Fibrinogen


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Jasmeen Kaur


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Ankit Jain


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Updated:
1/21/2019 10:25:01 AM

Indications

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.[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 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:

  • 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 trauma patients.[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 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 peri-operative 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 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.

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 1-3 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 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 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 [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]

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

  1. 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.

  2. Fibrinogen antigen test: It is a quantitative test which uses fibrinogen antibody to check the amount of fibrinogen in a blood sample.
  3. 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 the decreased amount of fibrinogen or the presence of dysfunctional fibrinogen.
  4. 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.[17]

    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.[18] 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.[19]

  5. 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 a variety of clinical settings including surgery, liver transplantation, cardiac surgery, and trauma.[21][22]


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Fibrinogen - Questions

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A 69-year-old male hypertensive patient presents in an emergency department with massive hematemesis. He has a past medical history of esophageal varices and had undergone sclerotherapy twice in the last two years. He has been admitted multiple times for alcohol de-addiction in the past but relapses every time. On physical examination, the patient has ascites, pedal edema, and spider nevi. Laboratory investigations are sent for a complete metabolic profile. Which of the following products is most appropriate for repleting the deficient clotting factor in this patient?



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A 78-year-old male chronic smoker is posted for redo coronary artery bypass grafting surgery. He has a history of hypertension and diabetes mellitus for the last twenty years. He is on aspirin, clopidogrel, metoprolol, amlodipine, and metformin. Pre-operatively, the complete metabolic profile is within normal limits. The patient bleeds profusely intra-operatively. He is transfused with blood and blood products. Which of the following investigation can best guide the transfusion strategy?



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A 7-year old girl presents to the emergency department because of prolonged bleeding from the oral cavity after minor trauma. The child is hypotensive and appears dehydrated. Laboratory investigations for complete metabolic profile and blood group are sent. She is started on intravenous hydration. On further evaluation, the mother gives a history of prolonged bleeding from the umbilical cord in the neonatal period and multiple episodes of spontaneous bleeding in childhood. A provisional diagnosis of a genetic disorder is made in which one of the clotting factors is absent. What is the minimal level of the missing clotting factor required for hemostasis?



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A 45-year-old male patient is admitted to the hospital after a motor vehicle accident. After doing a primary survey, he is immediately taken up for surgery. He is transfused with packed red blood cells, plasma, and platelets. After doing thromboelastogram, he was started on an infusion of fibrinogen concentrate. Soon after starting the infusion, mean arterial pressure fell from 65 mmHg to 40 mmHg, and the heart rate increased to 180 per minute. The peak airway pressure rose from 25 cm of H2O to 40 cm of H2O. What is the next step in management?



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A 32-year-old female with placenta percreta is posted for an elective caesarian section and obstetric hysterectomy. After delivery, there was massive blood loss, and blood transfusion protocol was initiated as per institutional guidelines. Thromboelastogram report showed increased K time and R time and normal maximum amplitude. What should be administered to the patient to aid in hemostasis?



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Fibrinogen - References

References

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Levy JH,Goodnough LT, How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015 Feb 26     [PubMed]
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Görlinger K, [Coagulation management during liver transplantation]. Hamostaseologie. 2006 Aug     [PubMed]
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Rahe-Meyer N,Solomon C,Hanke A,Schmidt DS,Knoerzer D,Hochleitner G,Sørensen B,Hagl C,Pichlmaier M, Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology. 2013 Jan     [PubMed]
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Wang L,Matsunaga S,Mikami Y,Takai Y,Terui K,Seki H, Pre-delivery fibrinogen predicts adverse maternal or neonatal outcomes in patients with placental abruption. The journal of obstetrics and gynaecology research. 2016 Jul;     [PubMed]
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da Luz LT,Nascimento B,Rizoli S, Thrombelastography (TEG®): practical considerations on its clinical use in trauma resuscitation. Scandinavian journal of trauma, resuscitation and emergency medicine. 2013 Apr 16;     [PubMed]
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Innerhofer P,Westermann I,Tauber H,Breitkopf R,Fries D,Kastenberger T,El Attal R,Strasak A,Mittermayr M, The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury. 2013 Feb;     [PubMed]
Peyvandi F,Haertel S,Knaub S,Mannucci PM, Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. Journal of thrombosis and haemostasis : JTH. 2006 Jul;     [PubMed]
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Rahe-Meyer N,Hanke A,Schmidt DS,Hagl C,Pichlmaier M, Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial. The Journal of thoracic and cardiovascular surgery. 2013 Mar     [PubMed]
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