Fibrinogen Human (DB09222): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Safety Profile

I. Introduction and Executive Summary

Fibrinogen human, also known as Coagulation Factor I, is a high-molecular-weight glycoprotein that represents a cornerstone of hemostasis. Synthesized primarily in the liver, it circulates in plasma as the soluble precursor to fibrin, the essential structural component of a blood clot.[1] As a therapeutic agent, Fibrinogen human is a sophisticated biotech product, classified as a blood factor and hematological agent, derived from large pools of human plasma and subjected to rigorous purification and viral inactivation processes.[3] Its fundamental therapeutic principle is replacement therapy: by supplementing deficient or consumed endogenous fibrinogen, it restores the body's capacity to form a stable fibrin clot and achieve hemostasis.[4]

The primary approved indications for Fibrinogen human have evolved significantly over time. Initially developed as a niche orphan drug for the treatment of acute bleeding episodes in patients with rare congenital fibrinogen deficiencies, such as afibrinogenemia and hypofibrinogenemia, its application has expanded dramatically.[7] Driven by a favorable safety profile compared to traditional blood components and robust clinical trial data, its use is now established for managing acquired fibrinogen deficiency (AFD)—a far more common condition encountered in settings of major trauma, complex surgery, and obstetric hemorrhage.[10]

The clinical utility of Fibrinogen human is defined by a critical benefit-risk balance. Its life-saving potential in controlling severe, otherwise unmanageable bleeding is weighed against two significant safety concerns: the risk of iatrogenic thromboembolic events and the potential for severe hypersensitivity or anaphylactic reactions.[8] The administration of this agent is therefore not a simple replacement but a complex intervention that requires careful patient selection, precise individualized dosing, and diligent clinical and laboratory monitoring to navigate the narrow therapeutic window between hemorrhage and thrombosis.

This monograph provides an exhaustive, expert-level analysis of Fibrinogen human (DrugBank ID: DB09222). It synthesizes the available evidence on its molecular and biochemical characteristics, pharmacodynamic mechanisms, pharmacokinetic profile, clinical efficacy, and safety. By integrating data from basic science, clinical trials, and regulatory documents, this report serves as a definitive, evidence-based resource for clinicians, pharmacologists, and researchers engaged in the study and application of this vital hemostatic therapy.

II. Molecular and Biochemical Profile

A comprehensive understanding of Fibrinogen human begins with its fundamental identity, structure, and physicochemical properties, which directly influence its formulation, handling, and biological function.

Identification and Nomenclature

Fibrinogen human is known by several names and is classified under specific regulatory and chemical identifiers. These designations are crucial for accurate identification in clinical, research, and regulatory contexts. The primary identifiers are the DrugBank Accession Number DB09222 and the Chemical Abstracts Service (CAS) Number 9001-32-5.[1] It is categorized under the Anatomical Therapeutic Chemical (ATC) classification system with the code B02BB01, designating it as a hemostatic agent.[14] Common synonyms include Human fibrinogen, Fibrinogen (human), and Coagulation Factor I.[1]

Physicochemical and Structural Properties

Fibrinogen is a large, soluble plasma glycoprotein with a molecular weight of approximately 340 kDa.[1] Its complex structure is fundamental to its function. The molecule is a hexamer, composed of two identical subunits joined by numerous disulfide bonds. Each subunit consists of three non-identical polypeptide chains designated Aα, Bβ, and γ.[2] These chains are encoded by three separate genes located on chromosome 4.[17]

Structurally, the mature fibrinogen molecule is an elongated, flexible protein array, approximately 45 to 47.5 nm in length.[2] It possesses a distinct tri-nodular arrangement, featuring a central nodule known as the "E domain" and two identical distal nodules known as the "D domains." These domains are interconnected by thin, flexible coiled-coil segments.[15] The central E domain is formed by the N-terminal portions of all six polypeptide chains, while the distal D domains are composed of the C-terminal portions of the Bβ and γ chains.[2]

Commercially, Fibrinogen human is supplied as a sterile, white to light pink, lyophilized (freeze-dried) powder or friable mass that is hygroscopic.[1] It is soluble in sterile water for injection, and upon proper reconstitution, it forms a colorless to faint yellow-light pink solution that is clear to slightly opalescent.[1] The reconstitution process is critical and demands specific handling to preserve the protein's integrity. The lyophilized powder and diluent should be warmed to 37°C, and the vial must be gently swirled—not shaken—to prevent foaming or protein precipitation. Incomplete solubilization or disturbance before the protein is fully dissolved can lead to precipitation, rendering the dose ineffective and potentially harmful.[18] This delicate nature underscores that its physical properties are not merely academic details but have direct implications for clinical efficacy and safety at the bedside.

Biological Source and Quality Attributes

The therapeutic Fibrinogen human products currently on the market are predominantly derived from pooled human plasma sourced from screened donors.[3] This sourcing method carries a theoretical, albeit significantly minimized, risk of transmitting blood-borne pathogens, a factor that has driven research into alternative production methods. Recombinant human fibrinogen, expressed in the milk of transgenic animals or in mammalian cell cultures (e.g., CHO cells), represents a promising future direction to circumvent the risks associated with plasma-derived products, though these are not yet in widespread commercial use.[21] The divergence between the established plasma-derived products and emerging recombinant technologies marks a critical axis of development in this therapeutic area, aimed at enhancing product safety.

A key quality attribute and measure of potency for any fibrinogen concentrate is the percentage of clottable protein. This metric ensures that the majority of the protein in the final product is functionally active and capable of participating in the coagulation cascade. Commercial preparations, such as those sold by Calbiochem or Merck, specify a high percentage of clottable protein, typically greater than 90% or 95%, which is a testament to manufacturing processes designed to maintain the protein's native conformation and biological activity.[14]

Table 1: Product Identification Summary

Attribute	Value	Source(s)
DrugBank ID	DB09222	5
CAS Number	9001-32-5	1
Synonyms	Fibrinogen (human), Human fibrinogen, Coagulation Factor I	4
Molecular Weight	~340 kDa	1
Molecular Structure	Glycoprotein hexamer; two identical subunits, each comprising three polypeptide chains (Aα, Bβ, and γ) linked by disulfide bonds. Tri-nodular structure with one central E domain and two distal D domains.	15
Drug Class	Biotech, Blood and Blood Forming Organs, Hematological Agent, Miscellaneous Coagulation Modifiers	4
ATC Code	B02BB01	14
Physical Form	Lyophilized, hygroscopic, white to light pink powder or friable mass.	1

III. Mechanism of Action and Pharmacodynamics

The pharmacodynamic effects of Fibrinogen human are centered on its indispensable role in the final stage of blood coagulation, but its biological activities extend to the regulation of hemostasis, platelet function, wound healing, and even pathological processes like inflammation.

The Coagulation Cascade and Conversion to Fibrin

Fibrinogen functions as the terminal substrate in the common pathway of the coagulation cascade.[2] Its conversion from a soluble plasma protein into an insoluble fibrin polymer is the ultimate step in forming a stable blood clot.[18] This transformation is catalyzed by thrombin (activated Factor II), a highly specific serine protease.[4] Thrombin acts on fibrinogen by proteolytically cleaving small peptides, known as fibrinopeptide A (FpA) and fibrinopeptide B (FpB), from the N-terminal ends of the Aα and Bβ chains, respectively.[2] The removal of these negatively charged fibrinopeptides exposes critical polymerization sites, known as "EA" sites, on the resulting fibrin monomer.[16]

Fibrin Polymerization and Clot Stabilization

Once formed, fibrin monomers spontaneously self-assemble in a structured manner. They polymerize end-to-end to form double-stranded protofibrils, which then aggregate laterally to create thicker, insoluble fibrin fibers.[16] This process results in a three-dimensional meshwork that entraps platelets and red blood cells, forming the structural backbone of the clot.

The initial fibrin network, held together by non-covalent forces, is then covalently stabilized by activated Factor XIII (FXIIIa).[5] FXIIIa, a transglutaminase that is also activated by thrombin, catalyzes the formation of strong ε-(γ-glutamyl)lysine isopeptide bonds between adjacent fibrin molecules.[16] This cross-linking process dramatically increases the mechanical strength, elasticity, and resistance of the clot to premature degradation by fibrinolytic enzymes, ensuring a durable hemostatic seal.[5]

Pleiotropic and Regulatory Functions

Beyond its structural role, fibrinogen and its derivative, fibrin, are active biological molecules with diverse functions.

• Platelet Aggregation: Fibrinogen is essential for primary hemostasis, acting as a molecular bridge that connects adjacent platelets. It binds to the GpIIb/IIIa integrin receptor on the surface of activated platelets, facilitating their aggregation and the formation of the primary platelet plug.[2]
• Wound Healing and Angiogenesis: The fibrin clot is not merely a passive plug but serves as a provisional extracellular matrix. It provides a scaffold that promotes the migration and proliferation of endothelial cells, fibroblasts, and other cells involved in tissue repair, angiogenesis, and revascularization, thereby actively contributing to the wound healing process.[2]
• Regulatory Feedback Loops: The fibrinogen-fibrin system incorporates sophisticated self-regulating mechanisms. The fibrin clot itself possesses low-affinity binding sites for thrombin, effectively sequestering the enzyme and limiting its activity. This function, known as "antithrombin I" activity, provides a negative feedback loop that prevents runaway coagulation.[2] Furthermore, fibrin modulates its own dissolution by enhancing the activation of plasminogen to plasmin by tissue plasminogen activator (tPA), thereby linking coagulation to the fibrinolytic system.[2] This demonstrates that administering fibrinogen is not simply adding a structural component but is an intervention in a finely tuned, dynamic homeostatic system.
• Inflammation and Neuropathology: Fibrinogen is a positive acute-phase protein, meaning its plasma concentration increases in response to systemic inflammation and tissue injury.[2] While beneficial systemically, its presence in normally protected compartments like the central nervous system (CNS) can be pathological. Following disruption of the blood-brain barrier (BBB), extravasated fibrinogen can deposit in the brain parenchyma. There, it acts as a potent signaling molecule, binding to the CD11b/CD18 integrin receptor (Mac-1) on microglia and macrophages, triggering a pro-inflammatory cascade.[26] This activation leads to neuroinflammation, axonal damage, induction of glial scar formation, and inhibition of remyelination. This pathological role implicates fibrinogen as a key molecular mediator in the progression of neurological diseases such as multiple sclerosis, Alzheimer's disease, and traumatic brain injury.[26] This dual identity—a vital hemostatic agent in the vasculature but a damaging inflammatory trigger in the CNS—presents a complex clinical consideration. The therapeutic use of systemic fibrinogen in a patient with a compromised BBB, such as in a polytrauma case with concurrent head injury, requires a careful weighing of the life-saving hemostatic benefits against the potential for exacerbating CNS injury. This also illuminates a novel therapeutic horizon: targeting the pathological fibrinogen-microglia interaction as a strategy for treating neuroinflammatory diseases.

IV. Pharmacokinetic Profile

The pharmacokinetic (PK) properties of Fibrinogen human, including its absorption, distribution, metabolism, and elimination, are essential for determining appropriate dosing regimens. Significant differences in PK parameters exist between commercially available products and across different patient populations, particularly between adults and children.

Route of Administration and Absorption

For systemic hemostasis, Fibrinogen human is administered exclusively by intravenous (IV) injection or infusion.[20] As a large protein therapeutic with a molecular weight of 340 kDa, it has negligible oral bioavailability and requires parenteral administration to enter the systemic circulation.[5] Following IV administration, it is immediately available in the plasma to participate in the coagulation process. Topical formulations, which combine fibrinogen and thrombin into a fibrin sealant, are also used for local hemostasis during surgery; these are not expected to result in significant systemic absorption.[24]

Distribution

The volume of distribution (Vd) of Fibrinogen human is relatively small, indicating that the drug is primarily confined to the intravascular compartment, consistent with its function as a plasma protein. However, there are notable differences between brands and age groups.

• RiaSTAP: The reported Vd is between 45 and 60 mL/kg.[27]
• Fibryga: This product exhibits a slightly larger Vd, reported as 70.2 mL/kg in adults and adolescents, 67.2 mL/kg in children aged 6 to <12 years, and 68.6 mL/kg in children <6 years.[27]

Metabolism and Elimination

As an endogenous protein, exogenous Fibrinogen human is presumed to be catabolized through the same physiological pathways as the body's own fibrinogen.[19] The elimination half-life is long, with a normal biological half-life of approximately 3 to 4 days.[2] This long half-life means that in the absence of ongoing consumption (e.g., active bleeding or disseminated intravascular coagulation), repeated dosing is not usually required daily.

The specific PK parameters again show variation by product and age:

• Half-Life (t1/2​):
• RiaSTAP: Ranges from 61 to 97 hours in adults. The half-life is shorter in pediatric patients, reported as approximately 69.9 hours in children <16 years of age.[8]
• Fibryga: Demonstrates a clear age-dependent decrease in half-life. It is 75.9 hours in adults and adolescents, 66.1 hours in children aged 6 to <12 years, and 56.9 hours in children <6 years.[27]
• Clearance:
• Fibryga: Clearance is faster in the youngest pediatric patients, consistent with the shorter half-life. The clearance rate is 0.7 mL/hr/kg in adults and older children but increases to 0.9 mL/hr/kg in children <6 years.[27]

These pharmacokinetic differences, particularly the faster clearance and shorter half-life in young children, are not merely academic observations. They form the direct physiological basis for the development of age-specific dosing formulas. Clinicians cannot simply scale adult doses by weight for pediatric patients; doing so would risk significant underdosing and therapeutic failure. This underscores the principle that children are not "little adults" in terms of drug metabolism and elimination, a critical concept for safe and effective therapy.

Peak Plasma Concentrations and Exposure

Following a standard dose of 70 mg/kg, the peak plasma concentration (Cmax) achieved varies by product and age, reflecting the differences in Vd and clearance.

• Cmax:
• RiaSTAP: Approximately 140 mg/dL.[27]
• Fibryga: 139 mg/dL in adults/adolescents, 112.4 mg/dL in children 6 to <12 years, and 99 mg/dL in children <6 years.[27]
• Area Under the Curve (AUC):
• The AUC, a measure of total drug exposure, is correspondingly lower in younger children for a given weight-based dose of Fibryga, further confirming their higher clearance rate.[27]

The subtle but consistent pharmacokinetic differences between brands like RiaSTAP and Fibryga, such as the variance in Vd, have direct clinical consequences. These differences are reflected in the distinct, product-specific divisors used in their respective dosing formulas (e.g., 1.7 for RiaSTAP vs. 1.8 for Fibryga in adults).[27] This implies that the products are not bioequivalent and cannot be used interchangeably without adjusting the dosing calculation, a critical detail for institutional formularies and clinical practice.

Table 2: Comparative Pharmacokinetic Parameters: RiaSTAP vs. Fibryga in Adult and Pediatric Populations

Pharmacokinetic Parameter	RiaSTAP	Fibryga	Source(s)
Peak Plasma Conc. (Cmax)	Adults: ~140 mg/dL (at 70 mg/kg)	Adults/Adolescents: 139 mg/dL Children (6 to <12y): 112.4 mg/dL Children (<6y): 99 mg/dL	27
Volume of Distribution (Vd)	Adults: 45-60 mL/kg	Adults/Adolescents: 70.2 mL/kg Children (6 to <12y): 67.2 mL/kg Children (<6y): 68.6 mL/kg	27
Elimination Half-Life (t1/2​)	Adults: 61-97 hr Children (<16y): ~69.9 hr	Adults/Adolescents: 75.9 hr Children (6 to <12y): 66.1 hr Children (<6y): 56.9 hr	8
Clearance	Not specified	Adults/Adolescents: 0.7 mL/hr/kg Children (6 to <12y): 0.7 mL/hr/kg Children (<6y): 0.9 mL/hr/kg	27

V. Clinical Efficacy and Therapeutic Indications

The clinical application of Fibrinogen human has undergone a significant paradigm shift, evolving from a niche therapy for rare congenital disorders to a vital component of mainstream critical care and surgical hemostasis.

Approved Indications

• Congenital Fibrinogen Deficiency: This is the foundational indication for fibrinogen concentrates. Products like RiaSTAP and Fibryga are approved for the treatment of acute bleeding episodes in both adult and pediatric patients with inherited quantitative fibrinogen deficiencies, namely afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (low levels of fibrinogen).[5] It is crucial to note that these products are explicitly not indicated for dysfibrinogenemia, which is a qualitative disorder characterized by dysfunctional fibrinogen protein rather than a lack of it.[8] This distinction is critical for appropriate use; administering fibrinogen concentrate in dysfibrinogenemia fails to correct the underlying functional defect and is therefore ineffective.
• Acquired Fibrinogen Deficiency (AFD): This represents a major expansion in the therapeutic landscape. AFD is a far more common condition where fibrinogen levels become critically low due to consumption or dilution during massive hemorrhage. Fibrinogen concentrates are now indicated for fibrinogen supplementation in bleeding patients with AFD, a scenario frequently encountered in major surgery (especially cardiac and abdominal), severe trauma, and postpartum hemorrhage.[5] This evolution positions fibrinogen concentrate as a direct and often superior alternative to traditional blood components like fresh frozen plasma (FFP) and cryoprecipitate.
• Adjunctive Surgical Hemostasis: In addition to systemic administration, fibrinogen is a key component of topical fibrin sealants (e.g., Evicel, VeraSeal). These products, which combine Fibrinogen human with Human thrombin, are applied directly to bleeding surfaces during surgery as an adjunct to standard hemostatic techniques like suture, ligature, or cautery, particularly for controlling oozing from capillaries and small venules.[5]

Clinical Trial Evidence and Efficacy

The efficacy of Fibrinogen human is supported by a growing body of clinical evidence from trials across its various indications.

• Surgical Hemostasis: A Phase 2/3 clinical trial (NCT01174992) demonstrated the safety and effectiveness of a fibrin sealant (Evicel) as an adjunct for achieving hemostasis during dural repair surgery, highlighting its utility in specialized surgical applications.[33]
• Optimizing Use: A completed Phase 4 trial (NCT01955811) was designed to compare the efficacy of fibrinogen concentrate against platelet transfusion in improving blood clotting, reflecting ongoing efforts to refine its precise role within broader transfusion algorithms.[34]
• Acquired Fibrinogen Deficiency (AdFIrst and FIBRES Trials): The approval for AFD was largely driven by pivotal Phase 3 trials. The AdFIrst trial showed that Grifols' fibrinogen concentrate (BT524) was non-inferior to the standard of care (cryoprecipitate or FFP) in controlling intraoperative bleeding during major abdominal or spinal surgery.[35] Similarly, the FIBRES study compared Fibryga to cryoprecipitate in patients with AFD after cardiac surgery.[36] Beyond demonstrating non-inferior efficacy in hemostasis, these trials revealed a powerful secondary finding: the incidence of thromboembolic events (TEEs) was statistically significantly lower in the patients receiving fibrinogen concentrate compared to those receiving cryoprecipitate.[35] This suggests that fibrinogen concentrate is not just an equivalent alternative but may offer a superior safety profile. This safety advantage, coupled with logistical benefits like rapid reconstitution, standardized dosing, and viral safety, provides a compelling rationale for shifting the standard of care away from cryoprecipitate towards purified fibrinogen concentrates for the management of AFD.
• Obstetric Hemorrhage: While large randomized trials are less common, extensive clinical experience and evolving guidelines support the early administration of fibrinogen concentrate in managing massive obstetric hemorrhage. The use of point-of-care viscoelastic testing to guide therapy in this setting is becoming increasingly standard.[37]

VI. Dosage, Administration, and Clinical Monitoring

The safe and effective use of Fibrinogen human is critically dependent on correct preparation, administration, individualized dosing, and diligent therapeutic monitoring. The protocols are highly specific and vary by product, indication, and patient population.

Reconstitution and Handling

Fibrinogen human is supplied as a lyophilized powder and must be reconstituted prior to IV administration. This process requires meticulous attention to detail to ensure the protein's stability and efficacy.

• Procedure: A specific volume of a suitable diluent, typically sterile water for injection (e.g., 50 mL for a 1-gram vial), is used for reconstitution.[20]
• Critical Handling Steps: To prevent protein denaturation and precipitation, the vial should not be shaken. Instead, it should be gently swirled until the powder is completely dissolved.[20] The product and diluent should be brought to room temperature (or up to 37°C) before mixing to facilitate dissolution.[18]
• Visual Inspection: Before administration, the reconstituted solution must be visually inspected. It should be colorless and clear to slightly opalescent. If the solution is cloudy or contains visible particulate matter, it must be discarded.[8]

Administration Guidelines

• Route and Equipment: Fibrinogen human is for intravenous (IV) use only. It must be administered through a separate, dedicated infusion line and should never be mixed with other medicinal products or intravenous solutions.[8] Aseptic technique is required throughout the process.[38]
• Infusion Rate: The rate of administration is a critical safety parameter to minimize the risk of adverse events. The maximum recommended rate varies by product and indication:
• RiaSTAP (Congenital Deficiency): Not to exceed 5 mL per minute.[8]
• Fibryga (Congenital Deficiency): Not to exceed 5 mL per minute.[10]
• Fibryga (Acquired Deficiency): A faster rate of up to 20 mL per minute is permitted.[27]

Dosing Strategies and Calculations

Dosing must be highly individualized, taking into account the patient's body weight, the clinical severity of bleeding, and, most importantly, baseline and target fibrinogen levels.

• Dose When Fibrinogen Level is Unknown: In emergency situations where laboratory results are unavailable, a standard empirical dose of 70 mg/kg of body weight is recommended for both adults and children.[8]
• Dose When Fibrinogen Level is Known: When baseline fibrinogen levels can be measured, a more precise dose can be calculated using a formula. It is critically important to use the correct, product-specific formula, as the in-vivo recovery differs between brands.
• RiaSTAP (Adults & Pediatrics): Dose(mg/kg)=1.7​ 8
• Fibryga (Adults & Adolescents ≥12 years): Dose(mg/kg)=1.8​ 10
• Fibryga (Children <12 years): Dose(mg/kg)=1.4​ 10

The different denominators in these formulas (1.7, 1.8, and 1.4) are derived from brand- and age-specific pharmacokinetic studies and reflect differences in in-vivo recovery. Using the wrong formula for a given product will result in inaccurate dosing, potentially leading to therapeutic failure or an increased risk of thrombosis. This underscores that the products are not interchangeable on a formulaic basis.

Therapeutic Monitoring and Target Levels

Continuous monitoring is essential to guide therapy and maintain fibrinogen levels within the therapeutic window.

• Monitoring Methods: Therapy should be guided by regular measurement of plasma fibrinogen levels (using the Clauss assay) and/or by point-of-care viscoelastic tests (VETs) such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM).[8] The increasing use of VETs represents a shift towards a more functional, goal-directed approach to hemostasis, as these tests assess the overall clot strength (e.g., FIBTEM Maximum Clot Firmness) rather than just the concentration of a single factor.[3]
• Target Levels: The target fibrinogen level depends on the clinical situation:
• Minor Bleeding/General Hemostasis: A target level of 100 mg/dL should be achieved and maintained until hemostasis is secure.[8]
• Major Bleeding: A higher target of 150 mg/dL is recommended.[10]
• Acquired Fibrinogen Deficiency: Repeat doses may be triggered if plasma levels are ≤200 mg/dL or if the ROTEM FIBTEM A10 value is ≤10 mm.[10]
• Maintenance: Once hemostasis is achieved, fibrinogen levels should be maintained above a minimum threshold (e.g., 80 mg/dL for minor bleeding, 130 mg/dL for major bleeding) with additional infusions as needed.[10]

Table 3: Dosing Regimens for Congenital and Acquired Fibrinogen Deficiency

Patient Population / Indication	Brand	Dose if Level Unknown	Dosing Formula if Level Known (mg/kg)	Target Fibrinogen Level	Max Infusion Rate
Congenital Deficiency (Adult & Pediatric)	RiaSTAP	70 mg/kg	1.7​	100 mg/dL	5 mL/min
Congenital Deficiency (Adults & Adol. ≥12y)	Fibryga	70 mg/kg	1.8​	Minor: 100 mg/dL Major: 150 mg/dL	5 mL/min
Congenital Deficiency (Children <12y)	Fibryga	70 mg/kg	1.4​	Minor: 100 mg/dL Major: 150 mg/dL	5 mL/min
Acquired Deficiency (AFD) (Adults)	Fibryga	4 g (total dose)	Dose adjusted by lab values	≤200 mg/dL or FIBTEM A10 ≤10 mm	20 mL/min
Acquired Deficiency (AFD) (Adol. ≥12y)	Fibryga	50 mg/kg	Dose adjusted by lab values	≤200 mg/dL or FIBTEM A10 ≤10 mm	20 mL/min
Acquired Deficiency (AFD) (Children <12y)	Fibryga	70 mg/kg	Dose adjusted by lab values	≤200 mg/dL or FIBTEM A10 ≤10 mm	20 mL/min

VII. Safety, Tolerability, and Risk Management

While Fibrinogen human is a highly effective hemostatic agent, its use is associated with significant safety considerations. The therapeutic challenge lies in balancing the urgent need to control hemorrhage against the potential for serious adverse reactions, primarily thrombosis and hypersensitivity.

Adverse Reactions Profile

The profile of adverse reactions varies depending on the patient population and the underlying indication.

• Most Serious Adverse Reactions: Across all products and indications, the most critical risks are thromboembolic episodes (including myocardial infarction, pulmonary embolism, deep vein thrombosis, and arterial thrombosis) and severe allergic-anaphylactic reactions.[8]
• Common Adverse Reactions:
• For RiaSTAP in congenital deficiency, the most common adverse reactions (frequency >1%) are relatively mild: fever and headache.[8]
• For Fibryga in congenital deficiency, the most common events (frequency >5%) include nausea, vomiting, pyrexia (fever), and thrombocytosis (elevated platelet count).[10]
• For Fibryga in acquired fibrinogen deficiency (AFD), the most common adverse reactions (frequency >5%) reflect the severity of the underlying patient condition and include abnormal hepatic function, acute kidney injury, anemia, atrial fibrillation, delirium, and renal failure.[10]
• Other Reported Events: A wide range of other adverse events have been reported, though their frequency is often not well-defined. These include chills, dyspnea (shortness of breath), rash, nausea, vomiting, dizziness, anxiety, and various signs and symptoms related to thrombosis (e.g., chest pain, limb swelling) or hypersensitivity (e.g., hives, angioedema).[12]

A crucial point of interpretation arises when comparing the adverse event profiles. The severe events like renal failure and atrial fibrillation reported commonly in the AFD population are more likely manifestations of the patients' critical illness (e.g., complications from major cardiac surgery) rather than direct drug toxicity. This contrasts with the milder profile seen in the more stable congenital deficiency population. This distinction is vital for a fair assessment of the drug's intrinsic safety profile.

Detailed Risk Analysis

• Thrombosis: This represents the most significant on-target toxicity. Patients with congenital fibrinogen deficiency have a baseline risk of thrombosis, which can be exacerbated by replacement therapy.[8] The risk of thromboembolic events is a primary warning for all fibrinogen concentrate products and requires a careful benefit-risk assessment in every patient, especially those with pre-existing cardiovascular disease, liver disease, or other prothrombotic risk factors.[29] The risk may be dose-dependent, potentially increasing when targeting higher plasma fibrinogen levels (e.g., 150 mg/dL for major bleeding).[10] This creates a delicate therapeutic balance: underdosing risks continued hemorrhage, while overdosing risks life-threatening thrombosis. This narrow margin for error reinforces the absolute necessity of individualized, goal-directed therapy with diligent monitoring.
• Hypersensitivity Reactions: As with any protein-based therapeutic derived from human plasma, there is a risk of allergic-type reactions. These can range in severity from mild skin reactions (e.g., hives, rash) to severe, life-threatening anaphylaxis characterized by bronchospasm, hypotension, and angioedema.[13]
• Transmissible Infectious Agents: Fibrinogen concentrates are manufactured from pooled human plasma. Although rigorous measures are in place—including careful donor screening, testing of plasma for viral markers, and multiple dedicated viral inactivation and removal steps (e.g., S/D treatment, pasteurization, nanofiltration)—a theoretical risk of transmitting infectious agents remains.[8] This includes known viruses (e.g., Hepatitis B and C, HIV, Parvovirus B19) and, theoretically, prions such as the agent causing Creutzfeldt-Jakob disease (CJD).[12] Patients should be informed of this remote risk.

Management of Adverse Reactions

• Hypersensitivity: Clinicians must be vigilant for early signs of hypersensitivity. If a reaction is suspected (e.g., rash, hives, wheezing, chest tightness, hypotension), the infusion must be stopped immediately. The subsequent management depends on the nature and severity of the reaction and follows standard clinical protocols, which may include antihistamines, corticosteroids, and, for anaphylaxis, epinephrine.[3]
• Thrombosis: Patients receiving Fibrinogen human must be closely monitored for clinical signs and symptoms of thrombosis, such as unexplained chest pain or dyspnea (suggesting pulmonary embolism), leg pain, swelling, or redness (suggesting DVT), or sudden neurological deficits (suggesting stroke).[13] If a thrombotic event is suspected, the product should be discontinued, and appropriate diagnostic imaging and anticoagulant therapy should be initiated promptly.

Table 4: Summary of Adverse Reactions by Frequency and System Organ Class

System Organ Class	Adverse Reaction	Frequency / Reported In	Source(s)
Cardiovascular	Thromboembolic Events (MI, PE, DVT, Arterial Thrombosis)	Most Serious Risk (All Products)	36
	Atrial Fibrillation	Common (>5%) in AFD (Fibryga)	10
General Disorders	Pyrexia (Fever)	Common (>1% RiaSTAP; >5% Fibryga-Congenital)	10
	Headache	Common (>1%) in RiaSTAP	40
	Chills, Nausea, Vomiting	Common (>5%) in Fibryga-Congenital; Also reported for RiaSTAP	10
Immune System	Allergic/Anaphylactic Reactions	Most Serious Risk (All Products)	36
	Hypersensitivity (Hives, Rash, Urticaria)	Incidence Not Defined	13
Blood & Lymphatic	Thrombocytosis	Common (>5%) in Fibryga-Congenital	10
	Anemia	Common (>5%) in AFD (Fibryga)	10
Renal & Urinary	Acute Kidney Injury, Renal Failure	Common (>5%) in AFD (Fibryga)	10
Nervous System	Delirium	Common (>5%) in AFD (Fibryga)	10
Hepatobiliary	Abnormal Hepatic Function	Common (>5%) in AFD (Fibryga)	10

VIII. Contraindications, Warnings, and Drug Interactions

The safe use of Fibrinogen human requires a thorough understanding of situations where its use is inappropriate, specific warnings that necessitate caution, and potential interactions with other medications.

Contraindications

• Absolute Contraindication: The primary contraindication for all Fibrinogen human products is a history of known anaphylactic or severe systemic hypersensitivity reactions to the active substance (human fibrinogen), to any of the excipients in the formulation, or to human plasma-derived products in general.[20]
• Topical Formulation Contraindications: Formulations intended for topical use as fibrin sealants have specific contraindications. They must never be applied intravascularly, as this can lead to severe, life-threatening thromboembolic complications and disseminated intravascular coagulation (DIC).[3] Furthermore, spray application of these sealants is contraindicated in endoscopic or laparoscopic procedures due to the risk of potentially fatal air or gas embolism.[46] They are also not intended for the treatment of severe or brisk arterial bleeding.[46]

Warnings and Precautions

• Thrombosis Risk: This is the most significant warning associated with fibrinogen replacement. Thromboembolic events may occur, and the benefit of administration must be carefully weighed against this risk in every patient. Caution is particularly warranted in individuals with a history of coronary artery disease, myocardial infarction, liver disease, or a prior stroke or blood clot, as well as in peri-operative and neonatal patients.[8]
• Inappropriate Use in Dysfibrinogenemia: A critical warning is that Fibrinogen human concentrate is not indicated for the treatment of dysfibrinogenemia.[8] This condition is a qualitative defect where fibrinogen protein is present but functions abnormally. Administering additional functional fibrinogen does not correct the underlying polymerization defect and is therefore ineffective and inappropriate. This distinction highlights the necessity for precise hematological diagnosis beyond a simple fibrinogen level measurement.
• Risk of Transmissible Agents: Although manufacturing processes include rigorous viral inactivation and removal steps, the products are derived from human plasma and thus carry a remote, theoretical risk of transmitting infectious agents. This risk should be discussed with patients.[8]
• Hypersensitivity Reactions: Clinicians must be prepared to recognize and manage allergic reactions, which can range from mild urticaria to severe anaphylaxis. The infusion should be discontinued immediately if a reaction occurs.[20]
• Use in Specific Populations:
• Pregnancy and Lactation: Formal reproductive studies have not been conducted. While clinical experience, particularly in obstetrics, has not suggested harmful effects, the decision to use Fibrinogen human during pregnancy or breastfeeding should be based on a careful assessment of the mother's clinical need versus any potential risks.[7]
• Geriatric Use: There is insufficient data to determine if geriatric patients respond differently than younger adults.[7]

Drug-Drug Interactions

The interaction profile of Fibrinogen human is primarily pharmacodynamic, based on its pro-coagulant mechanism. Formal pharmacokinetic interaction studies are largely absent.

• Pro-thrombotic Interactions (Increased Risk):
• Antifibrinolytic Agents: Drugs like aminocaproic acid and tranexamic acid inhibit fibrinolysis (clot breakdown). When used concomitantly with Fibrinogen human, they can create a potent pro-thrombotic state. While this combination can be therapeutically beneficial for controlling severe bleeding, it significantly increases the risk of thrombosis and requires careful monitoring.[5]
• Prothrombin Complex Concentrates (PCCs): These products also promote coagulation and may have an additive or synergistic effect on thrombotic risk when co-administered with fibrinogen.[25]
• Anti-thrombotic Interactions (Decreased Efficacy):
• Anticoagulants and Antiplatelet Drugs: The therapeutic effect of Fibrinogen human can be diminished by drugs that inhibit the coagulation cascade or platelet function. This includes direct oral anticoagulants (e.g., apixaban), heparins, direct thrombin inhibitors (e.g., argatroban, bivalirudin), and thrombolytics (e.g., alteplase).[5] In a patient actively receiving these medications, the efficacy of fibrinogen replacement will be blunted.
• Other Interactions:
• The overall data on specific drug-drug interactions is limited, with some databases listing few to no formal interactions.[12] This does not imply an absence of interactions but rather a lack of formal study. Clinicians must therefore rely on an understanding of pharmacodynamic principles to anticipate potential interactions.
• Topical fibrin sealant preparations can be denatured by exposure to antiseptic solutions containing alcohol, iodine, or heavy metals. The application site should be as free of these substances as possible before use.[46]

IX. Manufacturing and Regulatory History

The journey of Fibrinogen human from a laboratory curiosity to a regulated therapeutic product spans over a century, marked by advancements in protein purification, pathogen safety, and clinical evidence that have shaped its regulatory landscape in major markets.

Manufacturing and Sourcing

Modern fibrinogen concentrates are high-purity products derived from human plasma through a sophisticated, multi-step manufacturing process designed to maximize potency and safety.

• Source Material: The process begins with large pools of human plasma, typically starting with an enriched fraction like cryoprecipitate or Cohn Fraction I, which contains a high concentration of fibrinogen.[3]
• Purification: A series of biochemical steps are used to isolate fibrinogen and remove other plasma proteins and impurities. These methods include selective precipitation using agents like glycine, ethanol, or ammonium sulfate, followed by advanced chromatographic techniques such as ion exchange chromatography to achieve a high degree of purity.[15]
• Pathogen Safety: Ensuring the viral safety of a plasma-derived product is paramount. The manufacturing process incorporates multiple, redundant steps for viral inactivation and removal. These include:

1. Solvent/Detergent (S/D) Treatment: This chemical process effectively disrupts the lipid envelope of viruses like HIV, HBV, and HCV, rendering them inactive.[23]
2. Pasteurization: A heat treatment step that further inactivates viruses.[6]
3. Nanofiltration: A physical filtration step that removes viruses based on their size, providing an additional layer of safety, particularly for non-enveloped viruses.[23]

• Final Formulation: The highly purified fibrinogen is then formulated with stabilizers such as L-arginine, glycine, and sodium citrate to maintain its integrity. It is then lyophilized (freeze-dried) into a stable powder, filled into sterile vials, and sealed for distribution.[18]

Regulatory History and Approvals

The regulatory history of fibrinogen concentrate reveals a gradual evolution, driven by increasing safety standards and expanding clinical evidence.

• Early Development: The production of human fibrinogen concentrate began in the 1950s by Behringwerke. The first therapeutic license was granted in Brazil in 1963, followed by the first approval in the European Union (by Germany's Federal Ministry of Health) on January 4, 1966.[37]
• United States (FDA): The entry into the US market was significantly later, reflecting a different regulatory environment.
• RiaSTAP (CSL Behring): Was first approved by the FDA on January 16, 2009. It was granted orphan drug status for the treatment of acute bleeding in congenital fibrinogen deficiency.[9]
• Fibryga (Octapharma): Initially approved in 2017 for congenital deficiency. Its indications were expanded to include pediatric patients in 2020. A landmark approval was granted in January 2024 for the treatment of Acquired Fibrinogen Deficiency (AFD), making it the first and only fibrinogen concentrate with this broad indication in the US.[11]
• European Union (EMA and National Agencies): Fibrinogen concentrates have been available in various European countries for decades under different brand names.
• Haemocomplettan P (CSL Behring): This product, identical to RiaSTAP, has been licensed in numerous European countries since the 1980s and 1990s.[6]
• Fibryga (Octapharma): Received approval for use in AFD across 15 European countries in 2019, five years ahead of its US approval for the same indication. This was based on the results of the FORMA-05 study.[11]
• Fibrin Sealants: Combination products like VeraSeal have been authorized by the EMA for topical use since November 2017, with ongoing safety reviews related to their method of application.[32]

This history, particularly the multi-year lag between European and US approvals for the AFD indication, highlights different regulatory philosophies and evidence requirements. It demonstrates a product development trajectory from a rare orphan disease therapy to a broad critical care agent, a path paved by advancements in manufacturing safety and the execution of large-scale clinical trials that proved its value against the older standard of care.

Commercial Brand Names

A variety of Fibrinogen human products are available globally, formulated for either systemic (intravenous) or topical use.

• Systemic (IV) Formulations:
• RiaSTAP (CSL Behring) [58]
• Fibryga (Octapharma) [58]
• Haemocomplettan P (CSL Behring - brand name for RiaSTAP outside the US) [6]
• FibClot (LFB) [52]
• Topical/Sealant Formulations (in combination with thrombin):
• Evicel [4]
• TachoSil [59]
• Evarrest [59]
• Raplixa [59]
• Tisseel [5]
• VeraSeal [5]
• Vistaseal [5]

Table 5: Regulatory Approval Timelines (FDA & EMA) for Key Commercial Products

Product (Brand Name)	Company	Regulatory Agency	Indication	Approval/Expansion Date	Source(s)
RiaSTAP	CSL Behring	FDA (USA)	Congenital Fibrinogen Deficiency	January 16, 2009	9
Haemocomplettan P	CSL Behring	German Federal Ministry of Health (EU)	Congenital & Acquired Deficiency	January 4, 1966 (and later in other EU states)	52
Fibryga	Octapharma	FDA (USA)	Congenital Fibrinogen Deficiency (Adults/Adol.)	2017	11
Fibryga	Octapharma	FDA (USA)	Congenital Fibrinogen Deficiency (Pediatrics)	2020	11
Fibryga	Octapharma	FDA (USA)	Acquired Fibrinogen Deficiency (AFD)	January 2024	11
Fibryga	Octapharma	EMA (Europe)	Acquired Fibrinogen Deficiency (AFD)	2019	11
VeraSeal	Grifols/Instil Bio	EMA (Europe)	Adjunctive Surgical Hemostasis (Fibrin Sealant)	November 10, 2017	32

X. Synthesis and Expert Recommendations

Fibrinogen human has firmly established itself as an indispensable tool in the management of severe hemorrhage. Its evolution from a niche orphan drug to a cornerstone of modern hemostatic resuscitation reflects significant advancements in manufacturing, which have yielded a product with a superior safety and logistical profile compared to traditional blood components. The clinical challenge in its use, however, remains the navigation of a narrow therapeutic window, demanding a sophisticated approach to balance the life-saving benefit of hemorrhage control against the significant iatrogenic risk of thrombosis.

Integrated Benefit-Risk Assessment

The overall benefit-risk profile of Fibrinogen human is strongly positive for its approved indications. In patients with documented hypofibrinogenemia, whether congenital or acquired, the ability to rapidly deliver a standardized, virally-safe dose of functional coagulation factor to control life-threatening bleeding substantially outweighs the associated risks. The key to maintaining this favorable balance lies in strict adherence to clinical guidelines regarding patient selection, individualized dosing, and vigilant monitoring. The risks of thrombosis and hypersensitivity, while serious, are manageable through careful patient assessment and prompt clinical response.

Place in Therapy and Clinical Recommendations

Based on the comprehensive evidence analyzed, the following recommendations are put forth to optimize the clinical use of Fibrinogen human:

1. Position as First-Line Therapy: For patients with significant bleeding and documented hypofibrinogenemia (either congenital or acquired), fibrinogen concentrate should be considered the first-line therapeutic choice over cryoprecipitate. This recommendation is supported by evidence of at least non-inferior efficacy coupled with a potentially superior safety profile (lower risk of thromboembolic events) and clear logistical advantages (standardized dose, rapid availability, viral safety).[3]
2. Adopt a Goal-Directed Therapeutic Approach: The administration of Fibrinogen human should not be empirical. Therapy must be guided by objective measures. This involves using laboratory values (plasma fibrinogen levels via the Clauss assay) and/or point-of-care viscoelastic tests (e.g., ROTEM, TEG) to determine the need for intervention, to calculate an appropriate initial dose, and to titrate subsequent therapy to achieve and maintain specific hemostatic targets.[10]
3. Strict Adherence to Product-Specific Dosing: Clinicians and pharmacists must recognize that different commercial fibrinogen concentrates are not bioequivalent and their dosing formulas are not interchangeable. The correct, product-specific formula must be used for dose calculation to avoid potentially dangerous under- or over-dosing.[10]
4. Maintain High Vigilance for Key Adverse Events: All patients receiving Fibrinogen human must be monitored closely for the two primary risks:

• Thrombosis: Assess for clinical signs and symptoms of venous or arterial thrombosis.
• Hypersensitivity: Be prepared to recognize and immediately manage allergic reactions, including anaphylaxis, by stopping the infusion and initiating appropriate supportive care.

Future Research and Unmet Needs

While Fibrinogen human is a mature therapeutic, several areas warrant further investigation to refine its use and expand its potential:

• Advancement of Recombinant Technologies: The continued development and clinical validation of recombinant human fibrinogen remains a critical research priority. A successful recombinant product would eliminate the theoretical risk of blood-borne pathogen transmission, representing the next major step forward in the safety of this therapy.[21]
• Elucidation of the Role in Neuropathology: The emerging evidence of fibrinogen's detrimental role in the CNS following BBB disruption opens a new field of study. Research is needed to understand the clinical implications of systemic fibrinogen administration in patients with concurrent CNS injury and to explore the potential of targeting the fibrinogen-microglia signaling axis as a novel therapeutic strategy for neuroinflammatory and neurodegenerative diseases.[26]
• Optimization of Use in Acquired Fibrinogen Deficiency: Although its efficacy in AFD is now well-established, further prospective studies are needed to refine its use. Key questions include defining the optimal VET thresholds for initiating therapy, establishing precise target levels for different clinical scenarios (e.g., trauma vs. cardiac surgery vs. obstetrics), and determining the ideal duration of treatment.
• Addressing Dysfibrinogenemia: The development of therapies that can correct the functional protein defects in dysfibrinogenemia, rather than simply increasing the protein concentration, remains a significant unmet need for this patient population.

Works cited

1. CAS 9001-32-5: Fibrinogen - CymitQuimica, accessed August 5, 2025, https://cymitquimica.com/cas/9001-32-5/
2. Fibrinogen - Wikipedia, accessed August 5, 2025, https://en.wikipedia.org/wiki/Fibrinogen
3. Fibrinogen - StatPearls - NCBI Bookshelf, accessed August 5, 2025, https://www.ncbi.nlm.nih.gov/books/NBK537184/
4. Search Results | DrugBank Online, accessed August 5, 2025, https://go.drugbank.com/search?utf8=%E2%9C%93&query=FIBRINOGEN+HUMAN+AND+THROMBIN+HUMAN&search_type=drugs&button=
5. Fibrinogen human: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 5, 2025, https://go.drugbank.com/drugs/DB09222
6. Over 50 Years of Fibrinogen Concentrate - PMC, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4741261/
7. Fibrinogen (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 5, 2025, https://www.mayoclinic.org/drugs-supplements/fibrinogen-intravenous-route/description/drg-20084858
8. RIASTAP®, Fibrinogen Concentrate (Human) Lyophilized Powder for Solution for Intravenous Injection - CSL Behring Global, accessed August 5, 2025, https://labeling.cslbehring.com/pi/us/riastap/en/riastap-prescribing-information.pdf
9. RiaSTAP (Fibrinogen Concentrate (Human)) FDA Approval History - Drugs.com, accessed August 5, 2025, https://www.drugs.com/history/riastap.html
10. FIBRYGA - BLA 125612.178 USPI 06-19-25 CLEAN.docx - FDA, accessed August 5, 2025, https://www.fda.gov/media/105864/download
11. FDA approves fibryga® for acquired fibrinogen deficiency, potentially, accessed August 5, 2025, https://www.octapharma.com/news/press-release/2024/fda-approves-fibryga-for-acquired-fibrinogen-deficiency
12. Fibrinogen: Blood Clotting Uses, Side Effects, Dosage - MedicineNet, accessed August 5, 2025, https://www.medicinenet.com/human_fibrinogen/article.htm
13. Fibrinogen Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 5, 2025, https://www.drugs.com/sfx/fibrinogen-side-effects.html
14. HUMAN FIBRINOGEN | 9001-32-5 - ChemicalBook, accessed August 5, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4683502.htm
15. PURIFICATION OF FIBRINOGEN FROM HUMAN PLASMA - UNL Digital Commons, accessed August 5, 2025, https://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1012&context=chemengtheses
16. The Structure and Biological Features of Fibrinogen and Fibrin - e-Publications@Marquette, accessed August 5, 2025, https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1047&context=biomedsci_fac
17. Assembly and intracellular transport of a multichain protein: human fibrinogen, accessed August 5, 2025, https://www.fao.org/4/x5550e/x5550e0n.htm
18. Fibrinogen, Human Plasma Fibrinogen, CAS 9001-32-5 , is a soluble plasma glycoprotein that is synthesized in the hepatic parenchymal cells. Contains 90 clottable protein. 9001-32-5 - Sigma-Aldrich, accessed August 5, 2025, https://www.sigmaaldrich.com/NO/en/product/mm/341576m
19. Fibryga 1g Powder and solvent for solution for injection / infusion - Summary of Product Characteristics (SmPC) - (emc) | 10315, accessed August 5, 2025, https://www.medicines.org.uk/emc/product/10315/smpc
20. Fibrinogen (Human) Monograph for Professionals - Drugs.com, accessed August 5, 2025, https://www.drugs.com/monograph/fibrinogen-human.html
21. High-level expression and preparation of recombinant human fibrinogen as biopharmaceuticals - PMC, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4892781/
22. CAS 9001-32-5 | Sigma-Aldrich - Merck, accessed August 5, 2025, https://www.merckmillipore.com/AE/en/search/9001-32-5?focus=products&page=1&perpage=30&sort=relevance&term=9001-32-5&type=cas_number
23. US20150045539A1 - Process for production of fibrinogen and fibrinogen produced thereby - Google Patents, accessed August 5, 2025, https://patents.google.com/patent/US20150045539A1/en
24. Human thrombin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 5, 2025, https://go.drugbank.com/drugs/DB11571
25. Fibrinogen interaction with human platelets: effect of other coagulation factors, prostaglandins and platelet inhibitors - PubMed, accessed August 5, 2025, https://pubmed.ncbi.nlm.nih.gov/20217998/
26. Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics - PMC, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6743980/
27. RiaSTAP, Fibryga (fibrinogen, human) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed August 5, 2025, https://reference.medscape.com/drug/riastap-fibryga-fibrinogen-human-345044
28. Utility of an in vitro lymphatics on-chip model for rank ordering subcutaneous absorption of monoclonal antibodies - RSC Publishing, accessed August 5, 2025, https://pubs.rsc.org/en/content/articlehtml/2025/lc/d4lc00988f
29. London, 22 January 2009 EMEA/CHMP/BPWP/122007/2005 COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) GUIDELINE ON CORE SmPC - EMA, accessed August 5, 2025, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-core-smpc-human-fibrinogen-products-emeachmpbpwp1220072005_en.pdf
30. Fibryga® receives European label extension to treat acquired fibrinogen deficiency (AFD), accessed August 5, 2025, https://www.octapharma.com/news/press-release/2019/fibryga-receives-european-label-extension-to-treat-acquired-fibrinogen-deficiency-afd
31. Fibryga® Fibrinogen (Human) | For Healthcare Professionals, accessed August 5, 2025, https://fibrygausa.com/
32. VeraSeal | European Medicines Agency (EMA), accessed August 5, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/veraseal
33. Fibrinogen human Completed Phase 2 / 3 Trials for Dura Defects Prevention - DrugBank, accessed August 5, 2025, https://go.drugbank.com/drugs/DB09222/clinical_trials?conditions=DBCOND0040973&phase=2%2C3&purpose=prevention&status=completed
34. Fibrinogen human Completed Phase 4 Trials for Blood Platelet Transfusion / Blood Coagulation | DrugBank Online, accessed August 5, 2025, https://go.drugbank.com/drugs/DB09222/clinical_trials?conditions=DBCOND0042091%2CDBCOND0066145&phase=4&status=completed
35. Grifols positive fibrinogen phase 3 trial results published in The Lancets eClinicalMedicine, accessed August 5, 2025, https://www.grifols.com/en/view-news/-/news/grifols-positive-fibrinogen-phase-3-trial-results-published-in-the-lancets-eclinicalmedicine
36. Safety Profile | fibryga® Fibrinogen (Human), accessed August 5, 2025, https://fibrygausa.com/safety/
37. Evolution of the use of Therapeutic Fibrinogen Concentrate in the Massive Bleeding Guidelines - The Open Anesthesia Journal, accessed August 5, 2025, https://openanesthesiajournal.com/VOLUME/18/ELOCATOR/e25896458339158/PDF/
38. Dosing & Administration | fibryga® Fibrinogen (Human), accessed August 5, 2025, https://fibrygausa.com/dosing-administration/
39. About RiaSTAP: Dosing and Administration, accessed August 5, 2025, https://www.riastap.com/professional/about-riastap/dosing-and-administration.aspx
40. RiaSTAP Fibrinogen Concentrate (Human), accessed August 5, 2025, https://www.riastap.com/
41. For Congenital Fibrinogen Deficiency (CFD) - Fibryga, accessed August 5, 2025, https://fibrygausa.com/fibryga-for-cfd/
42. Package Insert - RIASTAP - FDA, accessed August 5, 2025, https://www.fda.gov/media/73604/download
43. Fibrinogen Uses, Side Effects & Warnings - Drugs.com, accessed August 5, 2025, https://www.drugs.com/mtm/fibrinogen.html
44. Fibrinogen Concentrate (Human) | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 5, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5975/Fibrinogen-Concentrate-Human
45. Core summary of product characteristics for human fibrinogen products - Scientific guideline, accessed August 5, 2025, https://www.ema.europa.eu/en/core-summary-product-characteristics-human-fibrinogen-products-scientific-guideline
46. Raplixa, INN- Human Fibrinogen, Human thrombin, accessed August 5, 2025, https://ec.europa.eu/health/documents/community-register/2018/20180307140347/anx_140347_en.pdf
47. Fibrinogen Concentrate - LITFL, accessed August 5, 2025, https://litfl.com/fibrinogen-concentrate/
48. Fibrinogen and thrombin, human (topical application route) - Side effects & uses, accessed August 5, 2025, https://www.mayoclinic.org/drugs-supplements/fibrinogen-and-thrombin-human-topical-application-route/description/drg-20146758
49. Fibrinogen concentrate (human): Drug information, accessed August 5, 2025, https://www.uptodateonline.ir/contents/mobipreview.htm?14/20/14659?source=see_link
50. Fibrinogen Interactions Checker - Drugs.com, accessed August 5, 2025, https://www.drugs.com/drug-interactions/fibrinogen.html
51. Fibrinogen, Human: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 5, 2025, https://www.rxlist.com/fibrinogen_human/generic-drug.htm
52. Evolution of the use of Therapeutic Fibrinogen Concentrate in the Massive Bleeding Guidelines - The Open Anesthesia Journal, accessed August 5, 2025, https://openanesthesiajournal.com/VOLUME/18/ELOCATOR/e25896458339158/FULLTEXT/
53. RIASTAP - FDA, accessed August 5, 2025, https://www.fda.gov/media/150426/download
54. CSL Behring Receives FDA Approval of RiaSTAP, First and Only Approved Treatment of Acute Bleeding Episodes in Patients with Congenital Fibrinogen Deficiency - Global Newsroom | CSL, accessed August 5, 2025, https://newsroom.csl.com/2009-01-16-CSL-Behring-Receives-FDA-Approval-of-RiaSTAP,-First-and-Only-Approved-Treatment-of-Acute-Bleeding-Episodes-in-Patients-with-Congenital-Fibrinogen-Deficiency
55. Long-Term Safety Analysis of a Fibrinogen Concentrate (RiaSTAP®/Haemocomplettan® P), accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11135097/
56. Octapharma Group delivered strong growth in both sales and operating income in 2019, accessed August 5, 2025, https://www.octapharmausa.com/news/press-release/2020/octapharma-group-delivered-strong-growth-in-both-sales-and-operating-income-in-2019
57. Human medicines European public assessment report (EPAR): VeraSeal, human fibrinogen,human thrombin, Date of authorisation: 10/11/2017, Revision, accessed August 5, 2025, https://efim.org/node/143944
58. Fibrinogen - FDA, accessed August 5, 2025, https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/fibrinogen
59. Fibrinogen - brand name list from Drugs.com, accessed August 5, 2025, https://www.drugs.com/ingredient/fibrinogen.html