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Abstract

Sepsis-induced coagulopathy (SIC) is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. The diagnostic criteria of SIC consist of three items, including Sequential Organ Failure Assessment (SOFA) score, platelet count, and prothrombin time (PT)-international normalized ratio (INR). SIC has a high prevalence and it can lead to a higher mortality rate and longer length of hospital and ICU stay. Thus, the early detection of SIC is extremely important. It is unfortunate that there is still no precise biomarker for early diagnosis and assessment of the prognosis of SIC. We reviewed the current literature and discovered that some potential biomarkers, such as soluble thrombomodulin (sTM), thrombin–antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), α2-plasmin inhibitor-plasmin complex (PIC), C-type lectin-like receptor 2 (CLEC-2), neutrophil extracellular traps (NETs), prothrombin fragment 1.2 (F1.2), Angiopoietin-2 (Ang-2), plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be useful for early diagnosis, evaluation, and prognosis of SIC. Early initiation of treatment without missing any therapeutic opportunities may improve SIC patients’ prognosis. Further large-scale clinical studies are still needed to confirm the role of these biomarkers in the diagnosis and prognosis assessment of SIC.

Keywords

sepsis-induced coagulopathy sepsis biomarker disseminated intravascular coagulation diagnosis

Introduction

Sepsis can lead to life-threatening multiple-organ dysfunction that is estimated to contribute to approximately 5 million deaths globally per year.^1,2 It is caused by a dysregulated host response to infection and is often complicated by coagulopathy and endothelial dysfunction.³ Sepsis-induced coagulopathy (SIC) criteria were developed by members of the Scientific and Standardization Committee (SSC) on Disseminated Intravascular Coagulation (DIC) of the International Society of Thrombosis and Haemostasis (ISTH) in 2017.⁴ The diagnostic criteria of SIC consist of three items, namely, Sequential Organ Failure Assessment (SOFA) score, platelet count and prothrombin time (PT)-international normalized ratio (INR). SIC is characterized by a prolonged INR and reduced platelet counts, which can be attributed to the elevated level of tissue factors on the surface of the circulating endothelial cells and the impaired counterbalance between anticoagulant and fibrinolytic pathways under septic exposure. Because of the lack of specific markers, it makes sense to diagnose SIC using a scoring system which combines multiple makers that show characteristic changes in SIC, SIC is defined as a score ≥4.⁵ SIC was regarded as an earlier phase of DIC due to the reason that SIC included most cases of ISTH overt DIC and SIC developed into overt DIC in every case.^6,7 The diagnostic criteria for SIC and overt DIC have been listed in Table 1.⁸

Table 1.

ISTH Overt DIC and SIC Scoring Systems.

		ISTH overt DIC	SIC
Item	Score	Range	Range
Platelet count (×10⁹/L)	2	<50	<100
Platelet count (×10⁹/L)	1	≥50, <100	≥100, <150
FDP/D-dimer	3	Strong increase	–
FDP/D-dimer	2	Moderate increase	–
PT/INR	2	≥6 s	>1.4
PT/INR	1	≥3 s,<6 s	>1.2, ≤1.4
Fibrinogen (g/L)	1	<1	–
SOFA score	2	–	≥2
SOFA score	1	–	1
Total score for DIC or SIC		≥5	≥4

Since the SIC score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, a secondary analysis of two randomized controlled trials indicated a prevalence of 22.1% (HYPRESS)-24.2% (SISPCT). SIC was either present at the time of sepsis diagnosis or occurred during the first 4 days following sepsis diagnosis.³ The incidence of coagulopathy, which was reportedly responsible for poor outcomes, was commonly seen among septic patients.^9,10 Coagulation activation is widely accepted to induce microvascular thrombosis leading to multiple organ dysfunction in sepsis,¹¹ and the severity of coagulopathy is known to be directly correlated with mortality.¹² Coagulopathy worsens the clinical outcomes of septic patients. SIC can lead to a higher mortality rate and longer length of hospital and ICU stay.¹³ Early identification and appropriate management in the initial hours after the development of sepsis can improve outcomes.¹⁴

Early identification of septic patients with high coagulopathy risks is of great importance. Although acknowledged markers such as PT, APTT, D-dimers, and platelets have been widely used to identify the development of DIC, those markers have low sensitivity in early diagnosis of SIC.¹⁵ Currently, there is a lack of reliable tools for the early prediction of coagulopathy in septic patients. As a result, we reviewed the current literature to find potential biomarkers for early diagnosis, evaluation, and prognosis of SIC.

Potential Biomarkers for SIC

sTM, TAT, t-PAIC, and PIC

Endothelium injury and coagulation dysfunction play an important role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), thrombin-antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), and α2-plasmin inhibitor-plasmin complex (PIC) are biomarkers of endothelium injury and coagulation dysfunction. TAT is considered to be a sensitive marker of thrombin generation, which plays a crucial role in DIC.¹⁶ T-PAIC is associated with organ failure caused by microthrombus formation.¹⁷ PIC is an indicator of plasmin generation, which varies among different underlying diseases,¹⁸ while endothelial cells injury reflected by sTM. A prospective observational study that included 444 patients with suspected DIC and 137 healthy people has indicated that the combination of the four biomarkers provided more reliable results than that when a single marker was applied. Moreover, TAT, t-PAIC, and sTM showed prognostic value in predicting poor outcomes.¹⁹

Thrombomodulin (TM), a trans-membrane glycoprotein, is abundant expressed on the endothelial surface. As an essential component of the protein C system, endothelial-bound TM plays important roles in anti-coagulation.²⁰ sTM is the product of proteolytic degradation of endothelial-bound TM. Under physiological conditions, sTM levels are in a stable range.²¹ If the endothelium is damaged, endothelial-bound TM is released from the endothelial surface, resulting in a significant increase in sTM concentrations.^22,23 Therefore sTM is considered to be a sensitive marker of endothelial damage. A prospective, observational cohort study involving 372 patients with sepsis, 210 patients with severe sepsis, and 98 patients with septic shock has demonstrated sTM was a valuable biomarker in the risk stratification and prognosis evaluation of emergency department sepsis. Furthermore, sTM can enhance the ability of the Mortality in Emergency Department Sepsis (MEDS) score in the prediction of severe sepsis and 30-day mortality.²⁴ Most patients developed coagulopathy which was closely linked to endothelial injury in the initial phase of sepsis, which was demonstrated by abnormalities in endothelial biomarkers sTM and their strong association with poor 60-day prognosis and development of septic shock and sepsis-induced DIC.¹⁵ A prospective pediatric study included 59 children showed that t-PAIC was significantly different between the subgroups with and without SIC.²⁵ A single-center, prospective observational study involving 77 patients indicated that TAT discriminated well between septic patients with and without developing overt DIC. Among the significant diagnostic markers for overt DIC, TAT was also good predictors of 28-day mortality.²⁶

sCLEC-2

C-type lectin-like receptor 2 (CLEC-2) is one of the platelet-activated receptors expressed on the surface of platelet membranes.^27–29 Soluble CLEC-2 (sCLEC-2) has been receiving attention as a predictive marker for thrombotic predisposition. Platelets are involved in both immune responses and hemostasis. These mechanisms work together in a complex and synchronous manner, making the contribution of platelets to sepsis of major importance.³⁰ A retrospective single-center observational study included 70 septic patients showed that C2PAC index (sCLEC-2/platelet count ratio) was significantly higher in the SIC group (2.6 ± 1.7) compared with the non-SIC group (1.2 ± 0.5). A sustained rise in the C2PAC index may be a predictor of progression to DIC. As a result, sCLEC-2, especially the C2PAC index, is a useful predictive marker for early assessment of coagulopathy and DIC diagnosis in sepsis.³¹

NETs

Neutrophil extracellular traps (NETs) produced by activated neutrophils have recently been shown to provide a novel link between thrombosis and inflammation.³² NETs are portion of the innate immune response to microbial infections, consisting of neutrophil granule proteins, cell-free DNA (cfDNA), and histones.³³ In accompany with platelets, red blood cells, and fibrin, NET components promote the formation of thrombi, especially in microvessels.^34,35 A prospective study involving 82 patients with sepsis suggested increased NETs formation was significantly associated with sepsis-induced DIC incidence and mortality in sepsis patients.³⁶ Coagulation activation induced by NETs represents important host defense mechanisms that contribute to the compartmentalization and killing of bacteria but may also initiate DIC. An in vitro study has shown that fibrin is colocalized with free DNA in blood clots, and increased levels of free DNA occur with deep vein thrombosis.³⁷ Coagulation activation that occurs with NETs is important in sepsis and DIC.³⁸ In septic DIC, varying degrees of thrombocytopenia will occur, and the magnitude of the platelet drop is reportedly associated with disease severity and mortality. Thrombocytopenia in septic patients also occurs owing to activated platelets adhering to neutrophils stimulated by NETs and is considered to be an effect of NETs formation with DIC.³⁹

F1.2

Prothrombin fragment 1.2 (F1.2) is an activation peptide generated when prothrombin is converted to thrombin,⁴⁰ which is released from prothrombin by the catalytic action of the prothrombinase complex.⁴¹ New criteria for DIC from the Japanese Society on Thrombosis and Hemostasis (JSTH) include these biomarkers of thrombin generation, TAT, and F1.2 to improve the sensitivity and specificity of the DIC criteria.⁴² F1.2 is a well-described marker of coagulation activation that is elevated in individuals with acute thrombosis^43,44 and individuals with hypercoagulable states.⁴⁵ In addition, it has been demonstrated to be a useful biomarker for prediction of venous thromboembolism in certain patient populations.⁴⁶ The PF1.2 is more specific than synchronously measured D-dimer in identifying patients who experienced thrombosis and is significantly associated with thrombotic manifestations in multivariable analyses while the D-dimer was not.⁴⁷ A multicenter randomized controlled trial included 800 adults with sepsis-associated coagulopathy showed that SIC patients treated with recombinant human soluble thrombomodulin having higher baseline thrombin generation biomarker(F1.2, TAT, d-dimer) levels had lower mortality.⁴⁸

Ang-2

Angiopoietin-2 (Ang-2) is a secreted protein produced in endothelial cells and pre-stored in the Weibel-Palade bodies together with von Willebrand factor (vWF). Release of Ang-2 from dysfunctional endothelial cells into the circulation may precede profound endothelial injury, including disruption of adherens junctions and shedding of endothelial proteoglycan into the circulation.⁴⁹ Angiopoietin-2 (Ang-2) is a promising endothelial biomarker that has been studied in critical illnesses.⁵⁰ It is a glycoprotein that binds to the Tie2 tyrosine kinase receptor in the endothelium to promote a proinflammatory state.^51–56 A prospective observational study involving 105 patients with severe sepsis showed that Ang-2 levels elevated according to the severity of sepsis progression and were correlated with important clinical parameters such as mean arterial pressure and platelets counts, procalcitonin, lactate levels, and SOFA score. Ang-2 levels accurately discriminated for sepsis and septic shock. Plasma Ang-2 levels may serve as an additional biomarker for severe sepsis and septic shock.⁵⁷ One study included 102 patients with sepsis and suspected DIC demonstrates that Ang-2 levels are significantly upregulated in SIC, and this biomarker can be used to risk stratify patients with sepsis into overt DIC and non-overt DIC. Furthermore, the Ang-2 level at ICU admission in a patient with sepsis and suspected DIC may provide a predictive biomarker for mortality outcome.⁵⁸

PAI-1

Plasminogen activator inhibitor-1 (PAI-1), a 48-kDa serine proteinase inhibitor (SERPIN), is produced by various cells such as vascular endothelial cells, smooth muscle cells, platelets, fibroblasts, adipose tissue, and monocytes/macrophages,⁵⁹ is the main physiological plasminogen activator inhibitor. PAI-1 can inhibit the plasmin-mediated dissolving of microthrombi in the microvasculature and thus contribute to DIC.⁶⁰ Previous retrospective single-center study of 186 patients with sepsis revealed that PAI-1 was the only independent predictive marker of 28-day mortality among sepsis biomarkers and fibrinolysis/coagulation markers, with the optimal cut-off value being 83 ng/mL.⁶¹ Another retrospective cohort study included 103 patients showed that patients with sepsis and PAI-1 levels of ≥83 ng/mL had elevated risks of coagulopathy, organ failure, and mortality. As a result, these results suggest that 83 ng/mL could be a useful cut-off value for prognostication based on PAI-1 levels in this setting.⁶² PAI-1 can predict prognosis in sepsis patients. PAI-1 reflects DIC with suppressed fibrinolysis and organ failure, with microthrombi leading to microcirculatory dysfunction.⁶² Plasma PAI-1 plays an important role in sustaining DIC in septic DIC cases and contributes to multiple organ failure and decreased survival in such patients.⁶³

TIMP-1

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a promising septic biomarker to assess septic patients’ therapeutic response and prognosis.^64,65 TIMP-1 plays a role in extracellular matrix (ECM) remodeling by regulating specifically the activity of matrix metalloproteinase-9 (MMP-9).⁶⁶ Both MMP-9 and TIMP-1 levels were found equally elevated in sepsis, a decrease in the MMP-9/TIMP-1 ratio is significantly associated with severity and mortality of septic patients. Studies also found the same results and concluded that the balance between MMP-9 and TIMP-1 is an essential biomarker of diagnosis and good prognosis in sepsis.^67,68 A multicenter, observational, and prospective study involving 295 patients with severe sepsis demonstrated that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome.⁶⁹ A prospective pilot study included 22 patients with severe sepsis showed that TIMP-1 was elevated in the early phase of sepsis-induced overt DIC, and it correlated both with degree of coagulopathy and disease severity. These findings suggested that TIMP-1 may play a role in the pathogenesis of DIC in septic patients.⁷⁰

Conclusion

SIC is a life-threatening complication characterized by the systemic activation of coagulation in sepsis. SIC is characterized by the suppression of fibrinolysis typical of DIC and can easily progress to multiple organ dysfunction and failure. Thus, the early detection of SIC is extremely important. Some potential biomarkers, such as sTM, TAT, t-PAIC, PIC, sCLEC-2, NETs, F1.2, Ang-2, PAI-1, and TIMP-1 may be useful for early diagnosis, evaluation, and prognosis of SIC. The biomarkers, key findings of the study, authors, and references are summarized in Table 2. Early initiation of treatment without missing any therapeutic opportunities may improve SIC patients’ prognosis. Further large-scale clinical studies are still needed to confirm the role of these biomarkers in the diagnosis and prognosis assessment of SIC.

Table 2.

Summary of Biomarkers for SIC.

Authors and references	Biomarkers	Key findings
Mei ¹⁹Boehme²³Li²⁵Koyama²⁶	sTM, TAT, t-PAIC, and PIC	Biomarkers of endothelium injury and coagulation dysfunction. Prognostic value in predicting poor outcome of SIC.
Ishikura³¹	sCLEC-2	A useful predictive marker for early assessment of coagulopathy and DIC diagnosis in sepsis.
Mao³⁶	NETs	NETs formation is significantly associated with sepsis-induced DIC incidence and mortality in sepsis patients.
Levi⁴⁸	F1.2	SIC patients treated with recombinant human soluble thrombomodulin having higher baseline thrombin generation biomarker(F1.2) levels had lower mortality.
Statz⁵⁸	Ang-2	Ang-2 levels are significantly upregulated in SIC, and this biomarker can be used to risk stratify patients with sepsis into overt DIC and non-overt DIC. The Ang-2 level at ICU admission in a patient with sepsis and suspected DIC may provide a predictive biomarker for mortality outcome.
Hoshino K⁶²Madoiwa⁶³	PAI-1	PAI-1 was the independent predictive marker of 28-day mortality among sepsis biomarkers and fibrinolysis/coagulation markers, with the optimal cut-off value being 83 ng/mL. Patients with sepsis and PAI-1 levels of ≥83 ng/mL had elevated risks of coagulopathy, organ failure, and mortality. Plasma PAI-1 plays an important role in sustaining DIC in septic DIC cases and contributes to multiple organ failure and decreased survival in such patients.
Sivula⁷⁰	TIMP-1	TIMP-1 is elevated in the early phase of sepsis-induced overt DIC, and it correlates both with degree of coagulopathy and disease severity. TIMP-1 may play a role in the pathogenesis of DIC in septic patients.

Footnotes

Acknowledgments

Not applicable.

Author Contributions

Conceptualization by DZ; writing—original draft by YL; writing (review and editing) by HL, YW, and JG. All authors read and approved the final manuscript.

Availability of Supporting Data

Not applicable.

Consent for Publication

Not applicable.

Consent to Participate

Not applicable.

Declaration of Conflicting Interests

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

Ethical Approval

Not applicable.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Key Research and Development Project (2022YFC2304600).

ORCID iD

Yuting Li

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Potential Biomarkers for Early Diagnosis,Evaluation,and Prognosis of Sepsis-Induced Coagulopathy

Abstract

Keywords

Introduction

Potential Biomarkers for SIC

sTM, TAT, t-PAIC, and PIC

sCLEC-2

NETs

F1.2

Ang-2

PAI-1

TIMP-1

Conclusion

Footnotes

Acknowledgments

Author Contributions

Availability of Supporting Data

Consent for Publication

Consent to Participate

Declaration of Conflicting Interests

Ethical Approval

Funding

ORCID iD

References