Severe coagulopathy poses a serious threat to human life and health, with disseminated intravascular coagulation (DIC) being a common severe coagulopathy characterized by rapid development, dangerous progression, and high mortality. In recent years, Professor Ben Lv from the Second Xiangya Hospital of Central South University has conducted a series of original research studies on the pathogenesis and targeted intervention of sepsis, discovering that the HMGB1-Caspase11 pathway mediates the immune response, which is a critical link leading to DIC, organ failure, and death in sepsis. This research provides potential biomarkers and drug intervention targets for the diagnosis and treatment of sepsis and has been published in internationally renowned academic journals such as Science, Nature, Immunity, Nature Communications, and Blood. At the just-concluded 13th National Conference on Hematopoietic Stem Cell Transplantation Academic Conference of the Chinese Medical Association, Professor Ben Lv delivered a brilliant report on “The Basic and Clinical Research of Severe Coagulopathy” and “Infection and DIC,” summarizing breakthrough research achievements in recent years in the fields of severe coagulopathy and sepsis, providing new directions for the development of diagnosis and treatment of severe coagulopathy. Oncology Frontier – Hematology Frontier hereby compiles and presents it for readers.
Epidemiology of Sepsis and its Association with Severe Coagulopathy
Multi-organ failure is a primary characteristic of critically ill patients and is the direct cause of death. Infection is the most common cause, with other triggers including trauma, heatstroke, etc. There are over 50 million cases worldwide annually, consuming significant medical resources. Targeted treatment measures are still lacking. Sepsis-induced multi-organ failure, known as septicemia, affects over 48.9 million patients annually, with over 11 million deaths per year, and a higher mortality rate in China.
Severe patients often present with coagulation dysfunction, with about 30% to 50% of septicemia patients having DIC, and around 80% of heatstroke patients having DIC. DIC is a critical factor in promoting death in septicemia patients. Once DIC occurs in septicemia patients, the prognosis is extremely poor, with a six-fold increase in mortality, characterized by decreased fibrinogen and increased D-dimer levels.
Research has found that severe coagulopathy significantly promotes organ failure and death. However, the pathogenesis of severe coagulopathy is still not clear. The prevailing view has been that infection induces an inflammatory storm, leading to DIC and organ failure, ultimately resulting in patient death. However, a large body of clinical research has shown that treatment aimed at counteracting the inflammatory storm does not improve the prognosis of septicemia patients. Therefore, how infection leads to DIC and organ failure remains a pressing medical issue.
Exploring the Mechanisms of Infection-Induced DIC and Organ Failure
Professor Ben Lv first proposed the idea of cell death-induced DIC based on clinical clues from a high-risk patient with acute promyelocytic leukemia (APL) who developed DIC, multi-organ failure, and ultimately died after daunorubicin chemotherapy. Chinese research experts have found that chemotherapy can induce pyroptosis, a form of programmed cell death mediated by Gasdermin protein.
HMGB1 (High Mobility Group Box 1) and Casp11 (Caspase 11) are key molecules involved in pyroptosis and inflammatory responses. In recent years, Professor Ben Lv has made a series of original breakthroughs in the field of basic research on severe coagulopathy, exploring the important mechanisms of infection-induced multi-organ failure: the HMGB1-Casp11 pathway mediates pyroptosis and DIC in sepsis.
Firstly, HMGB1 binding to LPS promotes multi-organ failure through Casp11. In October 2018, as a corresponding author, Professor Ben Lv published a study in the top immunology journal, Immunity, revealing a new function of HMGB1 protein as an endotoxin (LPS) transporter, explaining that the liver is the main source of circulating HMGB1, elucidating the mechanism by which infection leads to multi-organ failure, and providing potential biomarkers and drug targets. Additionally, in 2019, as a corresponding author, Professor Ben Lv published a study in the journal Nature Communications, confirming that HMGB1-Casp11 promotes multi-organ failure in allogeneic hematopoietic stem cell transplantation.
Figure 1: “HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis” paper
Figure 2: “Caspase-11 Signaling Enhances Graft-versus-Host Disease” paper
Furthermore, HMGB1-Casp11 promotes multi-organ failure by inducing DIC. In December 2019, Professor Ben Lv, as the corresponding author, published a study in Immunity, pointing out that Gasdermin-mediated pyroptosis is a crucial step in triggering DIC in sepsis. This study elucidated the molecular mechanisms of infection-induced coagulation and DIC, revealing the intrinsic connections among infection, immunity, and coagulation, and providing potential biomarkers for early DIC diagnosis. So how does infection activate Casp11 to promote DIC? In April 2020, Professor Ben Lv, as the corresponding author, published a study in the prestigious journal Blood addressing this question. This research found that HMGB1 and its upstream type I IFN activate Casp11 leading to DIC and multi-organ failure, further elucidating the mechanism of infection-induced multi-organ failure. Additionally, they established a new method that, for the first time, dynamically visualized the process of DIC formation at the in vivo level using live imaging technology. This paper became the featured article and cover paper of the Blood journal.
Figure 3: “Bacterial Endotoxin Activates Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure” paper
Figure 4: “Role of Type I Interferon in Gram-Negative Bacteria-Induced Coagulation” paper
Mechanisms of Thrombus Formation Induced by Pyroptosis
Pyroptosis induces thrombus formation through the activation of both extrinsic and intrinsic coagulation pathways and the release of circulating anticoagulant microparticles. Firstly, pyroptosis leads to the externalization of phosphatidylserine (PS) on the cell membrane. This directly activates tissue factor (TF), a key initiator of the extrinsic coagulation pathway. Once TF is activated, it initiates the coagulation cascade, thereby promoting fibrin formation and thrombus generation. Secondly, during pyroptosis, cellular contents such as nucleic acids are released. These substances can activate factor XII in the coagulation cascade, thereby activating the intrinsic coagulation pathway, further exacerbating thrombus formation. Additionally, pyroptosis also releases a large number of circulating anticoagulant microparticles. While these microparticles typically have anticoagulant properties under normal conditions, in the specific environment of pyroptosis, they may lose their anticoagulant function and instead become factors that promote thrombus formation.
Exploration of the Mechanisms of DIC and Organ Failure Induced by Heatstroke
Heatstroke, also known as severe heatstroke, is a life-threatening illness caused by heat stress and is associated with circulatory failure and multi-organ dysfunction. If global warming continues, heatstroke may become a more prominent cause of global mortality, but its pathogenesis remains unclear. Intracellular “temperature sensors” exist to induce programmed cell death, with scientific hypotheses suggesting that RIPK3-mediated necroptosis triggers DIC in heatstroke. In May 2022, Professor Ben Lv, as the corresponding author, published a study in Science, revealing a critical mechanism of heatstroke-related mortality. It was demonstrated that high body temperature induces excessive programmed cell death through Z-DNA binding protein 1 (ZBP1), leading to DIC and multi-organ damage.
Figure 5: “Z-DNA Binding Protein 1 Promotes Heatstroke-Induced Cell Death” paper
Additionally, in 2023, Professor Ben Lv, as the corresponding author, published a study in the journal Cell Research, revealing that the ZBP1-RIPK3 pathway promotes lung damage in COVID-19 [8]. This study provides new insights into how SARS-CoV-2 infection triggers inflammatory responses and pulmonary pathology, and suggests that targeting the ZBP1-RIPK3 axis has the potential to treat COVID-19 pneumonia.
Figure 6: “SARS-CoV-2 Z-RNA Activates the ZBP1-RIPK3 Pathway to Promote Virus-Induced Inflammatory Responses” paper
Targeted Intervention Strategies for Severe Coagulopathy
In order to preliminarily investigate whether the HMGB1-Caspase11 pathway could serve as a potential target for drug intervention in sepsis, Professor Ben Lv established a unique screening platform for HMGB1-Caspase11 pathway inhibitors based on previous findings. They aimed to identify lead molecules that selectively inhibit the activation of the Caspase-11 pathway. It was discovered that heparin efficiently and selectively inhibits the activation of Caspase-11.
Figure 7: High-Throughput Screening Platform for Specific HMGB1-Casp11 Pathway Inhibitors
In March 2021, Professor Ben Lv, as the corresponding author, published a study in the journal Immunity, elucidating that heparin could prevent organ damage, DIC occurrence, and death in sepsis by inhibiting the activation of Caspase-11, providing new insights into the prevention and treatment of sepsis. Heparin is widely used as an anticoagulant drug for the treatment of thrombotic diseases. This study further separated the anticoagulant effect of heparin from its anti-inflammatory effect and invented a new method for treating sepsis using non-anticoagulant heparin (heparin chemically modified to remove its anticoagulant activity, hence without bleeding risk). Unlike the application of heparin, increasing the dosage of non-anticoagulant heparin does not significantly affect the body’s coagulation response. However, non-anticoagulant heparin can efficiently block Caspase-11-mediated immune responses and lethality in sepsis. The above study preliminarily identified the HMGB1-Caspase11 pathway as a potential target for drug intervention in sepsis, elucidated the pharmacological mechanism of heparin in regulating immune responses, separated the anticoagulant and anti-inflammatory effects of heparin, and invented a new method for treating sepsis using non-anticoagulant heparin, providing new insights into the prevention and treatment of sepsis. This article was awarded “Best Paper of 2021 in China” by Cell Press.
Figure 8: “Heparin Prevents Caspase-11-Dependent Sepsis Mortality Independent of Anticoagulant Action” Paper
Subsequently, Professor Ben Lv validated the efficacy of heparin in sepsis through retrospective clinical studies and real-world research based on international multicenter large-scale data systems related to sepsis diagnosis and treatment, and initiated prospective RCT studies on heparin therapy for sepsis.
Conclusion
The series of studies conducted by Professor Ben Lv revealed that in sepsis, HMGB1 released by liver cells as a molecular partner can bind to LPS in the bloodstream and efficiently transport LPS into the cytoplasm, thereby activating the cytoplasmic receptor Caspase-11, leading to massive endothelial cell and macrophage pyroptosis, ultimately resulting in DIC, multiple organ dysfunction, and death. In addition, Professor Ben Lv found that heparin can target intervene in the activation of HMGB1-Casp11 in sepsis, providing new insights into the prevention and treatment of sepsis.
References:
Nature 2017, 547(7661):99-103.
Immunity 2018, 49:740-753
Nat Commun 2019, 10:4044-55
Immunity 2019, 51:983-996
Blood 2020, 135:1087-1100
Immunity 2021, 54,1-14
Science. 2022 May 6;376(6593):609-615
Cell Res 2023 Mar;33: 201-214
Immunity 2021, 54:454-467
Professor Ben Lv
Director, Xiangya Second Hospital, Central South University
Double PhD in Clinical Medicine and Immunology, Second-level Researcher, Associate Chief Physician
Recipient of National Outstanding Youth, China Young Science and Technology Award, the first Medical Field “Exploration Award”, China Youth Science and Technology Innovation Award, and Shulan Medical Young Award
National Excellent Youth
Member of the Medical Advisory Committee of the National Natural Science Foundation of China
Member of the Chinese Medical Association Hematology Branch
Standing Committee Member of the Critical Illness Branch of the Chinese Society of Pathophysiology
Member of the Intensive Care Medicine Branch of the Chinese Medical Association
Chairman of the Intensive Care Medicine Branch of the Hunan Provincial Medical Association
Vice Chairman of the Hematology Special Committee of the Hunan Medical Association
