Thesis Presentation

THE RELATIONSHIP BETWEEN D-DIMER LEVEL AND

PORTAL VEIN THROMBOSIS
IN LIVER CIRRHOSIS BASED ON CHILD PUGH CLASS

A Rahmawati, BJ Waleleng, K Pandelaki

 Chapter 1

Introduction
 BACKGROUND

1.16 million deaths

The 11th most common cause of death

The final stage of the process of progressive diffuse liver

LIVER fibrosis characterized by distortion of the liver
architecture and formation of regenerative nodules
CIRRHOSIS
Patients with cirrhosis are at increased risk of bleeding
and thrombosis

Increased INR in patients with cirrhosis may not provide

protection against thrombosis
 Blockage or narrowing of the portal vein by thrombus.

The cause of PVT is multifactorial : local risk factors and

systemic factors (prothrombotics)
Portal vein
PVT is a relatively common occurrence in cirrhotic
thrombosis patients but is rarely reported
(PVT)
PVT causes bleeding in portal hypertension and is
associated with a poor prognosis in cirrhotic patients.

Very often, the development thrombosis is asymptomatic

Chronic PVT patients will manifest with symptoms, signs
and complications of portal hypertension.
D- Dimer

Agarwal et al: it was reported that D-Dimer levels were increased in 63% of
patients with liver cirrhosis.

D-dimer levels were significantly higher in cirrhotic patients with PVT than in
those without PVT

Currently, it is still a dilemma for experts regarding the prophylaxis

and management of PVT in cirrhosis
 PROBLEMS

1. Are there any difference of D-dimer levels in the Child Pugh

group of patients with liver cirrhosis?
2. Are there any difference of D-dimer levels between portal
vein thrombosis and non portal vein thrombosis group in
liver cirrhosis?
3. Is there a relationship between D-dimer levels and the
incidence of portal vein thrombosis in patients with liver
cirrhosis?
AIM OF THE STUDY
1.3.1 General Purpose
To find out D-dimer levels in
child pugh class in liver
cirrhosis,
find out D-dimer levels in
PVT group liver cirrhosis and
relationship between D-
Dimer levels and the
incidence of PVT in liver
cirrhosis patient
1.3.2 Specific Purpose
1. To find out differences D-dimer levels in
Child Pugh A, B, and C groups in liver
cirrhosis.
2. To find out differences D-dimer levels
between portal vein thrombosis and non
portal vein thrombosis groups in liver
cirrhosis.
3. To find out the relationship between D-
Dimer levels and the incidence of portal
vein thrombosis in liver cirrhosis subjects
 THE BENEFITS OF RESEARCH

Scientific benefit
This study is expected to provide an understanding of the relationship
between D-Dimer levels and portal vein thrombosis in liver cirrhosis subjects

Clinical benefits
By knowing the relationship between D-Dimer levels with portal vein thrombosis
in liver cirrhosis subjects, it is hoped prophylactic and therapeutic in patients with
liver cirrhosis can be sought and can improve prognosis in patients liver cirrhosis
 Chapter 2

Literature Review
 Liver cirrhosis
• DEFINITION
The final stage of a progressive diffuse liver fibrosis process characterized by distortion
of the liver architecture and regenerative nodule formation

• ETIOLOGY
Viral, metabolic, cholestasis, and vascular
Western Countries: alcoholism, chronic hepatitis C virus infection, and Non Alcoholic
Fatty Liver Disease (NAFLD)
Asia Pacific: chronic hepatitis B
● Epidemiology

Globally, liver cirrhosis causes 1.16 million deaths, making it the 11th
common cause of death each year

US : The prevalence of cirrhosis in the United States (US) is estimated at

0.15% or 400.000 people.
The 9th leading cause of death and constitute 1.2% of all deaths in the US

Indonesia `
The average prevalence of liver cirrhosis is 3.5% of all patients treated in
internal medicine wards.
PATHOGENESIS

● Chronic injury to the liver

parenchyma
● Activation and proliferation
fibroblast and stellate cell
● Diffuse connective tissue
● Formation of the extracellular
matrix in the space of Disse
● Stimulate capillarization of blood
vessels
● Alter normal exchange of portal
veins with hepatocytes

Hypertension Portal and decrease

hepatocellular function
 Hemostasis Disorders in Liver Cirrhosis
LIVER  Plays a role in blood clotting, is the synthesis of almost all coagulation
factors and inhibitors

Impaired balance between clotting and fibrinolysis

FVIII
• Platelet vwF
• Vit K dependent tPA
Factor (II, VII, IX, X)
 INR
• Protein C and S
• PAI-1
• Anti thrombin
• α2-antiplasmin
• TAFI
The coagulation cascade and associated pathophysiological changes that occur with cirrhosis

Cirrhosis 
hyperfibrinolysis state
Evidence of increased
fibrinolytic activity
(increased levels of D-
dimer and fibrinogen
degradation products
along with low levels of
fibrinogen and
plasminogen)
D-dimer
The role of D-dimer examination

The end product of cross linked fibrin

degeneration by the action of plasmin in the
fibrinolytic system
Method

Detect abnormal blood clot formation or

thrombotic event (indirect) and to detect clot or
fibrinolytic processes (direct)
Interpretation

D-dimer levels that are more than the reference normal value
indicate the presence of fibrin degradation products in high levels,
which means thrombus formation and breakdown in the body
• Agarwal, et al : increased level D-Dimers in 63% of patients with liver cirrhosis
• Gursoy, et al : D-dimers were found to increase with increasing severity of hepatocyte
damage
• Cong, et al : There is a close association between the severity of cirrhosis and
hemostatic changes including increased fibrinolytic activity and impaired coagulation
function.
• D-dimer levels were significantly higher in cirrhotic patients with PVT than in
patients without PVT

False-positive results of D-dimer are in inflammation, malignancy, old age and

pregnancy
 Portal Vein Thrombosis
Definition : Obstruction of the portal vein or its branches by thrombus

Epidemiology
• The prevalence of PVT in non-tumor patients in cirrhosis varies
between 0.6-26%
• In a Danish study of 99,444 patients with thromboembolic disease,
cirrhosis had a 1.7-fold increased relative risk of venous
thrombosis compared with the general population.
• The risk of PVT can be as high as 40% in patients with
hepatocellular carcinoma
Etiology
 Stratification of PVT

Grade 1 < 50% PVT, with or without minimal extension into the superior mesenteric vein

Grade 2 > 50% occlusion of Portal vein, including total occlusion, with or without minimal extension
into the superior mesenteric vein

Grade 3 Complete thrombosis of both portal and superior mesenteric vein; the distal superior
mesenteric vein is patent
Virchow
Triad

Endothelial
injury
 Clinical
presentation
portal cavernoma

• Partially occlusive: asymptomatic or may be associated with mild abdominal pain, nausea,
vomiting, diarrhea and loss of appetite.
• Complete: abdominal pain, acute or progressive over a few days, and/ or with signs of
decompensation (variceal bleeding or ascites)
• Other symptoms : bloody diarrhea, peritonitis, intestinal ischemia, and portal
cholangiopathy intestinal infarct
 Chapter 3

Theory Frameworks, Concepts, Research

Variables, and Hypothesis
THEORY FRAMEWORK
CONCEPTUAL FRAMEWORK
 Variables of the study
Hypothesis 1
Independent variable : level of D-dimer
Dependent variable : Child Pugh liver cirrhosis

Hypothesis 2
Independent variable : level of D-dimer
Dependent variable : Porta Vein thrombosis

Hypothesis 3
Independent variable : D-dimer category
Dependent variable : Porta Vein thrombosis
 HYPOTHESIS

1. There are differences D-dimer levels in the Child-Pugh A, B, and C groups in

liver cirrhosis

2. There are differences D-dimer levels between portal vein thrombosis and
non portal vein thrombosis groups

3. There is a relationship between elevated D-dimer levels and the incidence of

portal vein thrombosis in patients with liver cirrhosis
 Chapter 4

Research Methodology
 Methodology
• Study Design : Cross Sectional Study (analytical observational)
• Places : Prof. DR. R. D. Kandou General Hospitals
• Times : December 2020 – June 2021
• Population : Liver cirrhosis Patients
• Samples : Consecutive Sampling
• Minimal Samples : 24 samples
N= number of sample
Zα= level of significance, Zα = 1,96
P= Proportion of categories that
are point of interest = 0.01
Q= 1-P
D= research precision
STUDY CRITERIA
IV.

Inclusion Criteria:
• Liver cirrhosis patients with or without hepatocellular carcinoma
• Willing to be involved in study by signing informed consent form

Exclusion Criteria:
1. Being in an infection or sepsis
2. Using anticoagulant drugs in the last 3 months
3. Using hormonal contraceptives
OPERATIONAL DEFINITION

1. Liver Cirrhosis
Liver cirrhosis is the final stage of the diffuse process of progressive liver fibrosis characterized by
distortion of the liver architecture and formation of regenerative nodules.
Dx Criteria : abdominal ultrasound, Transient elastography (Fibroscan), CT scan
Objective criteria:
Abdominal ultrasound: Echoparenkim rough and hyperechoic, the surface of the liver is very irregular due
to fibrosis, ascites, splenomegaly and dilation of the splenic and portal veins
Transient elastography (Fibroscan): measurement of liver stiffness ranges from 12.5 to 75.5 kPa
CT scan : surface liver nodularity and general heterogenecity of the liver parenchym, porta hepatis and
interlobar fissures widen, caudate lobe enlargement
2. CHILD PUGH SCORE
an internationally accepted system for assessing the severity of chronic liver diseases such as
cirrhosis

Dx Criteria :
SCORE 1 2 3

Encephalopathy None Controlled with therapy Less controlled

Ascites None Controlled with therapy Less controlled

Bilirubin (mg/dl) <2 2-3 >3

Albumin (g/dl) >3,5 1.8-3.5 <2.8

INR (second) <1.7 1.7-2.2 >2.2

Objective criteria : CP A: 5-6, CP B:7-9, CP C: 10-15 point

3. D-dimer

A degradation product of cross-linked fibrin and reflects ongoing

activation of the hemostatic system.

Dx Criteria : Taking blood specimens through peripheral veins and

measuring using the Enzyme Linked Fluorescent Immuno-Assay (ELFA)
method.

Objective criteria D-dimer levels are expressed in units of µg/mL.

Cut off levels of D-dimer will be calculated by ROC (Receiver Operating
Characteristic) test.
4. Portal Vein Thrombosis:
Portal vein thrombosis is obstruction of the portal vein or its branches by a thrombus

Method of examination: Doppler abdominal ultrasound

Objective criteria:
Portal vein thrombosis was diagnosed by the presence of hyperechoic material in the
vessel lumen with distension of the portal vein and its branches.
Doppler imaging shows complete or partial absence of flow in the lumen
5. Sepsis
Sepsis is a collection of symptoms as a manifestation of a systemic response to
infection.
Dx Criteria: history, physical examination, and supporting examinations.
Objective criteria:
Criteria for sepsis using quick SOFA, respiratory rate> 22 times per minute,
changes in mental status or consciousness, systolic blood pressure <100 mmHg,
the subject is said to be sepsis if ≥ 2
 Data Analysis

Descriptive statistical analysis

to see description of research variables to obtain the min., max. , average,
median, standard deviation & distribution of all variables

Differences D-dimer levels in the Child-Pugh A, B, and C groups in liver cirrhosis

ANOVA  data distribution is normal
Kruskal wallis test  data distribution is abnormal

Differences D-dimer levels between PVT and non PVT groups

t-test independent data distribution is normal
Mann whitney  data distribution is abnormal
 Data Analysis

Relationship between elevated D-dimer levels and the incidence of portal vein
thrombosis in patients with liver cirrhosis

• Chi-square  there are no cells with an expected frequency <5

• Fisher's exact  there are cells with an expected frequency >5
• ROC (Receiver Operating Characteristic) is used to determine the AUC (Area Under
Curve) and the value of the intersection of the variables
 .
Study Line
Stage 1
Liver cirrhosis patients based on anamnesis, physical examination, supporting examination, and
medical record

Exclusion Criteria

Agree and Sign the informed consent

Stage 2
D-dimer, Doppler abdominal ultrasonography

Stage 3
Data Analysis
 Chapter 5

Study result
 Subjects Characteristic
AGE 40-50 years : 29.1%
AGE 50-60 years : 70.83%

SEX Child Pugh Group

54.1
% 8.3 %
45.9 Child Pugh A
% 37.5 % Child Pugh B
Child Pugh C
54.1%

MALE FEMALE
Distribution of Samples Based on Etiology of Liver Cirrhosis
Baseline Characteristics of Liver Cirrhosis Patients according to Child Pugh

Variable CP A (n=9) CP B (n=13) CP C (n=2)

(Mean ± SD) (Mean ± SD) (Mean ± SD)

Total bilirubin (mg/dL) 1,33 ± 0,21 1,94 ± 0,28 9,07 ± 7,03

Platelet (/µL) 147.222,22 ± 28.212,87 104.846,15 ± 14.014,11 69.500 ± 39.500

Hb (g/dL) 13,2222 ± 0,75476 10,28 ± 0,82 8,05 ± 0,75

INR (sec) 1,12 ± 0,046 1,45 ± 0,062 1,63 ± 0,03

Albumin (g/dL) 3,70 ± 0,15 2,62 ± 0,18 2,34 ± 0,035

D-dimer (µg/mL) 0,86 ± 0,25 3,25 ±1,46 3,3 ± 0,90

n = Number of samples; CP = Child Pugh; Hb = Haemoglobin; INR = International

Normalized Ratio
Distribution of Samples Based on the Results of Abdominal Doppler USG
 Analysis of D-dimer levels differences among Child Pugh Groups
• In this study population, median D-dimer in Child Pugh A 0.5150 µg/ml (0.14 – 2.15 µg/ml),
Child Pugh B 1.4 µg/ml(0.4 – 20 µg/ml), Child Pugh C 3.3 µg/ml(2.4 – 4.2 µg/ml)
• Analysis test using Kruskal Wallis showed  a significant difference in D-dimer levels
between the Child Pugh A, B, and C groups (p = 0.038).
 Analysis of D-dimer levels differences between portal vein thrombosis and

non-portal vein thrombosis groups

• In this study population, Median D-dimer in the PVT group 2.4150 µg/ml (0.52 – 20 µg/ml).
Median D-dimer value in non PVT group 1.1850 µg/ml (0.14 - 5.88 µg/ml)
• Analysis test using Mann Whitney showed there is no significant difference in D-dimer
levels between the PVT and non PVT groups.
Association of D-dimer Levels and Portal Vein Thrombosis

Receiver Operating Characteristic

(ROC) test  D-dimer value had an
Area Under Curve (AUC) of 0.638
(0.286 – 0.989); p = 0.394.

D-dimer cut-off value of 4.1 µg/ml

sensitivity of 50%, specificity of
95%

ROC analysis of D-dimer levels to predict

the incidence of portal vein thrombosis
 Analysis of the association between D-dimer and portal vein thrombosis
Analysis test using Fisher exact showed  no significant relationship between D-
dimer and the incidence of portal vein thrombosis
Chapter 6

Discussion
 Discussion D-dimer – Child Pugh
Based on the results of the Kruskal Wallis test  There are significant difference level D-dimer
in Child Pugh’s A, B, and C group (p=0.038)

• Yun Li et al  D-dimer levels ​correlated with Child Pugh levels

• Cong et al  D-dimer levels increased gradually in Child-Pugh A,
B and C groups
• Violi et al  median D-dimer values ​increased with Child Pugh
levels 12

12. Li Y, Qi, Li H, Dai J, Deng H, Li J, et al. D-dimer level for predicting the in-hospital mortality in liver cirrhosis : A retrospective study.

Experimental and Therapeutic Medicine. 2017; 13 (1): 285–9

 Discussion D-dimer – Child Pugh
• Factor VIII (procoagulant) increases gradually in the advanced stages of
cirrhosis, in contrast to protein C (anticoagulant) which becomes lower
hypercoagulability. 5
• Cirrhosis is also considered a state of hyperfibrinolysis.
• D-dimer  a cross-linked cleavage product of fibrin is an accurate marker of
fibrinolytic activity. 11
• Increased value of D-dimer is also associated with the inflammatory process
that occurs in liver cirrhosis. 88

5. Manzano-robleda MC, Barranco-fragoso B, Uribe M, Méndez-sánchez N. Portal vein thrombosis : What is new ? 2015;14(1): 20–7
11. Dhanunjaya Y, Anand U, Cv A. A Study of Plasma D-dimer Levels in Various Stages of Liver Disease. 2013; 2(2): 2–4
88. Engelmann, C., Clària, J., Szabo, G., Bosch, J., & Bernardi, M. (2021). Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory
dysfunction, inflammation, metabolism and mitochondrial dysfunction. Journal of Hepatology, 75, S49–S66 .
 Discussion D-dimer – Porta Vein Thrombosis
Result
There was no significant difference in D-dimer levels between the portal vein thrombosis and non
portal vein thrombosis groups (p=0.394).

• Zhang et al D-dimer levels were significantly higher in cirrhotic

liver patients with PVT than without PVT
• In a retrospective study conducted by Junna et al  liver cirrhosis
patients with PVT had higher D-dimer values ​than those without
PVT, but there was no significant difference between the two
groups. 69
69. Dai J, Qi X, Peng Y, Hou Y, Chen J, Li H,et al. Association between D-dimer level and portal venous system
thrombosis in liver cirrhosis: A retrospective observational study. Int J Clin Exp Med. 2015; 8(9):15296–301
 Discussion D-dimer – Porta Vein Thrombosis
D-dimer value had an AUC of 0.638 (0.286-0.989); p = 0.394
a cut-off value D-dimer 4.1 µg/ml sensitivity of 50% and specificity of 95%

Zhang's study in 2006-2008

AUC of 0.782 and the cut off value of D-dimer was 0.52 mg/dL a sensitivity of 93%, a
negative predictive value of 95.7% and low specificity and positive predictive value. 69

Zhang's study in 2008-2011

cut off value of D-dimer 0.24 mg/L  a sensitivity of 100% and a negative predictive value
of 100% in ruling out the diagnosis of PVT , low specificity and positive predictive value. 65

69. Dai J, Qi X, Peng Y, Hou Y, Chen J, Li H,et al. Association between D-dimer level and portal venous system
thrombosis in liver cirrhosis: A retrospective observational study. Int J Clin Exp Med. 2015; 8(9):15296–301
65. Zhang DL, Hao JY, Yang N. Value of D-dimer and protein S for diagnosis of porta vein thrombosis in patients with
liver cirrhosis. J Int Med Res. 2013; 41: 664‑72
 Discussion D-dimer – Porta Vein Thrombosis
Result
This indicates no significant relationship between D-dimer levels and the incidence of porta vein
thrombosis in liver cirrhosis (p=0.061)

The retrospective study of Junna Dai et al There is no association between D-dimer

levels and the incidence of portal vein thrombosis.
Contrast to the study of Zhang et al  There is an association between high D-dimer
levels and the incidence of portal vein thrombosis.

The difference between these two studies

Zhang's study
Subjects had worse liver function Junna et al.
83% of cases were Child Pugh B and C 62.5% were Child Pugh B and C groups
groups
The results of this study were different from Zhang’s study  Portal vein thrombosis :
16.67% of the total sample population
PVT is more frequently detected in advanced stages of liver function. 90

Child Pugh A group : 9 people (33.3%)

PVT in compensated cirrhosis rarely found  spontaneous portal vein recanalization. 91

Child Pugh C Group less than Child Pugh A and B groups.

• The risk of developing PVT increased in more severe liver cirrhosis.
• In severe liver cirrhosis  portal venous flow rate is decreased. 91
• Plasma protein C decreased significantly in Child Pugh class B and class C. 92
NAFLD  8 people (33.3%)
The literature shows that the etiology of cirrhosis also plays a role in the development
of PVT.
NAFLD can be a significant independent risk factor for thrombotic events, including
PVT in patients with decompensated cirrhosis. 93

90. Dupuis M, Spahr, L, Giostra E, Elkrief L. Portal vein thrombosis in patients with cirrhosis. Revue Medicale Suisse. 2017; 13(572):1470–1473.
91. Qi X, Guo X, Yoshida EM, Méndez SN, De Stefano V, et al. Transient portal vein thrombosis in liver cirrhosis. BMC Medicine. 2018; 16(1): 1–11.
 92. El-Nemr S, Galal S, El-Hady H, Khalifa N. Value of Protein C and D-Dimer in Predicting Non Hepatocellular Carcinoma Portal Vein Thrombosis in
Patients with Liver Cirrhosis. Afro-Egyptian Journal of Infectious and Endemic Diseases. 2016; 6(9): 68–74

93. Faccia M, Ainora ME, Ponziani FR, Riccardi L, Garcovich M, Gasbarrini A, Pompili M, Zocco MA. Portal vein thrombosis in cirrhosis: Why a
well-known complication is still matter of debate. World J Gastroenterol. 2019; 25(31): 4437-4451.
 Limitation

• Limitation of this study is that no long-term

observations were made for the incidence of portal
vein thrombosis in Child Pugh groups A and B

• Limited sample size in advanced liver cirrhosis group

 Chapter 7

Conclusion and Suggestion

 Conclusion

1. The levels of D-dimer were significantly different in the Child

Pugh A, B, and C groups in liver cirrhosis
2. The level of D-dimer in the portal vein thrombosis group was
not significantly different from the non portal vein
thrombosis group.
3. There is no relationship between D-dimer levels and the
incidence of portal vein thrombosis in patients with liver
cirrhosis.
 Suggestion
1. It is necessary to do further research on the relationship of D-dimer
with the incidence of portal vein thrombosis in liver cirrhosis with
different sample sizes based on the severity of liver cirrhosis and
longer observations
2. Further research is needed on the role of NAFLD in liver cirrhosis on
the incidence of portal vein thrombosis.
3. It is necessary to evaluate factor VIII and protein C as prothrombotic
factors that contribute to the incidence of portal vein thrombosis.
4. Further research is needed on the role of thrombophilic conditions
(prothrombin G20210A mutation, factor V Leiden mutation, TT677
MTHFR gene mutation) on the incidence of portal vein thrombosis.
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