What fibrin modulators are in clinical trials currently?

Introduction to Fibrin Modulation
Fibrin is a pivotal protein involved in blood clotting, tissue repair, and wound healing. As the end product of the coagulation cascade, fibrin forms a polymeric mesh that stabilizes clots and helps to restore the integrity of damaged vessels. From a biomolecular perspective, fibrin’s mechanical properties and its interactions with various cellular and plasma proteins make it central not only to physiological hemostasis but also to pathological conditions where its modulation can be beneficial. In recent years, the therapeutic modulation of fibrin—by either enhancing, inhibiting, or modifying its function—has emerged as a promising strategy in managing bleeding, thrombotic disorders, wound healing challenges, and even aspects of inflammation and tissue regeneration.

Role of Fibrin in the Body
Fibrinogen, the soluble precursor of fibrin, circulates in the blood and is converted by thrombin into fibrin during the coagulation process. Once activated, fibrin fibers form a three-dimensional network that not only provides structural integrity to clots but also serves as a framework for cell migration, tissue regeneration, and even delivery of bioactive molecules. This natural scaffold is instrumental in wound repair where it promotes cellular ingrowth and serves as a target for various regenerative medicine approaches.

Importance of Modulating Fibrin
Given its central role, modulating fibrin dynamics represents a therapeutic opportunity. Agents that can either stabilize fibrin clots—thus controlling bleeding—or promote controlled fibrinolysis to prevent unwanted clot persistence have a considerable impact on clinical outcomes. In addition, fibrin-based biomaterials, when engineered appropriately, can enhance wound healing by promoting angiogenesis and tissue repair. The modulation can also be directed toward reducing inflammatory responses by targeting specific domains within the fibrin molecule that drive immune activation. Such modulation supports not only acute hemostatic regulation during surgery but spans across a wide spectrum of clinical settings including congenital deficiencies, surgical adjuncts, and even treatments for chronic wounds.

Current Fibrin Modulators in Clinical Trials
Recent clinical trials have evaluated an array of fibrin modifiers, ranging from sealants to fibrinogen concentrates and autologous fibrin constructs. These modulators are being tested either as adjuncts to traditional surgical hemostasis or as standalone treatments for congenital and acquired fibrinogen deficiencies.

List of Fibrin Modulators
The current fibrin modulators in clinical trials include:
- Fibrin Sealants:
– FS Grifols, a novel fibrin sealant product under evaluation against commercially available fibrin glue such as EVICEL®. Two notable clinical trials investigate the safety and efficacy of FS Grifols in pediatric patients undergoing surgical procedures. The trial designs are randomized and single-blind, focusing on reducing bleeding time and improving hemostasis during surgery.
– Tisseel® is being evaluated as an adjunct in procedures such as microsurgical digital nerve repair and for reinforcing esophagojejunal anastomoses. Additionally, there are evaluations of the fibrin sealant in ophthalmic surgeries such as eyelid surgeries to reduce postoperative bleeding.
- Fibrinogen Concentrates:
– Several studies examine human fibrinogen concentrates in both congenital and acquired fibrinogen deficiencies. For example, a single-arm, open-label, multicenter trial assesses the pharmacokinetics, efficacy, and safety of human fibrinogen in patients with congenital fibrinogen deficiency, while another similar study explores its use in adults, adolescents, and pediatric populations. These products aim to provide a controlled and safe dosing regimen to prevent bleeding complications.
– FGTW is another fibrinogen concentrate specifically being evaluated in pediatric patients with severe congenital fibrinogen deficiency.
- Autologous Platelet-Rich Fibrin Constructs:
– There is an ongoing randomized controlled trial that compares the efficacy of autologous platelet-rich fibrin therapy with hydrocolloid gel dressings in treating chronic non-healing cutaneous ulcers. This trial aims to harness the natural regenerative properties of fibrin in promoting wound healing as a substitute or adjunct to traditional wound care.
- Exploratory Hemostatic Agents:
– An exploratory phase I/II trial is studying a product termed DBT, described as a class 1 therapeutic biological product for hemostasis during liver, spleen, and pancreas resections. While not a traditional fibrin sealant per se, these agents are often designed to interact with the fibrin clot or modify its structure to enhance local hemostasis.
- Fibrin Sealant Products in Specific Surgical Settings:
– Additional trials, such as a multicenter clinical trial evaluating fibrin sealant used as a filling technique in EVAR for abdominal aortic aneurysm, expand the application of fibrin modulators into endovascular surgery.
– The Thai Red Cross Society fibrin sealants are also undergoing evaluation in randomized controlled trials for post-operative air leak reduction and for use in pterygium patients.

Each of these products is designed to either stabilize or modulate fibrin in ways that enhance therapeutic outcomes by promoting effective hemostasis, reducing bleeding risk, and supporting tissue repair.

Mechanisms of Action
The various fibrin modulators in clinical trials work through a mix of mechanisms:
- Sealants Enhancing Hemostasis:
Fibrin sealants like FS Grifols and Tisseel® mimic the final steps of the coagulation cascade. They provide an exogenous source of fibrinogen and thrombin that rapidly converts into a fibrin clot when applied topically during surgery. Their actions involve polymerization into a fibrin matrix that adheres to tissues, thereby reducing bleeding and creating a sealing barrier.
- Fibrinogen Replacement Therapy:
Human fibrinogen concentrates and products like FGTW are designed to restore normal fibrinogen levels in patients with congenital or acquired deficiencies. By providing a purified source of fibrinogen, these products ensure that natural clot formation proceeds efficiently, thereby limiting bleeding risks. Their pharmacokinetic profiles are often assessed to ensure rapid restoration of clot stability without provoking thrombosis.
- Autologous Fibrin Constructs:
Autologous platelet-rich fibrin therapy leverages the patient’s own blood components to create a fibrin matrix enriched with growth factors and cells. This matrix not only serves as a hemostatic agent but also supports wound healing by providing a scaffold for cellular migration and tissue regeneration.
- Adjunctive Hemostatic Enhancement:
Therapies like DBT or novel fibrin fillers used during major resections are intended to enhance local hemostasis at surgical sites. They may work by stabilizing the fibrin clot, reducing the time to achieve hemostasis, or even by reinforcing the fibrin matrix through inter- or intramolecular cross-linking that improves its mechanical strength.
- Fibrin Sealant in Endovascular Procedures:
In the context of EVAR for abdominal aortic aneurysm, fibrin sealants are tested for their ability to fill spaces and seal vascular defects, thereby preventing leakage and reducing the risk of further vascular complications.

These mechanisms highlight the multifaceted approach of fibrin modulation—from simple sealing and replacement strategies to more complex regenerative constructs—that are currently being trialed in hospitals and surgery centers worldwide.

Clinical Trial Landscape
Clinical trials evaluating fibrin modulators span multiple phases and involve diverse patient populations. The clinical trial landscape is characterized by rigorous study designs that ensure patient safety while exploring the efficacy of these devices and biological products.

Phases of Clinical Trials
The fibrin modulators currently under evaluation are in various phases of clinical development:
- Phase I/II Trials:
Early-phase trials, such as the studies assessing human fibrinogen concentrates and the exploratory trial of DBT, focus on determining pharmacokinetic profiles, safety, and establishing appropriate dosing regimens. These studies often recruit a small number of patients to determine whether the modulators can achieve the desired rapid hemostatic response without adverse events.
- Phase III Trials:
Trials evaluating fibrin sealants such as FS Grifols and fibrinolytic agents for specific surgical applications, as well as those comparing traditional dressings with autologous platelet-rich fibrin, have advanced into phase III. These trials involve larger cohorts and are designed to compare the new fibrin modulators against established treatments or placebos in terms of efficacy, safety, and long-term outcomes. For instance, the multicenter trial for the efficacy of FS Grifols is an active-controlled study that establishes its superiority or non-inferiority relative to EVICEL® in reducing bleeding time during pediatric surgeries.
- Sponsor Initiated Expanded Access Programs:
Some modulators are undergoing expanded access protocols, whereby patients with specific indications receive the novel fibrin modulator outside of a traditional clinical trial context, often to gather additional safety and efficacy data in broader patient populations.

Current Status and Results
Although many of the trials are ongoing, some preliminary outcomes have provided insights into the potential benefits:
- The FS Grifols studies have shown promising safety profiles in pediatric operations, with endpoints focused on time to hemostasis and reduction in bleeding complications. Early results support its use as an effective adjunct to surgical hemostasis.
- Fibrinogen concentrate trials have reported critical pharmacokinetic data alongside satisfactory safety outcomes, indicating that the use of human fibrinogen can effectively address congenital deficiencies while maintaining balanced coagulation parameters.
- Autologous platelet-rich fibrin therapy trials have demonstrated improved wound healing in chronic non-healing ulcers, with enhanced regeneration metrics and reduced healing times compared to standard dressings.
- In the endovascular arena, fibrin sealant application in EVAR is being evaluated for its ability to reduce postoperative leakage, and although detailed results are pending, the trial design incorporates precise measurements of leak rates and clot stability.
- Trials evaluating fibrin sealant applications in ocular and post-operative settings continue to enroll patients, with endpoints including rates of bleeding, scar formation, and surgical site complications.

The landscape is dynamic, with ongoing studies continuously refining the dosing, formulation, and application techniques based on interim data and evolving patient demographics.

Therapeutic Applications and Implications
The development of fibrin modulators in clinical trials holds potential benefits across several therapeutic areas, taking into account both their clinical efficacy and safety profiles. Their application spans across multiple domains including surgery, emergency medicine, and chronic wound management.

Potential Therapeutic Areas
- Surgical Hemostasis:
Fibrin sealants such as FS Grifols and Tisseel® are primarily designed to be used during surgical procedures to manage bleeding quickly and effectively. Their role is critical in pediatric surgeries, resection surgeries, and even in complex surgeries like those involving the liver, spleen, and pancreas. In vascular interventions, their utility in sealing endovascular repairs highlights their broad applicability.
- Management of Fibrinogen Deficiency:
In patients with congenital or acquired fibrinogen deficiency, the use of human fibrinogen concentrates can be life-saving. These products restore the necessary components for clot formation and are essential in preventing hemorrhagic episodes, especially in surgical or trauma settings.
- Wound Healing and Regenerative Medicine:
Autologous platelet-rich fibrin therapies are emerging as effective modalities for treating chronic wounds and non-healing ulcers. By combining the benefits of autologous growth factors with the scaffold properties of fibrin, these therapies promote accelerated healing and improved tissue regeneration.
- Specialist Indications:
Other specialized applications include the use of fibrin-based products in ophthalmic surgeries (such as eyelid surgery and pterygium treatment) and their potential roles in reducing post-operative air leak after lung surgery.
- Adjunct Therapy in Thromboembolic Conditions:
In conditions where localized clot stability is paramount, such as in cases of embolic stroke, experimental procedures might use fibrin modulators to ensure appropriate clot formation and prevention of hemorrhagic conversion. Although not as widely studied as other applications, these approaches represent an extension of the fibrin modulation concept.

Benefits and Risks
The benefits of using fibrin modulators in clinical practice stem from their natural compatibility with the body’s coagulation system. They have the following advantages:
- Enhanced Hemostasis:
Rapid clot formation and improved sealing of surgical sites reduce bleeding complications and minimize the need for blood transfusions.
- Biocompatibility and Biodegradability:
Products derived from human fibrinogen or autologous blood components display excellent biocompatibility, reducing the risk of adverse immune reactions. Their biodegradability means they are eventually absorbed and replaced by natural healing processes, leading to improved surgical outcomes.
- Customization and Precision:
The formulation techniques allow for modulation of mechanical properties such as tensile strength and adhesion, enabling tailored applications in different clinical scenarios—from fragile pediatric tissues to robust vascular repairs.
- Potential for Regenerative Use:
In wound healing, fibrin modulators can serve not only as hemostatic agents but also as scaffolds that actively promote tissue regeneration, reducing healing times and improving cosmetic and functional outcomes.

However, there are risks and challenges that must be carefully managed:
- Thrombotic Risk:
Overcorrection leading to excessive clot stabilization can result in thrombotic complications. Therefore, proper dosing and monitoring are critical in trials involving fibrinogen concentrates and sealants.
- Immunogenicity:
While products derived from autologous sources minimize immune reactions, those that are allogenic or recombinant may carry a risk of immunogenicity. Clinical trials usually include rigorous safety endpoints to monitor for adverse immune responses.
- Technical Challenges in Application:
The handling properties of fibrin sealants can be variable and are highly dependent on the environment (e.g., wet surfaces in surgery) and application techniques. Ongoing trials aim to optimize these protocols.
- Cost and Accessibility:
Advanced biological products such as human fibrinogen concentrates and autologous platelet-rich preparations can be expensive and may limit widespread adoption if not balanced by clear clinical benefits.

Future Directions
Looking beyond the short-term clinical targets, the field of fibrin modulation faces several challenges that are driving ongoing research and technological innovation.

Challenges in Development
One of the significant challenges lies in the intrinsic variability of fibrin structure and clot formation in different physiological and pathological conditions. Heterogeneity in patient responses, differences in surgical environments, and the interplay with other coagulation factors pose hurdles in creating a one-size-fits-all fibrin modulator. Other challenges include:
- Optimizing Formulation and Delivery:
It is crucial to balance the rapid action of fibrin sealants with the risk of inappropriate thrombosis. Achieving a controlled release of fibrinogen or localized activation in target tissues remains a complex task.
- Standardization of Clinical Endpoints:
Different clinical trials measure efficacy in varied ways—from time to hemostasis to wound healing metrics—creating challenges in comparing results across studies. Regulatory agencies require robust, standardized endpoints to validate therapeutic benefits.
- Manufacturing and Scalability:
The production of high-quality, sterile fibrin-based products requires complex manufacturing processes. Ensuring consistent product quality while scaling up for commercial use is a persistent challenge, particularly for biologically derived products.
- Risk Management and Overcorrection:
The need to fine-tune the balance between clot stabilization and fibrinolysis is paramount, especially in patients at risk of thromboembolic events. Future research must focus on precision medicine approaches that can individualize fibrin modulator doses based on patient-specific coagulation profiles.

Prospective Research and Innovations
Future directions in the field are likely to include:
- Improved Biomaterials:
Research is ongoing to enhance the mechanical properties of fibrin-based materials by combining them with synthetic polymers, such as polyethylene glycols, or by modifying fibrin structures to be more resistant to degradation. These novel biomaterials could provide stronger and more durable hemostatic support while maintaining biocompatibility.
- Personalized Therapeutics:
Advances in pharmacogenomics and real-time monitoring of coagulation parameters may allow for personalized dosing strategies that optimize the efficacy and safety of fibrin modulators. Such precision approaches will be beneficial in tailoring therapy for complex surgical cases or patients with underlying coagulation disorders.
- Dual-functional Agents:
Innovations are exploring the possibility of combining hemostatic and regenerative functions into a single therapeutic agent. For example, integrating growth factors into fibrin matrices could simultaneously stop bleeding and promote tissue repair, thereby reducing the overall treatment time and improving outcomes in wound healing.
- Novel Delivery Mechanisms:
Research into microscale or nanoparticle delivery systems is also underway. These systems could provide more controlled and targeted release of fibrinogen or fibrin sealants at the site of injury, thereby enhancing local efficacy while minimizing systemic side effects.
- Expansion into New Clinical Indications:
While current trials primarily address surgical and trauma-related bleeding as well as congenital fibrinogen deficiencies, the scope of fibrin modulation may extend into areas such as inflammatory diseases, cancer metastasis, and even neurodegenerative disorders where fibrin deposition may play a harmful role. Early studies evaluating fibrin-targeted immunotherapies in neurological conditions hint at the vast potential of this approach.

In summary, the current clinical trial landscape for fibrin modulators encompasses several classes of products, including fibrin sealants, human fibrinogen concentrates, autologous platelet-rich fibrin therapies, and exploratory hemostatic models. Coming from different technological and biological paradigms, these modulators are being studied in phase I/II and phase III trials across diverse surgical and chronic treatment settings. Their mechanisms—ranging from direct sealing and clot stabilization to replacement therapy and regenerative support—reflect the multifactorial role of fibrin in physiology and pathology. The clinical data so far indicate promising results in terms of efficacy and safety while also highlighting certain risks such as potential overcorrection and thrombotic complications.

Looking to the future, several challenges remain, including optimizing formulation, achieving personalized dosing, and fully understanding the long-term outcomes of fibrin modulation. Nonetheless, innovative strategies such as biomaterial integration, advanced delivery systems, and dual-function therapeutics are on the horizon. These advances hold the promise of expanding the therapeutic use of fibrin modulators well beyond current applications, ultimately leading to better surgical outcomes, improved wound healing, and perhaps novel treatments for inflammatory and degenerative diseases.

In conclusion, fibrin modulators in clinical trials today represent a cutting-edge intersection of biomaterials science, hemostasis regulation, and regenerative medicine. The promising clinical trial data from FS Grifols, various human fibrinogen concentrates, and novel fibrin-based therapies such as autologous platelet-rich fibrin demonstrate that these agents can significantly improve patient outcomes when used appropriately. Their mechanisms of action—improving clot stability, enhancing tissue repair, and providing controlled hemostatic support—are being refined through rigorous, multi-phase clinical testing. With further research to address challenges related to formulation, dosing standardization, and long-term safety, fibrin modulation is set to become a cornerstone in therapeutic strategies for diverse medical conditions. The continued collaboration between clinicians, researchers, and industry, grounded in robust clinical trial data from reliable sources like synapse, will be key to realizing the full potential of these innovative therapies.