jurnal

1. THE RELATIONSHIP OF SEPSIS-INDUCED COAGULOPATHY
(SIC) WITH CLINICAL OUTCOMES IN ISCHAEMIC STROKE
PATIENTS IN INTESIVE CARE UNIT (ICU) DR. KARIADI
GENERAL HOSPITAL, SEMARANG
Yudistira1
, Retnaningsih1
, Arinta Puspita Wati1
, Dodik Tugasworo1
, Maria Belladonna
Rahmawati1
1
Department of Neurology, Faculty of Medicine, Diponegoro University, Semarang,
Central Java, Indonesia
NEUROLOGY DEPARTMENT
FACULTY OF MEDICINE DIPONEGORO UNIVERSITY
DR. KARIADI GENERAL HOSPITAL
SEMARANG
2022

2. THE RELATIONSHIP OF SEPSIS-INDUCED COAGULOPATHY (SIC)
WITH CLINICAL OUTCOMES IN ISCHAEMIC STROKE IN INTESIVE
CARE UNIT (ICU) DR. KARIADI GENERAL HOSPITAL
Yudistira1
, Retnaningsih1
, Arinta Puspita Wati1
, Dodik Tugasworo1
, Maria Belladonna
Rahmawati1
1
Department of Neurology, Faculty of Medicine, Diponegoro University, Semarang,
Central Java, Indonesia
Email: yudistiraanwar@ymail.com
ABSTRACT
Introduction : Stroke is the major cause of death and disability in the world. One of the risk factors
for stroke is a disorder of the coagulation system. In stroke patients, complications of various types
of infections can occur, increasing the mortality rate. Coagulopathy in sepsis is affected by several
conditions such as the immune system and inflammation. Sepsis induced coagulopathy (SIC) is
characterized by a disturbance in the coagulation and fibrinolysis systems, which increases the risk
of organ dysfunction.
Methods: This research is a cross-sectional study. Data taken from medical records in January-
December 2021 includes demographic data, clinical outcomes, SOFA scores to asses sepsis, SIC
scores for diagnose SIC and laboratory results. analysis test using SPSS with Chi-Square study.
Results : There were 36 ischemic stroke patients in the ICU, 27 were male, most of whom were
more than 60 years old. History of hypertension and diabetes was most often found in the study
subjects. Laboratory results showed 83.3% thrombocytopenia, 69.4% increase in D-Dimer, and
83.3% prolongation of the prothrombin time. The highest SOFA score was 2. And the highest SIC
score was 4. 66.7% of patients were died. There is a relationship between SIC and clinical outcome
(p=0.004).
Discussion: Complications of sepsis can occur in stroke patients and are often followed by disorders
of the coagulation system. SIC can be detected by the SIC score. SIC score have two advantages: it
is relatively simple and easy to use and is suitable for assessing the mechanism of DIC associated
with sepsis. The SIC score was designed according to the Sepsis-3 criteria. Management of SIC
must be done quickly and comprehensively according to the underlying infection. Another strategy
is to suppress the prothrombotic effect. It aims to reduce mortality in patients.
Keywords: Stroke, Sepsis, Sepsis induced coagulopathy

3. INTRODUCTION
Stroke is the fifth leading cause of death in America as well as the leading
cause of death and disability in the world with an incidence of around 795,000 each
year. Several stroke risk factors such as hypertension, diabetes, atherosclerotic
disease, and disorders of the coagulation system. The incidence of infection has
been identified as one of the complications of stroke. In a crossover case analysis
from a cerebrovascular study in Japan in 2020, the incidence of infection in stroke
patients can increase mortality. Sepsis is a life-threatening state of organ
dysfunction caused by an inadequate host response to infection. Coagulopathy in
septic patients is caused by an excessive relationship between the immune system,
inflammation, and coagulation (interference with the anticoagulant system and
inhibition of fibrinolysis). 1,2
Sepsis induced Coagulopathy (SIC) was proposed in 2017 by members of
the International Society for Thrombosis and Haemostasis (ISTH) to categorize
patients with sepsis and coagulation disorders. The sepsis-induced coagulopathy
(SIC) score was developed for the evaluation of coagulation disorders in patients
with sepsis. The SIC score adopted the Sequential Organ Failure Assessment
(SOFA) scoring system as a screening tool to evaluate organ dysfunction, according
to a new definition of sepsis revised in 2016 (Sepsis definition-3).4
Kinasewitz et
al., previously introduced SIC diagnostic criteria as simpler than the diagnostic
criteria JAAM-DIC and consists of 3 indicators: platelet count, PT-INR, and SOFA
score.3
In an observational survey conducted in Japan, 1895 patients with sepsis
who were admitted to the intensive care unit 29% were diagnosed with sepsis-
induced coagulopathy (SIC). 3 One feature of SIC is excessive inhibition of
fibrinolysis caused by overproduction of plasminogen activator inhibitor-1 with
potential prothrombotic effects.5
Such inhibition occurs rarely in malignancy-
associated DIC. Organ dysfunction frequently develops in sepsis-associated DIC
due to decreased tissue perfusion, whereas systemic bleeding is a common feature
in fibrinolytic (non-septic) phenotypic DIC. In this study, researchers wanted to
know whether sepsis induced coagulopathy (SIC) could be used as a predictor of
clinical outcome in ischemic stroke patients in the ICU.5,6

4. METHOD
This is a cross sectional study with purposive sampling. This study was
conducted by analyzing the relationship between sepsis-induced coagulopathy
(SIC) and clinical outcomes in ischemic stroke patients in ICU Dr. Kariadi,
Semarang. The source of data is taken from the patient's medical record. The time
of this study was from January to December 2021. The target population in this
study were patients with an ischemic stroke diagnosis. The reachable population in
this study were patients diagnosed with ischemic stroke who were treated in the
ICU of RSUP Dr. Kariadi. The subjects of this study were patients who were
diagnosed with ischemic stroke who were treated in the ICU of Dr. Kariadi
Semarang and met the inclusion criteria. This study has received approval from the
Research Ethics Committee.
The inclusion criteria of this study were ischemic stroke patients, as
evidenced by MSCT examination of the head or MRI of the head, patients who had
a stroke for the first time, patients who underwent coagulation tests and entered
sepsis criteria based on the SOFA score. Exclusion criteria for these patients were
cerebral venous thrombosis (CVST) patients, ischemic stroke patients with
malignancy, history of gastrointestinal and urinary tract bleeding, and patients with
pregnancy. In this study, 36 patients met the inclusion and exclusion criteria. The
research was conducted in the ICU of RSUP dr. Kariadi in the January-December
2021 period. Data collection was done manually using medical records.
The data that has been collected is checked for completeness and
correctness, then cleaned, coding, editing, tabulating and entered into the computer
using the IBM SPSS Statistics for Windows version 22 program. In descriptive
statistics, categorical scale variables are described as frequency distributions (n).
After that, a comparison test was carried out with the Chi-square test. 95%
confidence level. The p value is considered significant if p <0.05.

5. RESULT
A. Characteristics of Ischemic Stroke Patients in ICU Dr. Kariadi
During January-December 2021 there were 36 patients being treated in the
ICU of RSUP Dr. Kariadi Semarang. The ischemic stroke patients were male
as many as 27 patients (75%) with the majority aged ≥ 60 years (55.6%). Most
patients were treated for 15-30 days in the ICU (58.3%) with the most
comorbid diseases namely hypertension (47.2%) and diabetes mellitus
(33.3%)
Table 1. Ischemic Stroke Patients Characteristic
Characteristic Frequency
(n)
%
Sex
Male
Female
27
9
75
25
Age
< 60 y.o
>60 y.o
16
20
44.4
55.6
Comorbid Disease
Hypertension
DM
Hyperlipidemia
Cardiovaskular Disease
17
12
4
2
47.2
33.3
11.1
8.3
B. Clinical Characteristics of Ischemic Stroke Patients in ICU Dr. Kariadi
As many as 36.1% of ischemic stroke patients who were treated in the ICU
Dr. Kariadi Semarang has an APACHE score of 20-24. During treatment in
the ICU, ischemic stroke patients experienced hypertension (69.4%) and
hyperglycemia (83.3%). 52.2% of patients had thrombocytopenia (83.3%),
prothrombin time was prolonged (83.3%), and D-Dimer levels were increased
(69.4%). The SOFA score as a predictor of sepsis in this study was 69.4%
with a score of  2, while the SIC score was 72% with a score of  4. A total
of 58.3% underwent treatment in the ICU for 15-30 days with 66.7% ends
with death.

6. Table 2. Clinical Characteristic
Characteristic Frequency
(n)
%
APACHE Score
10-12
15-19
20-24
25-29
>30
8
12
13
3
0
22.2
33.3
36.1
8.3
0
Hypertension
Yes
No
25
11
69.4
30.6
Blood Sugar Level
Normal
Increased
6
30
16.7
83.3
Trombosit Value
Normal
Increased
Low
15
2
19
41.7
5.6
52.8
Prothrombin Time (PT)
Normal
Elongated
6
30
16.7
83.3
D-Dimer Level
Normal
Increased
11
25
30.6
69.4
Length of Hospital Stay
< 15 days
15-30 days
>30 days
11
21
4
30.6
58.3
11.1
SOFA Score
 2
 2
25
11
69.4
30.6
SIC Score
 4
 4
26
10
72.2
27.8
Clinical Outcome
Survived
Died
12
24
33.3
66.7
C. Relationship between Sepsis-induced Coagulopathy (SIC) and Clinical
Outcomes in Ischemic Stroke Patients in ICU Dr. Kariadi
The results of the analysis of the relationship between Sepsis-induced
Coagulopathy (SIC) and clinical outcomes showed that 5 subjects (19.2%)
with SIC score  4 survived and 21 subjects (80.8%) with SIC score  4 died.
7 subjects (70%) with SIC score  4 survived and 3 subjects (30%) with SIC
score  4 died. The statistical test results obtained p = 0.004, so it can be
concluded that there is a significant relationship between the incidence of

7. Sepsis-induced Coagulopathy (SIC) and the clinical outcome of ischemic
stroke patients.
Table 3. Relation of Sepsis-induced Coagulopathy (SIC) and Clinical Outcome of
Ischemic Stroke Patients
SIC
Score
Outcome Total P Value
Survived Died
0.004*
N % N % N %
 4 5 19.2 21 80.8 26 100
 4 7 70 3 30 10 100
Total 12 33.3 24 66.7 36 100

8. DISCUSSION
In this study, the prevalence of men aged over 60 years was more. This is in
accordance with research by Renyu et al in China that the highest prevalence was
at age over 65 years and male sex (147/252). In this study, the highest APACHE
score was obtained in the range of 20-24, this is inversely proportional to the
research by Renyun et al., the APACHE score range was obtained between 10-17
with P=value 0.001. The laboratory results in this study showed low platelet levels,
increased D-Dimer and prolonged PT had a high prevalence. This is also in
accordance with research by Renyun et al. Low platelet levels, increased D-dimer
and prolonged PT have a higher prevalence.
Coagulation system disorders are one of the main causes of ischemic stroke
in adults. Evidence suggests that patients with cerebral thrombosis have a
hypercoagulable state prior to the onset of symptoms. Therefore, it is very important
to be able to evaluate patients at risk before stroke. Although many tests have been
applied to evaluate a patient's coagulation status, including prothrombin time,
partial thromboplastin, and activated clotting time. Most of the tests are performed
on plasma because it contains all the coagulation factors. The relationship between
stroke and coagulation has been studied for a long time, with limited and non-
specific results. Although between 5-10% of stroke cases are identified as caused
by primary coagulopathy. This is supported by examination of prothrombin time,
thromboplastin time or thrombin time which failed to provide a difference between
stroke patients and controls. Even analysis shows that hypercoagulopathy or
changes in coagulability can occur locally without involving the entire system. The
fact that fibrinogen has been shown to be elevated in stroke patients is an indication
that certain changes in coagulability may occur. The implication of altered
fibrinogen levels in coagulation is supported by the different amounts of fibrinogen
levels.9,12
Patients with sepsis are often found to be coagulopathic, requiring
comprehensive management. In patients with sepsis, an imbalance in clot formation
(coagulation) and clot breakdown (fibrinolysis) is an important response that occurs
because of the development of organ dysfunction. Vascular endothelial dysfunction
can lead to the formation of microvascular thrombosis. In addition, inhibition of the

9. fibrinolytic system results in thrombus accumulation which is proinflammatory. It
may also occur in coagulopathy settings with sepsis.6
The main pathways in sepsis-
induced coagulopathy and DIC include activation of coagulation, platelets, and
other inflammatory cells (eg, neutrophils, lymphocytes) and vascular endothelial
injury.7
Tissue factor is an important component of The extrinsic coagulation
pathway is expressed by macrophages and monocytes and plays an important role
in the initiation of coagulation. Tissue factor is expressed in extracellular vesicles
and phosphatidylserine residues. contact pathway initiators expressed on cell
membranes are known to initiate hemostasis.8
In sepsis, neutrophils are activated
and release extracellular traps to limit infection consisting of DNA, histones
(binding proteins for the structural integrity of DNA), and other neutrophil granule
proteins. In addition, the release of damage-associated molecular patterns from
disturbed host cells further enhances prothrombotic activity. In cell damage and
activation of hematopoietic cells, cell-free DNA and nuclear proteins are released
into the circulation, such as histones, which have strong procoagulant activity and
provide anticoagulant effects.8
The antithrombotic contribution of the vascular
endothelium also has an important role in sepsis. Vascular endothelial cells release
nitric oxide (NO) and prostacyclin thereby contributing to the normal
antithrombotic effect whereas endothelial cells enhance the prothrombotic effect in
septic conditions by expressing tissue factor and releasing von Willebrand factor.
Endothelial dysfunction and impaired anticoagulants can cause SIC. The
surface of the vascular endothelium is coated with membrane-binding
proteoglycans and glycosaminoglycan chains that exert an antithrombotic effect by
binding to antithrombin. 9 Endothelial cells also balance fibrinolysis by producing
plasminogen activator and plasminogen activator inhibitor-1. This balance can
inhibit fibrinolysis during sepsis. Coagulation or fibrinolytic disorders are another
feature of sepsis-induced coagulopathy.
In this study it was found that the SIC score  4 has a higher mortality rate.
This is in accordance with a study conducted by Renyun et al, in China that there
was a significant difference in the proportion of SIC patients who survived in the
ICU and those who did not survive (P=0.055). In the study of Toshiaki Iba et al in
Japan, explained the relationship between platelet count and mortality rate. The
mortality rate was less than 30% when the platelet count was more than 100,000

10. but increased to 35% when the platelet count was less than 100,000. In addition, the
mortality rate increased to 40% at a PT ratio of more than 1.4. Mortality also
increases with increasing SOFA score. SIC total score of 4 or more mortality
reaches 30% and increases more than 45% at a score of 6.10
The SIC score focuses on patients with coagulation disorders and sepsis.
The SIC scoring system has two advantages: it is relatively simple and easy to use,
and is suitable for assessing the mechanism of DIC associated with sepsis. The SIC
score was also designed to fit the Sepsis-3 criteria, and consists of only three
variables: platelet count, PT-INR, and SOFA score.7
In Sepsis-3, the SOFA score
plays an important role in identifying sepsis. Therefore, the SIC score is considered
a simpler and easier method to assess coagulation disorders than other DIC criteria.
In addition, sepsis-associated DIC is characterized by thrombocytopenia, increased
levels of fibrin-associated markers, and activation of coagulation with excessive
inhibition of fibrinolysis.7,9
The important thing in the management of SIC is prompt and timely
treatment according to the underlying infection. Another strategy that has been
studied extensively is to suppress the prothrombotic effect. Heparin and heparinoid
are the most popular anticoagulants used for various thromboembolic diseases but
their effectiveness in treating SIC or DIC is still debated. There are no currently
globally recommended therapeutic agents for the specific treatment of SIC. The
effectiveness of natural anticoagulants, such as antithrombin, activated protein C,
and tissue factor pathway inhibitors has been studied in controlled trials. A post hoc
analysis performed to examine the effect in a subgroup of DIC patients
demonstrated a beneficial effect of antithrombin and recombinant activated protein
C.11
The effectiveness of antithrombin for SIC has been studied extensively in Japan
and national database studies have shown improved clinical outcomes with
administration of antithrombin therapy.11
A meta-analysis also showed a good
prognosis with the use of antithrombin in septic patients with DIC.13
However, the
use of antithrombin has not been recommended in international sepsis guidelines.12
A randomized controlled phase III trial in SIC patients (with a platelet count of less
than 150 000 and prothrombin time ratio of more than 1.4) over 28 days mortality
increased by 2.6% in a total of 800 septic patients. In conclusion, the effectiveness
of natural anticoagulants has not been proven and further research is needed.

11. CONCLUSION
Stroke is the second major disease that causes high morbidity and mortality in the
world and in Indonesia. Approximately 15-20% of stroke patients require treatment
in the intensive care unit (ICU). Some of the complications that are commonly
found in strokes such as coagulation disorders and sepsis, both of which allow the
patient to require prompt and comprehensive treatment. The incidence of sepsis and
coagulation disorders can be identified by several types of scoring, one of which is
the SIC score. The higher the scoring results, the worse the prognosis obtained.
Early diagnosis of SIC is important for determining appropriate management of
patients with the hope of reducing mortality. In this study, it is known that there is
a relationship between the incidence of SIC and the clinical outcome of ischemic
stroke patients.
RESEARCH ETHICS
This research has received approval from the local Research Ethics Committee with
No.1297/EC/KEPK-RSDK/2022
AUTHOR'S STATEMENT
The authors have no conflict of interest

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