Portal Vein Thrombosis in Patients with Liver Cirrhosis: What Went Wrong?

Figures & data

Figure 1 The study participants inclusion flow-chart.

Abbreviation: SARS-COV2, severe acute respiratory syndrome-coronavirus 2.

Table 1 Demographic and Biologic Characteristics in Research Participants

Variables	PVT +	PVT -	CON	P1 PVT+ vs. CON	P2 PVT- vs. CON	P3PVT+ vs. PVT-
Age (years)	61.48±10.73	57.18±8.05	56.52±5.12	<0.0001	0.4899	0.0256
Gender ratio M/W	76%/24%	64%/36%	61%/39%	0.0027	0.6621	0.3594
U/R residence	68%/32%	68%/32%	78%/18%	0.1121	0.1121	1
Hb (g/dl)	10.75±1.49	10.89±2.38	12.56±1.02	<0.0001	<0.0001	0.7148
L/mm^3	7.33x10^3±2.94x10^3	6.30 × 10^3±1.84 × 10^3	5.8 × 10^3±0.9 x10^3	<0.0001	0.0155	0.0395
Plt/mm^3	196.32x10^3±152.92x10^3	240.10 × 10^3±104.18 × 10^3	285.50 × 10^3± 48.30 × 10^3	<0.0001	0.0051	0.0975
Plt<150x10^3	44%	36%	0%	<0.0001	<0.0001	0.4166
ALT (IU)	60.98±87.80	60.20±18.12	18. 78±5.22	<0.0001	<0.0001	0.9511
CRP (mg/dl)	1.68±1.15	0.52±0.11	0.21±0.03	<0.0001	<0.0001	<0.0001
TNF-alpha (pg/ml^2)	9.77±1.48	8.32±0.77	3.43±0.44	<0.0001	<0.0001	<0.0001
Creat (mg/dl)	1.17±0.78	1.03±0.40	0.71±0.09	<0.0001	<0.0001	0.2395
FPG (mg/dl)	102.10±23.97	97.80±8.55	87.21±5.67	<0.0001	<0.0001	0.2416
D-D (µg/mL)	0.72±1.27	0.24±0.05	0.13±0.014	<0.0001	<0.0001	0.0093
Alb (g/l)	3.31±0.54	3.61±0.36	4.81±0.25	<0.0001	<0.0001	0.0024
TB (mg/dl)	2.13±2.65	1.80±0.88	0.77±0.02	<0.0001	<0.0001	0.41
INR	1.678±1.448	1.138±0.199	0.92±0.05	<0.0001	<0.0001	0.0104
AFP (µg/mL)	7.455±4.768	7.222±3.993	2.54±0.49	<0.0001	<0.0001	0.7083
Overall DB	2.01±0.89	1.48±0.73	0.31±0.44	<0.0001	<0.0001	<0.0001
Increased LPS + bacteria (%)	53%	26%	0%	<0.0001	<0.0001	0.0001

Note: Bold p values indicate statistically significant.

Abbreviations: PVT, portal vein thrombosis; CON, controls; M/W, Men/Women; U/R, Urban/Rural; Hb, hemoglobin; L, leukocytes; Plt, platelets; ALT, alanine-aminotransferase; CRP, C-reactive protein; create, creatinine; TNF, tumor necrosis factor; FPG, fast plasma glucose; D-D, D-dimers; alb, albumin; TB, total bilirubin; INR, international normalized ratio; AFP, alpha-fetoprotein; DB, dysbiosis; LPS, lipopolysaccharides; g/dl, grams/deciliter; mm, millimeter; IU, international units; mg/dl, milligrams/deciliter; µg/mL, micrograms/milliliter; pg/mL, picograms/milliliter; ng/mL, nanograms/milliliter.

Table 2 Clinical Aspects in Research Population

Clinical Data	PVT (+)	PVT (-)	p
Smoking history	60%	32%	0.0052
BMI>30kg/m2	32%	10%	0.0072
Admission by ER	52%	24%	0.04
Variceal bleeding	48%	20%	0.03
Abdominal pain	1.48±0.86	0.66±0.52	<0.0001
Ascites	1.36±1.01	0.7±0.65	0.0002
Overt Encephalopathy	68%	48%	0.0438
Jaundice	38%	32%	0.5315
Child-Pugh score	10.06±2.50	8.68±2.22	0.0044
Viral etiology	24%	28%	0.6501
Toxic etiology (alcohol)	20%	28%	0.3514
Mixed toxic and viral etiology	24%	32%	0.3754
NAFLD related cirrhosis	30%	11%	0.0009
Miscellaneous etiology	2%	1%	0.5617
G-I associated conditions	52%	48%	0.6906
Complicated GSD	18%	0%	0.0018
Pancreatitis	4%	0%	0.1567
T2DM/IGT	48%	28%	0.0404
CKD	32%	28%	0.6641
C-V conditions	56	52	0.6897
Endoscopic Treatment	38%	12%	0.0028
Bleeding recurrence	4%	0%	0.1567
ACT	48%	0%	<0.0001
Insulin	8%	3%	0.1219
OAD Metformin	2%	10%	0.0175
Statins	11%	22%	0.0366
Inpatient mortality	8%	4%	0.4021
Outcome scoring	1.98±0.82	1.56±0.76	0.0093

Note: Bold p values indicate statistically significant.

Abbreviations: PVT, portal vein thrombosis; BMI, body mass index; NAFLD, nonalcoholic fatty liver disease; LC, liver cirrhosis; G-I, gastro-intestinal; GSD, gallstone disease; T2DM, type 2 diabetes mellitus; IGT, impaired glucose tolerance; CKD, chronic kidney disease; C-V, cardio-vascular; ACT, anticoagulant treatment; OAD, oral antidiabetics.

Table 3 Stool’s Microbiota Alterations in Study Group

Variables	Dysbiotic Patients with PVT
Overall DB score	2.31±0.52
F/B	2.77±0.68
Decreased F/B	64%
Enterotype 1	45%
Enterotype 2	43%
Enterotype 3	12%
Biodiversity Shannon-Wiener H index	2.68±0.51
Decreased Shannon-Wiener H index	76%
Increased LPS (+) bacteria	63%
Decreased mucin degrading bacteria	42%
Decreased mucosa protective bacteria	38%
Increased neuroactive bacteria	44%

Abbreviations: PVT, portal vein thrombosis; F/B, Firmicutes/Bacteroidetes; DB, dysbiosis; LPS, lipopolysaccharides.

Table 4 Morphologic Particularities of PVT in Study Group

Variables	Incidence
Occlusive	8%
Non occlusive	92%
Main portal vein thrombosis	78%
PV branches
Left	16%
Right	4%
Both	8%
Association main trunk - portal branches	16%
Mesenteric veins extension	4%
Acute	12%
Chronic without portal cavernoma	72%
Chronic with portal cavernoma	16%
Portal biliopathy	12%

Abbreviation: PV, portal veins.

Figure 2 Distribution of mucosa protective bacteria in patients with LC.

Abbreviation: PVT, portal vein thrombosis.

Figure 3 Distribution of neuroactive bacteria in patients with LC.

Abbreviation: PVT, portal vein thrombosis.

Figure 4 Distribution of mucin degrading bacteria in patients with LC.

Abbreviation: PVT, portal vein thrombosis.

Figure 5 Distribution of LPS (+) bacteria in patients with LC.

Abbreviations: LPS, lipopolysaccharide; PVT, portal vein thrombosis.

Figure 6 Correlations of PVT severity to biomarkers.

Abbreviations: PVT, portal vein thrombosis; AFP, alpha-fetoprotein; D-D, D-dimers; CRP, C-reactive protein; TNF, tumor necrosis factor.

Figure 7 Correlations of PVT severity to various clinical aspects.

Abbreviations: PVT, portal vein thrombosis; EV, esophageal varices; ABD, abdominal; EPH, encephalopathy.

Figure 8 LPS positive bacteria correlations in PVT group.

Abbreviations: LPS, lipopolysaccharide; PVT, portal vein thrombosis; AFP, alpha-fetoprotein; CRP, C-reactive protein; TNF, tumor necrosis factor.

Table 5 The Multivariate Analysis of the Clinical Variables

Table Analyzed	Multiple Regression of Clinical Variables
Dependent variable	PVT
Regression type	Least squares
Model
Analysis of Variance	SS	DF	MS	F (DFn, DFd)	P value
Regression	14.47	4	3.616	F (4, 95) = 21.78	P<0.0001
EV	3.546	1	3.546	F (1, 95) = 21.36	P<0.0001
Abd pain	0.7681	1	0.7681	F (1, 95) = 4.626	P=0.0340
E	0.3170	1	0.3170	F (1, 95) = 1.909	P = 0.1703
Age	2.640	1	2.640	F (1, 95) = 15.90	P = 0.0001
Residual	15.77	95	0.1661
Total	30.24	99
Parameter estimates	Variable	Estimate	Standard error	95% CI (asymptotic)	|t|	P value	P value summary
β0	Intercept	−1.155	0.4583	−2.065 to −0.2452	2.520	0.0134	*
β1	EV	0.2851	0.06169	0.1626 to 0.4076	4.621	<0.0001	****
β2	Abd PAIN	0.1143	0.05312	0.008791 to 0.2197	2.151	0.0340	*
β3	E	0.07720	0.05587	−0.03372 to 0.1881	1.382	0.1703	ns
β4	Age	0.02663	0.006679	0.01337 to 0.03989	3.987	0.0001	***
Goodness of Fit
Degrees of Freedom	95
R squared	0.4783

Notes: *Statistically significant, ***High statistical significance, ****Very high statistical significance.

Abbreviations: PVT, portal vein thrombosis; EV, esophageal varices; Abd, abdominal; E, encephalopathy; ns, not statistically significant.

Table 6 The Multivariate Analysis of the Biological Variables

Table Analyzed	Multiple Regression of Biological Variables
Dependent variable	PVT
Regression type	Least squares
Model
Analysis of Variance	SS	DF	MS	F (DFn, DFd)	P value
Regression	27.74	4	6.934	F (4, 95) = 263.1	P<0.0001
D-dimers	0.1855	1	0.1855	F (1, 95) = 7.038	P = 0.0094
CRP	0.4661	1	0.4661	F (1, 95) = 17.69	P<0.0001
TNF-alpha	6.900	1	6.900	F (1, 95) = 261.8	P<0.0001
LPS	0.01681	1	0.01681	F (1, 95) = 0.6378	P = 0.4265
Residual	2.504	95	0.02635
Total	30.24	99
Parameter estimates	Variable	Estimate	Standard error	95% CI (asymptotic)	|t|	P value	P value summary
β0	Intercept	−0.5908	0.08784	−0.7652 to −0.4164	6.726	<0.0001	****
β1	D-dimers	0.1945	0.07330	0.04894 to 0.3400	2.653	0.0094	**
β2	CRP	0.1494	0.03552	0.07887 to 0.2199	4.206	<0.0001	****
β3	TNF-alpha	0.1691	0.01045	0.1484 to 0.1899	16.18	<0.0001	****
β4	LPS	0.007304	0.009146	−0.01085 to 0.02546	0.7986	0.4265	ns
Goodness of Fit
Degrees of Freedom	95
R squared	0.9172

Notes: **Medium/high statistical significance, ****Very high statistical significance.

Abbreviations: PVT, portal vein thrombosis; CRP, C-reactive protein; TNF, tumor necrosis factor; LPS, lipopolysaccharides; ns, not statistically significant.