# Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications

Anais Curtiaud, Toshiaki Iba, Eduardo Angles-Cano, Ferhat Meziani, Julie Helms

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Anais Curtiaud, Toshiaki Iba, Eduardo Angles-Cano, Ferhat Meziani, Julie Helms. Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications. Annals of Intensive Care, 2025, 15 (1), pp.12. 10.1186/s13613-025-01434-2. hal-05503784

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# Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications

Anaïs Curtiaud¹,², Toshiaki Iba³, Eduardo Angles-Cano⁴, Ferhat Meziani¹,² and Julie Helms¹,²*

**Abstract**

Diagnosing coagulopathy in septic patients remains challenging in intensive care. Disseminated intravascular coagulation (DIC) indeed presents with complex pathophysiology, complicating timely diagnosis. Epidemiological data indicate a significant prevalence of DIC in septic patients, with mortality rates up to 60%. Despite advances, current biomarker-based diagnostic tools often fail to provide early and accurate detection. This review evaluates the utility and limitations of traditional and emerging biomarkers for diagnosing sepsis-induced coagulopathy (SIC) and DIC. We also assess the effectiveness of anticoagulant therapy guided by biomarker-based diagnostic criteria.

**Keywords** Disseminated intravascular coagulation, Coagulopathy, Sepsis, Septic shock

**Introduction**

Early diagnosis of coagulopathy in critically ill patients remains a significant challenge in the intensive care setting. Disseminated intravascular coagulation (DIC), depending on its etiology, presents with a complex pathophysiology and heterogeneous phenotypes, complicating timely and accurate diagnosis [1, 2].

Epidemiological data indicate that the frequency of DIC among septic patients varies significantly, with reported rates as high as 40.7% in the KyberSept trial and 22.4%

in the PROWESS study [3, 4]. Furthermore, DIC is consistently associated with a high mortality rate, which can reach up to 60% [5, 6], underscoring the need for early diagnosis and intervention. Although our understanding of DIC pathophysiology has improved, current diagnostic tools, primarily based on biomarkers, often fail to provide early and reliable detection. To avoid the misdiagnosis relying on a single biomarker, numerous scoring systems incorporating different hemostasis parameters have been developed.

This review evaluates the utility and limitations of existing biomarkers in diagnosing sepsis-induced coagulopathy (SIC) and overt DIC (Fig. 1). We will first summarize the mechanistic pathways of hemostasis and inflammation involved in DIC. Then, we will highlight biomarkers used for DIC/SIC diagnosis and their diagnostic performances, followed by a discussion on how biomarkers may aid clinicians in treating patients, particularly regarding anticoagulant therapy.

<figure><img src="image_3.png" /></figure>

<footnote>*Correspondence:
Julie Helms
Julie.helms@chru-strasbourg.fr

¹Faculté de Médecine, Service de Médecine Intensive-Réanimation,
Université de Strasbourg (UNISTRA), Hôpitaux universitaires de
Strasbourg, Nouvel Hôpital Civil, 1, place de l'Hôpital,
Strasbourg F-67091, cedex, France

²INSERM (French National Institute of Health and Medical Research), UMR
1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France

³Department of Emergency and Disaster Medicine, Juntendo University
Graduate School of Medicine, Tokyo, Japan

⁴Innovative Therapies in Haemostasis, Université Paris Cité - INSERM
U-1140, Paris 75006, France</footnote>
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Biomarkers for coagulation disorder in sepsis. Coagulation activation is initiated by tissue factor (TF) and phosphatidylserine expression on monocytes. Other cells, such as platelets, endothelial cells, and granulocytes, also contribute by expressing procoagulant factors. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests are commonly used to assess the extrinsic and intrinsic pathways of coagulation. Fibrin, the final coagulation product, is dissolved by plasmin into fibrin/fibrinogen degradation products and D-dimer. Thrombin, a key mediator of intravascular inflammation, is neutralized by antithrombin and converted into an antithrombotic agent by activated protein C. The thrombin generated can be measured as thrombin-antithrombin complex (TAT). Intravascular inflammation promotes interactions between cells, leading to the release of adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) into the plasma. Additionally, increased levels of plasminogen activator inhibitor-1 (PAI-1), angiopoietin-2 (Ang-2), and von Willebrand factor are known to reflect endothelial damage in sepsis</figcaption></figure>

## Mechanistic pathways of hemostasis and inflammation in DIC

In sepsis, DIC arises from a dysregulated immunothrombosis, driven by systemic inflammation and excessive activation of coagulation pathways. The underlying pathophysiological mechanisms encompass a complex interplay between the coagulation cascade, endothelial dysfunction, immune responses and fibrinolytic insufficiency.

### Coagulation activation

The systemic inflammatory response in sepsis leads to the overexpression of tissue factor on activated endothelial cells and monocytes. Tissue factor acts as a potent initiator of the extrinsic coagulation cascade, promoting thrombin generation and resulting in widespread fibrin deposition. Thrombin plays a pivotal role in balancing host defense and pathogenic outcomes during sepsis. Its generation supports pathogen containment through fibrin formation and immune modulation but becomes

deleterious when unregulated. Indeed, while localized thrombin activity facilitates pathogen entrapment and immune cell recruitment, systemic thrombin activation contributes to fibrin deposits, microvascular thrombosis, and tissue ischemia [7–9]. Experimental studies highlight that targeted inhibition of thrombin may impair bacterial clearance, underscoring its dual role [10]. Excessive thrombin not only forms fibrin clots but also activates protease-activated receptors on endothelial and immune cells, amplifying inflammation and coagulation activation. This pathological loop underpins the prothrombotic state characteristic of DIC [1, 11] and will be amplified by endothelial dysfunction.

### Endothelial dysfunction

Sepsis induces endothelial cell activation and dysfunction, driven by pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha. Endothelial cells lose their anticoagulant properties, including thrombomodulin, and release procoagulant microvesicles
(MVs) into the circulation [5, 12]. These MVs enhance thrombin generation and further amplify the coagulation cascade. Increased endothelial permeability due to cytokine-mediated damage leads to vascular leakage, tissue edema, and impaired organ perfusion [13]. While the endothelium plays a central role in amplifying coagulation activation, other vascular cells, including innate immune cells, significantly contribute through the process of immunothrombosis.

## Immunothrombosis dysregulation

Immunothrombosis, initially described as a defense mechanism [14], becomes dysregulated in sepsis. Activated neutrophils release procoagulant MVs, but also neutrophil extracellular traps (NETs), composed of chromatin fibers and granular proteins. While NETs help trap pathogens, they also serve as a scaffold for platelet aggregation and coagulation factor assembly. NETs promote excessive thrombin generation and inhibit fibrinolysis by binding plasminogen, further stabilizing clots [11], which exacerbates the procoagulant environment and contributes to the pathogenesis of DIC.

## Suppressed fibrinolysis

Fibrinolysis, the physiological process responsible for breaking down fibrin clots, is significantly impaired in sepsis-induced DIC. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) released by activated endothelial cells inhibit tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), reducing plasmin generation. Furthermore, neutrophil elastase from NETs is responsible for plasminogen degradation, leading to an insufficiency in plasmin generation [15]. As a result, fibrin degradation is hindered, promoting persistent microvascular thrombosis and exacerbating organ dysfunction.

## Microvascular thrombosis and organ failure

The combined effects of excessive coagulation, fibrinolytic suppression, and endothelial dysfunction culminate in widespread microvascular thrombosis. This impairs tissue perfusion, leading to ischemia and driving multi-organ failure, a hallmark of severe DIC [10]. Disseminated microthrombi within critical vascular beds, including the lungs, kidneys, and liver, exacerbate organ dysfunction and increase mortality in septic patients [16].

Understanding these mechanistic pathways underscores the rational for some biomarkers, particularly those associated with initiation of coagulation pathway, the protection of endothelial integrity and the restoration of fibrinolytic balance. Incorporating biomarkers that reflect these processes into clinical practice holds the promise of improving the accuracy of DIC diagnosis and optimizing its management in the context of sepsis.

## Diagnostic biomarkers for DIC and SIC

### Traditional hemostatic markers

Coagulation markers, including traditional markers such as prothrombin time (PT), fibrinogen levels, platelet count, and soluble fibrin monomers, have been fundamental in diagnosing DIC for decades (Supplementary Table 1). These markers are commonly used and are often included in diagnostic scoring systems like those proposed by the International Society on Thrombosis and Haemostasis (ISTH) [17] and the Japanese Association for Acute Medicine (JAAM) [18].

### Prothrombin time, platelet count, and fibrinogen

PT and platelet count are among the most used markers for assessing coagulation status in critically ill patients. PT evaluates the extrinsic pathway of coagulation and measures the time required for plasma to clot after the addition of thromboplastin, a reagent composed of tissue factor, phospholipids, and calcium. While PT is commonly used to diagnose coagulation disorders and can reflect the consumption of clotting factors when prolonged, its specificity for SIC or DIC is limited, especially in the early stages of these conditions. Studies, such as those by Asakura et al. have shown that while PT is indicative of coagulopathy, it often lacks the specificity needed to differentiate DIC from other conditions, like liver disease or vitamin K deficiency [19].

Similarly, platelet count, which is typically reduced in sepsis-induced DIC due to platelet consumption in the formation of microthrombi and associated to a worse prognosis, also suffers from reduced diagnostic specificity as thrombocytopenia is not exclusive to DIC [20, 21]. In sepsis, other than increased consumption, platelet count can decrease with bone marrow dysfunction. Platelets play a significant role in inflammation and immunity, and their depletion in sepsis often correlates with disease severity and the likelihood of multi-organ failure. Greco et al. have shown that sepsis can lead to a reduction in platelet count as well as impair platelet function, contributing to complications such as multi-organ dysfunction and poor patient outcomes [22]. Additionally, the relationship between platelet count and mean platelet volume (MPV) has been studied as an indicator of bone marrow response in septic patients. A decreasing platelet count and an increasing MPV could be indirect signs of bone marrow activation (?) in the course of sepsis [23]. These findings underscore the importance of monitoring platelet count and function as part of the management and prognosis of sepsis, especially in the context of bone marrow health.

Fibrinogen, a key coagulation factor converted to fibrin during clot formation, is generally decreased in DIC due to consumption. However, in sepsis-induced DIC, fibrinogen levels can be paradoxically normal or even elevated
<figure><img src="image_5.png" /><figcaption>**Fig. 2** Two step approach to diagnose disseminated intravascular coagulation in sepsis. Coagulation activation is a nearly universal event in sepsis. To screen for coagulation disorders, platelet count and prothrombin time-international normalized ratio (PT-INR) should be measured in all septic patients. If the patient meets the sepsis-induced coagulopathy (SIC) criteria, anticoagulant therapy may be considered. Additionally, fibrinogen and D-dimer levels should be assessed to determine if overt disseminated intravascular coagulation (DIC) is present</figcaption></figure>

[24], complicating the diagnostic process. Individually, each coagulation is limited by issues of sensitivity and specificity which has led to the development of comprehensive scoring systems. The Scientific and Standardization Committee of the ISTH recently introduced the SIC score. This score combines platelet count, PT, and the Sequential Organ Failure Assessment (SOFA) to diagnose DIC at an early stage, before it progresses to overt DIC. The ISTH recommends a two-step diagnostic approach (Fig. 2): first applying the SIC score followed by the overt DIC score if SIC is positive [25]. This approach system represents a significant advance in timely diagnosis without overlooking and may facilitate earlier and more targeted interventions [26].

### Soluble fibrin and fibrin monomers

Soluble fibrin and fibrin monomers are considered more specific markers of thrombin generation and have been shown to be particularly useful in diagnosing DIC. Wada et al. demonstrated that elevated levels of soluble fibrin are strongly associated with overt DIC, particularly in patients with sepsis, where early diagnosis is critical [27]. However, these markers also suffer from some limitations. Soluble fibrin and fibrin monomers can be elevated

in other thrombotic disorders such as myocardial infarction, cancer, and thrombosis. Their measurement is not widely available in all clinical settings and is further hindered by a lack of standardization across laboratories, which significantly limits their practical utility [28, 29].

Emerging evidence suggests that these markers, when used in conjunction with other clinical findings and laboratory tests, can significantly improve the accuracy of DIC diagnosis. For instance, integrating soluble fibrin levels with D-dimer and fibrin/fibrinogen degradation products (FDPs) in a comprehensive scoring system could provide a more nuanced and early diagnosis, particularly in septic patients at high risk for DIC. Elevated levels of soluble fibrin and fibrin monomer indicate ongoing thrombin activity and clot formation, while increases in FDPs and D-dimer also reflect fibrin breakdown. Measuring both offers insight into both the generation and degradation of fibrin, improving diagnostic precision in DIC [30].

### Fibrinolysis markers

Sepsis-induced DIC is characterized by a suppressed fibrinolysis, disrupting the balance between clot formation and its dissolution. This imbalance can lead to
excessive clotting, suggesting that fibrinolysis markers
might be valuable for diagnosing DIC (Supplementary
Table 2).

D-dimers and fibrin degradation products

D-dimers, produced from the degradation of fibrin by
plasmin, are among the most specific markers of fibri-
nolysis. Elevated D-dimer levels are a hallmark of DIC
and are commonly used in clinical practice to both diag-
nosing the condition and monitoring its progression.
Studies, including those of Watanabe et al. [31] have
demonstrated that D-dimer levels are significantly higher
in patients with DIC, particularly in those with sepsis-
induced coagulopathy.

However, the clinical utility of D-dimers is limited by
their lack of specificity. Elevated D-dimer levels can occur
in a wide range of conditions, including venous throm-
boembolism, malignancy, and inflammation, making it
challenging to use D-dimers alone as a definitive diagnos-
tic tool for DIC. Furthermore, the suppressed fibrinoly-
sis interferes with the increase of D-dimer, especially in
severe cases. Another drawback of D-dimer is the lack of
standardization, including significant variations in refer-
ence ranges across measurement kits, the absence of a
universal threshold, and the use of different monoclonal
antibodies, all of which contribute to inconsistent results
[27, 32, 33]. It should also be cautioned that D-dimer lev-
els are also affected by age, pregnancy, and other health
conditions [34]. As a result, D-dimer levels are typically
interpreted alongside other clinical findings and labora-
tory tests to improve diagnostic accuracy.

FDPs are another marker that reflects fibrinolysis. Like D-dimers, FDPs are elevated in DIC and are often used in combination with other markers in diagnostic scoring systems. FDP levels are generally more sensitive than D-dimer for detecting fibrinolysis and clot degradation, especially in the early stages of DIC. FDP can indicate both fibrin and fibrinogen breakdown, which gives a broader assessment of fibrinolysis compared to D-dimer [35]. Studies have shown that FDPs levels correlate well with disease severity in DIC, with higher levels associated with worse outcomes. However, like D-dimers, FDPs lack specificity and can be elevated in various conditions, highlighting the importance of integrating them into a comprehensive diagnostic approach.

Plasmin-α2-antiplasmin complexes

Plasmin-α2-antiplasmin complexes are specific markers
of fibrinolytic activity, directly reflecting both the plas-
min protein and its active site. When plasmin acts on
fibrin, it generates D-dimers, while its interaction with
α2-antiplasmin forms an inactive complex. Together,
D-dimers and plasmin-α2-antiplasmin offer complemen-
tary insights: D-dimers reflect plasmin's role in fibrin

degradation, whereas plasmin-α2-antiplasmin complexes
indicate the regulation of plasmin activity, capturing the
balance between fibrinolysis and its inhibition. Stud-
ies by Wada et al. [36] and others have highlighted the
diagnostic value of these complexes in DIC, particularly
in patients with hematologic malignancies where fibri-
nolysis is often upregulated [37]. In DIC, α2-antiplasmin
levels are often reduced due to increased consumption,
reflecting a compensatory response to ongoing fibrinoly-
sis [19, 38].

While plasmin-α2-antiplasmin complexes are valu-
able markers of fibrinolytic activity, their levels can be
affected by underlying disease and other thrombotic or
inflammatory conditions. This variability underscores
the importance of interpreting these markers within the
broader clinical context.

Antifibrinolytic markers

Besides α2-antiplasmin, other antifibrinolytic proteins including PAI-1 and thrombin-activatable fibrinolysis inhibitor (TAFI), play critical roles in regulating fibrinolysis and maintaining hemostatic balance. In DIC, particularly sepsis-induced DIC, these proteins are often dysregulated (Supplementary Table 2), contributing to the complex pathophysiology of the condition.

PAI-1 is a potent inhibitor of fibrinolysis, primarily by
inhibiting tPA and uPA. Elevated PAI-1 levels are com-
monly observed in sepsis-induced DIC and are associ-
ated with a hypofibrinolytic state, where clot breakdown
is impaired. Studies by Asakura et al. [39] and others have
shown that high PAI-1 levels correlate with increased
mortality in septic patients with DIC, suggesting that
PAI-1 could serve as a prognostic marker.

TAFI modulates fibrinolysis by cleaving C-terminal
lysine residues on fibrin, thereby inhibiting plasminogen
binding and prevents fibrin degradation [40, 41]. The
role of TAFI in DIC remains unclear, with studies report-
ing conflicting results regarding TAFI activity in DIC
patients. Some studies suggest that reduced TAFI activity
may contribute to hyperfibrinolysis in DIC, while other
studies have found no significant differences in TAFI
levels between DIC and non-DIC patients [31, 42–44].
These inconsistencies highlight the need for further
investigation to determine the role of TAFI in DIC and its
potential as a diagnostic or prognostic marker.

Other than PAI-1 and TAFI, circulating DNA released
from NETs during sepsis can inhibit fibrinolysis by bind-
ing to plasmin and impairing its ability to degrade fibrin.
This results in clots that are resistant to breakdown, exac-
erbating the risk of microvascular thrombosis [45].

Anticoagulant markers in DIC

The anticoagulant pathways and vascular endothelial
function are profoundly affected in DIC, particularly in
the context of sepsis. Markers such as antithrombin (AT), protein C, protein S have been extensively studied for their roles in diagnosing and managing DIC (Supplementary Table 3).

## Antithrombin and protein C systems

AT is a key inhibitor of thrombin and factor Xa, that plays a central role in regulating coagulation. In DIC, AT levels are often reduced due to increased consumption, impaired synthesis, extravasation, and degradation by neutrophil elastase. Several studies, including those by Asakura et al. [19] and Takemitsu et al. [46], have demonstrated that low AT levels are a hallmark of DIC, particularly in sepsis-induced DIC. Low levels of AT in sepsis-associated DIC are highly correlated with increased severity. Studies have shown that AT provides a strong prognostic indicator for the severity of DIC and the likelihood of mortality in patients with sepsis [47]. In addition, combining AT with other markers like thrombin-antithrombin complexes (TAT) improves the diagnostic accuracy for DIC, especially in the early stages, and can help predict the development of overt DIC in septic patients [48]. AT is therefore included in the JAAM-DIC score [49].

The protein C system, which includes protein C and its cofactor protein S, is another essential anticoagulant pathway. Activated protein C (aPC) inactivates factors Va and VIIIa, thereby downregulating thrombin generation [50, 51]. In DIC, the levels of protein C and protein S are often significantly reduced due to consumption and decreased synthesis, contributing to the prothrombotic state observed in these patients [47]. Gando et al. [52] reported that low protein C levels were associated with increased DIC severity and poorer outcomes, highlighting the importance of the protein C pathway in maintaining hemostatic balance.

## Emerging biomarkers

### Emerging coagulation, inflammation, and endothelial markers

The integration of coagulation markers with biomarkers of inflammation and organ dysfunction is an area of active research (Supplementary Table 4). For example, the combination of PT, soluble fibrin, and fibrin monomers with markers such as C-reactive protein (CRP) or interleukin-6 (IL-6) could potentially enhance the sensitivity and specificity of SIC and DIC diagnosis. Thrombomodulin (TM), and other vascular endothelial markers like microvesicles (MVs) and markers of neutrophil activation like NETs have also been extensively studied for their roles in diagnosing and managing DIC. New biomarkers, such as NETs, MVs and angiopoietin-2 (Ang2), show promise for enhancing the diagnosis of SIC and DIC. However, their widespread clinical adoption faces

significant challenges. For some biomarkers, real-time measurement remains constrained by the need for specialized laboratory expertise and advanced technologies, limiting their practicality in time-sensitive clinical settings. Furthermore, their specificity for DIC may be reduced by confounding factors such as systemic inflammation or coexisting conditions, complicating their interpretation.

### Thrombomodulin and vascular endothelial markers

Thrombomodulin (TM), an endothelial cell membrane protein, plays a crucial role in the activation of protein C. In DIC, endothelial injury causes to the shedding of thrombomodulin from the cell surface, resulting in elevated levels of soluble thrombomodulin (sTM) in the plasma. This increase reflects endothelial dysfunction and disruption in the anticoagulant pathway. Studies by Lin et al. [53] and Zhang et al. [33] have shown that high sTM levels are associated with poor outcomes in DIC, suggesting that sTM could serve as a marker of endothelial damage and a predictor of DIC development in septic patients.

Other vascular endothelial markers, such as MVs and Ang-2, are increasingly recognized for their roles in DIC. MVs, small vesicles released from activated endothelial cells, platelets, and leukocytes, are potent pro-inflammatory and pro-coagulant mediators. Delabranche et al. [5] and Stiel et al. [6] identified elevated levels of endothelial-derived MVs in septic patients with DIC, suggesting their potential as early diagnostic markers. However, the role of MVs in DIC is complex and sometimes contradictory, with some studies reporting decreased MV levels during sepsis [54]. This variability may be due to differences in the cellular origin of MVs or the stage of the disease.

Ang-2, a protein involved in angiogenesis and endothelial activation, is another promising marker. Elevated Ang-2 levels have been associated with endothelial dysfunction and inflammation, making it relevant in the context of DIC. Studies by Statz et al. [55] demonstrated that Ang-2 levels were significantly elevated in DIC patients, suggesting its potential as a marker for monitoring disease progression.

The interactions between platelets, leukocytes, and endothelial cells are vital in determining the severity of sepsis and sepsis-induced DIC [11]. Circulating levels of adhesion molecules are therefore considered to be useful markers for assessing the severity of DIC. Elevated levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) have been observed in patients with sepsis and are associated with worse clinical outcomes [56]. Although soluble adhesion molecules like ICAM-1 and VCAM-1 are associated with sepsis severity, their sensitivity and specificity for sepsis-induced endothelial damage and organ
dysfunction are not high in DIC, and their performance
may not be superior to other sepsis biomarkers like pro-
calcitonin or interleukin-6 [57].

Neutrophil extracellular traps as a biomarker of DIC

NETs are web-like structures composed of DNA strands and proteins released by neutrophils during a process called NETosis. NETs play a significant role in host defense by trapping and killing pathogens, but in the setting of sepsis-induced DIC, NETs contribute to a procoagulant environment as DNA provides a procoagulant surface for the assembly of coagulation factors (Supplementary Table 5). Delabranche et al. [16] and Stiel et al. [58] have demonstrated that NET formation is increased in septic patients with DIC, promoting thrombin generation and exacerbating coagulopathy. Measuring NETs in a clinical setting, potentially using surrogate markers like neutrophil side scatter fluorescence (NEUT-SFL), could offer a valuable tool for the early diagnosis and management of DIC [59].

Role of biomarkers in patient management

The diagnostic performance of traditional hemostasis
markers alone unfortunately remains limited in the con-
text of sepsis-induced DIC. To address this limitation,
several diagnostic scoring systems have been proposed.
The ISTH recommends a two-step diagnostic process
[25]. The first step involves the SIC score, which com-
bines PT, platelet count, and the SOFA score to identify
early coagulopathy. A positive SIC score prompts further
evaluation using the ISTH overt DIC scoring system,
which integrates platelet count, PT, fibrinogen levels,
and fibrin-related markers such as D-dimers or FDPs. A
cumulative ISTH score of ≥5 confirms overt DIC [25, 26].
This two-step scoring approach aims at facilitating the
simple identification of patients with sepsis-induced DIC,
allowing for timely intervention [60].

The main limitations of scores are their complexity for
bedside application and their inability to facilitate early
diagnosis. Also, their utility, and the diagnostic per-
formance of these scores vary. Studies have shown that
the ISTH DIC score has good specificity (approximately
91%) but moderate sensitivity (around 50%) for identify-
ing DIC in septic patients [26]. In contrast, the SIC score
provides higher sensitivity for early-stage coagulopathy
but lower specificity, potentially leading to overdiagnosis
in certain contexts like acute on chronic liver failure or
treatment by oral anticoagulant. Combining these tools
improves diagnostic accuracy by balancing early detec-
tion with specificity for overt DIC.

To date, most clinical trials evaluating anticoagulant
treatments for sepsis-induced DIC have included patients
with sepsis or septic shock regardless of their SIC or DIC
status. As a result, based on the prevalence of DIC in

septic shock, 60 to 70% of the participants in these trials
likely did not meet the criteria for SIC or DIC, potentially
diluting the observed treatment effects, as illustrated
in the following section. The goal of existing diagnostic
scores and novel biomarkers should be to enable the early
identification of patients who could benefit from targeted
treatment for SIC/DIC.

Heparin is the only anticoagulant widely used for sep-
sis worldwide. However, the effectiveness of heparin in
treating sepsis has not been proven yet and is a subject
of ongoing debate. A systematic review and meta-analysis
investigating unfractionated or low molecular heparin
administered to patients with sepsis, severe sepsis, septic
shock, or disseminated intravascular coagulation associ-
ated with infection reported that heparin, particularly in
low doses, might reduce mortality (Risk Ratio [RR]: 0.88,
95% Confidence Interval [CI]: 0.77-1.00). Meanwhile,
heparin was not significantly associated with increased
major hemorrhage (RR: 0.79; 95% CI: 0.53-1.17) [61].
While heparin can reduce mortality, it should be cau-
tioned that the effect may be due to lower the risk of
thrombosis and not improve coagulation disorder and
organ dysfunction. A retrospective analysis - including
3,377 patients with sepsis according to Sepsis 3.0 crite-
ria and a SIC score ≥4 - revealed the association between
the treatment with unfractionated heparin and decreased
intensive care unit mortality in septic patients (Hazard
Ratio [HR]: 0.64, 95% CI: 0.49-0.84), and stratification
analysis demonstrated the survival advantage was seen
only among patients with a SIC score of 4 (HR: 0.56,
95% CI: 0.38-0.81) [62]. Another recent observational
study has also reported similar results, and its sub-anal-
ysis revealed that significant survival benefits associated
with heparin were seen only in the sepsis patients with
SIC scores of 3 or 4, and the authors concluded early
heparin administration upon admission was associated
with lower mortality, especially in moderate SIC without
increasing the risk of complications [63]. However, since
these results were obtained by the retrospective studies,
large clinical trials are needed to confirm the potential
benefit of heparin in SIC/DIC and facilitate the develop-
ment of robust, high-evidence-level recommendations.

While other anticoagulants - such as antithrombin
supplementation and recombinant activated protein C -
have shown potential benefits in preclinical sepsis / sep-
tic shock models, most clinical trials involving patients
with sepsis or septic shock, of whom only some had SIC
or DIC, failed to demonstrate a survival benefit and were
associated with an increased risk of bleeding [64, 65].

Recombinant thrombomodulin (rhTM) has also shown
potential for restoring anticoagulant balance and modu-
lating inflammation. SCARLET study is the first interna-
tional randomized controlled trial comparing rhTM to
placebo, including only patients with sepsis-associated
coagulopathy [66]. While no significant reduction in 28-day mortality was observed in the overall population, rhTM demonstrated greater effectiveness in subgroups of patients with persistent coagulopathy at the time of the first dose (about 20% had already corrected SIC by the time they received the treatment) and in those not receiving concomitant heparin therapy for thromboprophylaxis. These findings were further supported by a post hoc analysis of the French patient cohort [67]. Despite its promise as a treatment for DIC, larger-scale randomized controlled trials are needed to confirm the efficacy and safety of rhTM in broader septic populations.

In summary, future clinical trials evaluating treatments for SIC/DIC should exclusively enroll patients diagnosed with SIC or DIC, selecting them based on SIC and/or ISTH scoring criteria. Integrating novel biomarkers that reflect underlying pathophysiological processes into clinical practice holds the potential to significantly improve the precision of DIC diagnosis and facilitate the timely initiation of targeted therapies to treat sepsis-induced DIC [1].

## Conclusion

The diagnosis of sepsis-induced DIC remains a significant challenge due to the complex and dynamic nature of the condition. While traditional biomarkers such as PT, platelet count, fibrinogen, and D-dimers, have provided the foundation for DIC diagnosis, their limitations necessitate the development and integration of more specific and sensitive markers. The identification of emerging biomarkers, particularly those reflecting endothelial dysfunction and the anticoagulant pathways, represents a promising avenue for improving diagnostic accuracy and guiding therapeutic interventions, but require further validation. Moreover, real-time measurement of most novel biomarkers remains challenging, as it often requires specialized laboratory expertise and advanced technologies, which currently limit their feasibility in time-sensitive clinical settings.

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13613-025-01434-2.

Supplementary Material 1

Supplementary Material 2

Supplementary Material 3

Supplementary Material 4

Supplementary Material 5

## Acknowledgements

We thank ADIRAL for its financial support.

## Author contributions

All the authors have contributed to writing and have revised the manuscript.

## Funding

NA.

## Data availability

NA.

## Declarations

### Ethics approval and consent to participate

NA.

### Consent for publication

NA.

### Competing interests

JH has received honoraria for lectures from Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, Inotrem, MSD, Shionogi and Asahi Kasei. TI participated in advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. EAC and FM have no conflict of interest to declare.

Received: 10 September 2024 / Accepted: 6 January 2025

Published online: 17 January 2025

## References

1. Helms J, Iba T, Connors JM, Gando S, Levi M, Meziani F, et al. How to manage coagulopathies in critically ill patients. Intensive Care Med mars. 2023;49(3):273–90.

2. Girardis M, David S, Ferrer R, Helms J, Juffermans NP, Martin-Loeches I et al. Understanding, assessing and treating immune, endothelial and haemostasis dysfunctions in bacterial sepsis. Intensive Care Med 2 sept 2024 [cité 9 sept 2024]; Disponible sur: https://link.springer.com/https://doi.org/10.1007/s00134-024-07586-2

3. Warren BL, Eid A, Singer P, Pillay SS. High-Dose Antithrombin III in Severe Sepsis.

4. Dhainaut, Dhainaut JF, Laterre PF, Janes JM, Bernard GR, Artigas A, et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med juin. 2003;29(6):894–903.

5. Delabranche X, Boisramé-Helms J, Asfar P, Berger A, Mootien Y, Lavigne T, et al. Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care Med oct. 2013;39(10):1695–703.

6. Stiel L, Delabranche X, Galoisy AC, Severac F, Toti F, Mauvieux L, et al. Neutrophil fluorescence: a New Indicator of Cell Activation during septic shock–Induced disseminated Intravascular Coagulation. Crit Care Med Nov. 2016;44(11):e1132–6.

7. Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood 15 oct. 2005;106(8):2605–12.

8. Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemostasis mars. 2016;14(3):427–37.

9. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemostasis janv. 2016;14(1):28–39.

10. Claushuis TAM, De Stoppelaar SF, Stroo I, Roelofs JJTH, Ottenhoff R, Van Der Poll T, et al. Thrombin contributes to protective immunity in pneumonia-derived sepsis via fibrin polymerization and platelet-neutrophil interactions. J Thromb Haemostasis avr. 2017;15(4):744–57.

11. Delabranche X, Helms J, Meziani F. Immuno-haemostasis: a new view on haemostasis during sepsis. Ann Intensive Care 2 déc. 2017;7:117.

12. Delabranche X, Berger A, Boisramé-Helms J, Meziani F. Microparticles and infectious diseases. Médecine et Maladies Infectieuses août. 2012;42(8):335–43.

13. Levi M, Van Der Poll T. Endothelial injury in sepsis. Intensive Care Med oct. 2013;39(10):1839–42.
14. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol Janv. 2013;13(1):34–45.

15. Cruz DBD, Helms J, Aquino LR, Stiel L, Cougourdan L, Broussard C, et al. DNA-bound elastase of neutrophil extracellular traps degrades plasminogen, reduces plasmin formation, and decreases fibrinolysis: proof of concept in septic shock plasma. FASEB J déc. 2019;33(12):14270–80.

16. Delabranche X, Quenot JP, Lavigne T, Mercier E, François B, Severac F, et al. Early detection of disseminated intravascular coagulation during septic shock: a Multicenter prospective study. Crit Care Med oct. 2016;44(10):e930–9.

17. Taylor F, Toh CH, Hoots K, Wada H, Levi M. Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for disseminated intravascular coagulation: on behalf of the Scientific Subcommittee on disseminated intravascular coagulation (DIC) of the International Society on thrombosis and haemostasis (ISTH). Thromb Haemost. 2001;86(11):1327–30.

18. Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria*. Crit Care Med mars. 2006;34(3):625–31.

19. Asakura H, Ontachi Y, Mizutani T, Kato M, Ito T, Saito M et al. Depressed plasma activity of plasminogen or á2 plasmin inhibitor is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation.

20. Thiery-Antier N, Binquet C, Vinault S, Meziani F, Boisramé-Helms J, Quenot JP. Is Thrombocytopenia an early prognostic marker in septic shock? Crit Care Med avr. 2016;44(4):764–72.

21. Leone M, Nielsen ND, Russell L. Ten tips on sepsis-induced thrombocytopenia. Intensive Care Med Juill. 2024;50(7):1157–60.

22. Greco E, Lupia E, Bosco O, Vizio B, Montrucchio G. Platelets and multi-organ failure in Sepsis. IJMS. oct 2017;20(10):2200.

23. Becchi C, Al Malyan M, Fabbri LP, Marsili M, Boddi V, Boncinelli S. (2006) Mean platelet volume trend in sepsis: is it a useful parameter? Minerva Anestesiol 72: 749–756. [cité 3 sept 2024]. Disponible sur: https://www.minivamedica.it/en/getfreepage/eE1rOU81a0RLMk5deJNTVG1ubzBTUkhnc2pDWGtjcy8yYzN5NEpkSHFVQW13dk52WTc2ZE2EWnU1RIB4ZDd5dQ%253D%253D/R02Y2006N09A0749.pdf

24. Meziani F, Iba T, Levy JH, Helms J. Sepsis-induced coagulopathy: a matter of timeline. Intensive Care Med août. 2024;50(8):1404–5.

25. Iba T, Levy JH, Yamakawa K, Thachil J, Warkentin TE, Levi M. Proposal of a two-step process for the diagnosis of sepsis-induced disseminated intravascular coagulation. J Thromb Haemost. 2019;17(8):1265–8.

26. Iba T, Levi M, Thachil J, Helms J, Scarlatescu E, Levy JH. Communication from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis on sepsis-induced coagulopathy in the management of sepsis. J Thromb Haemost janv. 2023;21(1):145–53.

27. Wada H, Sase T, Matsumoto T, Kushiya F, Sakakura M, Mori Y, et al. Increased Soluble Fibrin in plasma of patients with disseminated intravascular coagulation. Clin Appl Thromb Hemost Juill. 2003;9(3):233–40.

28. Masuda T, Shoko T, Deguchi Y. Clinical Investigation of Coagulation Markers for Early Detection of Sepsis-Induced disseminated intravascular coagulation: a Single-Center, prospective observational study. Clin Appl Thromb Hemost oct. 2018;24(7):1082–7.

29. Park KJ, Kwon EH, Kim HJ, Kim SH. Evaluation of the diagnostic performance of Fibrin Monomer in disseminated intravascular coagulation. Korean J Lab Med Juill. 2011;31(3):143–7.

30. Ieko M, Nakabayashi T, Tarumi T, Naito S, Yoshida M, Kanazawa K, et al. Soluble fibrin monomer degradation products as a potentially useful marker for hypercoagulable states with accelerated fibrinolysis. Clin Chim Acta 1 nov. 2007;386(1):38–45.

31. Watanabe R, Wada H, Watanabe Y, Sakakura M, Nakasaki T, Mori Y, et al. Activity and Antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. Thromb Res oct. 2001;104(1):1–6.

32. Wada H, Kobayashi T, Abe Y, Hatada T, Yamada N, Sudo A, et al. Elevated levels of soluble fibrin or D-dimer indicate high risk of thrombosis. J Thromb Haemostasis juin. 2006;4(6):1253–8.

33. Zhang J, Xue M, Chen Y, Liu C, Kuang Z, Mu S, et al. Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation. Ann Palliat Med. oct 2021;10(10):10170–84.

34. Haase C, Joergensen M, Ellervik C, Joergensen MK, Bathum L. Age- and sex-dependent reference intervals for D-dimer: evidence for a marked increase by age. Thromb Res déc. 2013;132(6):676–80.

35. Borschneck C, Dreyfus M, Bridey F, Edouard D, Meyer D. [Assay of products of fibrin and fibrinogen degradation in disseminated intravascular coagulations. Evaluation of a new technique]. Presse Med. 6 mai 1995;24(17):799–802.

36. Wada H, Gabazza E, Nakasaki T, Shimura M, Hiyoyama K, Deguchi K, et al. Diagnosis of disseminated intravascular coagulation by hemostatic molecular markers. Seminars Thromb Hemost 31 déc. 2000;26:17–22.

37. Kawasugi K, Wada H, Hatada T, Okamoto K, Uchiyama T, Kushimoto S, et al. Prospective evaluation of hemostatic abnormalities in overt DIC due to various underlying diseases. Thromb Res août. 2011;128(2):186–90.

38. Koyama K, Madoiwa S, Nunomiya S, Koinuma T, Wada M, Sakata A, et al. Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study. Crit Care. 2014;18(1):R13.

39. Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Asakura Blood 1994.

40. Bajzar L, Morser J, Nesheim M, TAFI, or Plasma Procarboxypeptidase B. Couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem Juill. 1996;271(28):16603–8.

41. Sellen M, Declerck PJ. Thrombin activatable fibrinolysis inhibitor (TAFI): an updated narrative review. Int J Mol Sci. 2021;22(7):3670.

42. Emonts M, De Bruijne ELE, Guimarães AHC, Declerck PJ, Leebeek FWG, De Maat MPM, et al. Thrombin activatable fibrinolysis inhibitor is associated with severity and outcome of severe meningococcal infection in children. J Thromb Haemostasis févr. 2008;6(2):268–76.

43. Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis. Thromb Res janv. 2006;118(2):205–12.

44. Chen CC, Lee KD, Gau JP, Yu YB, You JY, Lee SC, et al. Plasma antigen levels of thrombin-activatable fibrinolysis inhibitor did not differ in patients with or without disseminated intravascular coagulation. Ann Hematol oct. 2005;84(10):675–80.

45. Gould TJ, Vu TT, Stafford AR, Dwivedi DJ, Kim PY, Fox-Robichaud AE, et al. Cell-free DNA modulates clot structure and impairs Fibrinolysis in Sepsis. ATVB déc. 2015;35(12):2544–53.

46. Takemitsu T, Wada H, Hatada T, Ohmori Y, Ishikura K, Takeda T, et al. Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation. Thromb Haemost. 2011;105(01):40–4.

47. Choi Q, Hong KH, Kim JE, Kim HK. Changes in Plasma Levels of Natural Anticoagulants in Disseminated Intravascular Coagulation: High Prognostic Value of Antithrombin and Protein C in Patients with Underlying Sepsis or Severe Infection. Ann Lab Med. 1 mars. 2014;34(2):85–91.

48. Guo Q, Han F, Peng J, Hou M, Shan T, Xu M. The proactive diagnostic value of Thrombin-Antithrombin Complex and Antithrombin III in disseminated intravascular coagulation. Blood 2 nov. 2023;142(Supplement 1):1268–1268.

49. Iba T, Di Nisio M, Thachil J, Wada H, Asakura H, Sato K, et al. Revision of the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) diagnostic criteria using antithrombin activity. Crit Care déc. 2016;20(1):287.

50. Esmon CT. The endothelial cell protein C receptor. Thromb Haemost Mai. 2000;83(5):639–43.

51. Esmon CT, Ding W, Yasuhiro K, Gu JM, Ferrell G, Regan LM, et al. The protein C pathway: new insights. Thromb Haemost Juill. 1997;78(1):70–4.

52. Gando S, Sawamura A, Hayakawa M, Hoshino H, Kubota N, Nishihira J. High Macrophage Migration Inhibitory factor levels in disseminated intravascular coagulation patients with systemic inflammation. Inflamm 21 juin. 2007;30(3-4):118–24.

53. Lin SM, Wang YM, Lin HC, Lee KY, Huang CD, Liu CY, et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis*. Crit Care Med mars. 2008;36(3):683–9.

54. Meng S, Kang K, Fei D, Yang S, Gu Q, Pan S, et al. Preliminary study of microparticle coagulation properties in septic patients with disseminated intravascular coagulation. J Int Med Res 25 mai. 2021;49(5):03000605211014094.

55. Statz S, Sabal G, Walborn A, Williams M, Hoppensteadt D, Mosier M, et al. Angiopoietin 2 levels in the risk stratification and mortality outcome prediction of Sepsis-Associated Coagulopathy. Clin Appl Thromb Hemost Nov. 2018;24(8):1223–33.

56. Gando S, Kameue T, Matsuda N, Hayakawa M, Hoshino H, Kato H. Serial changes in neutrophil-endothelial activation markers during the course of
sepsis associated with disseminated intravascular coagulation. Thromb Res janv. 2005;116(2):91-100.

57. Reinhart K, Bayer O, Brunkhorst F, Meisner M. Markers of endothe-
lial damage in organ dysfunction and sepsis. Crit Care Med Mai.
2002;30(Supplement):S302-12.

58. Stiel L, Mayeur-Rousse C, Helms J, Meziani F, Mauvieux L. First visualization of circulating neutrophil extracellular traps using cell fluorescence during human septic shock-induced disseminated intravascular coagulation. Thromb Res Nov. 2019;183:153-8.

59. Helms J, Meziani F, Mauvieux L, Iba T. The detection of Neutrophil activation by automated blood cell counter in Sepsis. Juntendo Med J. 2024;70(2):114-7.

60. Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the manage-
ment of sepsis. Ann Intensive Care. sept 2024;20(1):148.

61. Zarychanski R, Abou-Setta AM, Kanji S, Surgeon AF, Kumar A, Houston DS, et al. The efficacy and safety of heparin in patients with Sepsis: a systematic review and Metaanalysis*. Crit Care Med mars. 2015;43(3):511-8.

62. Huang JJ, Zou ZY, Zhou ZP, Liu Y, Yang ZJ, Zhang JJ, et al. Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy. Front Pharmacol 15 mai. 2023;14:1173893.

63. Ushio N, Yamakawa K, Mochizuki K, Hisamune R, Umemura Y, Takasu A. Efficacy of unfractionated heparin in patients with moderate sepsis-induced coagulopathy: an observational study. Thromb Res sept. 2024;241:109095.

64. Allingstrup M, Wetterslev J, Ravn FB, Møller AM, Afshari A. Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequen- tial analysis. Intensive Care Med avr. 2016;42(4):505-20.

65. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S et al. Drotrecogin Alfa (Activated) in Adults with Septic Shock. N Engl J Med. 31 mai. 2012;366(22):2055-64.

66. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY et al. Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial. JAMA. 28 mai. 2019;321(20):1993.

67. François B, Fiancette M, Helms J, Mercier E, Lascarrou JB, Kayanoki T, et al. Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET. Ann Intensive Care déc. 2021;11(1):53.

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