Fibrinogen is a 340kDa hexameric plasma glycoprotein synthesized by the liver. There are three different genes on chromosome 4 which encode the synthesis of fibrinogen. The plasma concentration is approximately 200-400mg/dL. It has the maximum concentration amongst all the coagulation factors.[1] It is the major structural component of a clot. The plasma half-life is three to four days.[2] The minimum level required to maintain hemostasis is 100mg/dL.[1]

Fibrinogen disorders:

The type of fibrinogen disorders that require replacement therapy can be congenital or acquired. There can be an abnormality in the amount or function of circulating fibrinogen. Classification of these disorders are as follows:

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

Indications for fibrinogen replacement therapy include the following conditions:

1. Congenital disorders: The patients with congenital afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia presenting with clinically significant bleeding should be given fibrinogen concentrate to raise levels to 100-150mg/dL. However, a higher target of 150-200mg/dL is necessary for more severe bleeding (intracerebral bleeding).[3] A target fibrinogen level of 50mg/dL is usually necessary for wound healing after achieving hemostasis.
2. 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 with the use of fibrinogen concentrates in patients with trauma.[4][5]
3. Disseminated intravascular coagulation (DIC): DIC is a syndrome characterized by widespread activation of intravascular coagulation leading to deposition of fibrin clots in blood vessels and organ failure. It can also present with bleeding manifestations due to the consumption of platelets and coagulation factors. The laboratory abnormality in DIC is 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 (<100mg/dL) can be corrected with cryoprecipitate or fibrinogen concentrate after failed treatment with FFP with the target to keep levels above 100mg/dL.[6]
4. Liver diseases: It can correlate with both dysfibrinogenemia and hypofibrinogenemia.  The abnormal fibrinogen has an increased amount of sialic acid that causes a delay in fibrin aggregation. It can present in various liver diseases like 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.
5. Cardiac surgery: The patients undergoing cardiovascular surgeries involving cardiopulmonary bypass often have peri-operative 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 appear to be an independent predictor of perioperative bleeding and transfusion requirement. Studies have reported the role of fibrinogen concentrate on reducing transfusion requirement in major aortic and coronary artery bypass graft surgeries.[7][8]]
6. Obstetric hemorrhage: The normal concentration of fibrinogen in the third trimester is close to 500mg/dL.[9] 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 200mg/dL as a predictor of progression to massive blood loss and massive transfusion.[10][11]

Fibrinogen is a substrate for three 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 it also supports platelet aggregation. The fibrin clot also activates the fibrinolytic system; thus the balance between coagulation and fibrinolysis determines the clinical manifestations.

Formation of fibrin: When thrombin (factor IIa) binds to fibrinogen, it releases fibrinopeptide A and B (FPA & FPB  respectively) from A alpha and B beta chains. The resultant molecule is a fibrin monomer that spontaneously polymerizes to form a fibrin clot. Once polymerized, factor XIIIa activates cross-linking of fibrin which strengthens the clot and prevents against mechanical or enzymatic disruption.

Fibrinogen replacement therapy can be provided intravenously using fresh frozen plasma (FFP), cryoprecipitate and fibrinogen concentrate and topically using liquid adhesives.

1. Fresh frozen plasma:

Plasma has extensive usage in trauma and massive transfusion to replenish coagulation factors. However, this is not an ideal source for fibrinogen repletion as the concentration is 1-3 mg/ml. It also requires larger volumes if only FFP is used for supplementation of coagulation factors which can cause complications associated with fluid overload.[12][1] 

2. Cryoprecipitate:

It is a concentrate of high-molecular-weight plasma proteins prepared by the thawing of FFP. It contains fibrinogen, factor VIII, VWF, factor XIII, and fibronectin. Each unit of 10-20 ml contains approximately 200-250 mg of fibrinogen.[1] One unit raises plasma fibrinogen levels by 7-10 mg/dL. The average half-life is approximately four days. Infusion must be through a filter with a rate of at least 200ml/hour. The dose for minor and severe bleeding is 1 unit per 5 kg and 10kg  of body weight, respectively. The administration of the repeat dose is by checking the plasma fibrinogen level at appropriate intervals. The disadvantages include [12]

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

3. Fibrinogen concentrate: 

Commercial fibrinogen concentrates are obtained from pooled human plasma by a cryoprecipitation procedure. It is available as a lyophilized powder at room temperature, and that can be quickly reconstituted using sterile water. There are four fibrinogen concentrates commercially available; however, only one is available globally. In contrast to FFP and cryoprecipitate, it has the following advantages [12]

• It has a 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 bleeding and 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 is 1.7 to 1.8; check the package insert for the product to determine which to use.

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

The extensive use of point of care test using ROTEM/TEG intraoperatively in determining the dose of fibrinogen has undergone study in various clinical trials.[1][13][14]

4. Liquid adhesives 

It is available as liquid fibrin glue and stiff fibrin patch. It contains a freeze-dried concentrate of clotting proteins, mainly fibrinogen, Factor XIII and fibronectin (the sealant) and freeze-dried thrombin (the catalyst). It acts by participating in the formation of a fibrin clot in the coagulation cascade. It is effective and preferred in patients with disorders of the coagulation pathway. The utmost care should be taken to avoid intravascular administration to avoid the risk of thromboembolism. The use of tranexamic acid-containing adhesives should be avoided in cerebrospinal fluid leakage or dural tear to prevent neurotoxicity. It is available as liquid fibrin glue which is used to control bleeding from a large and regular raw surface, and stiff fibrin patch which is usable for irregular or deep raw surfaces.[15]

The adverse effects associated with fibrinogen concentrate include:

1. Allergic-anaphylactic reactions: It can range from an allergic symptom 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.
2. Thromboembolic complications: Reports exist of thrombosis in patients with congenital fibrinogen deficiency with or without fibrinogen replacement therapy.[16] Patients under treatment with fibrinogen concentrate can also present with signs and symptoms of pulmonary embolism, myocardial infarction, deep vein thrombosis, and arterial thrombosis.
3. Generalized reactions: these include symptoms such as chills, fever, nausea, and vomiting.

Fibrinogen concentrate is contraindicated in individuals who have manifested immediate hypersensitivity or anaphylaxis to fibrinogen concentrate or its components.