Development and Validation of a Novel Prognostic Score Based on Thrombotic and Inflammatory Biomarkers for Predicting 28-Day Adverse Outcomes in Patients with Acute Pancreatitis

Figures & data

Table 1 Characteristics of Patients in the Derivation Group According to the Severity of Acute Pancreatitis

Variable	MAP (n=58)	MSAP (n=129)	SAP (n=253)	P-value
Baseline variables
Age (years)	47.0 (39.8–58.3)	46.0 (38.0–55.0)	48.0 (39.5–59.0)	0.518
Male, n (%)	32 (55.2%)	75 (58.1%)	160 (63.2%)	0.410
Etiology, n (%)				0.108
Gallstone	15 (25.9%)	44 (34.1%)	95 (37.6%)
Hyperlipemia	25 (43.1%)	53 (41.1%)	85 (33.6%)
Alcohol abuse	3 (5.1%)	13 (10.1%)	34 (13.4%)
Unknown	15 (25.9%)	19 (14.7%)	39 (15.4%)
BMI	24.6 (22.3–27.3)	26.0 (23.4–28.2)	25.8 (23.2–27.7)	0.175
Temperature (°C)	36.6 (36.4–37.0)	36.7 (36.4–37.1)	36.8 (36.5–37.3)	0.109
Heart rate (beats/min)	93.0 (±19.6)	97.3 (±21.5)	110.0 (±24.1)	<0.001
Breathing rate (beats/min)	20.0 (20.0–21.0)	20.0 (20.0–22.0)	22.0 (20.0–26.0)	<0.001
MAP (mmHg)	97.8 (±14.8)	97.4 (±14.1)	99.0 (±15.6)	0.590
SPO2 (%)	96.0 (94.0–98.0)	96.0 (93.0–97.5)	95.0 (92.0–97.0)	0.006
WBCs (10^9/L)	11.10 (8.38–14.51)	13.61 (9.71–16.62)	13.45 (10.48–17.48)	0.012
PLT (10^9/L)	165.00 (122.75–212.75)	160.00 (125.00–201.50)	159.00 (120.50–209.50)	0.916
Hb (g/L)	130.97 (±22.44)	134.41 (±20.99)	131.08 (±32.45)	0.528
HCT (%)	39 (35–42)	39 (36–42)	39 (33–45)	0.823
TBIL (μmol/L)	17.80 (12.85–24.65)	19.40 (12.05–28.70)	21.30 (13.60–38.35)	0.014
ALT (IU/L)	29.00 (18.75–52.50)	27.00 (16.50–50.00)	37.00 (18.00–76.00)	0.091
AST (IU/L)	27.00 (19.00–39.25)	28.00 (19.00–46.50)	42.00 (25.00–88.00)	<0.001
Albumin (g/L)	41.70 (36.25–45.10)	38.90 (34.20–42.55)	34.60 (29.75–39.00)	<0.001
Cr (μmol/L)	63.50 (53.50–79.00)	65.00 (49.50–81.50)	72.00 (57.00–107.00)	<0.001
BUN (mg/dL)	4.61 (3.24–5.37)	4.28 (2.93–5.90)	5.40 (3.74–8.33)	<0.001
CHOL (mmol/L)	4.61 (3.24–5.37)	4.28 (2.93–5.90)	5.40 (3.74–8.33)	0.011
HDL-C (mmol/L)	1.00 (0.72–1.30)	0.97 (0.76–1.20)	0.66 (0.40–1.09)	<0.001
LDL-C (mmol/L)	1.60 (0.75–2.41)	1.61 (0.92–2.36)	1.33 (0.66–2.21)	0.146
LIP (IU/L)	132.50 (57.00–557.25)	212.00 (94.50–647.50)	329.00 (92.00–1071.00)	0.001
AMY (IU/L)	126.00 (68.50–312.25)	174.00 (87.50–473.50)	310.00 (90.00–922.50)	0.001
Ca (mmol/L)	2.17 (2.05–2.33)	2.15 (2.02–2.28)	2.01 (1.82–2.17)	<0.001
PT (s)	12.10 (11.55–12.95)	12.70 (11.95–13.40)	13.40 (12.20–14.70)	<0.001
APTT (s)	30.35 (27.25–33.43)	29.70 (27.15–33.60)	31.20 (28.10–36.45)	0.016
Fib (g/L)	3.73 (3.05–4.77)	4.38 (3.06–6.72)	4.51 (3.35–6.96)	0.060
D-dimer (mg/L)	1.19 (0.40–2.62)	2.59 (1.00–5.00)	4.41 (2.19–8.69)	<0.001
CRP (mg/L)	88.40 (28.40–157.25)	135.00 (49.50–230.00)	189.00 (118.00–289.00)	<0.001
PCT (ng/mL)	0.14 (0.07–0.41)	0.28 (0.09–0.92)	0.70 (0.29–2.58)	<0.001
IL-6 (pg/mL)	41.84 (16.76–91.25)	55.19 (16.79–143.05)	109.40 (55.37–223.95)	<0.001
Lac (mmol/L)	1.30 (1.20–1.80)	1.40 (1.20–1.90)	1.70 (1.30–2.60)	<0.001
Scores
APACHE II	4 (3–7)	5 (3–7)	8 (5–11)	<0.001
SOFA	2 (1–3)	2 (1–4)	4 (2–6)	<0.001
BISAP	1 (1–2)	2 (1–2)	2 (2–3)	<0.001
Outcomes
Death, n (%)	0 (0.0%)	1 (0.8%)	26 (10.3%)	<0.001
MV, n (%)	0 (0.0%)	4 (3.1%)	130 (51.4%)	<0.001
ICU admission, n (%)	0 (0.0%)	4 (3.1%)	79 (31.2%)	<0.001

Abbreviations: BMI, body Mass Index; SPO₂, oxygen saturation; WBC, white blood cell; PLT, platelets; HB, hemoglobin; HCT, hematocrit; TBIL, total bilirubin; Cr, creatinine; BUN, blood urea nitrogen; CHOL, cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LIP, lipase; AMY, amylase; Ca, calcium; PT, prothrombin time; APTT, activated partial thromboplastin time; Fib, fibrinogen; PCT, procalcitonin (PCT); CRP, C-reactive protein; IL-6, interleukin-6; LAC, lactate; APACHE II, Acute physiology and chronic health evaluation scoring system; SOFA, Sequential Organ Failure Assessment; BISAP, bedside index for severity in AP; MV, Mechanical ventilation; ICU, Intensive Care Unit.

Figure 1 Receiver operating characteristic curve analysis of the prediction of 28-day mortality using inflammatory biomarkers (IL-6, CPR, PCT and WBC).

Figure 2 Receiver operating characteristic curve analysis of the prediction of 28-day mortality using thrombotic biomarkers (PT, APTT, Fib, D-dimer and PLT).

Table 2 Method for Calculating the Thrombo-Inflammatory Prognostic Score (TIPS) Using PT and IL-6 Levels

PT (s)	IL-6 (pg/mL)	TIPS
<13.65	<78	0
<13.65	≥78	1
≥13.65	<78	1
≥13.65	≥78	2

Abbreviations: TIPS, thrombo-inflammatory prognostic score; PT, prothrombin time; IL-6, interleukin-6.

Table 3 Comparison Among Patients with Different “TIPS” Values (Derivation Group)

Variable	TIPS 0 (n=158)	TIPS 1 (n=188)	TIPS 2 (n=94)	P-value
General information
Age (years)	46.0 (36.0–57.3)	45.0 (39.0–55.0)	51.5 (42.8–62.3)	0.017
Male, n (%)	87 (55%)	117 (62%)	31 (67%)	0.145
BMI	25.8 (23.4–28.2)	25.6 (22.5–27.6)	25.7 (24.1–27.7)	0.186
Temperature (°C)	36.6 (36.4–37)	36.8 (36.5–37.2)	36.8 (36.5–37.3)	0.002
Heart rate (beats/min)	92.66 (±22.05)	107.84 (±21.90)	115.52 (±22.75)	<0.001
Breathing rate (beats/min)	20.0 (20.0–22.0)	22.0 (20.0–25.0)	23.0 (20.0–28.0)	<0.001
MAP (mmHg)	98.43 (±15.00)	99.11 (±15.33)	96.94 (±14.61)	0.520
SPO2 (%)	96.00 (93.00–97.25)	95.00 (92.00–97.00)	95.00 (93.00–97.00)	0.118
Laboratory examination
WBCs (10^9/L)	11.43 (8.42–15.25)	14.01 (10.63–17.38)	14.31 (10.62–19.05)	<0.001
PLT (10^9/L)	169.00 (128.75–221.50)	159.50 (123.25–199.75)	146.00 (99.75–202.50)	0.069
Hb (g/L)	128.98 (±22.06)	133.85 (±30.00)	133.59 (±33.50)	0.235
HCT (%)	0.38 (0.35–0.42)	0.39 (0.34–0.44)	0.40 (0.33–0.46)	0.202
TBIL (μmol/L)	18.25 (12.13–28.05)	20.80 (13.40–32.50)	23.65 (14.10–43.58)	0.058
ALT (IU/L)	31.00 (17.83–94.25)	28.50 (18.00–51.75)	35.00 (16.00–78.75)	0.426
AST (IU/L)	31.00 (21.00–72.75)	32.00 (22.00–56.00)	44.00 (24.50–89.25)	0.080
Albumin (g/L)	39.45 (34.75–43.85)	35.60 (30.70–39.88)	34.40 (29.78–37.70)	<0.001
Cr (μmol/L)	64.00 (51.00–75.25)	65.50 (52.00–89.00)	104.50 (67.00–166.25)	<0.001
BUN (mg/dL)	4.56 (3.12–5.52)	4.69 (3.21–6.57)	7.70 (4.51–11.71)	<0.001
CHOL (mmol/L)	4.42 (3.50–5.53)	4.00 (3.19–7.00)	3.48 (2.37–5.49)	0.002
HDL-C (mmol/L)	0.98 (0.60–1.32)	0.80 (0.48–1.11)	0.71 (0.39–1.06)	<0.001
LDL-C (mmol/L)	1.94 (1.27–2.62)	1.26 (0.63–2.10)	1.04 (0.52–1.59)	<0.001
LDH (U/L)	243.50 (181.75–386.75)	348.50 (247.50–512.00)	397.00 (243.50–620.00)	<0.001
LIP (IU/L)	177.50 (77.00–748.00)	243.00 (88.50–764.75)	450.50 (140.75–1069.50)	0.017
AMY (IU/L)	151.50 (81.50–424.25)	228.00 (80.00–634.00)	476.50 (103.00–934.25)	0.003
Ca (mmol/L)	2.19 (2.04–2.30)	2.05 (1.88–2.18)	1.96 (1.78–2.14)	<0.001
PT (s)	12.30 (11.50–12.90)	12.80 (12.00–13.80)	14.65 (14.00–16.20)	<0.001
APTT (s)	29.00 (26.80–31.65)	30.85 (28.03–34.20)	35.40 (30.45–39.63)	<0.001
Fib (g/L)	4.07 (2.94–6.17)	4.55 (3.46–6.96)	4.66 (3.46–6.96)	0.018
D-dimer (mg/L)	2.12 (0.85–4.83)	3.79 (1.62–6.77)	4.60 (2.66–10.28)	<0.001
CRP (mg/L)	77.95 (25.10–148.50)	195.00 (125.25–306.50)	227.50 (146.50–309.75)	<0.001
PCT (ng/mL)	0.17 (0.08–0.44)	0.62 (0.27–1.58)	1.46 (0.32–5.84)	<0.001
IL-6 (pg/mL)	25.81 (12.24–51.02)	125.20 (71.67–212.90)	191.95 (113.43–306.00)	<0.001
Lac (mmol/L)	1.35 (1.10–1.60)	1.70 (1.30–2.50)	2.00 (1.50–2.93)	<0.001

Abbreviations: BMI, body Mass Index; SPO2, oxygen saturation; WBC, white blood cells; PLT, platelets; HB, hemoglobin; HCT, hematocrit; TBIL, total bilirubin; Cr, creatinine; BUN=blood urea nitrogen; CHOL, cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LDH, lactic dehydrogenase; LIP, lipase; AMY, amylase; Ca, calcium; PT, prothrombin time; APTT, activated partial thromboplastin time; Fib, fibrinogen; PCT, procalcitonin (PCT); CRP, C-reactive protein; IL-6, interleukin 6; LAC, lactate.

Figure 3 Correlation coefficient heat map of APACHE II, SOFA, BISAP and Balthazar CT scores with the TIPS. **P<0.001.

Abbreviations: APACHE II, acute physiology and chronic health evaluation II; SOFA, sequential organ failure assessment; BISAP=bedside index for severity in acute pancreatitis; TIPS, thrombo-inflammatory prognostic score.

Figure 4 The 28-day mortality (A), AICU (B), MV (C), and POF (D) rates in individuals with different TIPS values. *P<0.05, ***P<0.001.

Abbreviations: AICU, admission to intensive care unit; MV, mechanical ventilation; POF, persistent organ failure; TIPS, thrombo-inflammatory prognostic score.

Table 4 Logistic Regression Analysis Regarding Correlations Between Clinical Outcomes and TIPS

Clinical Outcomes	TIPS
	OR	95% CI for OR		P-value
		Lower	Upper
28-day mortality
Unadjusted	10.476	4.414	24.866	<0.001
Adjusted^a	11.796	4.695	29.637	<0.001
AICU
Unadjusted	3.023	2.116	4.320	<0.001
Adjusted^a	2.922	2.026	4.215	<0.001
MV
Unadjusted	2.896	2.135	3.927	<0.001
Adjusted^a	2.874	2.095	3.941	<0.001
POF
Unadjusted	2.774	2.071	3.714	<0.001
Adjusted^a	2.761	2.051	3.717	<0.001

Note: ^aRisk factors adjustment included age, gender, BMI, etiology.

Abbreviations: TIPS, thrombo-inflammatory prognostic score; AICU, admission to intensive care unit; MV, mechanical ventilation; POF, persistent organ failure; OR, odds ratio; IC, confidence interval.

Figure 5 AUCs of the prediction of 28-day mortality based on the TIPS, APACHE II, SOFA, BISAP and Balthazar CT scores.

Abbreviations: TIPS, thrombo-inflammatory prognostic score; APACHE II, acute physiology and chronic health evaluation II; SOFA, sequential organ failure assessment; BISAP, bedside index for severity in acute pancreatitis.

Table 5 Comparison Among Patients with Different “TIPS” Values (Validation Group, n = 358)

28-Day Clinical Outcomes of AP	TIPS 0 (n=139)	TIPS 1 (n=144)	TIPS 2 (n=75)	p-value
Proportion of mortality, % (n)	0 (0)	9.7% (14)	21.3% (16)	<0.001
Proportion of MV, % (n)	7.2% (10)	27.1% (39)	57.3% (43)	<0.001
Proportion of AICU, % (n)	5.0% (7)	15.3% (22)	34.7% (26)	<0.001
Proportion of POF, % (n)	6.5% (9)	34.0% (49)	70.7% (53)	<0.001

Abbreviations: TIPS, thrombo-inflammatory prognostic score; MV, mechanical ventilation; AICU, admission to intensive care unit; POF, persistent organ failure.