Elevated plasma D-dimer level and the presence of septic shock in patients with sepsis

Abstract

Background: Sepsis induces dysfunction in organ systems, including the hemostatic system. D-dimer is generated during disseminated intravascular coagulation (DIC), and so elevated D-dimer levels may be associated with progression of sepsis to septic shock.

Objective: We evaluated whether abnormal D-dimer levels were associated with presence of septic shock.

Design: Retrospective cross- sectional study.

Methods: We studied 137 patients diagnosed with sepsis who underwent testing for D-dimer. D-dimer level below 0.4 mg/L fibrinogen equivalent unit (FEU) was considered unchange. D-dimer level above 0.4 and below 4 mg/L FEU was considered moderate elevation, D-dimer level above 4 mg/L FEU was considered strong elevation.

Results: Septic shock was diagnosed in 52 (38%) patients. DIC occurred in 38 (27.7%) patients. Patients with unchanged, moderately elevated and strongly elevated D dimer levels were 1(7%), 43 (31.4%) and 93 (67.9%); respectively. Compared to the patients with sepsis without shock, those with septic shock had a longer activated partial thromboplastin time (APTT) (37.5 vs 34.5 s), higher D-dimer level (7.65 vs 5.15 mg/L FEU), higher procalcitonin level (13.5 vs 5.57 ng/mL), but a lower platelet count (93 vs 130 × 10⁹/L), (p < .05). The frequency of septic shock in patients with DIC was higher than that in patients group without DIC (50% vs 33.3%), but the difference was not statistically significant (p = .072). Univariate regression analysis showed that prolonged APTT, high D-dimer level, high procalcitonin level, and low platelet count were associated with the presence of septic shock. However, multivariate regression analysis determined that only a low platelet count was significantly associated with septic shock.

Conclusion: Among the patients with sepsis, thrombocytopenia but not elevated plasma D-dimer level is associated with risk of septic shock.

Keywords

D-dimer elevated D-dimer level sepsis septic shock fibrinolysis

Introduction

Sepsis is an emergency with high rate of mortality (ranges: 15–25%).¹ Sepsis was previously defined as host’s systemic inflammatory response syndrome (SIRS) to infection with at least two in the following: tachypnoea, tachycardia, fever or hypothermia, and leukocytosis, leukopenia or neutrophilia.¹ However, based on this definition, it is difficult to distinguish sepsis from severe infections. Therefore, since 2015, sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.² Septic shock is a subtype of sepsis with hyperlactatemia and persistent hypotension requiring vasopressor treatment. The mortality rate of septic shock can be up to 30–50%.^1,2 This new definition aimed to emphasize that sepsis induces dysfunction in organ systems, including the hemostatic system. Hemostatic abnormalities range from subclinical coagulopathy to disseminated intravascular coagulation (DIC). Subclinical coagulopathy without excessive consumption of coagulation factors, platelets, and fibrinogen, is also known as “non-overt DIC”. DIC with clinical evidence of thrombosis and/or bleeding due to overt consumptive intravascular coagulopathy is also known that “overt DIC”.^3–5 Another alternative concept of “sepsis-induced coagulopathy” (SIC) determines cases at early stage of DIC, so that coagulopathy is still reversible.³ Mechanisms of hemostatic dysfunction include excessive activation of the coagulation pathway, the suppression of natural anticoagulants, and the imbalance of fibrinolysis.^3–5 Initially, activated monocytes release vehicles which express tissue factor (TF), endothelial damage exposes TF, leading activation of extrinsic pathway.^3,6 Aditionally, neutrophillia increases coagulation activity through activation of neutrophil extracellular traps (NETs).^3,7,8 Inflammatory cytokines, bacterial endotoxins also activate the blood coagulation.^3,9,10 Natural anticoagulants such as antithrombin, protein C, tissue factor pathway inhibitor (TFPI) are decreased in sepsis due to reduced synthesis, increased degradation.^3,9,10 The balance between tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI-1) is responsible for fibrinolysis. At the early sepsis, due to the enhanced effect of t-PA, plasminogen is converted to plasmin so the fibrinolysis is increased. However, this phase is transient. Subsequently, the fibrinolysis is impaired by elevated PAI-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) levels.^3,11–13

D-dimer is soluble fibrin degradation product. Elevated D-dimer levels are associated with fibrinolysis, and also reflect activation of coagulation, so could it be considered to be associated to the severity of sepsis? Some studies showed that elevated plama D-dimer levels were associated with adverse prognosis in patients with sepsis.^14–19 However, there were still controversial opinions.^20–22 We evaluated whether abnormal D-dimer levels were associated with presence of septic shock.

Materials and methods

Design

Retrospective cross-sectional study.

Patients

A retrospective cross-sectional study was conducted in Bach Mai hospital.

Inclusion criteria: adult patients who diagnosed with sepsis in an intensive care unit (ICU) from March 2022 to September 2022 and underwent for D-dimer testing were consecutively enrolled into this study.

Exclusion criteria: patients with negative blood culture results.

D-dimer assay test

The plasma D-dimer level was assayed using HemosIL D-dimer HS 500 kit on the ACL TOP 750. In the cases, where D-dimer level was higher than 7.65 mg/L fibrinogen equivalent unit (FEU), D-dimer level was further assayed using AcuStar D-dimer Assay kit on the ACL AcuStar for the more accurate level determination.

Collected data

Laboratory indices included peripheral blood cells such as hemoglobin level, white blood cell (WBC) count and platelet count, coagulation such as prothrombin%, activated partial thromboplastin time (APTT), fibrinogen level, and D-dimer level, biochemical indices such as glucose, urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, conjugated bilirubin, albumin, and procalcitonin levels reported within 24 h at the time of diagnosis were collected. The results of the pathogen culture from blood samples, previous comorbidities, septic shock, and DIC were collected.

Sepsis and septic shock were diagnosed according to SEPSIS 3.² DIC was defined according to the International Society on Thrombosis and Haemostasis’s DIC diagnostic criteria (ISTH criteria).²³ D-dimer level below 0.4 mg/L FEU was considered unchange (0 score). D-dimer level above 0.4 and below 4 mg/L FEU was considered moderate elevation (2 score), D-dimer level above 4 mg/L FEU was considered strong elevation (3 score).²⁴

Statistical analysis

Patients were groups according to the presence of septic shock. Quantitative variables including D-dimer level were compared between 2 groups using the independent sample t test or the Mann U Whitney test according to the normal or nonnormal distributed variable. Qualitative variables such as pathogen type of culture (negative gram, positive gram or fungus) and DIC were also compared between 2 groups using Fisher’s exact or Chi square test. Variables with significant difference found were analyzed using logistic regression analysis to determine whether they were associated with septic shock. p < .05 was considered a statistically significant difference.

The bias was controlled because there were no missing data. The study reported conforms to STROBE’s guideline.²⁵

Results

Patients data

This study included 137 patients with sepsis diagnosed. The median age was 57 years (range: 16–100 years). The male was 63.5%. The characteristics of the patients are shown in Table 1. The frequency of negative gram infection was highest with 53.3%, followed by positive gram (31.4%) and fungus (15.3%). Septic shock was diagnosed in 52 (38%) patients. DIC occured in 38 (27.7%) patients. Patients with unchanged, moderately elevated and strongly elevated D-dimer levels were 1 (7%), 43 (31.4%) and 93 (67.9); respectively.

Table 1.

Patients characteristics.

Characteristic	Frequency	Percent
Previous Comorbidity
Diabetes	15	10.9
Hypertension	19	13.9
Myocardial Infarction	9	6.6
Atrial fibrillation	2	1.4
Stroke	7	5.1
Cirrhosis	3	2.2
Systemic Lupus Erythematosous (SLE)	10	7.3
Nephritis	6	4.4
Hematological disease	7	5.1
Pathogen type of culture
Negative gram	73	53.3
Positive gram	43	31.4
Fungus	21	15.3
Septic shock
No	85	62.0
Yes	52	38.0
DIC
No	99	72.3
Yes	38	27.7
Classification of D-dimer according to DIC score
0 score (<0.4 mg/L FEU): No change	1	7
2 score (0.4-4 mg/L FEU): Moderate rise	43	31.4
3 score (>4 mg/L FEU): Strong rise	93	67.9

Note. DIC: Disseminated intravascular coagulation, FEU: Fibrinogen equivalent unit.

Table 2 shows that compared to the patients with sepsis without shock, those with septic shock had a longer APTT (37.5 vs 34.5 s), higher D-dimer level (7.65 vs 5.15 mg/L FEU), higher procalcitonin level (13.5 vs 5.57 ng/mL), but a lower platelet count (93 vs 130 × 10⁹/L), (p < .05). The frequency of septic shock in patients with DIC was higher than that in patients group without DIC (50% vs 33.3%), but the difference was not statistically significant (p = .072). We also did not find that strongly elevated D-dimer (according to ISTH) may be more specific for septic shock (p = .068).

Table 2.

Laboratory indices according to the presence of septic shock.

Index	Septic shock	Mean ± SD	Median	p
Hemoglobin (g/L)	No	97.06 ± 20.82		>.05
Hemoglobin (g/L)	Yes	98.48 ± 19.11		>.05
WBC count (×10⁹/L)	No		13.8	>.05
WBC count (×10⁹/L)	Yes		8.51	>.05
Platelet count (×10⁹/L)	No		130	<.001
Platelet count (×10⁹/L)	Yes		93	<.001
Prothrombin (%)	No	73.16 ± 21.53		>.05
Prothrombin (%)	Yes	66.30 ± 24.82		>.05
APTT (sec)	No		34.5	.011
APTT (sec)	Yes		37.5	.011
Fibrinogen (g/L)	No	4.59 ± 1.79		>.05
Fibrinogen (g/L)	Yes	4.10 ± 1.56		>.05
D-dimer (mg/L FEU)	No		5.15	.016
D-dimer (mg/L FEU)	Yes		7.65	.016
Glucose (mmol/L)	No		9.7	>.05
Glucose (mmol/L)	Yes		8.1	>.05
Urea (mmol/L)	No		9.85	>.05
Urea (mmol/L)	Yes		7.9	>.05
Creatinine (µmol/L)	No		100.5	>.05
Creatinine (µmol/L)	Yes		93	>.05
AST (U/L)	No		63.5	>.05
AST (U/L)	Yes		59	>.05
ALT (U/L)	No		46.5	>.05
ALT (U/L)	Yes		44	>.05
Total bilirubin (mg/dL)	No		10.7	>.05
Total bilirubin (mg/dL)	Yes		15.9	>.05
Conjugated Bilirubin (mg/dL)	No		7.3	>.05
Conjugated Bilirubin (mg/dL)	Yes		12.4	>.05
Albumin (g/L)	No		28.45	>.05
Albumin (g/L)	Yes		25.2	>.05
Procalcitonin (ng/mL)	No		5.57	.02
	Yes		13.5	.02

Factor		Septic shock		p
Factor		Yes n (%)	No n (%)	p
DIC	No	33 (33.3)	66 (66.7)	.072
DIC	Yes	19 (50.0)	19 (50.0)	.072
D-dimer (mg/L FEU)	<0.4 (no change)	0 (0)	1 (100)	.068
	0.4-4 (moderate rise)	11 (25.6)	32 (74.4)
	>4 (strong rise)	41 (44.1)	52 (55.9)
Pathogen type of culture	Negative Gram	26 (35.6)	47 (66.4)	.603
	Positve Gram	16 (37.2)	27 (62.8)
	Fungus	10 (47.6)	11(52.4)

Note. SD: standard deviation, WBC: white blood count, FEU: Fibrinogen equivalent unit, APTT: activated partial thrombin time, AST: aspartate transaminase, ALT: alanine transaminase, DIC: Disseminated intravascular coagulation.

Association between D-dimer level and the presence of septic shock

Univariate logistic regression analysis showed that prolonged APTT, high D-dimer level, high procalcitonin level, and low platelet count were associated with the presence of septic shock (Table 3). However, multivariate regression analysis determined that only a low platelet count was significantly associated with septic shock. We did not find any association between high D-dimer and septic shock (Table 4).

Table 3.

Univariate regression analysis for factors associated with the presence of septic shock.

Factor	B	S.E.	Wald	p	OR	95% CI
Factor	B	S.E.	Wald	p	OR	Lower	Upper
Platelet	−0.006	0.002	10.287	.001	0.991	0.994	0.998
APTT	0.031	0.012	6.443	.011	1.031	1.007	1.056
D-dimer	0.148	0.069	4.581	.032	1.160	1.013	1.328
Procalcitonin	0.014	0.006	6.647	.010	1.015	1.003	1.026

Note. APTT: activated partial thrombin time.

S.E: standard error.

CI: confidence interval.

Table 4.

Multivariate regression analysis for factors associated with the presence of septic shock.

Factor	B	S.E.	Wald	p	OR	95% CI
Factor	B	S.E.	Wald	p	OR	Lower	Upper
Platelet	−0.004	0.002	5.593	.018	0.996	0.992	0.999
APTT	0.018	0.013	1.959	.162	1.018	0.993	1.043
D-dimer	0.073	0.082	0.783	.376	1.075	0.916	1.263
Procalcitonin	0.008	0.006	1.985	.159	1.008	0.997	1.020

Note. APTT; activated partial thrombin time.

S.E: standard error.

CI: confidence interval.

Discussion

D-dimer is a fibrin degradation product, so it is related to fibrinolysis and also reflects excessive activation of coagulation. Some authors hoped to use D-dimer as a simple predictor of mortality and severity of sepsis. Wang et al., Tang et al., and Abdelazid et al. showed that elevated D-dimer levels were associated with mortality in children with sepsis.^14,16,17 Sharma et al. demonstrated that the frequency of elevated D-dimer was higher in patients group with severe sepsis and septic shock.¹⁵ Rodelo et al. suggested that high D-dimer was significant prognostic factor in patients with sepsis.¹⁹ However, Meini et al. determined that prognostic ability of D-dimer depended on the pathogen. Elevated D-dimer levels were associated with mortality and severity of sepsis in patients infected with Neisseria meningitidis but not in patients infected with Streptococcus pneumoniae.¹⁸ Additionally, Semeraro et al. suggested that in patients with severe sepsis with normal D-dimer level, the mortality was highest.²²

On the other hand, Naderpour et al. did not find any correlation between high D-dimer and mortality rate or severity of sepsis.²⁰ Iba et al. suggested that soluble fibrin degradation products (FDPs) were not correlated with 28-days mortality in patients with sepsis associated coagulopathy.²¹ Similarly, our study showed that after multivariate analysis, high D-dimer was not associated with the presence of septic shock. We also found no association between strong elevation of D-dimer (with level above 4 mg/L FEU accounts for 3 score in the DIC calculation according to ISTH) and septic shock. We used the cut off value of D-dimer according to ISTH criteria when calculating the DIC score.^23,24 However, there may be other cut off values used.^26,27 We also hope to continue this study to compare different cut off values of D-dimer, from which we can make recommendations on which cut off value to use.

In fact, the mechanisms of hemostatic abnormalities in sepsis are very complex. In the cases of SIC, a hypercoagulable tendency predominates due to excessive activation of the coagulation, the suppression of natural anticoagulant, and the impairment of fibrinolysis (phase of hyperfibirinolysis is transient as mentioned above).^3,4,28 This impairment of fibrinolysis contributes to the strengthening of the fibrin network at the site of infection, limiting the spread of infection. But, it also reduces oxygen flow to these tissues, leading to hypoxia and the development of organ dysfunction.^3,11,13,28 Some authors have used the term “fibrinolysis shutdown’ to refer to the impairment of fibrinolysis.^12,29,30 Schmitt et al. demonstrated that acute fibrinolysis shutdown was associated with increased mortality in patients with septic shock.¹² Therefore, according to these studies, low D dimer levels may be a poor prognostic factor in sepsis.

On the other hand, during the period of increased consumption, hypocoagulation ensues after overt DIC. Therefore, elevated D-dimer levels may be associated mortality and severity of sepsis.^14,16,17,19 Additionally, hyperfibrinolysis due to specific pathogen such as Leptospira, Staphyloccocus aureus, may be associated with poor outcome.^31,32 However, hemostatic abnormalities and DIC are pathological spiral, so it is not easy to clearly analyze the stages. Therefore, association between elevated D-dimer levels and mortality, severity of sepsis or the presence of septic shock was not defined.^20,21 After multivariate analysis, our study did not identify an association between high D-dimer level and the presence of septic shock.

Some authors suggested that soluble fibrin monomers may be more effective than D-dimer in the assessment of DIC and risk stratification in sepsis.^3,33,34 However, there have not been consensus.^35,36 On the other hand, fibrin monomers only reflect the formation of fibrin and are not involved in the fibrinolysis.

Overall, it is not possible to conclude the prognostic value of D-dimer in sepsis. More research is needed to determine the value of D-dimer in prognosticating sepsis and predicting the presence of septic shock.

Limitation of our study

Our study was a cross-sectional study. D-dimer testing was also not performed at various times. Patients were not followed up. We were unable to assess the event as well as progression of septic shock. We also did not perform tests for Antithrombin III and Protein C, therefore, the cases of non-overt DIC were not determined according to ISTH criteria 2001.³⁷

Conclusion

Our study did not find that elevated plasma D-dimer level was associated with the presence of septic shock. Hemostatic abnormalities include excessive activation of coagulation, suppression of natural anticoagulant, and impairment of fibrinolysis as well as DIC according to the stage of sepsis, are very complex. Whether coagulation indices such as D-dimer can be used as a prognostic tool remains an open question. More research is needed to clarify its role.

Footnotes

Acknowledgements

The authors thank all technicians in Coagulation Lab-Hematology and Blood Transfusion Center-Bach Mai Hospital, for thesis efforts in supporting research.

ORCID iD

Minh Phuong Vu

Statements and declarations

Author contributions

Thi Tuyet Mai Nguyen: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft.

Minh Phuong Vu: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing.

Tuan Tung Nguyen: Formal analysis, Writing – original draft.

Thi Tuyet Mai Nguyen:Investigation, Writing – original draft.

Hoang Vu: Formal analysis, Writing – original draft.

Hai Yen Duong: Formal analysis, Writing – original draft.

Phuong Thao Pham: Formal analysis, Writing – original draft.

Thi Hue Hoang: Formal analysis, Writing – original draft.

Thi Van Oanh Kieu: Formal analysis, Writing – original draft.

All authors have read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data can be obtained from the corresponding author upon request.*

References

Hotchkiss

Moldawer

Opal

, et al. Sepsis and septic shock. Nat Rev Dis Primers 2016; 2: 16045.

Singer

Deutschman

Seymour

, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315(8): 801–810.

Tsantes

Parastatidou

Tsantes

, et al. Sepsis-induced coagulopathy: an update on pathophysiology, biomarkers, and current guidelines. Life (Basel) 2023; 13(2): 350.

Iba

Levi

Levy

. Sepsis-induced coagulopathy and disseminated intravascular coagulation. Semin Thromb Hemost 2020; 46(1): 89–95.

Iba

Helms

Connors

, et al. The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation. J Intensive Care 2023; 11(1): 24.

Sachetto

ATA

Mackman

. Monocyte tissue factor expression: lipopolysaccharide induction and roles in pathological activation of coagulation. Thromb Haemost 2023; 123(11): 1017–1033.

Kapoor

Opneja

Nayak

. The role of neutrophils in thrombosis. Thromb Res 2018; 170: 87–96.

Nguyen

TTM

, et al. Association of the neutrophil-to-lymphocyte ratio with the occurrence of venous thromboembolism and arterial thrombosis. J Int Med Res 2024; 52(4): 3000605241240999.

Schouten

Wiersinga

Levi

, et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83(3): 536–545.

10.

Giustozzi

Ehrlinder

Bongiovanni

, et al. Coagulopathy and sepsis: pathophysiology, clinical manifestations and treatment. Blood Rev 2021; 50: 100864.

11.

Gando

. Role of fibrinolysis in sepsis. Semin Thromb Hemost 2013; 39(4): 392–399.

12.

Schmitt

FCF

Manolov

Morgenstern

, et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 2019; 9(1): 19.

13.

Madoiwa

. Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC. J Intensive Care 2015; 3: 8.

14.

Wang

Liu

, et al. Elevated plasma D-dimer levels are associated with the poor prognosis of critically ill children. Front Pediatr 2022; 10: 1001893.

15.

Sharma

Sikka

Gomber

, et al. Plasma fibrinogen and D-dimer in children with sepsis: a single-center experience. Iran J Pathol 2018 Spring; 13(2): 272–275.

16.

Tang

Yuan

, et al. The predictive value of heparin-binding protein and D-dimer in patients with sepsis. Int J Gen Med 2023; 16: 2295–2303.

17.

Abdelaziz

Mohamed

MAA

Ismail

, et al.

A prospective cohort study of severe sepsis-induced dyslipidemia and changes in D-dimer levels in children: do they affect the prognosis?

Egypt Pediatric Association Gaz 2023; 71: 93.

18.

Meini

Sozio

Bertolino

, et al. D-dimer as biomarker for early prediction of clinical outcomes in patients with severe invasive infections due to Streptococcus pneumoniae and Neisseria meningitidis. Front Med (Lausanne) 2021; 8: 627830.

19.

Rodelo

De la Rosa

Valencia

, et al. D-dimer is a significant prognostic factor in patients with suspected infection and sepsis. Am J Emerg Med 2012; 30(9): 1991–1999.

20.

Naderpour

Momeni

Vahidi

, et al. Procalcitonin and D-dimer for predicting 28-day-mortality rate and sepsis severity based on SOFA score; A cross-sectional study. Bull Emerg Trauma 2019; 7(4): 361–365.

21.

Iba

Di Nisio

Thachil

, et al. A proposal of the modification of Japanese society on thrombosis and hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria for sepsis-associated DIC. Clin Appl Thromb Hemost 2018; 24(3): 439–445.

22.

Semeraro

Ammollo

Caironi

, et al.

Low D-dimer levels in sepsis: good or bad?

Thromb Res 2019; 174: 13–15.

23.

Asakura

Takahashi

Uchiyama

, et al. Proposal for new diagnostic criteria for DIC from the Japanese society on thrombosis and hemostasis. Thromb J 2016; 14: 42.

24.

Patel

Walborn

Rondina

, et al. Markers of inflammation and infection in sepsis and disseminated intravascular coagulation. Clin Appl Thromb Hemost 2019; 25: 1076029619843338.

25.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61(4): 344–349.

26.

Gao

Yang

Zhou

, et al. Analysis of D-dimer cut-off values for overt DIC diagnosis in exertional heat illness. Medicine (Baltim) 2020; 99(52): e23831.

27.

Suzuki

Wada

Imai

, et al. A re-evaluation of the D-dimer cut-off value for making a diagnosis according to the ISTH overt-DIC diagnostic criteria: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16(7): 1442–1444.

28.

Williams

Zou

Pittet

, et al. Sepsis-induced coagulopathy: a comprehensive narrative review of pathophysiology, clinical presentation, diagnosis, and management strategies. Anesth Analg 2024; 138(4): 696–711.

29.

Lampridou

Sokou

Tsantes

, et al. ROTEM diagnostic capacity for measuring fibrinolysis in neonatal sepsis. Thromb Res 2020; 192: 103–108.

30.

Semeraro

Colucci

Caironi

, et al. Platelet drop and fibrinolytic shutdown in patients with sepsis. Crit Care Med 2018; 46(3): e221–e228.

31.

Medcalf

Keragala

. Fibrinolysis: a primordial system linked to the immune response. Int J Mol Sci 2021; 22(7): 3406.

32.

Whyte

. All tangled up: interactions of the fibrinolytic and innate immune systems. Front Med (Lausanne) 2023; 10: 1212201.

33.

Toh

Ken-Dror

Downey

, et al. The clinical utility of fibrin-related biomarkers in sepsis. Blood Coagul Fibrinolysis 2013; 24(8): 839–843.

34.

Singh

Pati

Tyagi

, et al. Evaluation of the diagnostic performance of fibrin monomer in comparison to d-dimer in patients with overt and nonovert disseminated intravascular coagulation. Clin Appl Thromb Hemost 2017; 23(5): 460–465.

35.

Zheng

Chen

Zhang

, et al. Use of fibrin monomer and D-Dimer in assessing overt and nonovert disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2021; 32(4): 248–252.

36.

Park

Kwon

Kim

, et al. Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation. Korean J Lab Med 2011; 31(3): 143–147.

37.

Toh

Hoots

. SSC on disseminated intravascular coagulation of the ISTH. The scoring system of the scientific and standardisation committee on disseminated intravascular coagulation of the international society on thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost 2007; 5(3): 604–606.