Continuing Education Activity

Fibrinogen is a 340kDa hexameric plasma glycoprotein synthesized by the liver and is the major structural component of a clot. 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. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of fibrinogen replacement so that providers can direct patient therapy to optimal outcomes.

Objectives:

• Describe the different forms of fibrinogen replacement therapy.
• Summarize the indications for initiating fibrinogen replacement therapy.
• Explain the monitoring that must take place when administering fibrinogen replacement therapy.
• Review interprofessional team strategies for improving care coordination and communication to advance fibrinogen therapy and improve outcomes.

Indications

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: Patients with congenital afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia, who present 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 using 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]

Mechanism of Action

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 provides prevention against mechanical or enzymatic disruption.

Administration

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 to 3 mg/ml. It also requires larger volumes if only FFP is used to supplement 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 to 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 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 testing using ROTEM/TEG intraoperatively in determining the dose of fibrinogen has been a focus of 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, 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 controls bleeding from a large and regular raw surface, and stiff fibrin patch, which is usable for irregular or deep raw surfaces.[15]

Adverse Effects

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.

Contraindications

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

Monitoring

• Clotting tests: The prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) usually detect 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), another screening test, is useful as it is not affected by 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.

• Fibrinogen antigen test: A quantitative test uses the fibrinogen antibody to check the amount of fibrinogen in a blood sample.
• Fibrinogen activity test: It measures the time taken to form a fibrin clot after adding a standard amount of thrombin to the plasma. Since this test 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): It is a viscoelastic hemostatic assay that measures the physical properties of clot formation. It is a point-of-care test that 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 latency time 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 the time taken to achieve a specific clot strength (amplitude of 20 mm).

  •  Alpha angle (degrees): It measures the rate at which fibrin builds up and cross-linking occurs and thus assesses the rate of clot formation. It also depends on 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.[17]

  •  LY30 (%): It is the percentage decrease in amplitude 30 minutes post maximum amplitude. It provides information about fibrinolysis. The CRASH-2 randomized controlled trial data signifies the importance of using antifibrinolytic within three hours of trauma in reducing mortality.[18] Thus, the early diagnosis of hyper-fibrinolysis is important in guiding antifibrinolytic treatment and the appropriate use of fibrinogen and cryoprecipitate.[19]

• 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

Enhancing Healthcare Team Outcomes

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.[20] Fibrinogen administration has been proven to help control the bleeding in multiple randomized control trials in various clinical settings, including surgery, liver transplantation, cardiac surgery, and trauma.[21][22]

The key to optimizing clinical care in patients requiring fibrinogen replacement therapy is judicious use of the drug and adequate monitoring. An interprofessional team of clinicians, mid-level practitioners, nurses, and pharmacists is required to accomplish this goal. The clinician must review the patient scenario and laboratory parameters thoroughly prior to initiating this therapy. The critical care nurse is essential in monitoring the patient during therapy and to ensure no adverse reactions occur. 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 greatly increase the efficacy of this treatment and help improve patient outcomes in a variety of clinical scenarios. [Level 5]