In December 2024, Professor Tang Xiaopeng’s team from the School of Basic Medical Sciences at Qingdao University, in collaboration with several renowned domestic research institutions and organizations, published a significant research finding in Blood (IF=21, top journal in the medical field, Q1) titled “Deficiency of neutrophil gelatinase-associated lipocalin elicits Hemophilia-like bleeding and clotting disorder.” This study reveals the crucial role of neutrophil gelatinase-associated lipocalin (NGAL) in coagulation, hemostasis, and thrombosis.

Studies have shown that NGAL significantly influences the coagulation process by enhancing tissue factor expression, promoting coagulation activity, and facilitating platelet aggregation. In NGAL-knockout mice, coagulation function is markedly impaired, leading to prolonged bleeding time and reduced thrombus formation, resembling hemophilia-like symptoms. In contrast, NGAL overexpression or exogenous supplementation accelerates coagulation and thrombus formation. Moreover, intervention with an anti-NGAL monoclonal antibody effectively reduces inflammation-associated thrombosis. This study is the first to elucidate NGAL as a critical mediator linking innate immunity and coagulation regulation, providing a novel target for antithrombotic drug development and suggesting that modulating NGAL levels may help balance thrombosis and hemorrhagic risks.

Focus: Innovations in Antithrombotic Drug Development

RWD: Could you briefly outline the research rationale and key innovations of this study?

Professor Tang: This study originated from our efforts to identify potential regulators of coagulation by examining plasma samples from patients with venous thrombosis using differential proteomics. Using DIA-MS technology, we successfully identified neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator that is significantly upregulated in the plasma of these patients. We then conducted a comprehensive investigation into the specific mechanisms of NGAL in coagulation, hemostasis, and thrombosis using various coagulation indexes and animal models. A key highlight of this study is its expansion of the connection between innate immunity and the regulation of coagulation, hemostasis, and thrombosis. This research not only enhances our understanding of the complex mechanisms governing coagulation homeostasis but also provides new insights into the pathogenesis of hemophilia.

RWD: What do you consider the most significant challenge encountered during this investigation?

Professor Tang： The most significant challenge in NGAL research was validating the regulatory role of this innate immune molecule in coagulation homeostasis. Traditional views suggest that coagulation regulation primarily depends on classical factors such as thrombin and fibrinogen, while immune molecules are thought to be involved only in inflammatory responses. However, after identifying a strong association between NGAL and thrombosis in differential proteomics, we did not adhere to existing theories but instead boldly hypothesized its direct involvement in coagulation.

To test this hypothesis, we abandoned conventional in vitro coagulation experiments and instead developed an NGAL-knockout mouse model. This decision was initially controversial due to the extended timelines and high costs associated with animal models. However, our team remained convinced that this was the only way to uncover the complex regulatory mechanism in vivo. Ultimately, this model not only confirmed that NGAL deficiency leads to a hemophilia-like bleeding phenotype but also unexpectedly revealed its role in modulating platelet-endothelial cell interactions to influence thrombus stability. This discovery directly led to three patent applications, including the design of a peptide inhibitor targeting the NGAL-coagulation pathway, marking a significant departure from the conventional approach to antithrombotic drug design.

RWD: How does this research advance the clinical management of thrombotic disorders or the development of related therapeutics?

Professor Tang：It is well known that existing drugs in clinical practice often carry a high risk of hemorrhage, which severely limits their application. Our previous research proposed that targeting coagulation regulators rather than directly acting on coagulation factors could achieve antithrombotic effects while reducing hemorrhagic risk. Therefore, targeted drugs designed for coagulation regulators hold great potential for clinical application. In recent years, we have been actively advancing the clinical translation of innovative antithrombotic drugs that target coagulation regulators.

Moreover, investigating new mechanisms and regulatory networks of coagulation is crucial for a deeper understanding of hemostasis and thrombosis. This knowledge provides a foundation for designing innovative drugs that can modulate thrombosis without disrupting hemostasis. For example, NGAL, as a novel “hemophilia-associated factor,” offers valuable insights into the mechanisms underlying both hemorrhagic and thrombosis regulation, paving the way for new therapeutic strategies.

RWD: Could you share your team’s forthcoming initiatives?

Professor Tang: Our team’s main goal is to uncover the complex mechanisms of coagulation regulation. We are systematically studying common thrombotic risk factors, such as cancer, pregnancy, diabetes, and metabolic disorders, and exploring their molecular mechanisms to design safe and effective antithrombotic drugs.

For example, pregnancy is a well-known thrombotic risk factor, and the use of related medications involves the health of both the mother and the fetus, requiring utmost caution. Therefore, we plan to conduct in-depth research on the specific pathological mechanisms of pregnancy-induced thromboembolism, based on new insights into coagulation regulation. This will allow us to design safe and effective drugs based on these novel mechanisms, which will be a key focus of our team’s future research.

Efficiency: Chinese Technologies Empowering Thrombosis Research

RWD: Regarding this particular study, what specific role did the RWD Laser Speckle Contrast Imaging System play in your experimental workflow?

Professor Tang: RWD’s Laser Speckle Contrast Imaging System has become the “gold standard” in our laboratory for thrombosis research and evaluation. This instrument is indispensable in observing arteriovenous thrombosis.

Not only does it provide high-resolution imaging capabilities, but it also enables real-time monitoring of hemodynamics, offering invaluable data support for our studies on thrombus formation and dissolution. This system allows us to perform in-depth analyses of physiological and pathological changes associated with thrombosis, thereby revealing more complex blood flow mechanisms and thermoregulatory processes.

For instance, when investigating the impact of various factors on thrombogenesis, we’ve captured numerous subtle yet crucial changes using this system, which has significantly enriched our research experience and database. Such an efficient and precise research tool allows us to develop a comprehensive understanding of the biological characteristics and clinical significance of thrombosis.

RWD: We understand you have utilized RWD equipment since your graduate studies, and you were awarded the RWD Scholarship! As an “old friend”, could you share your perspective on our technological solutions?

Professor Tang: What makes RWD most appealing extends beyond product performance to its core value of “innovation driven by academic needs.” During my student years, budget constraints prevented me from purchasing imported equipment, and RWD’s laser speckle system resolved this dilemma by offering equivalent performance at a lower cost.

Moreover, the RWD Scholarship Program provides not just financial support but also fosters interdisciplinary collaboration through its Young Scholars Forum. It was through this platform that I established connections with clinical thrombosis experts from partner institutions, paving the way for subsequent translational research. RWD has evolved beyond being merely an equipment supplier to becoming a co-builder of academic ecosystems. Looking ahead, I anticipate deepening collaboration with RWD in “precision thrombus imaging technology,” integrating clinical demands with engineering innovation to propel domestic scientific instruments to international forefront status.

Reflection: Advancing Through inquiry, Innovating Through Discovery

RWD: Your research has consistently focused on thrombotic disorders. What motivates your sustained dedication to this field?

Professor Tang：I completed both my Master’s and Ph.D. research at the Kunming Institute of Zoology, Chinese Academy of Sciences, under the mentorship of Professor Lai Ren, a renowned authority in toxin research. Professor Lai profoundly shaped my approach to science, often saying, “Textbook knowledge represents past discoveries, and future breakthroughs are hidden in overlooked corners.” This mindset drove me to explore uncharted territories, including a toxic mammal species that was initially met with skepticism by my team. However, this journey led to the discovery of a novel toxin molecule with serine protease inhibitory activity from the venom of this species.

Further investigation revealed a unique mechanism of coagulation regulation, which was entirely different from the mechanisms found in snake venom and leeches. This discovery challenged conventional theories and suggested the existence of many unidentified, novel regulatory pathways in the coagulation system. I then used this toxin molecule as a tool to uncover additional regulatory mechanisms, which continue to drive my ongoing focus on coagulation and thrombosis research.

RWD: As a professor, do you employ distinctive pedagogical approaches in mentoring your students?

Professor Tang：In both undergraduate teaching and graduate mentorship, I consistently emphasize to students: “Don’t just accept the knowledge from the textbooks — dare to challenge established views in academic literature True innovation often stems from bold thinking and exploration, not mere repetition of existing research.” In scientific inquiry, following trends often results in superficial studies lacking depth and originality. Therefore, I encourage students to maintain intellectual curiosity and critical thinking, actively seek novel questions and theories, and boldly experiment with diverse research approaches.

I firmly believe that only through questioning and exploration can we genuinely advance science and unravel unsolved mysteries. When confronting complex scientific problems, we must cultivate independent thinking abilities, examine issues from multiple perspectives, and conduct in-depth investigations integrating multidisciplinary knowledge. Concurrently, I urge students to continuously master new technologies and methodologies, leveraging cutting-edge research tools to transcend traditional boundaries. This spirit of daring exploration constitutes the driving force behind scientific progress.

RWD: As for the emphasis on questioning and exploration, does this originate from your mentor’s philosophy or your own scientific ethos? Could you share an impactful anecdote in this context?

Professor Tang：During my time in Professor Lai’s team, his encouragement of “unconventional research paths” left a lasting impression on me. For example, at the time, the mainstream view was that coagulation regulation mechanisms were primarily focused on snake venom or leech toxins, with little research on mammalian toxins. However, Professor Lai often said, “Textbook knowledge represents past discoveries, and future breakthroughs are often hidden in overlooked corners.” He encouraged me to explore obscure species and to boldly hypothesize.

It was in this environment that I chose to study the “Linnaeus,” a small toxic mammal. Initially, both within and outside the team, there was skepticism about this direction, with doubts that its toxins might merely replicate known mechanisms. However, Professor Lai continued to support my exploration and even personally guided the experimental design. Eventually, we unexpectedly discovered that the serine protease inhibitor in its toxin regulated coagulation through a mechanism completely different from snake venom: it could indirectly influence the coagulation cascade by binding to the non-catalytic domains of coagulation factors. This discovery completely overturned traditional understanding and reinforced the idea that questioning “common knowledge” and exploring unknown fields is often the key to unlocking new scientific frontiers. This philosophy later became the cornerstone of our team’s research approach.

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Please click here to access the original publication：https://doi.org/10.1182/blood.2024026476

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