normal value) in 2/43 (4.7%) PTS+ vs. 7/57 (12.3%) PTS -. Comorbidities:16 had cancer, 6 had CHF, 4 had collagen-vascular disease, 2 had sepsis and 1 had inflammatory bowel disease27Roumen-Klappe 2009IL-6?15 pg/ml (80th percentile of day 0 concentration),*adjusted RR 0.6, 95% CI 0.2–1.4.IL-6 levels below detection limit at day 7, 30 and 90 for all patients.*Adjusted for age, sex, BMI, CRP, D-dimer12Shbaklo 2009Mean± SD 7.35 pg/ml±14.26 in PTS+ vs. 4.60 pg/ml±4.90 in PTS-; p=0.03. IL-6?3.04 pg/ml (median level in patients with no PTS) OR 1.66, 95% CI 1.05-2.62; p=0.030. *Adjusted OR 1.55, 95% CI 0.97–2.47; p=0.064.8% of patients had cardiovascular comorbidity, 10% had active cancer.*Adjusted for BMI23Bouman 2014Median 1.6 pg/mL, IQR 1.1-2.8 in PTS+ vs. 1.7 pg/mL, IQR 1.2-2.0 in PTS-; P=0.735.24Bittar 2015Median 1.26 pg/mL, IQR 0.83 - 1.78 in PTS+ vs. 1.14 pg/mL, IQR 0.80 - 2.08 in PTS-; P=0.83.30Rabinovich 2015Day 0, median 5.02 pg/mL, IQR 2.69-10.01 in PTS+ vs. 4.71 pg/mL, IQR 2.40-9.87 in PTS-; P=0.29. IL-6? 4.9 pg/mL (median for all patients) *adjusted RR 1.00 (95% CI 0.85-1.18). *Adjusted RR (95% CI) Q2 vs. Q1 0.96 (0.76-1.22), Q3 vs. Q1 0.97 (0.77-1.23), Q4 vs. Q1 0.99 (0.79-1.26); ?P=0.92. 1 month, median 2.89 pg/mL, IQR 1.71-4.95 in PTS+ vs. 2.45 pg/mL, IQR 1.34-4.16 in PTS-; P=0.005. IL-6? 2.8 pg/mL (median for all patients) *adjusted RR 1.05 (95% CI 0.89-1.25). *Adjusted RR (95% CI) Q2 vs. Q1 1.03 (0.80-1.32), Q3 vs. Q1 1.06 (0.82-1.36), Q4 vs. Q1 1.08 (0.84-1.40); ?P=0.50.6 months, median 2.35 pg/mL, IQR 1.41-4.09 in PTS+ vs. 2.00 pg/mL, IQR 1.20-3.74 in PTS-; P=0.04. IL-6? 2.2pg/mL (median for all patients) *adjusted RR 1.07 (95% CI 0.90-1.28). *Adjusted RR (95% CI) Q2 vs. Q1 1.04 (0.80-1.34), Q3 vs. Q1 1.12 (0.87-1.45), Q4 vs. Q1 1.07 (0.82-1.40); ?P=0.53.* Adjusted for treatment arm (active or placebo stockings), age, sex, BMI, infectious or inflammatory conditions, CHF, stroke or MI within 1 month, smoking, type of DVT (unprovoked, vs. secondary), extent of DVT (popliteal, femoral, common femoral or iliac vein), use of anti-platelet agents, non-steroidal anti-inflammatory drugs, steroids, and statins within 30 days before DVT diagnosis.? P value for trendCHF- congestive heart failure, BMI- body mass index, MI-myocardial infarction ELISA- enzyme linked immunosorbent assay, OR- odds ratio, RR- relative risk, CI- confidence interval, IQR- inter quartile range, SD- standard deviation, Q1 (0-<25th percentile), Q2 (25th-<50th), Q3 (50th-<75th), Q4 (75th-100th).Table S4. Studies analyzing the association between other interleukines and PTSRefAuthor/ yearCytokine Association with PTScomments26Marchena-Yglesias 2006IL-8IL-8?10pg/ml (cut off for normal value) in 1/43 (2.3%) PTS+ vs. 2/57 (3.5%) PTS -. Comorbidities:16 had cancer, 6 had CHF, 4 had collagen-vascular disease, 2 had sepsis and 1 had inflammatory bowel disease12Shbaklo 2009IL-8, IL-10IL-8: mean± SD 4.47pg/ml ± 12.12 in PTS+ vs. 4.14 ± 9.77 in PTS-; p=0.79. Median 1.77pg/ml, IQR 0.35–4.97 in PTS+ vs. 2.10pg/ml, IQR 0.35–4.07 in PTS-; p=0.7863.IL-10: mean± SD 4.53 pg/ml ± 25.13 in PTS + vs. 3.04 ± 7.10 in PTS-; p= 0.47.Median 1.63 pg/ml, IQR 0.94–2.69 in PTS+ vs. 1.52 pg/ml, IQR 0.85–2.89 in PTS-; p= 0.8419.8% of patients had cardiovascular comorbidity, 10% had active cancer.23Bouman 2014IL-8Median 3.0 pg/mL, IQR 2.3-4.8in PTS+ vs. 3.1 pg/mL, IQR 2.8-4.0 in PTS-; p=0.824.24Bittar 2015IL-8Median 23.03 pg/mL, IQR 16.03 - 30.02 in PTS+ vs. 18.20 pg/mL, IQR 10.92 - 22.66 in PTS-; p=0.04.30Rabinovich 2015IL-10Day 0, median 9.57 pg/mL, IQR 5.78-15.14 in PTS+ vs. 8.53 pg/mL, IQR 5.06-14.97 in PTS-;p=0.13. IL-10? 9.2 pg/mL (median for all patients) *adjusted RR 1.08 (95% CI 0.92-1.27). *Adjusted RR (95% CI) Q2 vs. Q1 1.07 (0.85-1.34), Q3 vs. Q1 1.19 (0.95-1.49), Q4 vs. Q1 1.04 (0.82-1.32); ?p=0.48.1 month, median 8.05 pg/mL, IQR 5.27-13.38 in PTS+ vs. 7.44 pg/mL, IQR 4.70-11.49 in PTS-;p=0.08. IL-10? 7.8 pg/mL (median for all patients) *adjusted RR 1.08 (95% CI 0.92-1.27). *Adjusted RR (95% CI) Q2 vs. Q1 1.17 (0.93-1.48), Q3 vs. Q1 1.12 (0.88-1.41), Q4 vs. Q1 1.24 (0.98-1.56); ?p=0.08.6 months median 7.81 pg/mL, IQR 5.16-12.32 in PTS+ vs. 6.47 pg/mL, IQR 4.13-10.91 in PTS-; P=0.003. IL-10? 7.1 pg/mL (median for all patients) *adjusted RR 1.27 (95% CI 1.07-1.51). *Adjusted RR (95% CI) Q2 vs. Q1 1.20 (0.92-1.57), Q3 vs. Q1 1.43 (1.11-1.83), Q4 vs. Q1 1.37 (1.06-1.77); ?p=0.01.* Adjusted for treatment arm (active or placebo stockings), age, sex, BMI, infectious or inflammatory conditions, CHF, stroke or MI within 1 month, smoking, type of DVT (unprovoked, vs. secondary), extent of DVT (popliteal, femoral, common femoral or iliac vein), use of anti-platelet agents, non-steroidal anti-inflammatory drugs, steroids, and statins within 30 days before DVT diagnosis.? P value for trendCHF- congestive heart failure, BMI- body mass index, MI-myocardial infarction ELISA- enzyme linked immunosorbent assay, OR- odds ratio, RR- relative risk, CI- confidence interval, IQR- inter quartile range, SD- standard deviation, Q1 (0-<25th percentile), Q2 (25th-<50th), Q3 (50th-<75th), Q4 (75th-100th).Table S5. Other Markers in association with PTSRefAuthor /yearmarkerAssociation with PTScomments26Marchena-Yglesias 2006ESRESR >20mm/1hr in 14/43 (32.6%) PTS+ vs. 26/57 (45.6%) PTS-; OR 0.40, 95%CI 0.15-1.08; p=0.05. Mean± SD ESR 17.8±14.5mm/1hr PTS+ vs. 31.8±27.4mm/1hr PTS-; p=0.orbidities: 16 had cancer, 6 had CHF, 4 had collagen-vascular disease, 2 had sepsis and 1 had inflammatory bowel disease12Shbaklo2009MCP-1ICAM-1VCAM-1MCP-1: Mean± SD 49.43±40.46pg/mL in PTS+ vs. 50.41±70.37pg/mL in PTS-; p= 0.88. Median 42.44 pg/mL, IQR 30.52–54.36 in PTS+ vs. 38.76 pg/mL, IQR 29.92–51.59 in PTS-; p= 0.5435.ICAM-1: Mean± SD 179.83±56.83 ng/ml in PTS+ vs. 173.40±87.41 ng/mL in PTS-. ICAM-1? 157.62 ng/mL (median levels in patients with no PTS) OR for PTS 1.63, 95% CI 1.03- 2.58; p=0.035. *Adjusted OR 1.74, 95% CI 1.10–2.99; p=0.046.VCAM-1: Mean± SD 377.00±113.16 ng/ml in PTS+ vs. 370.67±113.48 ng/mL in PTS-. Median 358.41 ng/mL, IQR 303.38–424.92 in PTS+ vs. 357.12 ng/mL, IQR 296.88–432.69 in PTS-; p= 0.7462.8% of patients had cardiovascular comorbidity, 10% had active cancer.*Adjusted for BMI23Bouman 2014ICAM-1VCAM-1MMP-9P-selectinICAM-1: Median 266 ng/mL, IQR 240-358 in PTS+ vs. 278 ng/mL, IQR 245-318 in PTS-; p= 0.749.VCAM-1: Median 437ng/mL, IQR 409-553 in PTS+ vs. 427 ng/mL, IQR 364-515 in PTS-; p= 0.337.MMP-9: Median 47ng/mL, IQR 31-75 in PTS+ vs. 38 ng/mL, IQR 32-53 in PTS-; p= 0.244.P-selectin: Median 38 ng/mL, IQR 31-51 in PTS+ vs. 42 ng/mL, IQR 31-55 in PTS-; p= 0.624.24Bittar 2015TNF-αMedian 3.15 pg/mL, IQR 1.93 - 4.41 in PTS+ vs. 2.15 pg/mL, IQR 1.50 - 4.06 in PTS-; p= 0.33.30Rabinovich 2015ICAM-1Day 0, median 292.05 ng/mL, IQR 249.65-348.13 in PTS+ vs. 276.84 ng/mL, IQR 235.76-332.33 in PTS-; p=0.009. ICAM-1? 286ng/mL (median for all patients) *adjusted RR 1.14 (95% CI 0.98-1.34). *Adjusted RR (95% CI) Q2 vs. Q1 1.13 (0.88-1.44), Q3 vs. Q1 1.20 (0.95-1.52), Q4 vs. Q1 1.24 (0.98-1.58); ?P=0.08.1 month, median 281.50 ng/mL, IQR 235.02-337.05 in PTS+ vs. 263.38 ng/mL, IQR 223.72-310.74 in PTS-; p=0.002. ICAM-1? 275ng/mL (median for all patients) *adjusted RR 1.23 (95% CI 1.05-1.45). *Adjusted RR (95% CI) Q2 vs. Q1 0.93 (0.72-1.19), Q3 vs. Q1 1.14 (0.91-1.42), Q4 vs. Q1 1.24 (0.99-1.56); ?p=0.01.6 months, median 265.07 ng/mL, IQR 224.61-321.80 in PTS+ vs. 246.71 ng/mL, IQR 213.00-296.08 in PTS-; p=0.0009. ICAM-1? 257ng/mL (median for all patients) *adjusted RR 1.25 (95% CI 1.05-1.48). *Adjusted RR (95% CI) Q2 vs. Q1 0.99 (0.76-1.29), Q3 vs. Q1 1.16 (0.90-1.49), Q4 vs. Q1 1.33 (1.05-1.68); ?p=0.01.* Adjusted for treatment arm (active or placebo stockings), age, sex, BMI, infectious or inflammatory conditions, CHF, stroke or MI within 1 month, smoking, type of DVT (unprovoked, vs. secondary), extent of DVT (popliteal, femoral, common femoral or iliac vein), use of anti-platelet agents, non-steroidal anti-inflammatory drugs, steroids, and statins within 30 days before DVT diagnosis.? P value for trendCHF- congestive heart failure, BMI- body mass index, ELISA- enzyme linked immunosorbent assay, OR- odds ratio, RR- relative risk, CI- confidence interval, IQR- inter quartile range, SD- standard deviation, ESR- erythrocyte sedimentation rate, MMP-9, matrix metalloprotease 9, TNF-α- Tumor necrosis factor α. ................
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