Continuing Education Activity

Fibrinogen is a 340 kDa hexameric plasma glycoprotein synthesized by the liver and serves as the principal structural component of a clot. Disorders requiring fibrinogen replacement can be either congenital or acquired, and may involve either quantitative or qualitative deficiencies. This educational activity presents detailed information on the indications for fibrinogen replacement, mechanisms of action, administration methods, and monitoring parameters essential for safe and effective use. Clinically relevant data on toxicity, contraindications, and adverse effects are discussed to support optimal therapeutic decision-making.

Healthcare providers gain evidence-based insights into fibrinogen pharmacology and the clinical rationale behind individualized treatment strategies. Special emphasis is placed on recognizing the collaborative role of the interprofessional healthcare team in administering and monitoring fibrinogen therapy. By reviewing current clinical practices and therapeutic considerations, this activity enhances knowledge and supports improved outcomes in patients requiring fibrinogen supplementation.

Objectives:

• Identify the different forms of fibrinogen replacement therapy.
• Determine the indications for initiating fibrinogen replacement therapy.
• Assess the adverse reactions associated with fibrinogen replacement therapy.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from fibrinogen replacement therapy.

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Indications

Fibrinogen is a 340 kDa hexameric plasma glycoprotein synthesized by the liver. There are 3 different genes on chromosome 4 that code for fibrinogen. Plasma concentrations typically range between 200 and 400 mg/dL. Of all the coagulation factors, fibrinogen has the highest concentration and is the major structural component of a clot. The plasma half-life is 3 to 4 days.[1] The minimum level required to maintain hemostasis is 100 mg/dL.[2]

Fibrinogen disorders requiring replacement therapy can be either congenital or acquired, typically involving an abnormality in the amount or function of circulating fibrinogen. Classification of these disorders is as follows:

• Afibrinogenemia: An absence of circulating fibrinogen
• Hypofibrinogenemia: Reduced levels of circulating fibrinogen (<150 mg/dL)
• Dysfibrinogenemia: Circulating fibrinogen is dysfunctional
• Hypodysfibrinogenemia: Circulating fibrinogen is reduced in quantity and is functionally abnormal

FDA-Approved Indications

The fibrinogen concentrate (Riastap) is indicated for acute bleeding episodes in adults and pediatric patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Riastap is not approved for the treatment of dysfibrinogenemia. 

Another fibrinogen concentrate (Fibryga) is FDA-approved for acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. However, it is not approved for the treatment of dysfibrinogenemia. Fibryga received FDA approval in 2024 for patients with acquired fibrinogen deficiency.

Both formulations are FDA-approved for the treatment of congenital disorders. Patients with congenital afibrinogenemia, hypofibrinogenemia, or who present with clinically significant bleeding should be given fibrinogen concentrate to raise levels to 100 to 150 mg/dL. However, a higher target of 150 to 200 mg/dL is necessary for more severe bleeding (intracerebral bleeding).[3][4] A target fibrinogen level of 50 mg/dL is usually necessary for wound healing after achieving hemostasis.

Off-Label Uses

• Massive trauma: The patients with severe trauma often present with massive hemorrhage and impaired hemostasis. Retrospective studies have shown the reduced requirement of RBCs and platelets using fibrinogen concentrates in patients with trauma.[5][6][7][8]

• Disseminated intravascular coagulation (DIC): DIC is a syndrome characterized by widespread activation of intravascular coagulation, leading to fibrin clot deposition in blood vessels and subsequent organ failure. This condition can also present with bleeding manifestations due to the consumption of platelets and coagulation factors. Laboratory abnormalities in DIC include thrombocytopenia, elevated fibrin degradation products, prolonged PT, aPTT, and low fibrinogen. The treatment for DIC includes fresh frozen plasma (FFP), platelets, packed red cells, cryoprecipitate, and fibrinogen concentrate, depending on laboratory abnormalities. Severe hypofibrinogenemia (<100 mg/dL) can be corrected with cryoprecipitate or fibrinogen concentrate after failed treatment with FFP, with the target to keep levels above 100 mg/dL.[9] 

• Liver diseases: These conditions can correlate with both dysfibrinogenemia and hypofibrinogenemia. The abnormal fibrinogen has an increased amount of sialic acid that causes a delay in fibrin aggregation. Clotting abnormalities can be present in various liver diseases, such as biliary obstruction, chronic liver disease, cirrhosis, and hepatoma. When the synthetic function is severely depressed in cases of advanced liver disease, it causes reduced production of fibrinogen.

• Cardiac surgery: Patients undergoing cardiovascular surgery involving cardiopulmonary bypass often have perioperative coagulopathic bleeding, which requires transfusion of blood and blood products. The multiple risk factors affecting bleeding include the type of procedure, bypass time, re-operation, and comorbidities. Pre-operative fibrinogen levels are an independent predictor of perioperative bleeding and transfusion requirement. Studies have reported the role of fibrinogen concentrate in reducing transfusion requirements in major aortic and coronary artery bypass graft surgeries.[10][11][12][13]

• Obstetric hemorrhage: The normal fibrinogen concentration in the third trimester is nearly 500 mg/dL.[14] The minimum amount of fibrinogen and other coagulation factors required for hemostasis is 40% to 50% and 20% to 25% of normal levels, respectively. Various studies have calculated the cutoff value of fibrinogen level less than 200 mg/dL as a predictor of progression to massive blood loss and massive transfusion.[15][16]

• According to the American Association for the Study of Liver Diseases (AASLD), reduced fibrinogen levels are associated with an elevated risk of bleeding in critically ill patients diagnosed with cirrhosis. Replenishment using cryoprecipitate and fibrinogen factor replacements constitutes a low-volume product that effectively augments fibrinogen levels.[17]

Mechanism of Action

Fibrinogen is also known as coagulation factor I. Fibrinogen is a substrate for 3 major enzymes: thrombin, plasmin, and factor XIIIa. Due to various functional interactions, it plays a crucial role in hemostasis. Fibrinogen is the soluble precursor to insoluble fibrin and supports platelet aggregation. The fibrin clot also activates the fibrinolytic system; thus, the balance between coagulation and fibrinolysis determines the clinical manifestations.[18]

When thrombin (factor IIa) binds to fibrinogen, it releases fibrinopeptide A and B (FPA & FPB, respectively) from A α and B β chains. The resultant molecule is a fibrin monomer that spontaneously polymerizes to form a fibrin clot. Once polymerized, factor XIIIa activates the cross-linking of fibrin, thereby strengthening the clot and protecting it against mechanical or enzymatic disruption. Administration of fibrinogen concentrates in congenital/acquired fibrinogen deficiency complements the lacking coagulation factor and increases low plasma fibrinogen levels.

Pharmacokinetics

Absorption: Both fibrinogen concentrates, Riastap and Fibryga, are administered intravenously, resulting in immediate and complete bioavailability.

Distribution: The volume of distribution at steady state ranges from approximately 50 mL/kg (Riastap) to around 70 mL/kg (Fibryga), with pediatric patients exhibiting slightly higher volumes, reflecting the distribution of the plasma compartment.

Metabolism: Both products undergo proteolytic degradation similar to endogenous fibrinogen, with no hepatic metabolism involved.

Elimination: Clearance averages about 0.6 mL/h/kg for Riastap and 0.7 mL/h/kg for Fibryga in adults, with higher clearance and shorter half-life observed in pediatric patients. The half-life ranges from approximately 57 hours in young children to around 79 hours in adults.[19]

Administration

Available Dosage Forms and Strengths

Fibrinogen concentrate is available in 2 lyophilized forms: one with 900 to 1300 mg per vial and another with approximately 1 g per vial. Both are reconstituted with 50 mL sterile water. Fibrinogen replacement therapy can be provided intravenously using fresh frozen plasma (FFP), cryoprecipitate, and fibrinogen concentrate or topically using liquid adhesives.

Adult Dosing

Fresh frozen plasma: FFP is extensively used in trauma and massive transfusion to replenish coagulation factors. However, this is not an ideal source for fibrinogen repletion as the concentration is 1 to 3 mg/mL. Patients also require larger volumes if only FFP is used to supplement coagulation factors, which can cause complications associated with fluid overload.[20]

Cryoprecipitate: This is a concentrated preparation of high-molecular-weight plasma proteins, prepared by thawing FFP. Cryoprecipitate contains fibrinogen, factor VIII, VWF, factor XIII, and fibronectin. Each 10- to 20-mL unit contains approximately 200 to 250 mg of fibrinogen.[2] One unit raises plasma fibrinogen levels by 7 to 10 mg/dL. The average half-life is approximately 4 days. Infusion must be conducted through a filter at a rate of at least 200 mL/h. The dose for minor and severe bleeding is 1 unit per 5 kg and 10 kg of body weight, respectively. The repeat dose is administered by checking the plasma fibrinogen level at appropriate intervals. The disadvantages of cryoprecipitate are listed below.[20]

• Requires ABO compatibility
• Requires thawing before administration, which causes a delay during massive transfusion
• Cryoprecipitate carries the risk of pathogen transmission
• Larger volumes are required as compared to fibrinogen concentrate (but lower than FFP)

Fibrinogen concentrate: Commercial fibrinogen concentrates are obtained from pooled human plasma by cryoprecipitation. Fibrinogen concentrate is available as a lyophilized powder at room temperature, which can be quickly reconstituted with sterile water. Four fibrinogen concentrates are commercially available; however, only 2 are available in the US. In contrast to FFP and cryoprecipitate, fibrinogen concentrate offers the following advantages.[20]

• Minimal risk of infections because of viral inactivation during the manufacturing process
• Accurate and consistent dosing because of standardized concentration
• Low volume infusion
• Rapid administration, as it doesn’t require thawing or cross-matching

The initial dose depends on the degree of bleeding and the initial fibrinogen concentration. Dose calculation uses the following formula:

[Target fibrinogen (mg/dL) - measured fibrinogen (mg/dL)] / correction factor

The correction factor for various commercial products ranges from 1.7 to 1.8; refer to the package insert for the specific product to determine which correction factor to use.

Subsequent doses can be calculated based on the patient’s trough plasma fibrinogen level. Fibrinogen concentrate should never be mixed with other medicinal products or intravenous solutions and should be administered slowly through a separate injection site.

The standard intravenous dose for adults is 4 grams (Fibryga). When the fibrinogen level is unavailable, 70 mg/kg can be administered (Riastap).

The extensive use of point-of-care testing, utilizing ROTEM/TEG intraoperatively, has been a focus of study in various clinical trials, particularly in determining the dose of fibrinogen.[2][21][22]

Liquid adhesives: These are available as liquid fibrin glue, which controls bleeding from a large and regular raw surface, and a stiff fibrin patch, usable for irregular or deep raw surfaces.[23] Each adhesive contains a freeze-dried concentrate of clotting proteins, primarily fibrinogen, factor XIII, and fibronectin (the sealant), as well as freeze-dried thrombin (the catalyst), which promotes the formation of a fibrin clot within the coagulation cascade. Liquid adhesives are practical and preferred in patients with disorders of the coagulation pathway. The utmost care should be taken to avoid intravascular administration and the risk of thromboembolism. Tranexamic acid-containing adhesives should be avoided in cerebrospinal fluid leakage or dural tears to prevent neurotoxicity.

Specific Patient Populations

Hepatic impairment: No dosage modifications are provided in the product labeling.

Renal impairment: No dosage modifications are provided in the product labeling.

Pregnancy considerations: Afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia can cause bleeding, thrombosis, and pregnancy loss.[24] If functional fibrinogen is less than 0.5 g/L, consider prophylactic fibrinogen concentrate (50 to 100 mg/kg twice weekly), adjusted to maintain trough levels greater than 1 g/L, with increased dosing as pregnancy progresses. During labor, maintain a fibrinogen level of greater than 1.5 g/L for at least 3 days. Tranexamic acid may be used for minor bleeding. Management should consider personal or family history of bleeding or thrombosis; expectant management is advised if absent. Fibrinogen replacement therapy carries a high risk of thrombosis; thromboprophylaxis with low-molecular-weight heparin should be considered for patients with thrombotic risk factors. Avoid central neuraxial anesthesia, NSAIDs, and intramuscular injections in patients with severe deficiency or a bleeding history unless adequate replacement is ensured.[25][26] Using viscoelastic hemostatic assays (VHA) to guide early treatment with fibrinogen concentrate, when fibrinogen levels are ≤2 g/L, can help reduce the progression of postpartum hemorrhage (PPH).[27]

Breastfeeding considerations: There is a lack of data on the presence of human fibrinogen concentrate in breast milk, its effects on the breastfed infant, and its impact on milk production. Benefits of breastfeeding should be weighed against the mother’s clinical need for fibrinogen concentrate and potential risks to the infant from the treatment or underlying condition.

Pediatric patients: The recommended dose of fibrinogen concentrate for adolescents aged 12 years and older is 50 mg/kg body weight. The dose for children younger than 12 years is 70 mg/kg body weight.

Older patients: Clinical studies of human fibrinogen concentrate in congenital fibrinogen deficiency included an insufficient number of patients aged 65 or older to determine whether their response differs from that of younger patients. Consider risk-benefit evaluation.

Adverse Effects

The adverse effects associated with fibrinogen concentrate include:

• Allergic-anaphylactic reactions: They can range from allergic symptoms to early signs of hypersensitivity reactions (hives, urticaria, wheezing, hypotension, and anaphylaxis). In such cases, immediately discontinue administration, and further treatment depends on the severity of the reaction.

• Thromboembolic complications: Reports exist of thrombosis in patients with congenital fibrinogen deficiency with or without fibrinogen replacement therapy.[28][29] Patients receiving treatment with fibrinogen concentrate can also present with signs and symptoms of pulmonary embolism, myocardial infarction, deep vein thrombosis, and arterial thrombosis.

• Generalized reactions: These include symptoms such as chills, fever, nausea, and vomiting.

Contraindications

Fibrinogen concentrate is contraindicated in individuals with immediate hypersensitivity or anaphylaxis to fibrinogen concentrate or its components.[30]

Warning and Precautions

• Monitor patients for hypersensitivity or allergic reactions. If these occur, discontinue treatment and initiate appropriate medical management.

• Thrombotic events have been reported with the use of human fibrinogen concentrate. In some cases, thrombosis occurred even when plasma fibrinogen levels were below 150 mg/dL, and the risk may increase as levels approach this threshold. Clinicians should weigh the benefits of fibrinogen replacement against the risk of thrombosis, particularly when aiming for higher plasma concentrations.[31]

• As the product is derived from pooled human plasma, there is a potential risk of transmitting infectious agents, including viruses and, theoretically, Creutzfeldt-Jakob disease (CJD) or its variant form (vCJD). Standard viral inactivation steps are employed, but the theoretical risk remains.[32]

Monitoring

Clotting tests: The prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) usually detects fibrinogen levels less than 100 mg/dL. Although TT is a screening test, its specificity is poor because various common causes can lead to its prolongation. Reptilase time (RT), another screening test, is useful as heparin does not affect it. Mixing study done in any of these tests may show correction in afibrinogenemia and hypofibrinogenemia, but not in dysfibrinogenemia, because dysfunctional fibrinogen acts as an inhibitor in the mixing study.

Fibrinogen antigen test: A quantitative test uses the fibrinogen antibody to check the amount of fibrinogen in a blood sample.

Fibrinogen activity test: This test measures the time it takes to form a fibrin clot after adding a standard amount of thrombin to the plasma. Since it requires the addition of thrombin, it bypasses other coagulation factors and tests specifically for fibrinogen. The time required for clot formation depends on the amount of active fibrinogen in a test sample. Prolonged time can result from a decreased amount of fibrinogen or the presence of dysfunctional fibrinogen.

Thromboelastography (TEG): This is a viscoelastic hemostatic assay that measures the physical properties of clot formation.[33] TEG is a point-of-care test that can be rapidly performed, easily compared and contrasted, and requires multiple daily calibrations. This test measures the speed and strength of clot formation and helps analyze coagulation, platelet function, and fibrinolysis. The various parameters studied include:

• R time (reaction time): This is the latency time from the start of the test to initial fibrin formation and is dependent on clotting factors.
• K (seconds): This depends on fibrinogen and signifies the time to achieve a specific clot strength (amplitude of 20 mm).
• Alpha angle (degrees): This measures the rate at which fibrin builds up and cross-links, thus assessing the rate of clot formation. The alpha angle is dependent on fibrinogen levels.
• Maximum amplitude (mm): This represents the ultimate clot strength, which is a function of platelets (80%) and fibrin (20%). Maximum amplitude helps identify whether the bleeding source is due to coagulopathy or mechanical disruption.[34]
• LY30 (%): This is the percentage decrease in amplitude 30 minutes post-maximum amplitude. The LY30 provides information about fibrinolysis. The CRASH-2 randomized controlled trial data signify the importance of using antifibrinolytics within 3 hours of trauma in reducing mortality.[35] Thus, the early diagnosis of hyper-fibrinolysis is essential in guiding antifibrinolytic treatment and the appropriate use of fibrinogen and cryoprecipitate.[36]

• Rotational thromboelastometry (ROTEM): This is an alternative viscoelastic hemostatic assay similar to TEG with different nomenclature and technical differences.[37] The corresponding terminology for ROTEM is listed below.[38]
  •  Clotting time (CT) - R-value
  •  Alpha angle and clot formation time - K value and alpha angle
  •  Maximum clot firmness (MCF) - MA
  •  Clot lysis - LY30

Toxicity

Signs and Symptoms of Overdose

Human fibrinogen concentrate has demonstrated a favorable safety profile in both animal studies and clinical trials. Reported adverse effects are rare but include thromboembolic events (eg, myocardial infarction, pulmonary embolism, graft occlusion, and deep vein thrombosis) primarily in perioperative or high-risk settings. Additional events such as atrial fibrillation, renal failure, and neurological complications have been observed less frequently in treated patients than in controls. Long-term pharmacovigilance, including 22 years of surveillance of Haemocomplettan P, supports a low incidence of thrombotic events. No significant effects were noted on hematologic, cardiovascular, or respiratory parameters.

Management of Overdose

Human overdose data are unavailable. In animal models, no adverse effects were observed at doses of up to 1000 mg/kg in mice and 300 mg/kg in rats, indicating a broad safety margin. In the event of overdose, the primary concern is hypercoagulability and potential thromboembolic complications. Management is supportive; clinical monitoring is essential, and anticoagulation should be considered if thrombosis is suspected.[39][30]

Enhancing Healthcare Team Outcomes

Fibrinogen concentrate is a valuable alternative to other methods of providing fibrinogen in clinical states of coagulation abnormality resulting from either qualitative or quantitative deficiencies of fibrinogen. Studies have proven that fibrinogen concentrate delivers a safe and reliable dose of fibrinogen.[40] Fibrinogen administration has been proven to help control bleeding in multiple randomized controlled trials in various clinical settings, including surgery, liver transplantation, cardiac surgery, and trauma.[41][42]

The key to optimizing clinical care in patients requiring fibrinogen replacement therapy is the judicious use of drugs and adequate monitoring. Hematologists evaluate and diagnose bleeding disorders that require fibrinogen replacement, determining the appropriate dosage based on coagulation status. Internal medicine physicians manage overall patient care, monitor underlying conditions, and assess laboratory parameters prior to therapy. Advanced practice providers deliver clinical care and collaborate with specialists to enhance treatment outcomes. The critical care nurse is essential in monitoring the patient during therapy to ensure adverse drug reactions are minimized. Many patients requiring this therapy are critically ill and receive multiple intravenous transfusions. Close cardiopulmonary observation by the bedside nurse is needed to prevent fluid overload and other complications. Communicating with the clinician when signs of fluid overload or thrombosis occur can help minimize adverse outcomes. The pharmacist can assist the medical team in adjusting the dosage and rate of transfusion in complicated cases to decrease patient morbidity and mortality. A collaborative interprofessional team can significantly increase the efficacy of this treatment and help improve patient outcomes in various clinical scenarios. An interprofessional team of physicians, advanced practice providers, nurses, and pharmacists is crucial to decreasing potential adverse effects and improving patient outcomes related to fibrinogen concentrate therapy.

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Disclosure: Jasmeen Kaur declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Ankit Jain declares no relevant financial relationships with ineligible companies.