A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective

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Article

Reference

A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective

multicenter cohort study

SCHNEGG-KAUFMANN, Annatina, et al .

Abstract

Essentials Predictive ability of pro-hemostatic Gas6 for recurrent venous thromboembolism (VTE) is unknown. We measured Gas6 levels in 864 patients with VTE over 3 years. High Gas6 (> 157%) at diagnosis is associated with VTE recurrence, major bleeding and mortality.

Gas6 plasma levels measured 12 months after the index VTE are discriminatory for VTE recurrence. SUMMARY: Background Growth arrest-specific gene 6 (Gas6) is a prohemostatic protein with an unknown predictive ability for recurrent venous thromboembolism (VTE). In the elderly, VTE results in higher mortality but does not have a higher rate of recurrence than in younger patients. Consequently, anticoagulation management in the elderly is challenging.

Objective To prospectively investigate the performance of Gas6 in predicting VTE recurrence, major bleeding and mortality in the elderly. Methods Consecutive patients aged ≥ 65 years with acute VTE were followed for a period of 3 years. Primary outcomes were symptomatic VTE recurrence, major bleeding, and mortality. Plasma Gas6 was measured with ELISA.

Results Gas6 levels were measured in 864 patients at [...]

SCHNEGG-KAUFMANN, Annatina, et al . A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective

multicenter cohort study. Journal of Thrombosis and Haemostasis , 2019, vol. 17, no. 2, p.

306-318

DOI : 10.1111/jth.14365 PMID : 30570809

Available at:

http://archive-ouverte.unige.ch/unige:129138

Disclaimer: layout of this document may differ from the published version.

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Supporting information

Table S1. Incidence rates of VTE recurrence, major bleeding and mortality rates by level of Gas6 measured at the time of the index VTE

Primary

outcome Gas6 level, categorized at the time of the

index VTE

Patients,

n Number of events/ person-

years

Incidence rate (95% confidence interval)

VTE recurrence

Up to 6 months All 864 24 / 398.7 6.0 (4.0 to 9.0)

Low (<109%) 216 2 / 105.2 1.9 (0.5 to 7.6) Medium (109-157%) 435 11 / 202.9 5.4 (3.0 to 9.8) High (>157%) 213 11 / 90.6 12.1 (6.7 to 21.9)

Low (<109%) 216 17 / 386.7 4.4 (2.7 to 7.1) Medium (109-157%) 435 41 / 710.7 5.8 (4.2 to 7.8) High (>157%) 213 25 / 293.2 8.5 (5.8 to 12.6) Up to 36 months All 864 100 / 1778.6 5.6 (4.6 to 6.8)

Low (<109%) 216 26 / 500.1 5.2 (3.5 to 7.6) Medium (109-157%) 435 44 / 915.4 4.8 (3.6 to 6.5) High (>157%) 213 30 / 363.1 8.3 (5.8 to 11.8) Major bleeding

Low (<109%) 216 13 / 200.6 6.5 (3.8 to 11.2) Medium (109-157%) 435 40 / 377.0 10.6 (7.8 to 14.5)

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High (>157%) 213 29 / 158.5 18.3 (12.7 to 26.3)

Low (<109%) 216 20 / 505.1 4.0 (2.6 to 6.1) Medium (109-157%) 435 61 / 898.4 6.8 (5.3 to 8.7) High (>157%) 213 37 / 349.5 10.6 (7.7 to 14.6) Overall mortality

Low (<109%) 216 20 / 528.4 3.8 (2.4 to 5.9) Medium (109-157%) 435 73 / 967.4 7.5 (6.0 to 9.5) High (>157%) 213 77 / 386.6 19.9 (15.9 to 24.9) Abbreviations: VTE, venous thromboembolism

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Table S2. Sensitivity analyses: from baseline onward using baseline Gas6 (T1), excluding patients with cancer

n/N (%) Crude SHR or HR (95%-CI) P

value Adjusted SHR

or HR (95%-CI) P value VTE recurrence

Up to 6 months Gas6 T1

(categorized) Low (<109%) 2/191 (1.0) Ref. Ref.

Medium (109-

157%) 9/370 (2.4) 2.35 (0.51 to

10.91) 0.274 2.50 (0.51 to

12.30) 0.261

High (>157%) 9/146 (6.2) 6.10 (1.31 to

28.27) 0.021 6.52 (1.39 to

30.70) 0.018

Log-transformed

Gas6 T1 Continuous (per

log-unit) 20/707

(2.8) 5.33 (1.96 to

14.52) 0.001 5.25 (2.03 to

13.62) 0.001

Medium (109-

157%) 19/370

(5.1) 1.43 (0.60 to

3.40) 0.415 1.43 (0.58 to

3.49) 0.438

High (>157%) 14/146

(9.6) 2.78 (1.13 to

6.88) 0.027 2.75 (1.05 to

7.22) 0.039

Log-transformed

log-unit) 40/707

(5.7) 3.12 (1.28 to

7.62) 0.012 2.88 (1.14 to

7.27) 0.026

Major bleeding Up to 6 months Gas6 T1

Medium (109-

157%) 23/370

(6.2) 2.02 (0.82 to

4.97) 0.125 1.84 (0.74 to

4.59) 0.193

High (>157%) 13/146

(8.9) 2.91 (1.11 to

7.65) 0.030 2.55 (0.89 to

7.30) 0.081

Log-transformed

log-unit) 42/707

(5.9) 2.64 (1.07 to

6.46) 0.034 2.42 (0.86 to

6.79) 0.094

(categorized) Low (<109%) 10/191

(5.2) Ref. Ref.

Medium (109-

157%) 29/370

(7.8) 1.54 (0.75 to

3.15) 0.239 1.43 (0.69 to

2.94) 0.334

High (>157%) 19/146

(13.0) 2.60 (1.22 to

5.58) 0.014 2.30 (1.03 to

5.12) 0.041

Log-transformed

log-unit) 58/707

(8.2) 2.74 (1.24 to

6.06) 0.013 2.47 (1.04 to

5.91) 0.042

(6.8) Ref. Ref.

Medium (109-

157%) 40/370

(10.8) 1.65 (0.88 to

3.08) 0.116 1.53 (0.81 to

2.86) 0.187

High (>157%) 22/146

(15.1) 2.36 (1.19 to

4.68) 0.014 2.10 (1.03 to

4.28) 0.040

Log-transformed

log-unit) 75/707

(10.6) 2.37 (1.20 to

4.68) 0.013 2.12 (1.02 to

4.44) 0.045

Overall mortality Up to 6 months Gas6 T1

Medium (109-

157%) 15/370

(4.1) 7.94 (1.05 to

59.88) 0.044 9.13 (2.39 to

34.83) 0.001

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4 High (>157%) 14/146

(9.6) 19.53 (2.58 to

147.75) 0.004 19.97 (5.32 to

75.04) <0.001 Log-transformed

log-unit) 30/707

(4.2) 8.33 (4.06 to

17.08) <0.001 8.39 (2.88 to

24.49) <0.001 Up to 12 months

Gas6 T1

Medium (109-

157%) 21/370

(5.7) 5.61 (1.32 to

23.81) 0.019 4.90 (1.35 to

17.82) 0.016

High (>157%) 17/146

(11.6) 12.06 (2.80 to

51.94) 0.001 11.00 (2.99 to

log-unit) 40/707

(5.7) 6.94 (3.64 to

13.22) <0.001 7.47 (3.03 to

18.43) <0.001 Up to 24 months

Gas6 T1

Medium (109-

157%) 35/370

(9.5) 2.76 (1.23 to

6.15) 0.013 2.22 (1.00 to

4.92) 0.049

High (>157%) 30/146

(20.5) 6.40 (2.84 to

14.45) <0.001 5.01 (2.14 to

log-unit) 72/707

(10.2) 7.72 (4.25 to

14.02) <0.001 7.98 (3.94 to

16.15) <0.001 Up to 36 months

Gas6 T1

(5.8) Ref. Ref.

Medium (109-

157%) 42/370

(11.4) 2.12 (1.10 to

4.08) 0.024 1.59 (0.82 to

3.08) 0.173

High (>157%) 34/146

(23.3) 4.75 (2.43 to

9.29) <0.001 3.47 (1.71 to

7.06) 0.001

Log-transformed

log-unit) 87/707

(12.3) 5.70 (3.10 to

10.47) <0.001 5.15 (2.52 to

10.53) <0.001 Abbreviations: Ref., Reference; T1, baseline; VTE, venous thromboembolism

Adjustments: VTE recurrence was adjusted for age, provoked VTE, prior VTE, overt PE, renal disease, and periods of AC (oral or parenteral anticoagulation) as a time-varying covariate.(1-12)

Major bleeding was adjusted for age, provoked VTE, prior VTE, overt PE, renal disease, history of majorbleeding, anemia, antiplatelet therapy, and periods of AC as a time-varying covariate.

Mortality was adjusted for age, gender, provoked VTE, prior VTE, overt PE, renal disease, history of major bleeding, heart failure, chronic lung disease, high pulse, low blood pressure, low oxygen, and periods of anticoagulation as a time-varying covariate.(7, 12)

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Table S3. Sensitivity analyses: from baseline onward using baseline Gas6 (T1), excluding patients with cancer and provoked VTE

n/N (%) Crude SHR or

HR (95%-CI) p-value Adjusted SHR or HR (95%-CI)

P value

VTE recurrence Up to 6 months Gas6 T1

Medium (109-

157%) 7/275 (2.5) 1.85 (0.38 to

8.92) 0.443 2.05 (0.39 to

10.79) 0.399

High (>157%) 7/104 (6.7) 4.99 (1.04 to

24.06) 0.045 5.03 (1.03 to

24.54) 0.046

Log-transformed

log-unit) 16/522

(3.1) 4.78 (1.64 to

13.92) 0.004 4.37 (1.60 to

11.90) 0.004

Medium (109-

157%) 17/275

(6.2) 2.28 (0.77 to

6.80) 0.139 2.22 (0.73 to

6.81) 0.162

High (>157%) 11/104

(10.6) 4.04 (1.28 to

12.73) 0.017 3.69 (1.14 to

11.98) 0.029

Log-transformed

log-unit) 32/522

(6.1) 4.12 (1.80 to

9.42) 0.001 3.51 (1.47 to

8.38) 0.005

Major bleeding Up to 6 months Gas6 T1

Medium (109-

157%) 18/275

(6.5) 3.20 (0.94 to

10.91) 0.063 2.92 (0.85 to

10.00) 0.088

High (>157%) 8/104 (7.7) 3.78 (1.00 to

14.30) 0.050 3.44 (0.86 to

13.73) 0.080

Log-transformed

log-unit) 29/522

(5.6) 2.38 (0.89 to

6.38) 0.085 2.36 (0.76 to

7.31) 0.135

Medium (109-

157%) 21/275

(7.6) 2.27 (0.86 to

6.01) 0.099 2.11 (0.80 to

5.57) 0.132

High (>157%) 12/104

(11.5) 3.47 (1.23 to

9.81) 0.019 3.12 (1.10 to

8.88) 0.033

Log-transformed

log-unit) 38/522

(7.3) 2.52 (1.02 to

6.18) 0.044 2.42 (0.92 to

6.41) 0.074

Medium (109-

157%) 30/275

(10.9) 2.07 (0.95 to

4.49) 0.067 1.90 (0.88 to

4.12) 0.102

High (>157%) 15/104

(14.4) 2.78 (1.18 to

6.53) 0.019 2.45 (1.03 to

5.81) 0.042

Log-transformed

log-unit) 53/522

(10.2) 2.17 (1.03 to

4.56) 0.042 1.95 (0.88 to

4.34) 0.101

Overall mortality Up to 6 months Gas6 T1

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6 Medium (109-

157%) 12/275

(4.4) 6.41 (0.84 to

49.01) 0.074 9.02 (2.53 to

32.18) 0.001

High (>157%) 10/104

(9.6) 14.80 (1.91 to

114.82) 0.010 13.63 (2.93 to

63.39) 0.001

Log-transformed

log-unit) 23/522

(4.4) 7.21 (3.17 to

16.38) <0.001 6.57 (1.63 to

26.55) 0.008

Medium (109-

157%) 17/275

(6.2) 4.60 (1.07 to

19.78) 0.040 4.59 (1.16 to

18.17) 0.030

High (>157%) 12/104

(11.5) 9.02 (2.03 to

40.06) 0.004 7.40 (1.71 to

32.12) 0.008

Log-transformed

log-unit) 31/522

(5.9) 5.91 (2.81 to

12.39) <0.001 5.68 (1.68 to

19.21) 0.005

Medium (109-

157%) 27/275

(9.8) 2.15 (0.95 to

4.90) 0.067 1.83 (0.80 to

4.18) 0.153

High (>157%) 21/104

(20.2) 4.72 (2.03 to

10.99) <0.001 3.53 (1.42 to

8.79) 0.007

Log-transformed

log-unit) 55/522

(10.5) 6.47 (3.26 to

12.82) <0.001 6.58 (2.69 to

16.08) <0.001 Up to 36 months

Gas6 T1

(7.0) Ref. Ref.

Medium (109-

157%) 32/275

(11.6) 1.80 (0.89 to

3.62) 0.100 1.44 (0.70 to

2.96) 0.321

High (>157%) 25/104

(24.0) 4.05 (1.97 to

8.35) <0.001 2.93 (1.34 to

6.40) 0.007

Log-transformed

log-unit) 67/522

(12.8) 5.23 (2.63 to

10.40) <0.001 4.74 (2.04 to

11.02) <0.001 Abbreviations: Ref., Reference; T1, baseline; VTE, venous thromboembolism

Adjustments: VTE recurrence was adjusted for age, prior VTE, overt PE, renal disease, and periods of AC (oral or parenteral anticoagulation) as a time-varying covariate.(1-12) Major bleeding was adjusted for age, prior VTE, overt PE, renal disease, history of major bleeding, anemia, antiplatelet therapy, and periods of AC as a time-varying covariate.(9, 13-27) Mortality was adjusted for age, gender, prior VTE, overt PE, renal disease, history of major bleeding, heart failure, chronic lung disease, high pulse, low blood pressure, low oxygen, and periods of anticoagulation as a time-varying covariate.(7, 12)

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Table S4. Association between Gas6 measured 12 months after the index VTE in patients off oral anticoagulation and VTE recurrence from 12 months after the index VTE onward

n/N (%) Crude SHR

(95%-CI) p-

value Adjusted SHR

(95%-CI) P

value Up to 12 months

Gas6 T2

(categorized) Low (<77%) 1/34 (2.9) Reference Reference Medium (77-

112%) 14/151

(9.3) 3.22 (0.41 to

25.19) 0.264 3.08 (0.40 to

23.92) 0.282

High (>112%) 10/81

(12.3) 4.40 (0.55 to

35.31) 0.164 4.25 (0.53 to

34.40) 0.175

Log-transformed

log-unit) 25/266

(9.4) 6.78 (1.14 to

40.11) 0.035 8.27 (1.33 to

51.44) 0.024

(categorized) Low (<77%) 2/34 (5.9) Reference Reference Medium (77-

112%) 20/151

(13.2) 2.30 (0.54 to

9.88) 0.261 2.11 (0.50 to

8.94) 0.309

High (>112%) 13/81

(16.0) 2.82 (0.63 to

12.55) 0.174 2.82 (0.63 to

12.58) 0.173

Log-transformed

log-unit) 35/266

(13.2) 3.69 (0.84 to

16.19) 0.083 4.68 (1.00 to

21.83) 0.050

Abbreviation: VTE, venous thromboembolism

Adjustments: VTE recurrence was adjusted for age, cancer, provoked VTE, prior VTE, and periods of AC (oral or parenteral anticoagulation) as a time-varying covariate.(1-12)

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Supplementary Figure: Relative subhazards for VTE recurrence and relative hazards for overall mortality. (A) Relative subhazards for VTE recurrence up to 12 months. Subhazard

ratios with 95% confidence intervals from a fractional polynomial competing risk model with robust standard errors. (B) Hazard ratios with 95% confidence intervals from a fractional polynomial Cox-proportional hazards model with robust standard errors.

Gas6 values measured at the time of the index VTE (T1) were log-transformed and centered

at the mean. The plot was truncated at the 2.5

^th

and 97.5

^th

percentile of Gas6 (75.1% and

258.1%, respectively). Both axes are shown on a natural-log scale.

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11 Supplementary Figure

A

B

.25.5124Crude subhazard ratio

80 100 120 140 160 180 200 220 240 260 Gas6 T1 [%]

.25.5124Crude hazard ratio

80 100 120 140 160 180 200 220 240 260 Gas6 T1 [%]