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. 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 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:
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 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.
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. 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 
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 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) 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 that measures the 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 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.
The key to optimizing clinical care in patients requiring fibrinogen replacement therapy is a judicious use of the drug and adequate monitoring. An interprofessional team of clinicians, nurses and pharmacists are 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 V)
|||Levy JH,Goodnough LT, How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015 Feb 26 [PubMed PMID: 25519751]|
|||Collen D,Tytgat GN,Claeys H,Piessens R, Metabolism and distribution of fibrinogen. I. Fibrinogen turnover in physiological conditions in humans. British journal of haematology. 1972 Jun [PubMed PMID: 5064500]|
|||Casini A,de Moerloose P, Management of congenital quantitative fibrinogen disorders: a Delphi consensus. Haemophilia : the official journal of the World Federation of Hemophilia. 2016 Nov; [PubMed PMID: 27640400]|
|||Schöchl H,Nienaber U,Maegele M,Hochleitner G,Primavesi F,Steitz B,Arndt C,Hanke A,Voelckel W,Solomon C, Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Critical care (London, England). 2011; [PubMed PMID: 21375741]|
|||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 PMID: 23000050]|
|||Venugopal A, Disseminated intravascular coagulation. Indian journal of anaesthesia. 2014 Sep [PubMed PMID: 25535423]|
|||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 PMID: 23249928]|
|||Solomon C,Schöchl H,Hanke A,Calatzis A,Hagl C,Tanaka K,Rahe-Meyer N, Haemostatic therapy in coronary artery bypass graft patients with decreased platelet function: comparison of fibrinogen concentrate with allogeneic blood products. Scandinavian journal of clinical and laboratory investigation. 2012 Apr [PubMed PMID: 22233480]|
|||Szecsi PB,Jørgensen M,Klajnbard A,Andersen MR,Colov NP,Stender S, Haemostatic reference intervals in pregnancy. Thrombosis and haemostasis. 2010 Apr; [PubMed PMID: 20174768]|
|||Era S,Matsunaga S,Matsumura H,Murayama Y,Takai Y,Seki H, Usefulness of shock indicators for determining the need for blood transfusion after massive obstetric hemorrhage. The journal of obstetrics and gynaecology research. 2015 Jan; [PubMed PMID: 25164603]|
|||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 PMID: 27075198]|
|||Franchini M,Lippi G, Fibrinogen replacement therapy: a critical review of the literature. Blood transfusion = Trasfusione del sangue. 2012 Jan [PubMed PMID: 22153684]|
|||Schöchl H,Maegele M,Solomon C,Görlinger K,Voelckel W, Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scandinavian journal of trauma, resuscitation and emergency medicine. 2012 Feb 24 [PubMed PMID: 22364525]|
|||Görlinger K, [Coagulation management during liver transplantation]. Hamostaseologie. 2006 Aug [PubMed PMID: 16953295]|
|||Chiara O,Cimbanassi S,Bellanova G,Chiarugi M,Mingoli A,Olivero G,Ribaldi S,Tugnoli G,Basilicò S,Bindi F,Briani L,Renzi F,Chirletti P,Di Grezia G,Martino A,Marzaioli R,Noschese G,Portolani N,Ruscelli P,Zago M,Sgardello S,Stagnitti F,Miniello S, A systematic review on the use of topical hemostats in trauma and emergency surgery. BMC surgery. 2018 Aug 29 [PubMed PMID: 30157821]|
|||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 PMID: 16839371]|
|||Ganter MT,Hofer CK, Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesthesia and analgesia. 2008 May; [PubMed PMID: 18420846]|
|||Roberts I,Shakur H,Coats T,Hunt B,Balogun E,Barnetson L,Cook L,Kawahara T,Perel P,Prieto-Merino D,Ramos M,Cairns J,Guerriero C, The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health technology assessment (Winchester, England). 2013 Mar; [PubMed PMID: 23477634]|
|||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 PMID: 23587157]|
|||Solomon C,Gröner A,Ye J,Pendrak I, Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. Thrombosis and haemostasis. 2015 Apr [PubMed PMID: 25502954]|
|||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 PMID: 23410777]|
|||Weber CF,Görlinger K,Meininger D,Herrmann E,Bingold T,Moritz A,Cohn LH,Zacharowski K, Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012 Sep [PubMed PMID: 22914710]|