From: Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., “Coagulation.” In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.
Related Information
Activated Partial Thromboplastin Time
Clot Retraction
Coagulation Factor Assays
D-Dimers and Fibrin Degradation Products
Disseminated Intravascular Coagulation Screen
Factor XIII
Hypercoagulation Panel
Mixing Studies
Prothrombin Time
Thrombin Time
Synonyms Factor I
Applies to Acute Phase Reactant; Afibrinogenemia; Dysfibrinogenemia; Plasmin; Sedimentation Rate; Thrombin
Abstract Fibrinogen is converted into fibrin clot by thrombin. Fibrinogen levels <100 mg/dL can be associated with bleeding. Acquired decreases in fibrinogen (eg, with liver dysfunction or DIC) are much more common than hereditary deficiencies.
Specimen Plasma
Container Blue top (sodium citrate) tube
Collection Routine venipuncture. If multiple tests are being drawn, draw blue top tubes after any red top tubes but before any lavender top (EDTA), green top (heparin), or gray top (oxalate/fluoride) tubes. Immediately invert tube gently at least 4 times to mix. Tubes must be appropriately filled. Deliver tubes immediately to the laboratory.
Storage Instructions Separate plasma from cells as soon as possible. Store plasma at room temperature for up to 2 hours, at 2degrees C to 8degrees C for up to 4 hours, or store frozen.
Causes for Rejection Specimen received more than 4 hours after collection, tubes not filled, clotted specimen
Turnaround Time Less than 1 day
Reference Interval Approximately 150-400 mg/dL
Use One of several tests performed in a DIC panel, a prolonged PT or PTT evaluation, and an evaluation of a patient with an unexplained bleeding history
Limitations Heparin concentrations >0.6 units/mL can falsely decrease the result with the Clauss method (described below). Usual therapeutic doses of heparin do not significantly affect PT-based methods. The Ellis method is more sensitive to heparin than the Clauss method. Some reagents contain hexadimethrine bromide (Polybrene) to neutralize heparin, allowing fibrinogen to be measured in specimens containing heparin. Fibrin degradation products (FDP) >30-100 microg/mL may decrease fibrinogen values with the Clauss method. Hirudin or argatroban anticoagulation may falsely decrease fibrinogen levels levels with the Clauss and Ellis method, and possibly the PT-based method.
Methodology
Functional (activity) assays: The majority of clinical laboratories use the Clauss1 method, which is essentially a dilute thrombin time. A high concentration of thrombin is added to dilute patient plasma, which converts fibrinogen into fibrin clot. The clotting time is inversely proportional to the amount of fibrinogen in the sample. In the Ellis2method, a lower amount of thrombin is added to undiluted patient plasma and change in turbidity is measured in a spectrophotometer. In the PT-based method,3,4 thromboplastin (tissue factor with phospholipid) is added to undiluted patient plasma to generate endogenous thrombin, and light scatter or turbidity is measured. The measured optical change (before and after fibrin clot formation) is proportional to the amount of fibrinogen in the sample.
Antigen assays (immunoassays) for fibrinogen measure the quantity of fibrinogen without assessing fibrinogen function. This method is not routinely indicated and is usually a send-out test (see Additional Information for its use in dysfibrinogenemia evaluations).
Additional Information Fibrinogen decreases with liver disease, due to decreased hepatic synthesis. However, fibrinogen may be normal or even elevated until late stages of hepatic disease. Fibrinogen decreases in DIC due to excessive thrombin generation, which converts fibrinogen into fibrin. Fibrinogen also decreases with thrombolytic therapy and fibrinolysis because plasmin breaks down fibrinogen in addition to fibrin.
Fibrinogen becomes elevated during acute phase reactions and during pregnancy. As with certain other acute phase reactants (eg, C-reactive protein), elevated fibrinogen has been associated with an increased risk of myocardial infarction.5
Hereditary deficiencies of fibrinogen are rare. The PT and PTT may be prolonged. Bleeding symptoms may include bruising, epistaxis, menorrhagia, bleeding with surgery, trauma, dental extractions, and postpartum, and bleeding in the gastrointestinal or genitourinary tract. Miscarriage and poor wound healing are also complications of fibrinogen deficiency. Umbilical stump bleeding and bleeding with circumcision may be noted in newborns with afibrinogenemia. Intracranial hemorrhage has been reported with afibrinogenemia.6,7,8 In general, deficiencies of fibrinogen tend to be milder than factor VIII or IX deficiencies (hemophilia).
There are three major types of fibrinogen deficiency. The homozygous quantitative form, called afibrinogenemia, results in a severe quantitative deficiency of fibrinogen and an increased risk for bleeding. The heterozygous form of this deficiency is hypofibrinogenemia, with less severe reductions in the fibrinogen level and little or no bleeding.7 Fibrinogen consists of two copies of each of three polypeptide chains called alpha, beta , and gamma . Among the afibrinogenemia mutations that have been characterized thus far, most have been found in the alpha-fibrinogen chain gene.9
Dysfibrinogenemia is a qualitative fibrinogen deficiency, characterized by the production of dysfunctional fibrinogen.6,8,10 Many different mutations are known to cause hereditary dysfibrinogenemia. Most patients with hereditary dysfibrinogenemia are heterozygous. Rare homozygous cases have been reported. Dysfibrinogenemia patients are usually asymptomatic or have mild bleeding, but severe bleeding has been reported. Interestingly, some dysfibrinogenemia cases are associated with thrombosis, with or without bleeding. Dysfibrinogenemia has an estimated prevalence of 0.8% in patients with venous thrombosis.6 Arterial thrombosis is less frequent than venous thrombosis in these patients. Acquired forms of dysfibrinogenemia, of uncertain clinical significance, can be seen with liver disease or acute phase reactions with generation of high levels of fibrinogen (Galanakis D, personal communication 1999). The thrombin time and Reptilase® time, which measure the clotting time during the conversion of fibrinogen into fibrin, are often prolonged in dysfibrinogenemia. The PT and PTT may also be prolonged. In dysfibrinogenemia, assays that measure fibrinogen function show lower levels than assays that measure fibrinogen quantity (immunological or “antigen” assays), because fibrinogen function is impaired but fibrinogen quantity is not. This potentially diagnostic disparity between functional and antigen levels may be less pronounced with PT-based functional fibrinogen assays than with Clauss-based functional assays.3 See Table 3 in Coagulation Factor Assays.
See Thrombin Time.
Footnotes
1. Clauss A, “Rapid Physiological Coagulation Method for the Determination of Fibrinogen [German],”Acta Haematol, 1957, 17:237-46.
2. Ellis BC and Stransky A, “A Quick and Accurate Method for the Determination of Fibrinogen in Plasma,”J Lab Clin Med, 1961, 58:477-88.
3. Rossi E, Mondonico P, Lombardi A, et al, “Method for the Determination of Functional (Clottable) Fibrinogen by the New Family of ACL Coagulometers,”Thromb Res, 1988, 52(5):453-68.
4. Tan V, Doyle CJ, and Budzynski AZ, “Comparison of the Kinetic Fibrinogen Assay With the von Clauss Method and the Clot Recovery Method in Plasma of Patients With Conditions Affecting Fibrinogen Coagulability,”Am J Clin Pathol, 1995, 104(4):455-62.
5. Ma J, Hennekens CH, Ridker PM, et al, “A Prospective Study of Fibrinogen and Risk of Myocardial Infarction in the Physician’s Health Survey,”J Am Coll Cardiol, 1999, 33(5):1347-52.
6. Haverkate F and Samama M, “Familial Dysfibrinogenemia and Thrombophilia. Report on a Study of the SSC Subcommittee on Fibrinogen,”Thromb Haemost, 1995, 73(1):151-61.
7. Al-Mondhiry H and Ehmann WC, “Congenital Afibrinogenemia,”Am J Hematol, 1994, 46(4):343-7.
8. Galanakis DK, “Fibrinogen Anomalies and Disease. A Clinical Update,”Hematol Oncol Clin North Am, 1992, 6(5):1171-87.
9. Neerman-Arbez M, de Moerloose P, Bridel C, et al, “Mutations in the Fibrinogen Aalpha Gene Account for the Majority of Cases of Congenital Afibrinogenemia,”Blood, 2000, 96(1):149-52.
10. Cote HC, Lord ST, and Pratt KP, “gamma -Chain Dysfibrinogenemias: Molecular Structure-Function Relationships of Naturally Occurring Mutations in the gamma Chain of Human Fibrinogen,”Blood, 1998, 92(7):2195-212.
References
Giangrande PLF, “Other Inherited Disorders of Blood Coagulation,”Haemophilia and Other Inherited Bleeding Disorders, Rizza C and Lowe G, eds, London: WB Saunders Co, 1997, 291-307.
