Received: 30 August 2024 Revised: 12 December 2024 Accepted: 13 December 2024

DOI: 10.1002/mco2.70058

REVIEW

Disseminated intravascular coagulation: cause, molecular

mechanism, diagnosis, and therapy

Fangchen Gong1,# Xiangtao Zheng1,# Shanzhi Zhao1,# Huan Liu1

Erzhen Chen1,2,∗ Rongli Xie3,∗ Ranran Li4,∗ Ying Chen1,5,∗
1 Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Shanghai Institute of Aviation Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
3 Department of General Surgery, Ruijin Hospital Lu Wan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, China
4 Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
5 Department of Emergency and Critical Care Medicine, Ruijin Hospital Wuxi Branch, Shanghai Jiao Tong University School of Medicine, Wuxi, China

∗ Correspondence

Ying Chen, Department of Emergency, Abstract

Ruijin Hospital, Shanghai Jiao Tong Disseminated intravascular coagulation (DIC) is a complex and serious condi-
University School of Medicine, Shanghai,
China. tion characterized by widespread activation of the coagulation cascade, resulting
Email: [email protected] in both thrombosis and bleeding. This review aims to provide a comprehensive
Rongli Xie, Department of General overview of DIC, emphasizing its clinical significance and the need for improved
Surgery, Ruijin Hospital Lu Wan Branch, management strategies. We explore the primary causes of DIC, including sepsis,
Shanghai Jiaotong University School of
Medicine, Shanghai, China. trauma, malignancies, and obstetric complications, which trigger an overac-
Email: [email protected] tive coagulation response. At the molecular level, DIC is marked by excessive
Ranran Li, Department of Critical Care thrombin generation, leading to platelet and fibrinogen activation while simul-
Medicine, Ruijin Hospital, Shanghai Jiao taneously depleting clotting factors, creating a paradoxical bleeding tendency.
Tong University School of Medicine,
Shanghai, China. Diagnosing DIC is challenging and relies on a combination of existing diagnostic
Email: [email protected] criteria and laboratory tests. Treatment strategies focus on addressing the under-
Erzhen Chen, Department of Emergency, lying causes and may involve supportive care, anticoagulation therapy, and other
Ruijin Hospital, Shanghai Jiao Tong supportive measures. Recent advances in understanding the pathophysiology of
University School of Medicine, Shanghai,
China. DIC are paving the way for more targeted therapeutic approaches. This review
Email: [email protected] highlights the critical need for ongoing research to enhance diagnostic accuracy
and treatment efficacy, ultimately improving patient outcomes in those affected
Funding information
National Natural Science Foundation of by DIC.
China, Grant/Award Numbers: 82300100,
82270087, 82372203, 82300106; Project of KEYWORDS
Shanghai Municipal Health Commission, coagulation, disseminated intravascular coagulation, fibrinolysis, sepsis, trauma
Grant/Award Number: 202340068;

# Fangchen Gong, Xiangtao Zheng and Shanzhi Zhao contributed equally to this work.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

MedComm. 2025;6:e70058. wileyonlinelibrary.com/journal/mco2 1 of 24

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Physician-Scientist Project of Shanghai

Jiaotong University, Grant/Award
Number: 20240804; Shanghai Shenkang
Hospital Development Center Clinical
Science and Technology Innovation
Project, Grant/Award Number:
SHDC22021316;SHDC22023218; National
Key Research and Development Program
of China, Grant/Award Number:
2024YFC3044600

1 INTRODUCTION improve outcomes for patients affected by this potentially

devastating syndrome.
Disseminated intravascular coagulation (DIC) is an
acquired syndrome characterized by widespread microvas-
cular thrombosis and simultaneous consumption of 2 EPIDEMIOLOGY, ETIOLOGY, AND
platelets and clotting factors. This leads to multiple organ CAUSES OF DIC
dysfunction and uncontrolled bleeding, contributing sig-
nificantly to morbidity and mortality in sepsis and other Elucidating the epidemiology of DIC should not ignore its
critical illnesses.1 DIC imposes a substantial economic heterology. DIC is a complication of many diseases, such
burden, with patients experiencing higher mortality rates, as severe systemic infections, trauma, malignant tumors,
prolonged hospital stays, and increased medical costs. vascular malformations, severe immune reactions, heat-
These factors underscore the urgent need for effective stroke, and so on (Table 1).
diagnostic and treatment strategies to alleviate the human Although the clinical manifestations are diverse, essen-
and financial toll of DIC.2,3 tially, DIC is caused by coagulative disorders imbalanced
The clinical importance of DIC lies in its potential to by endogenous anticoagulant and fibrinolytic mecha-
cause widespread organ damage due to microvascular nisms. Excessive activation of thrombin leads to proteolytic
thrombosis and subsequent hemorrhage due to consump- conversion of fibrinogen and the formation of fibrin within
tive coagulopathy and fibrinolysis. The scope of this review the vasculature. If the consumption of coagulation fac-
encompasses the pathophysiological mechanisms of DIC, tors exceeds the hepatic output of synthesis, consumptive
with a particular focus on the role of microthrombi in the coagulopathy occurs, accompanied by thrombocytopenia,
context of underlying diseases. which signals an increased risk of bleeding. Statistics
Furthermore, we will delve into the molecular mech- on the incidence and outcome of DIC varied because
anisms of DIC, highlighting the interplay between the patients with this condition often have underlying dis-
immune system and coagulation, anticoagulant activity, eases and additional causes, leading to diagnostic delay
the end-stage consumption of coagulant factors, and fib- and inaccuracy.4 Besides, different DIC score has been
rinolysis system. The activation of coagulative disorders established, this may lead to statistical differences in the
is secondary to many clinical conditions, and timely diag- disease across different countries and hospitals, depending
nosis and treatment of DIC are vital to prevent disease on the score system that has been employed. The differ-
progression and reduce mortality. We will explore the cur- ences and linkage between different score system will be
rent diagnostic criteria for DIC and the challenges they discussed in the diagnosis section.
present in the early identification of the hypercoagulable The incidence of DIC ranges from 18 to 32% in intensive
state, which is crucial for initiating prompt and effective care unit (ICU) patients based on ISTH diagnostic crite-
treatment. ria, while the incidence is 8.5% base on JAAM DIC.4–7
The review also addresses the challenges of current The 28-day mortality rate for DIC is about 20–50%. Sep-
treatment strategies for DIC, which vary greatly depending sis and septic shock can lead to the occurrence of DIC
on the underlying causative diseases. There is a pressing due to factors such as the cytokine storm and endothelial
need for clinicians to better understand the importance injury, while the progression of DIC can further exacer-
of DIC, especially in recognizing the early signs of the bate organ dysfunction. Sepsis is the most common cause
hypercoagulable state and initiating appropriate therapeu- of DIC. The incidence of DIC in patients with sepsis is high
tic interventions. By providing a comprehensive overview as 46.8% based on JAAM DIC.2 The prevalence ranges from
of DIC, this review aims to guide clinical management and 56.1 to 60.8% base on ISTH SIC criteria.3,8 In Europe, SIC
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 3 of 24

TA B L E 1 DIC causes.
Etiology category Causes Estimated incidence Prognosis
Infectious diseases Sepsis, bacterial pneumonia 30–50% Mortality rate 40%; timely antibiotic
treatment and supportive care are crucial.
Trauma Severe injury, traffic 10–50% head trauma 36–41% Mortality rate 25–34%; related to the
accidents severity of trauma and timely medical
intervention; may progress to multiple
organ failure
Solid tumors15 Pancreatic, gastric, lung 5–15% Related to cancer type, stage, and
cancer treatment. Compared with patients
without DIC, those with early and
late-stage malignant tumors who
developed DIC had lower survival rates.
Hematological ALL 15–20%
cancers16–18 APL 70–80% Mortality rate 20% (30 days)
AML 20% Mortality rate 42.5% (30 days)
Obstetric Abruptio placentae, severe 1% Mortality rate 1%; emergency situations
complications19 preeclampsia 0.2% requiring rapid diagnosis and
management; prognosis is related to
maternal and fetal conditions.
Heat stroke20–22 Heat stroke due to high 9.6–28.4% Mortality rate 26%
temperatures
Snake bite23,24 Snake bite 25–50%, geographically
dependent
Out-of-hospital 10–30% Mortality rate 83%
cardiac arrest25
Vascular A small percentage
abnormality
Immune-mediated Systemic lupus Small proportion Related to disease control and
diseases erythematosus, immunosuppressive therapy; may affect
antiphospholipid syndrome long-term prognosis
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia.

prevalence was 22.1% according to the HYPRESS trial, in The prognosis of DIC is closely tied to the underlying
which sepsis diagnosis based on SEPSIS-3 was evaluated.9 cause and the speed of diagnosis and treatment. Mortality
The mortality of sepsis-associated DIC amounts to 30%, rates are high, particularly in cases driven by sepsis, can-
irrespective of the diagnostic standards used. Trauma, par- cer, or major trauma. Early recognition and treatment of
ticularly severe injury associated with substantial tissue the underlying disorder, along with supportive care, can
damage and shock, can account for a considerable per- improve outcomes (Table 1).
centage of DIC cases. Patients with head trauma could
have incidence of DIC amount to 30–40%.10,11 Approxi-
mately 7% of individuals with solid malignancies exhibit 3 PATHOPHYSIOLOGY
DIC, a figure that escalates with the progression of the
disease and in those considered at risk for thrombotic 3.1 Waterfall theory and the cell-based
events.12 Furthermore, DIC is identified in a consider- theory
able proportion of patients afflicted with hematological
malignancies, with a heightened incidence in cases of DIC is characterized by a disruption in the balance
acute leukemia (15–17%).13 Complications such as abrup- between coagulation and bleeding within the body. To
tio placentae, amniotic fluid embolism, and eclampsia are understand its pathophysiological mechanisms, two the-
significant causes of DIC in pregnant women.14 Other ories are pivotal: the waterfall theory and the cell-based
causes of DIC are associated with vascular abnormalities, theory.
liver diseases, immune reactions, toxins, and transfusion In the early 1960s, MacFarlane, Davie, and Ratnoff put
reactions, all having their instinct pathophysiology. forward the “waterfall theory” of coagulation.26,27 They
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 24 GONG et al.

F I G U R E 1 Cell-based model of coagulation. The cell-based model of DIC emphasizes the role of cellular interactions in coagulation.
Initiation occurs on TF-bearing cells via the extrinsic pathway, leading to thrombin generation. This thrombin activates more coagulation
factors and platelets, amplifying the response. The propagation phase, primarily on platelet surfaces, generates a large burst of thrombin
necessary for fibrin clot formation, a key step in the coagulation process.

proposed that blood coagulation factors exist in an inactive sue factor (TF) expression on TF bearing cells. Coagu-
proenzyme form, and the activation of one factor triggers lation commences when TF binds to factor VII, form-
a sequence of proteolytic reactions. This cascade activates ing the extrinsic tenase complex. This complex activates
subsequent enzymes, leading to the formation of throm- FIX and FX at the site of injury.31 FXa is quickly neu-
bin, which cleaves fibrinogen to form a fibrin clot, causing tralized by TF pathway inhibitor (TFPI), resulting in a
blood to coagulate. Despite its wide recognition, this the- small amount of thrombin production. The thrombin
ory cannot explain certain phenomena, such as the lack spark emerges as the central event in the amplifica-
of bleeding in patients with deficiencies in coagulation tion and propagation phase. Thrombin activates platelets
factor XII (FXII), prekallikrein (PK), and high-molecular- via protease-activated receptors (PARs), notably PAR-4.32
weight kininogen, despite their prolonged activated partial This activation leads to the exposure of procoagulant
thromboplastin time (APTT).28 Hemophilia patients with phospholipids, such as phosphatidylserine and phos-
deficiencies in FVIII and FIX also have a significantly phatidylethanolamine, on the platelet surface to activate
prolonged APTT, but show a clear bleeding tendency. coagulation factors.33 This activation results in the expo-
The cell-based hemostasis model that has developed in sure of procoagulant phospholipids, like phosphatidylser-
the past decade can better explain the hemostasis process ine and phosphatidylethanolamine, on the platelet sur-
and is gradually being accepted29 (Figure 1). It proposed face, which further activates coagulation factors.34 Throm-
that coagulation occurs not as a cascade, but is regu- bin also activates FXI, FVIII, and FV by binding to the
lated by properties of cell surfaces. The process is divided GP1b receptors on the platelet surface, thus initiating
into three overlapping steps: initiation, amplification, and the amplification phase. FXIa amplifies the conversion of
propagation.30 FIX to FIXa by the extrinsic tenase. Thrombin interacts
During the initiation phase, various factors, such as with PAR-1 on endothelial cells, activating inflamma-
endothelial injury or inflammatory stimuli induced tis- tory signaling pathways that lead to the release of von
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 5 of 24

Willebrand factor (vWF), angiopoietin-2, and P-Selectin,

thereby amplifying the inflammatory response and induc-
ing microthrombus formation.35 During the propagation
phase, FVIIIa and FIXa form the intrinsic tenase com-
plex, generating a substantial amount of FXa. FXa with
FVa forms the prothrombinase complex, which converts
prothrombin to thrombin in large quantities.36 Thrombin
also transforms fibrinogen into fibrin, cross-links platelets
via the GPIIb/IIIa receptor, creating a stable clot. Platelet
provide a reaction platform to generate a large amount
of thrombin, which in turn recruits and activates more
platelets, so thrombin activating platelets is an important
step in coagulation.
Coagulation termination is regulated by physiologi-
cal anticoagulant pathways, including antithrombin (AT),
activated protein C (APC), and TFPI. Fibrin within blood
vessels triggers the plasmin-mediated breakdown of fib-
rin itself. The fibrinolytic system, which is central to
this process, is primarily composed of plasmin, plasmino-
gen activators (PAs), and plasminogen activator inhibitors
F I G U R E 2 DIC course: imbalance of coagulative system,
(PAIs).37
anticoagulant activity, and fibrinolysis system. Two phenotypes of
Together, the waterfall theory and the cell-based theory
DIC: thrombotic and fibrinolytic. The thrombotic phenotype
provide a more complete understanding of the complex
includes coagulation activation, insufficient anticoagulation, and
processes involved in DIC. The waterfall theory provides hypofibrinolysis, indicating a proclivity for clot formation.
a foundational framework for the sequence of coagula- Conversely, the fibrinolytic phenotype is characterized by
tion events, while the cell-based theory adds depth by hyperfibrinolysis, which suggests an increased risk of bleeding due
accounting for the cellular interactions and regulatory to excessive clot breakdown.
mechanisms that are crucial for maintaining hemosta-
sis and preventing pathological thrombosis. Ultimately,
DIC presents a prothrombotic state marked by thrombin-
induced platelet activation, intensification of the coag- the formation of microvascular fibrin thrombi and subse-
ulation sequence, and fibrin clot formation. Yet, with quent organ dysfunction. Additionally, the overproduction
the progression of DIC, the consumption of coagulation of thrombin depletes platelets and coagulation factors,
factors and platelets leads to a transition toward hypo- resulting in a condition known as consumption coagulopa-
coagulability, which in turn, increases the propensity for thy. This is evidenced by slow, seeping bleeding, often in
bleeding. mucosal areas, puncture sites of blood vessels, and regions
of injury or surgical intervention.37 It is important to rec-
ognize that the thrombotic form of DIC is also associated
3.2 Phenotypes of DIC with a certain level of consumptive hemorrhage.
DIC with a fibrinolytic phenotype is defined by excessive
The essence of DIC pathophysiology lies in the disruption thrombin generation and systemic pathological hyperfibri-
of the equilibrium between procoagulant and anticoagu- nolysis due to the underlying disease, which leads to severe
lant forces. This imbalance leads to an uneven consump- bleeding as a result of excessive plasmin formation.39 In
tion of various components, which is difficult to predict sepsis-related DIC, the typical pathological scenario is an
and fluctuates throughout the disease’s progression, ulti- excessive clotting process accompanied by a suppression
mately influencing the dominant clinical phenotype. DIC of fibrinolysis, which results in thrombotic organ dam-
is classified into thrombotic and fibrinolytic phenotypes, age. In contrast, DIC linked to trauma is characterized
based on the extent of thrombosis and hemorrhage, with by severe coagulation factors consumption coupled with
each phenotype being characterized by thrombosis and sudden hyperfibrinolysis.40
bleeding, respectively38 (Figure 2). It is of utmost importance to understand the molecu-
Thrombotic DIC is marked by the activation of coag- lar mechanisms that link physiological processes in DIC,
ulation, insufficient anticoagulation, endothelial damage, as this knowledge is essential for developing effective
and inhibition of fibrinolysis by PAI-1. These factors lead to diagnostic and therapeutic strategies.
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 24 GONG et al.

4 MOLECULAR MECHANISM formation.55 Additionally, TF vesicles from noncancer

cells and circulating tumor cells contribute to coagulation.
4.1 Initiation of coagulative disorders Soluble TF, which lacks transmembrane and cytoplasmic
domains, may also be associated with EVs on cancer cells,
4.1.1 Increased TF activity potentially enhancing procoagulant activity. Silencing
TF within tumors can effectively curb metastasis and
The TF–FVIIa complex is the principal initiator of coagu- mitigate cancer-associated hypercoagulability in mouse
lation activation. TF, serving as a high-affinity receptor and models.56
cofactor for factor FVII/VIIa, is ubiquitously expressed on
various cell types, including monocytes, endothelial cells,
platelets, lymphocytes, and cancer cells.41–43 During acute 4.1.2 Platelet
inflammation or sepsis, pattern recognition receptors
(PRRs) bind to both pathogen-associated molecular pat- Platelet activation and aggregation are crucial in clot
terns (PAMPs) and damage-associated molecular patterns formation during DIC. Platelets are the first respon-
(DAMPs), inducing TF expression primarily on mono- ders to damaged blood vessels, and underlying causes
cytes and initiating procoagulant responses.44,45 Activated of DIC, such as endothelial damage, pathogen contact,
monocytes also releases extracellular vesicles expressing or inflammatory factors, trigger platelet aggregation.57
TF and phosphatidylserine on their surfaces, activate Cell-free DNA and histones, bacterial lipopolysaccha-
the intrinsic and extrinsic coagulation pathways.46 These rides (LPSs), and neutrophil extracellular traps (NETs)
macrovesicles, rich in TF, can attach to activated platelets, in sepsis can directly activate platelets. The activation
neutrophils, and endothelial cells. The inflammatory of the coagulation cascade by TF and the subsequent
response triggered by PAMPs also induces TF expression production of thrombin promote not only fibrin forma-
on endothelial cells, further promoting the coagulation tion but also strong platelet activation. Once activated,
cascade.47,48 Activated vascular endothelial cells, platelets, platelets provide more and higher-affinity binding sites
and extracellular vesicles amplify TF responses, accel- for activated coagulation factors.58 Activated platelets
erating the procoagulant state.49 Intracellular immune can further promote monocyte TF expression and fib-
sensors, such as DAMP-induced inflammasomes, also rin formation by expressing P-selectin and facilitate the
stimulate TF release through pyroptosis.50 In addition adhesion of platelets to leukocytes and the vascular wall.
to coagulation initiation, TF also plays a crucial role in Additionally, large amounts of vWF released due to
inflammation, serving as a link between the inflammatory inflammation-induced endothelial damage contribute to
and coagulation pathways. TF possesses signaling activity increased platelet-vessel wall interactions in DIC. vWF,
that promotes a range of inflammatory responses. This an acute-phase factor upregulated and released during
signaling occurs through PARs in conjunction with other systemic inflammation, enhances platelet adhesion and
coagulation factors, leading to the expression of proin- aggregation in the microcirculation.59 Patients with DIC
flammatory cytokines and the modulation of endothelial exhibit higher platelet activation than those without
phenotype.51 A recent study found that TF binds to the DIC.60 While platelet count is considered a criterion in
interferon-alpha receptor 1 and antagonizes its signal- DIC diagnosis, examining platelet function is also vital for
ing, preventing spontaneous sterile inflammation and identifying patients at high risk of developing DIC.
maintaining immune homeostasis.52 In animal models
of sepsis, the genetic deletion of TF or its inhibition with
neutralizing antibodies can prevent coagulation initiation 4.2 Crosstalk between inflammation
and reduce mortality rates.53,54 However, due to TF’s and DIC
significant physiological role in sepsis, clinical research
on systemic TF inhibitors is challenging. In the context of The relationship between the inflammatory response and
cancer, TF increases the clotting propensity of tumors and DIC is complex, involving numerous molecular mecha-
facilitates interactions between platelets and cancer cells, nisms (Figure 3). When the immune system encounters
playing a crucial role in tumor dissemination through stimuli such as infections or trauma, it initiates a cas-
the bloodstream.54 Cancer-derived TF vesicles play a cade that activates coagulation pathways. Monocytes and
pivotal role in coagulation. These vesicles activate the macrophages, equipped with PRRS like Toll-like receptors,
extrinsic coagulation cascade, leading to fibrin deposition Fcγ-receptors, and G-protein-coupled receptors, identify
and thrombus formation. Cancer-derived TF vesicles PAMPs. This detection process leads to the convergence
are instrumental in activating the extrinsic coagulation of the innate immune response and the coagulation path-
cascade, leading to fibrin deposition and thrombus way. Proinflammatory cytokines, including tumor necrosis
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GONG et al. 7 of 24

F I G U R E 3 Crosstalk between inflammation and DIC. Schematic representation of the interplay between trauma, pathogen-associated
molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), immune response, and coagulation pathways leading to
thrombus formation. Trauma and pathogens trigger neutrophil activation, resulting in the release of NETs and monocyte activation. The
activated monocytes express TF, further amplifying the coagulation cascade. Intracellular immune sensors, such as DAMP-induced
inflammasomes, also stimulate TF release through pyroptosis. Complement components C3a and C5a also contribute to platelet aggregation,
which together with the coagulation cascade, leads to thrombus formation.

factor (TNF)-α, interleukin-1β (IL-1β), and IL-6, may act production and fibrin clotting. The interaction between
as procoagulants, although the exact mechanisms are NETs and platelets is reciprocal; platelets can activate neu-
not fully understood.61 For instance, TNF-α exposure to trophils, and NET components, in turn, activate platelets.
whole blood leads to platelet aggregation and activation. In thrombus formation, platelets are recruited to NETs
However, TNF-α can also decrease platelet activation by through interactions involving C3b deposits and histones,
inhibiting thrombi formation through NO generation.62,63 serving as a scaffold for thrombus formation. NETs can
IL-6 has been suggested to potentially play a role in the also carry neutrophil-derived TF into the extracellular
coagulation activation by inducing TF triggered by endo- space and activate factor XII, enhancing thrombin gener-
toxins. However, it seems that IL-6 does not contribute to ation through both the intrinsic and extrinsic coagulation
coagulation activation caused by LPSs in humans.64 In the pathways. Moreover, NETs, composed of DNA, histones,
body’s complex environment, interactions between inflam- and granular proteins released from activated neutrophils,
matory cytokines and other molecules can produce varying can mediate inflammatory responses and lead to microvas-
coagulation effects. cular thrombosis and tissue ischemia.66
HMGB1, a nonhistone nuclear protein, plays a signifi-
cant role in coagulation, particularly in platelet activation.
4.2.1 DAMPs and DIC In HMGB1-deficient platelets, bleeding time is prolonged,
and platelet aggregation, thrombus formation, inflamma-
Growing evidence suggests that DAMPs, such as NETs, tion, and organ damage are reduced during experimental
extracellular DNA, high mobility group box 1 protein trauma/hemorrhagic shock.67 HMGB1 is also able to acti-
(HMGB1), S100 proteins, and circulating histones, play a vates the process of NETosis and triggers the expression of
crucial role in DIC development.65 DAMPs can directly TF in monocytes.68 In sepsis, HMGB1 levels in the blood-
influence the coagulation process. NETs facilitate clot stream correlate with DIC scores and the sequential organ
formation by providing a surface for blood cells and proco- failure assessment, which are crucial for tracking sepsis
agulant factors to interact, thereby accelerating thrombin severity in the ICU.69
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8 of 24 GONG et al.

S100A9, a member of the S100 family, forms calpro- The term “immunothrombosis” describes the innate
tectin with S100A8. This heterodimer regulates myeloid intravascular immune response that triggers thrombin
function and modulates intracellular calcium signaling, production and microthrombi formation.77 Initially,
enhancing platelet thrombogenicity by inducing phos- immunothrombosis creates an intravascular scaffold
phatidylserine exposure and microparticle release.70 Acti- that aids in pathogen recognition and eradication,
vated neutrophils transfer calprotectin to platelets, which improving endothelial integrity.78 However, uncontrolled
increases platelet adhesiveness and aggregation.71 A recent immunothrombosis can cause tissue damage and con-
study found that S100A8/S100A9, by interacting with the tribute to organ dysfunction. The interaction of these
GPIbα receptor on platelets, induced the expression of P- elements with the coagulation system can result in a
selectin, activated GPIIb/IIIa, and promoted the release hypercoagulable state, exacerbating the clinical mani-
of microvesicles from platelets to form procoagulant festations of DIC.79 As a result, PAMPs, DAMPs, NETs,
platelets.72 A recent study found that S100A8/S100A9, by activated immune cells, endothelial cells, and damaged
interacting with the GPIbα receptor on platelets, induced host cells propagate prothrombotic and proinflammatory
the expression of P-selectin, activated GPIIb/IIIa, and responses and coagulopathies. Therefore, there must be
promoted the release of microvesicles from platelets to many regulatory mechanisms in normal human tissues
form procoagulant platelets. Calprotectin binding to gly- that control this central aspect of the coagulation response.
coprotein 1b on platelets can potentiates VWF-mediated
aggregation, underscoring its role in coagulation.
4.3 Amplification of coagulant activity

During the procoagulant state of DIC, natural anticoagu-

4.2.2 Pyroptosis and DIC lant mechanisms are suppressed.80 Endothelial dysfunc-
tion, consumption and liver synthesis disorders lead to
Pyroptosis, an inflammatory form of cell death, is char-
decreased levels of AT, thrombomulin, protein C (PC),
acterized by the release of inflammatory mediators upon
protein S (PS) and TFPI levels. The reductions in antico-
cell demise, thereby triggering an inflammatory response.
agulant factors, in turn, exacerbate anticoagulant activity.
This process is a crucial component of the innate immune
Restoration of the function of the anticoagulant molecules
system and significantly contributes to the activation
is a promising treatment in DIC.
of coagulation.46 When caspase-11 detects intracellular
bacterial LPS, it cleaves gasdermin D (GSDMD) into
fragments that form nano-pores in the cell membrane, 4.3.1 Antithrombin
leading to pyroptosis. The formation of GSDMD pores ini-
tiates a systemic coagulation response; the calcium influx AT stands as the principal endogenous coagulant inhibitor,
through these pores activates transmembrane protein 16F a 58-kDa plasma glycoprotein synthesized by the liver and
(TMEM16F), a scramblase that promotes the exposure of endothelial cells, and a member of the serine protease
phosphatidylserine on the cell surface.73 This exposure sig- inhibitor family.81 AT inhibits IIa, Xa, and IXa, and also
nificantly boosts the pro-coagulant activity of TF, thereby has a mild inhibitory effect on factors XIa and VIIa. It
activating the coagulation cascades.50 can suppress platelet aggregation and attachment and pos-
sesses anti-inflammatory properties by reducing cytokine
production by neutrophils and endothelium, preventing
4.2.3 Complement system and DIC neutrophil rolling and adhesion, and decreasing interac-
tions between neutrophils and endothelium.82 Acquired
The complement system is closely intertwined with coag- AT deficiency is common in DIC, caused by ongoing
ulation pathways, amplifying both inflammatory and thrombin generation, degradation by enzymes released
thrombotic responses. Components such as C3a and from neutrophils, loss from circulation due to capillary
C5a, generated during complement activation, can stim- leakage, and impaired synthesis from liver failure.83 In
ulate the assembly of prothrombinase, leading to throm- sepsis-related DIC, decreased AT levels were associated
bin generation.74,75 Additionally, complement activation with poor prognosis.84 AT is necessary for effective antico-
upregulates the expression of adhesion molecules on agulation with heparin or low-molecular-weight heparin
endothelial cells, promoting the attachment and activation (LMWH), and insufficient AT levels in sepsis patients may
of leukocytes, which further contributes to a procoagulant reduce the effectiveness of heparin.85 In trauma patients,
state.76 Complement activation products also interact with AT deficiency is linked to higher injury severity, hemor-
platelets, enhancing their activation and aggregation, and rhage, mortality, and fewer ventilator-free days, indicating
thus playing a role in thrombus formation. its potential in risk assessment.86 This highlights the
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GONG et al. 9 of 24

importance of monitoring and managing AT levels for substance.98 TFPI primarily functions by inhibiting the
effective treatment strategies. TF–VIIa complex formation, preventing its activity and
thus blocking the initiation of the extrinsic coagulation
pathway. Additionally, TFPI can bind to Xa, forming an
4.3.2 Thrombomodulin Xa complex, which then combines with the TF–VIIa
complex to form a quaternary complex, exerting its anti-
Thrombomodulin is a key endothelial cell surface glyco- coagulant effect. Administering recombinant TF pathway
protein that plays a significant role in the regulation of inhibitor (rTFPI) to hinders the formation of blood clots
the coagulation system.87 It forms a complex with throm- and fibrin accumulation, alleviates fatality rates from sep-
bin, thereby inhibiting thrombin’s pro-coagulant activity tic shock, and guards against the onset of DIC.99 Studies
and promoting the activation of PC, an important natural have detected high levels of TFPI in individuals with
anticoagulant.88 The thrombomodulin–thrombin complex sepsis-induced DIC, which coincide with high levels of
accelerates the conversion of PC to its activated form, APC, TF, indicating an insufficiency of TFPI to counteract the
which possesses anticoagulant, anti-inflammatory, and TF-triggered coagulation process.
profibrinolytic properties.89 In conditions like sepsis and
systemic inflammation, the expression of thrombomod-
ulin in endothelial cells is reduced, and its functionality is 4.4 Altered fibrinolytic system
compromised.
The fibrinolytic system plays a crucial role in the patho-
genesis of DIC, representing an ongoing physiological
4.3.3 Activated protein C mechanism for the dissolution of fibrin clots. This system
maintains the equilibrium between achieving hemosta-
APC and PS are essential anticoagulant molecules. PC is a sis following vascular injury and ensuring uninterrupted
double-chain glycoprotein synthesized by liver megakary- blood flow to vital organs. Plasminogen, a zymogen syn-
ocytes and endothelial cells and is a vitamin K-dependent thesized by the liver, circulates in plasma and, upon
factor.90 PC can bind to the endothelial PC receptor on activation by tissue-type PA (tPA) or urokinase-type PA
endothelial cells, while thrombin also binds to the throm- (uPA), is converted into plasmin. Plasmin degrades the
bin receptor.87 PC forms a 1:1 complex with thrombin, fibrin mesh structure, forming soluble fibrin degradation
which leads to the cleavage and activation of PC into products (FDPs), thereby dissolving blood clots.100
APC. On phospholipid surfaces, APC inhibits the coagu- The fibrinolytic system, while regulating thrombus for-
lation pathway by specifically cleaving the peptide bonds mation, is also controlled by various inhibitors. PAI-1,
of factors VIIIa and Va with its cofactor, PS, achieving synthesized by endothelium and megakaryocytes and
an anticoagulant effect. The primary function of PS is stored in platelets, regulates fibrinolysis by inhibiting the
to act as a cofactor for PC, enhancing its inactivation activity of tPA and uPA. α2-Antiplasmin prevents exces-
effects.91 PC can also lead to a decrease in levels of PAI- sive fibrinolysis by directly inhibiting plasmin activity.101
1 and thrombin-activatable fibrinolysis inhibitor (TAFI), TAFI, synthesized in the liver and activated by throm-
promoting fibrinolysis.92 A substantial reduction in the bin with thrombomodulin, functions by cleaving lysine
PC system can severely disrupt the proper regulation residues from fibrin to inhibit plasmin formation and
of activated coagulation. In addition to its anticoagulant fibrin degradation.102
functions, APC can also mediate anti-inflammatory effects Following major trauma, alterations occur in the coag-
and increase endothelial barrier function.93–95 Clinical tri- ulation and fibrinolytic systems. Endothelial cells release
als, such as the PROWESS trial, have demonstrated the tPA to initiate fibrinolysis, while PAI-1 levels remain
benefits of APC in treating sepsis by leveraging both its unchanged. Imbalances of tPA and PAI-1 induce a hyper-
anticoagulant and anti-inflammatory properties, although fibrinolytic phenotype in trauma patients during the initial
the use has been refined over time to target specific hours. This phase of enhanced fibrinolysis is short-lived,
patient populations based on ongoing research and clinical typically ending a few hours after PAI-1 secretion by
experience.96,97 endothelial cells and, in some cases, platelets. This rapid
transition is referred to as “fibrinolytic shutdown.”103 In
sepsis, fibrinolysis is characterized by heightened coagu-
4.3.4 TF pathway inhibitor lation and fibrin production, altered clot structure that is
less prone to lysis, and reduced fibrinolysis due to ele-
TFPI is a plasma serine protease inhibitor synthesized vated PAI-1, leading to microthrombi and organ failure.104
by endothelial cells and is an important anticoagulant PAI-1 is associated with the incidence of DIC and can be
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10 of 24 GONG et al.

a prognostic indicator for sepsis.105,106 In acute promyelo- on the phase of DIC they are in. The systemic activation
cytic leukemia (APL), reduced expression of PAI-1 promote of the coagulation system in DIC can result in consump-
the hyper-fibrinolytic state.107,108 Numerous tumors can tive coagulopathy, which manifests as bleeding at various
exhibit plasminogen-activating factors such as uPA and sites. This includes dermatologic bleeding, encephalor-
tPA, potentially leading to hyperfibrinolysis.109 In con- rhagia, gastrointestinal bleeding, airway bleeding, geni-
trast, some cancers produce PAI-1, which counteracts tourinary tract bleeding, and bleeding from surgical sites.
fibrinolysis.48 These bleeding episodes can lead to persistent hypoten-
In conclusion, fibrinolysis may exhibit reduced sion, shock, and organ dysfunction. Thrombosis in DIC
(hypofibrinolysis) or increased (hyperfibrinolysis) activity, may be less apparent and often subclinical. For instance,
depending on the pathophysiological characteristics of the pulmonary thrombosis can impair gas exchange and dam-
underlying disease. The treatment should be cautious to age the alveolar–capillary barrier, leading to hypoxemia
restore the impaired fibrinolysis. and acute respiratory distress syndrome. Microthrombi in
the glomeruli and renal tubules can also decrease per-
fusion, resulting in acute kidney injury. Distinguishing
4.5 Endothelial cells—throughout the whether organ failure is due to the underlying condition
entire coagulation process or to microvascular clot formation can be challenging,
complicating diagnosis and potentially leading to delays.
Endothelial cells play a pivotal role in coagulation and The clinical features of DIC are related to its various
fibrinolysis.110 As the primary producers and repositories causes. Sepsis, a primary cause of DIC, often presents
of vWF, they facilitate platelet adhesion at sites of vascu- as a thrombotic type of DIC with organ dysfunction. In
lar injury by interacting with the glycoprotein Ib receptor contrast, trauma-related DIC is characterized by an early
on platelets. However, during the procoagulant phase of fibrinolytic phenotype followed by a subsequent throm-
DIC, endothelial cells become damaged or activated. This botic response. This difference underscores the need for
injury results in the loss of glycocalyx and surface proteins, vigilant monitoring and tailored management strategies in
thereby reducing anticoagulant activity.111 The activated different patient populations.
endothelium exposes TF, which promotes coagulation,
and have decreased thrombomodulin, thus reducing PC
activation. The endothelial surface also hosts TFPI, and 6 DIAGNOSIS
a reduction in its levels can enhance thrombin produc-
tion. Vascular damage can lead to a decrease in endothelial Considering the diverse pathogenic factors and complex
TFPI, as observed in thrombotic microangiopathy (TMA) mechanisms involved in DIC, definitive diagnosis of DIC
patients with reduced TFPI levels. Imbalances in TF cannot be achieved with a single clinical test or exami-
and thrombomodulin on endothelial cells can increase nation index. Current DIC diagnostic algorithms mainly
thrombin formation, converting fibrinogen to fibrin and utilize a combination of conventional coagulation indica-
activating platelets. Endothelial cells also produce tPA and tors to facilitate ease of use and rapid detection of DIC
uPA, regulating fibrinolysis through PAI-1. Disruption of (Table 2). The main DIC scoring systems, which are con-
the endothelium can decrease fibrinolysis and fibrin clear- tinuously updated, have been established by the ISTH,
ance. Elevated PAI-1 levels are associated with a higher JAAM, JMHLW, and JSTH.113,114 In China, the Throm-
thrombotic risk. Endothelial injury leads to reduced fib- bosis and Hemostasis Group of the Hematology Branch
rinolytic activity and increased PAI-1, creating an antifib- of the Chinese Medical Association has developed the
rinolytic environment.112 Furthermore, various adhesion Chinese Disseminated Intravascular Coagulation Scoring
molecules expressed on the endothelial surface modulate System through multicenter, large-sample retrospective
the binding and activation of leukocytes to the vessel wall, and prospective studies.115
triggering the release of multiple cytokines that can fur- The ISTH first defined overt DIC in 2001 with crite-
ther mediate coagulation activation and suppression of ria that include thrombocytopenia, significant prolonga-
endogenous fibrinolysis. tion of prothrombin time (PT), moderate to high levels
of fibrin-related markers, and reduced fibrinogen levels.
These markers suggest severe, widespread activation of
5 CLINICAL MANIFESTATIONS OF the coagulation system, resulting in both clot formation
DIC and breakdown.116 The overt DIC scoring system is widely
being applied and has adequately precise for diagnosing
Patients with DIC can experience bleeding and throm- DIC in ICU patients.6 However, a primary limitation of this
bosis, either independently or simultaneously, depending scoring system is that by the time overt DIC is detected, the
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 11 of 24

TA B L E 2 Diagnostic criteria for DIC.

Measurement Score ISTH overt JAAM SIC
Platelet (109 /L) 0 >100 ≥120 ≥150
1 ≤100 ≥80, <120 <150
2 <50 <100
3 <80
PT (s) 0 <3 <1.2 (PT ratio)
1 ≥3, <6 ≥1.2 ≥1.2, < 1.4
2 ≥6 INR > 1.4
FDPs (mg/L) 0 DDI < 1 FDP < 10
1 10 ≤ FDP < 25
2 1 ≤ DDI < 5
3 DDI ≥ 5 ≥25
Fg (g/L) 0 >1.0 >3.5
1 ≤1.0 ≤3.5
SIRS score 0–2 0
≥3 1
Organ dysfunction 1 SOFA = 1
2 SOFA ≥ 2
DIC score DIC ≥ 5 DIC ≥ 5 ≥4
Abbreviations: FDPs, fibrin degradation products; PT, prothrombin time; SIRS, systemic inflammatory response syndrome.

condition may have advanced to a point where treatment as an early warning signal for impending sepsis-related
responses are suboptimal. Therefore, identifying nonovert damage.9,118,119 The European Society of Cardiology and
DIC and the early stages of DIC remains a significant chal- ISTH’s joint consensus statement on antithrombotic ther-
lenge and a critical area for improvement in DIC diagnosis apy in severe infections references SIC for coagulopathy
and management. diagnosis and advocates SIC score-guided therapy.120 The
The initial ISTH scoring system for nonovert DIC incor- SIC score shows potential in identifying high-risk patients
porates a kinetic component that compares results from for early DIC development.
two consecutive measurements. A deterioration in the The JAAM criteria was also introduced to provide a
parameters raises the score, whereas an improvement practical and clinically applicable approach for diagnosing
lowers it. This method enhances the sensitivity of the nonovert DIC, particularly in patients with acute condi-
parameters but necessitates daily measurements, which tions such as sepsis.7 These include decreased levels of AT,
may not be practical in all clinical settings. Moreover, stud- PC, and increased thrombin–AT (TAT) complexes. How-
ies have not yet established that the nonovert DIC score ever, the molecular markers used for diagnosing nonovert
can reliably distinguish between nonovert DIC and overt DIC are not widely implemented due to their complexity
DIC. and cost. The JAAM DIC criteria have been proved to be
In light of these limitations, especially regarding early outdated, particularly after the update of the sepsis defi-
detection and specific contexts such as sepsis, the ISTH nition to Sepsis-3. In response, the JAAM DIC score was
introduced the sepsis-induced coagulopathy (SIC) criteria recently modified to align with the new definition of sepsis,
in 2017. These criteria were designed to address the short- JAAM-2 DIC criteria, replacing the systemic inflammatory
comings of existing criteria and provide a more accurate response syndrome (SIRS) criterion.121 The alignment of
tool for the early identification of DIC in septic patients.117 this set of criteria with the SIC guidelines put forth by the
SIC includes a SOFA (sequential organ failure assess- ISTH remains to be confirmed.
ment) score greater than 2 points, platelet count, and
PT, thus it is easy to calculate clinically. The total score
helps to categorize the degree of coagulation dysfunction 6.1 Potential diagnostic markers
and determine the appropriate clinical management. The
SIC criteria is increasingly adopted in clinical practice. Current DIC score algorithms provided an venue for
Studies have showed that SIC is associated with higher simple and rapid diagnosis for DIC. When overt DIC is
incidence and mortality rates and could be interpreted detectable, it may have progressed to an irreversible state,
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
12 of 24 GONG et al.

making it too late for effective treatment. Attempts has an alternative laboratory approach for the rapid diagno-
been made to detect DIC in its early stages (nonovert, sis and prognosis of DIC.128 Traditional coagulation tests
compensatory) before it reaches an irreversible phase. require up to 40–60 min for results while viscoelastic
Thrombotic and fibrinolytic phenotype have distinct tests offer real-time data, aiding in the swift identifica-
molecular process. DIC diagnosis combined with molec- tion of patients at high risk for severe bleeding. These
ular markers could be more sensitive for monitoring the tests assess not only coagulation time but also velocity, clot
coagulation/fibrinolysis state. Biomarkers indicative of firmness, and lysis index, offering more comprehensive
thrombin generation (such as TAT, prothrombin fragment information about clot formation capabilities than APTT
1 + 2, ex vivo TG assay),122,123 fibrinolysis activity (plas- and PT.129 However, the efficacy of standard viscoelastic
minogen, PAP complex, tPA, α2-antiplasmin, PAI-1, TAFI, tests in detecting early procoagulant activity before overt
plasma-based fibrin formation and lysis assays) are uti- DIC is not yet conclusively proven. Conversely, a reduc-
lized to evaluate the DIC phenotype, along with its severity tion in clot formation ability as assessed by TEG/ROTEM
and progression.124,125 By using new models incorporating is associated with overt DIC, as defined by the ISTH DIC
these markers, more specific and adequate DIC manage- scoring, and is correlated with higher mortality rates in
ment could become possible. In addition, DIC is a complex several sepsis cohorts.130 Moreover, viscoelastic tests are
process involving platelets, coagulation factors, endothe- sensitive to overt hyperfibrinolysis, which can guide treat-
lium, and the immune system. The assessment of DAMPs, ment decisions for DIC patients with bleeding who may
such as HMGB1, netosis, nucleosomes, extracellular be candidates for antifibrinolytic drugs, such as those with
histones, and cell-free DNA, in combination with other trauma-induced coagulopathy.131
indicators might offer supplementary insights for diagno-
sis in sepsis-associated DIC.126 Platelet function analysis
such as soluble P-selectin, Beta-thromboglobulin, soluble 6.3 Advancements in DIC screening
glycoprotein, platelet aggregation test, platelet adhesion technologies
index is also under investigation.60 Platelet-derived pro-
coagulant microparticles play a significant role in DIC, Recent advancements in nanotechnology and point-
and these platelet-derived microparticles could become a of-care devices have introduced innovative methods
new biomarker for DIC. Recently, microthrombi, which for diagnosing and screening DIC. Advanced microflu-
are considered to be amyloid-fibrin(ogen) aggregates, are idic systems are now capable of mimicking blood
shown to be associated with a variety of conditions, and coagulation processes under physiological conditions,
in sepsis, SARS-CoV-2 infection. Studies indicate that facilitating molecular-level assessments of coagulation
microthrombi in critically ill patients are correlated with events.132 These devices can rapidly measure various
the diagnosis of sepsis, and can predict sepsis-related parameters—electrochemical, optical, and mechanical—
coagulopathy and adverse clinical outcomes.127 The diag- providing coagulation test results within minutes,
nostic and prognostic value of these biomarkers remains which is essential for urgent diagnostic and therapeutic
to be established in large-scale studies. As the afore- interventions.133 Nanomaterials, including gold nanopar-
mentioned research progresses, the understanding of the ticles and graphene oxide, have demonstrated enhanced
detailed pathophysiological differences between under- sensitivity and specificity in DIC diagnostics due to their
lying diseases continues to advance, and disease-specific unique physicochemical characteristics.134 Photoacoustic
diagnostic criteria for DIC are very important for future imaging, which combines the deep penetration of acoustic
development. waves with the high contrast of optical imaging, has been
used for real-time monitoring of circulating clots and
blood coagulation in tissue.135 This technology has shown
6.2 Point-of-care tests promise in the detection of heparin and LMWH, with a
significant and dose-dependent increase in photoacoustic
While the JAAM DIC criteria and SIC are effective for iden- signal in the presence of these anticoagulants.136,137 Elec-
tifying thrombotic DIC, they are less suitable for detecting trochemical sensors, particularly those based on aptamers,
early bleeding, or the enhanced fibrinolysis type of DIC, have been developed for the detection of thrombin, a key
which is often seen in trauma and obstetric emergen- enzyme in the coagulation cascade. These sensors offer
cies. Beyond traditional coagulation indicators, there is an rapid, selective, and sensitive detection of thrombin,
ongoing effort to quickly identify early-stage DIC to pre- which is crucial for the diagnosis of DIC.138 Fluorescent
vent its progression to a severe and potentially irreversible probes have been used to track clot molecules and cells,
state.126 Viscoelastic tests such as thromboelastography allowing for the quantitative measurement of multiple
(TEG) or rotational thromboelastometry (ROTEM) present targets simultaneously. This enhances the visualization of
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GONG et al. 13 of 24

clot dynamics and may facilitate noninvasive imaging of with hyperfibrinolysis. Plasma exchange is recommended
early-stage thrombosis in clinical settings.139 for certain TMA cases like TTP but not for DIC. AT
Notably, the progress in AI and machine learning has concentrate and recombinant thrombomodulin are com-
led to the development of algorithms that can monitor var- monly used for DIC, while eculizumab is effective for
ious parameters concurrently, enabling the identification complement-mediated TMA, such as aHUS, and rituximab
of unique patterns in patients. This capability is instru- is beneficial for TTP in patients with high ADAMTS13
mental in determining the most appropriate treatment inhibitor titers.
or diagnosing, especially for patients with unique condi-
tions, including those undergoing newer anticoagulation
therapies.140,141 8 TREATMENT
Overall, for suspected DIC cases, it is recommended
to use a validated scoring system integrating various lab Given the intricate pathophysiology of DIC, its treatment
tests for reference. Since DIC can fluctuate between differ- is a multifaceted challenge that demands a personalized
ent phenotypes, parameter changes should be monitored approach tailored to the clinical context and the specific
regularly. Underlying DIC-associated causes should be underlying cause. In the case of nonovert DIC, address-
considered for accurate predictive value, other coagulation ing the root cause is crucial, as effectively managing the
disruptors should also be considered to avoid miscalcu- underlying issue can often lead to the resolution of the
lating the DIC score. New technologies in the diagnosis coagulopathy. However, as DIC advances, initiating effec-
and treatment of DIC offer significant advancements, tive anticoagulation therapy during the hypercoagulable
potentially revolutionizing patient care. These innovations phase becomes necessary. Despite this, determining the
hold significant promise for more accurate, efficient, and optimal timing for starting anticoagulation and assessing
personalized DIC management. the potential risks, such as bleeding, remain significant
challenges in the field (Figure 4).
The use of blood products and clotting factor concen-
7 DIFFERENTIAL DIAGNOSIS OF DIC trates may be necessary to manage bleeding resulting from
AND TMA the consumption of platelets and coagulative factors. In
essence, the overarching goal is to restore the pathological
TMA, manifests as a clinical syndrome characterized coagulopathy to a physiological hemostatic state, a concept
by microangiopathic hemolytic anemia, is increasingly that is currently the subject of extensive research.
gaining the attention of clinicians. TMA encompasses
hemolytic anemia, thrombocytopenia, and organ dysfunc-
tion, particularly affecting the kidneys and central nervous 8.1 Basic treatment
system, as well as other organs.142 Thrombocytopenia and
potential organ dysfunction are common clinical features Treatment of the underlying disorder is the most impor-
of DIC and TMA, thus differential diagnosis between DIC tant principle in DIC management. For instance, DIC
and TMA is important (Table 3). The core pathogenesis due to sepsis or septic shock should focus on the basic
of TMA lies in the abnormal activation and consump- tenets of sepsis care, which includes early identification
tion of platelets, as well as endothelial cell dysfunction, and treatment of the infection, hemodynamic support, and
while coagulation and fibrinolytic system were not acti- management of organ dysfunction. In trauma, this may
vated in most circumstances.143 TMA is more commonly involve surgery to control bleeding and repair damaged
associated with concurrent conditions such as infections, tissues. Timely etiological treatment helps to reverse and
pregnancy, autoimmune diseases, or malignant hyperten- even repair the DIC process.
sion. Thrombotic thrombocytopenic purpura (TTP) and
hemolytic uremic syndrome (HUS) are used to be consid-
ered as the primary causes of TMA syndromes. Unlike DIC 8.2 Anticoagulant treatment
that has no specific markers, TMA has some diagnostic
markers. TTP requires a markedly decreased ADAMTS13 Anticoagulant therapy is recommended when the coagula-
level, that of STEC–HUS requires the detection of a tion system activation and systemic thrombin production
STEC infection. aHUS involves identifying abnormali- overwhelms fibrinolysis and consumption coagulopa-
ties in the complement system.144 Concerning treatment, thy. In sepsis, procoagulant activity and fibrinolytic
platelet transfusion is contraindicated for TMA, whereas is suppression lead to thrombin formation and organ dys-
advised for DIC with thrombocytopenia and major bleed- function, where anticoagulant treatment is recommended.
ing. Antifibrinolytic therapy is suggested for DIC patients DIC in some solid cancers is mainly characterized by
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
14 of 24 GONG et al.

TA B L E 3 Differential diagnosis of DIC and TMA.

DIC TMA
Clinical manifestations
Thrombocytopenia Frequent Frequent
Bleeding and bleeding tendency Frequent Frequent
Anemia Often Usually
Shock or micro circulation dysfunction Often Rare
Organ dysfunction Lung, kidney, shock Kidney, CNS
Hematuria Sometimes Frequent
Pathological mechanisms
Microvascular thrombosis Mostly in venules Mostly in arterioles
Platelet activation Yes Yes
Endothelial dysfunction Endothelial injury Edema of endothelial cells and
subendothelial spaces, accompanied by
thickening of vascular walls and platelet
microthrombus
Activation of coagulation system Yes No
Fibrinolysis Secondary No
Laboratory data
Platelet count Low Low
Hemoglobin Often low Low
Fibrin related markers Significantly high Slightly high
Prothrombin time Prolong Normal
Antithrombin Low Normal
Albumin Low Normal
Creatinine Often high High
Total bilirubin, LDH Often high High
Treatment Recommendation: Recommendation:
Supportive therapy, blood Supportive therapy, blood transfusion
transfusion (RBC, FFP, PC), (RBC, FFP), PE/FFP, hemodialysis,
anticoagulant, AT, rhTM, MABs (on condition), etc.
etc.
Abbreviations: AT, antithrombin; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; MABs, monoclonal antibodies.; PC, platelet concentrate;
PE, plasma exchange; RBC, red blood cell; rhTM, recombinant human thrombomodulin; TMA, thrombotic microangiopathy.

procoagulant activity and fibrin deposition, appropriate system by neutralizing thrombin and other coagulation
anticoagulant treatment is also suggested. While there is factors. In DIC, where there is an overwhelming activation
no definitive guideline on the optimal duration for antico- of coagulation pathways, AT levels can be significantly
agulant treatment, evidence indicates that initiating ther- depleted, leading to a hypercoagulable state.147 In sepsis,
apy promptly, ideally within 24 h, is crucial to capitalize on where AT activity is markedly suppressed, the use of
therapeutic windows in sepsis-induced DIC.145,146 Notably, AT concentrate has been extensively studied, with a
in cases of DIC induced by severe trauma and traumatic significant reduction in 28-day mortality observed in
shock, accompanied by critical bleeding attributed to both patients with sepsis-associated DIC treated with AT. The
consumption coagulopathy and excessive fibrinolysis, benefits were particularly pronounced when AT was not
anticoagulants are considered contraindicated. co-administered with heparin.148,149 However, a meta-
analysis did not find a significant reduction in overall
mortality with AT treatment across all critically ill patients,
8.2.1 AT treatment and subgroup analyses also suggested no potential ben-
efits in patients with DIC and sepsis.150 Additionally, AT
As previously mentioned, AT is a serine protease inhibitor treatment appears to increase the risk of bleeding, as noted
that plays a crucial role in the natural anticoagulation in a Cochrane review that included 30 RCTs; however,
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 15 of 24

F I G U R E 4 The causes and treatments of DIC. Treatment is divided into addressing the underlying condition and specific management
for asymptomatic patients, thromboembolism, and bleeding, with recommendations for LMWH prophylaxis, antithrombin, platelet
concentrates, and other supportive therapies based on clinical presentation.

the concurrent use of heparin should be considered a mortality in sepsis, particularly in patients with high
risk factor.151 The Japanese sepsis guidelines recommend severity.156 The application of heparin in sepsis-associated
the use of AT for sepsis-associated DIC, supported by DIC is complex, as it may influence not only coagula-
a propensity score-matched analysis showing improved tion pathways but also inflammatory processes, which
survival rates.152,153 The rationale for this recommendation are pivotal to sepsis pathophysiology.157,158 A recent study
is based on the understanding that severe insults leading showed that heparin could prevent caspase-11-dependent
to systemic thrombin generation can overwhelm the immune responses and sepsis lethality, independent of its
body’s natural anticoagulant mechanisms, including AT. anticoagulant effects.159
Restoring these pathways with AT concentrate is thought In a randomized controlled study aiming at evaluating
to mitigate the hypercoagulable state and reduce the effect of LMWH in COVID-19 patients at risk of throm-
associated mortality. Recent evidence on the efficacy bosis (plasma D-dimer level greater than four times the
and safety of AT has become more favorable in sepsis upper limit or SIC score ≥4), therapeutic doses of LMWH
and sepsis-associated DIC, although optimal dosing and reduced major thromboembolism and death compared
patient selection for AT therapy remain contentious issues with institutional standard heparin thromboprophylaxis,
that require further research.154,155 AT administration while the treatment effect was not observed in criti-
could also be considered in acquired AT deficiency such cally ill patients.160 Heparins may be most effective when
as DIC-associated trauma, burns, complicated pregnancy. administered early in the disease course to prevent both
macrovessel and microvascular thrombosis in this condi-
tion. Prophylactic use of heparin or LMWH is advocated
8.2.2 Heparin treatment in critically ill, nonbleeding DIC patients to prevent venous
thromboembolism.
In DIC cases where thrombosis is the predominant clinical Heparin use should be approached with caution or sus-
feature, the ISTH recommends the use of unfractionated pended in DIC patients experiencing bleeding, those at
heparin or LMWH. However, no randomized controlled high risk of bleeding, or when platelet counts drop below
trials (RCTs) have yet demonstrated a clinically signifi- 20 × 109 /L.161 For patients with APL-related DIC, heparin
cant outcome for DIC patients. A meta-analysis suggested use requires careful consideration, with platelet counts
potential benefits of unfractionated heparin in reducing ideally above 20 × 109 /L and bleeding risk factored into
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
16 of 24 GONG et al.

decisions. In obstetric DIC, which mainly presents with ence in mortality risk reduction in SIC without increasing
bleeding, the use of unfractionated heparin or LMWH the bleeding risk.169 Though the results differ to some
is uncertain and should be reserved for situations where extent, overall, the data support the positive effects of
thrombosis is a more immediate concern. using rhTM for the treatment of DIC. Ongoing research
Heparin-induced thrombocytopenia (HIT), marked by a aims to clarify the ideal role of rTM in treating DIC and
decrease in platelet count and an increased risk of venous DIC-associated causes.
or arterial thrombosis, is a severe complication of hep-
arin therapy.162 HIT is caused by synthesis of antibodies
targeting platelet factor 4 (PF4) modified by heparin.163 8.3.2 Recombinant APC
When HIT is suspected, heparin therapy should be dis-
continued immediately, a Doppler ultrasound of the lower Recombinant APC (rAPC) was the first natural anticoag-
limbs conducted, and an alternative anticoagulant such as ulant to be approved for the treatment of sepsis, following
danaparoid sodium or argatroban prescribed.164 the results of the PROWESS trial, which showed a bene-
ficial effect in patients with severe sepsis.170 A subgroup
analysis of the PROWESS trial indicated an even more
8.3 Other anticoagulant proteins beneficial effect on survival in patients with overt DIC.
However, subsequent trials failed to demonstrate a con-
During the hypercoagulable phase of DIC, major anticoag- sistent benefit of rAPC, and it was associated with an
ulant substances, including APC, TFPI, and the endothe- increased risk of bleeding, leading to its withdrawal from
lial thrombomodulin, are suppressed. Therefore, drugs the market.171,172 The withdrawal of rAPC from the mar-
that can restore the impaired anticoagulant pathways are ket highlights the complexity and challenges in treating
also under investigation. Here is an introduction of the DIC. While rAPC showed promise in certain patient pop-
current clinical research about main anticoagulant sub- ulations, its broader application was limited due to safety
stances: APC, TFPI, and thrombomodulin. It is worth concerns.173 This underscores the need for a nuanced
noting that the clinical application potential of these approach to the use of anticoagulants in DIC, where the
anticoagulant substances is still under investigation and risk of bleeding must be carefully balanced against the
requires further validation. potential benefits of treatment.

8.3.1 Recombinant human soluble 8.3.3 Recombinant TF pathway inhibitor

thrombomodulin
TFPI is an endogenous inhibitor of the coagulation sys-
In DIC, where the equilibrium between coagulation tem that directly inhibits factor Xa and the TF/factor
and anticoagulation is disrupted, thrombomodulin has VIIa complex. Given its role in inhibiting the initiation of
emerged as a promising therapeutic option. Clinical trials, the coagulation cascade, TFPI theoretically represents a
particularly in Japan, have investigated the use of recom- promising target for the treatment of DIC. Early studies,
binant human soluble thrombomodulin (rTM) in patients including animal models and trials in healthy individuals,
with DIC stemming from hematologic malignancies or suggested that rTFPI could be a viable treatment option.174
severe infections, showing potential benefits.165 A meta- However, the transition from theoretical promise to clini-
analysis encompassing 1409 patients from three RCTs and cal efficacy has been challenging. A phase II trial of rTFPI
nine observational studies revealed a reduced risk of death in patients with severe sepsis reported a nonsignificant
in sepsis-induced DIC patients treated with rTM, suggest- reduction in 28-day mortality.175 The subsequent phase 3
ing better outcomes.166 However, the SCARLET study, a trial, known as the OPTIMIST trial, failed to show a sur-
RCT investigated the effect of rTM on 28-day mortality in vival benefit for patients with severe sepsis receiving rTFPI
patients with SIC showed no risk reduction in the inter- compared with placebo.176 These results highlight the gap
vention group compared with the placebo group, while between the theoretical mechanisms of action and the
the risk of major bleeding is increasing.167 Yet, a post-hoc clinical outcomes in complex conditions such as DIC.
analysis of the SCARLET study indicated that the mor- In conclusion, while thrombomodulin, APC, and TFPI
tality risk reduction was most pronounced in subgroups have shown theoretical promise in the treatment of DIC,
of patients with increased levels of TAT and prothrombin their clinical efficacy has been variable. Thrombomodulin,
fragment suggesting that rTM may be particularly effec- particularly in its recombinant form, has demonstrated
tive in patients with higher disease severity.168 A following the most consistent potential benefit, especially in patients
updated meta-analysis found statistically significant differ- with more severe disease manifestations. The challenges
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 17 of 24

faced by rAPC and rTFPI in clinical trials emphasize the is not recommended, unless hyperfibrinolysis is clearly
need for a more tailored approach to treatment, taking into indicated. There is limited evidence regarding their ben-
account the specific characteristics and severity of DIC in efits or safety in this context. In the setting of trauma,
individual patients. Ongoing research and clinical trials initial activation of fibrinolysis induced extensive tissue
are essential to refine our understanding of these treat- injury and massive bleeding are common, antifibrinolytic
ments and to identify the patient populations most likely agents such as tranexamic acid (TXA) play a crucial role.
to benefit from them. The CRASH-2 trial demonstrated that early administra-
tion of TXA within 3 h of injury reduced mortality in
bleeding trauma patients.46 Hyperfibrinolysis significantly
8.4 Fibrinolysis restoration contributes to bleeding and coagulopathy in peripartum
hemorrhage. Early use of TXA in critically ill postpartum
In the context of sepsis, where fibrinolysis is frequently patients with hemorrhage is recommended.183 In APL,
disrupted, there is a significant interest in developing ther- a condition where both DIC and hyperfibrinolysis coex-
apeutic agents that target proteins that inhibit fibrinolysis. ist, antifibrinolytic therapy may be appropriate. The use
Particularly, the inhibition of PAI-1 is seen as valuable due of TXA in these scenarios is supported by clinical data,
to its strong correlation with poor outcomes.106 The devel- emphasizing the importance of timely intervention.
opment of small-molecule PAI-1 antagonists has shown
potential in inhibiting thrombus formation and has been
deemed safe in animal models.177 PAI-1 inhibitor has the 8.6 Substitution therapy in bleeding
ability to restore clot lysis in plasma and decrease pul- and overt DIC
monary microthrombus formation and hemorrhage in a
murine sepsis model.178 Despite these promising results, Substitution therapy is a critical component in the man-
clinical trials for PAI-1 inhibitors are still pending. PAI-1 agement of DIC, particularly in patients with active
inhibitor does not influence thrombus formation or fibri- bleeding or at high risk of bleeding complications.184,185
nolysis in a range of established human plasma and whole This therapy involves the transfusion of platelets, fresh
blood systems.179 In a Japanese trial for COVID-19 pneu- frozen plasma (FFP), and the use of coagulation factor
monia, PAI-1 inhibitor showed nonsignificant trends in concentrates. The ISTH provides guidance on treatment
improved oxygenation and reduced oxygen therapy days thresholds for these therapies. Platelet concentrates are
compared with placebo, but larger studies are needed to recommended for DIC patients experiencing significant
confirm its efficacy.180 bleeding, with a threshold set at 50 × 109 /L. For DIC
The use of profibrinolytic therapies like recombinant patients with minimal or no bleeding, a lower threshold of
tissue PA (rtPA) for sepsis-induced DIC has also been 20 × 109 /L is generally accepted. Substitution with coagula-
reported.181 rtPA treatment can effectively suppress PAI-1 tion factors is advised for patients with major bleeding and
activity in the LPS-induced DIC model in rats and improve significantly prolonged APTT or PT. FFP is the preferred
organ dysfunction.182 However, systemic administration initial treatment. Prothrombin complex concentrate (PCC)
of rtPA has been linked to a significant risk of bleeding is also an alternative, containing vitamin K-dependent
complications, including intracranial hemorrhages, which factors but lacking some crucial ones. PCC can be used
poses safety concerns, particularly for DIC patients who with caution in actively bleeding patients, but the risk
are prone to both microthrombi and bleeding. So far, there of thromboembolism must be monitored. Vitamin K can
have been no prospective studies assessing the systemic help with deficiencies in vitamin K-dependent factors but
use of recombinant tPA in the context of sepsis or DIC. Still, takes over 6 h to be effective. For low fibrinogen levels,
with the appropriate selection of targets and the design fibrinogen concentrate or cryoprecipitate is used, aim-
of optimal administration methods, rtPA may offer a new ing to maintain levels above 1.5 g/L, or above 2.0 g/L
therapeutic agent for DIC and is worth considering for for postpartum hemorrhage. The role of recombinant
future study. human activated factor VII (rhFVIIa) in severe bleeding
DIC has also being explored, with no proven effective-
ness and potential risks. However, it should be noted that
8.5 Antifibrinolysis treatment for now no clinical trials has been established to prove
the efficacy of such treatment. During the hypercoagula-
In DIC, the system that regulates fibrinolysis can become ble phase, blood transfusions should be avoided. In the
overwhelmed or suppressed, depending on the patho- consumption coagulopathy and overwhelmed fibrinolysis
physiology of underlying diseases. In sepsis, fibrinolysis induced bleeding, transfusion therapy could be imple-
system is commonly impaired, antifibrinolysis treatment mented. Correctly assessing the pathological process of
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
18 of 24 GONG et al.

DIC before initiating replacement therapy is crucial, dur- therapies, with a focus on individualized patient care and
ing substitution treatment, coagulation indicators should the integration of emerging evidence into clinical prac-
be monitored dynamically to avoid potential risks, such as tice. This shift toward precision medicine in DIC treatment
thrombosis. has the potential to significantly improve patient outcomes
and revolutionize the management of this complex and
often devastating condition.
8.7 Experimental and emerging
therapies targeting immunothrombosis
9 CONCLUSION AND PERSPECTIVE
The intricate interaction between the innate immune
system and coagulation following infection or injury, DIC is a complex syndrome characterized by systemic acti-
a process known as immunothrombosis, is a primary vation of coagulation, leading to thrombosis and bleeding.
cause of DIC. Identifying new therapies to block the Diagnosis remains challenging due to varying etiolo-
immunothrombotic triggering of TF, which may involve gies and presentations, prompting the search for novel
inhibiting pyroptosis to limit TF release or using cysteine biomarkers to enhance early detection, especially in sep-
modification therapies to directly target TF unmasking, sis, trauma, and obstetric emergencies where DIC can be
shows potentiality.73 The potential of drugs like dimethyl elusive. The design of clinical trials for novel therapies
fumarate and 4-octyl itaconate to suppress TF release is a promising avenue, aiming to address the underlying
by inhibiting IFN and caspase-11 pathways highlights cause and the coagulopathy itself. Considering the hetero-
the promise of this strategy in controlling TF-mediated geneity of DIC across different patient populations, future
coagulopathy.186 research may unveil more targeted personalized treatment
We agree with the view that the new directions in DIC strategies to improve outcome. As our understanding of
therapy tend to develop safer and more effective treatment DIC’s pathophysiology deepens, the prospects for precise,
strategies that target not only coagulation pathways but patient-specific treatments become increasingly feasible,
also anti-inflammatory and cytoprotective mechanisms.187 offering hope for better management of this multifaceted
These new therapies aim to reduce the risk of bleeding condition.
while providing the benefits of antithrombotic and anti-
inflammatory effects. For example, by targeting adhesion
AU T H O R CO N T R I B U T I O N S
molecules on platelets (P-selectin, GPIb, αIIbβ3) and neu-
Fangchen Gong, Xiangtao Zheng, and Shanzhi Zhao con-
trophils, the formation of neutrophil-platelet aggregates
tributed equally to this work. Fangchen Gong, Xiangtao
can be inhibited, improving microvascular dysfunction
Zheng, and Shanzhi Zhao were responsible for the con-
and inflammation.187 These new therapeutic approaches
ception and design of the review. Huan Liu performed
are still under investigation.
the literature search and data analysis. Erzhen Chen and
The above content includes the routine treatment pro-
Rongli Xie contributed to the interpretation of the find-
cedures for DIC, as well as novel clinical studies that
ings and critically revised the manuscript. Ranran Li and
are still under exploration. Overall, etiology identification
Ying Chen provided overall guidance and supervision, and
and management are the cornerstones of DIC. The man-
also contributed to the final revision of the manuscript. All
agement of DIC necessitates a delicate balance between
authors have read and approved the final version of the
treating the coagulopathy and avoiding exacerbation of
manuscript.
the underlying condition. For future treatment, the inte-
gration of advanced diagnostic tools, such as microfluidic
devices, and novel molecular markers, allows for a more AC K N OW L E D G M E N T S
personalized approach for therapy. These provide real- All figures in our submission have been created by us
time data on coagulation dynamics, enabling clinicians using PowerPoint and our own original content. This work
to make informed decisions about the timing and type of was supported by National Natural Science Foundation of
therapeutic interventions. With an evolving understand- China (82300100, 82270087, 82372203, 82300106), Shang-
ing of DIC’s complex pathophysiology, the development hai Shenkang Hospital Development Center Clinical Sci-
of precise, patient-specific treatments is becoming more ence and Technology Innovation Project (grant numbers
attainable, offering new hope for management. The design SHDC22021316; SHDC22023218), National Key Research
of clinical trials for novel therapies presents a promising and Development Program of China (2024YFC3044600),
avenue to not only address the coagulopathy itself but Shanghai Municipal Health Commission (202340068), and
also to target the underlying causes of DIC. The future of Physician-Scientist Project of Shanghai Jiaotong Univer-
DIC treatment lies in the continued exploration of novel sity (20240804).
 26882663, 2025, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.70058 by Cochrane Peru, Wiley Online Library on [04/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
GONG et al. 19 of 24

C O N F L I C T O F I N T E R E S T S TAT E M E N T 11. Sawamura A, Hayakawa M, Gando S, et al. Application of

The authors have declared that no conflict of interest exists. the Japanese Association for Acute Medicine disseminated
intravascular coagulation diagnostic criteria for patients at an
early phase of trauma. Thrombosis Research. 2009;124(6):706-
D A T A AVA I L A B I L I T Y S T A T E M E N T
710.
Not applicable.
12. Levi M. Clinical characteristics of disseminated intravascular
coagulation in patients with solid and hematological cancers.
E T H I C S S TAT E M E N T Thrombosis research. 2018;164(Suppl 1):S77-s81.
Not applicable. 13. Ten Cate H, Leader A. Management of disseminated intravas-
cular coagulation in acute leukemias. Hamostaseologie.
ORCID 2021;41(2):120-126.
Rongli Xie https://orcid.org/0000-0002-5266-383X 14. Erez O. Disseminated intravascular coagulation in
pregnancy—Clinical phenotypes and diagnostic scores.
Thrombosis research. 2017;151(1):S56-S60.
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