Thrombin Time and Fibrinogen Evaluation

Physiologic Role of Fibrinogen

Fibrinogen is a plasma glycoprotein with a multitude of activities in the hemostasis system. The protein is a product of three genes FGA , FGB , and FGG and is primarily synthesized by hepatocytes, although extrahepatic fibrinogen synthesis has been observed in lung, kidney, and other tissues. Fully assembled fibrinogen is a hexamer of three dimers Aα, Bβ, and γ chains. The nomenclature refers to the small polypeptides A and B that are cleaved from Aα and Bβ chains by thrombin during conversion of fibrinogen to fibrin (see Chapter 115 ).

In addition to the plasma fibrinogen pool, the protein is also stored in the platelet alpha granules. The platelet fibrinogen pool provides a localized boost in fibrinogen concentration at the site of platelet activation. Fibrinogen serves as a scaffold for platelet aggregation via the activated form of integrin αIIbβ3 (also known as glycoprotein IIb/IIIa). Platelet aggregation via fibrinogen cross-linking provides an initial hemostatic barrier following blood vessel injury as part of the rapid primary hemostatic response. Subsequently, thrombin activation on the platelet surface leads to conversion of fibrinogen to fibrin and the formation of a more durable hemostatic barrier consisting of platelets and fibrin. During the conversion of fibrinogen to fibrin, thrombin cleaves fibrinopeptides A and B from fibrinogen Aα and Bβ chains, respectively, forming so-called fibrin monomers. Fibrin monomers polymerize into a noncovalently linked, staggered, linear network that stabilizes the initial platelet plug. Fibrin fibers are subsequently covalently cross-linked by activated factor XIII, a step that prevents premature dissolution of the fibrin clot. Subsequent degradation of fibrin requires action of plasmin. Paradoxically, fibrinogen also possesses antithrombotic activity, as it sequesters thrombin at nonsubstrate sites. Thus lack of fibrinogen in afibrinogenemia can lead to hemorrhagic and thrombotic complications. Dysfibrinogenemia can also present as either hemorrhagic and/or thrombotic complications, as abnormal fibrin results not only in defective clots but also may be resistance to plasmin cleavage and lysis.

Clinical Significance

Functional fibrinogen concentration is an important physiologic parameter. The normal concentration of clottable fibrinogen is approximately 150–400 mg/dL of plasma, although the normal ranges may vary somewhat from laboratory to laboratory and from method to method. A substantial decrease in clottable fibrinogen below 100 mg/dL can lead to hemorrhage, as fibrinogen becomes a limiting reagent in the formation of a hemostatic plug. Functional fibrinogen concentrations above 150–200 mg/dL may be needed for optimal hemostasis in the setting of trauma resuscitation and major surgery.

Hemostatic function of fibrinogen can be compromised by either quantitative or qualitative changes in the molecule. Substantial quantitative abnormalities of fibrinogen are most often acquired. Dramatic declines in fibrinogen concentrations are frequently seen in conditions of hemostatic stress, such as significant trauma, hemorrhage, and disseminated intravascular coagulation (DIC). Low fibrinogen level in the setting of trauma is an independent predictor of poor survival. Severely compromised liver synthetic function due to synthesis inhibitor antileukemic drug l -asparaginase, and occasionally liver failure can also significantly reduce fibrinogen concentrations. Congenital decrease in fibrinogen concentration due to mutations in fibrinogen genes leading to hypofibrinogenemia or afibrinogenemia is rare.

Increased fibrinogen concentration is most often seen in inflammation. Fibrinogen is a classic acute phase reactant. Hepatic synthesis of fibrinogen can increase up to 20-fold from baseline levels under conditions of severe stress. Genetic and environmental factors can also play a role in a subset of patients with high fibrinogen concentration. Persistently elevated fibrinogen levels have been linked to atherosclerosis risk.

Qualitative fibrinogen defects (dysfibrinogenemia) can be either congenital or acquired. Acquired dysfibrinogenemia is frequently seen in liver disease due to aberrant fibrinogen with increased amount of sialic acid. This modification is similar to fetal fibrinogen and likely has only modest, if any effect on bleeding risk. Dysfibrinogenemia associated with kidney disease such as nephrotic syndrome and renal cell carcinoma has also been reported. Congenital disorders of fibrinogen are discussed in Chapter 115 .

Testing Overview