Fibrinogen is a 340kDa hexameric plasma glycoprotein synthesized by the liver. There are three different genes on chromosome 4 which encode synthesis of fibrinogen. The plasma concentration is approximately 200-400mg/dL. It has the maximum concentration amongst all the coagulation factors. It is the major structural component of a clot. The plasma half-life is three to four days. The minimum level required to maintain hemostasis is 100mg/dL.
The type of fibrinogen disorders which 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:
Indications for fibrinogen replacement therapy include the following conditions:
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 which 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.
It is a concentrate of high-molecular-weight plasma proteins prepared by 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. One unit raises plasma fibrinogen level by 7-10 mg/dL. The average half-life is approximately four days. Infusion must be through a filter with the 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. Administration of the repeat dose is by checking plasma fibrinogen level at appropriate intervals. The disadvantages include 
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 
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.
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.
The adverse effects associated with fibrinogen concentrate include:
Fibrinogen concentrate is contraindicated in individuals who have manifested immediate hypersensitivity or anaphylaxis to fibrinogen concentrate or its components.
Clotting tests: The prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) usually detects fibrinogen less than 100mg/dL. Although TT is a screening test, its specificity is poor because various common causes can lead to its prolongation. Reptilase time (RT) which is another screening test is useful as it is not affected by the presence of heparin. 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 mixing study.
Thromboelastography (TEG): It is a viscoelastic hemostatic assay which measures physical properties of clot formation. It is a point of care test which can be rapidly performed and easily compared and contrasted and requires multiple daily calibrations. It measures the speed and strength of clot formation and helps in analyzing the coagulation, platelet function, and fibrinolysis. The various parameters studied include:
R time (reaction time): It is the time of latency from the start of the test to initial fibrin formation. It is dependent on clotting factors.
K (seconds): It is dependent on fibrinogen and signifies time taken to achieve a specific clot strength (amplitude of 20 mm)
Alpha angle (degrees): It measures the rate at which fibrin build up and cross-linking takes place and thus assesses the rate of clot formation. It also depends on the fibrinogen levels.
Maximum amplitude (mm): It represents the ultimate clot strength which is a function of platelets (80%) and fibrin (20%). It helps to identify whether the source of bleeding is due to coagulopathy or mechanical disruption.
LY30 (%): It is the percentage decrease in amplitude 30 minutes post maximum amplitude. It provides information about fibrinolysis. The data from CRASH-2 randomized controlled trial signifies the importance of using antifibrinolytic within three hours of trauma in reducing mortality. Thus the early diagnosis of hyper-fibrinolysis is not only important in guiding antifibrinolytic treatment but also for the appropriate use of fibrinogen and cryoprecipitate.
Rotational thromboelastometry (ROTEM): It is an alternative viscoelastic hemostatic assay similar to TEG with different nomenclature and technical differences. The corresponding terminology for ROTEM is:
Clotting time (CT) - R-value
Alpha angle and clot formation time - K value and alpha angle
Maximum clot firmness (MCF) - MA
Clot lysis - LY30
Thus, in conclusion, the fibrinogen concentrate is a great alternative to other ways of providing fibrinogen in clinical states of coagulation abnormality that results from either qualitative or quantitative deficiencies of fibrinogen. Studies have proven that fibrinogen concentrate delivers a safe and reliable dose of fibrinogen. Fibrinogen administration has been proven to help control the bleeding in multiple randomized control trials in a variety of clinical settings including surgery, liver transplantation, cardiac surgery, and trauma.
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