Diagnostics
The outcome is a reduced ability to form blood clots which can lead to excessive bleeding if left untreated. Indeed, low fibrinogen levels have been correlated to excessive blood loss during trauma, surgery and to the severity of postpartum haemorrhage, both of which present an increased risk of mortality (Frith et al., 2010; Rainer et al., 2011; Cortet et al., 2012; Gielen et al., 2014; Walden et al., 2014; Liu et al., 2018). Fibrinogen replenishment has been shown to improve outcome and therefore early assessment of fibrinogen levels and activity should be a key consideration for perioperative management (Mallaiah et al., 2015; Matsunaga et al., 2017; Li et al., 2018).
Fibrinogen replenishment may prevent excessive bleeding and save lives. Early assessment of fibrinogen deficiency using reliable and rapid diagnostic tests should therefore be at the forefront of perioperative management.
Figure 10. Quantitative and functional assays for measuring fibrinogen levels and activity. ELISA, enzyme-linked immunosorbent assay; FF, functional fibrinogen; FIBTEM, fibrin-based extrinsically activated test; PT, prothrombin time; ROTEM, rotational thromboelastometry; TEG, thromboelastography.
In this section, we discuss and compare the available diagnostic tools for measuring fibrinogen levels (quantitative assays) and quality (functional assays) (Figure 1). We also highlight recent data on the increasing use and reliability of point-of-care viscoelastic functional assays such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG).
Traditional functional assays
The Clauss assay is the most commonly used assay for measuring fibrinogen function in the clinic (Clauss, 1957; Besser & McDonald, 2016). Other traditional functional assays from which fibrinogen function is derived include prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT) and reptilase time (RT).
Clauss Assay
The Clauss assay, also known as the von Clauss assay, is the most commonly used assay for measuring fibrinogen function in the clinic, with a turnaround time of 30 to 60 minutes (Huissoud et al., 2009; Solomon et al., 2011). Plasma is typically diluted to 1:10 and mixed with a high concentration of thrombin (usually 100 U/mL), phospholipid and calcium, all at body temperature (37°C). Plasma dilution reduces the effect of plasma factors that negatively impact on clotting efficiency during the reaction. The use of a high thrombin concentration ensures that thrombin does not become a limiting factor in the reaction.
Clot formation is measured by the time it takes for the reaction to achieve either:
- an optical density threshold, or
- a mechanical end point that measures the tensile strength of the clot
The latter is measured through loss of contact between a steel ball and a magnetic sensor, the result of their incorporation into the developing fibrin network (Schlimp et al., 2015). To correlate clotting time to fibrinogen levels, the clotting time is placed on to a calibration curve, created using a dilution range of plasma or standard with known fibrinogen concentrations, measured in g/L, plotted against clotting time. Importantly, fibrinogen concentration is inversely proportional to clotting time.
There are limitations to the Clauss assay. Optical density measurements may give false reads when fibrin monomer polymerisation is slow, however the assay is good for detecting weak fibrin formation. The presence of factors such as bile pigment and free haemoglobin can also impact on optical density readings (Mackie et al., 2003). Mechanical end points are sensitive at a low fibrinogen concentration; however, read-outs can be influenced by the presence of heparin, an anticoagulant drug that may have been administered to patients experiencing cardiac complications.
Prothrombin time (PT)-derived fibrinogen assay
The prothrombin time-derived fibrinogen assay, or PT-derived fibrinogen assay, is an indirect measure of fibrinogen concentration (Mackie et al., 2003; Undas et al., 2016). The prothrombin time, which has a normal range of 11 to 13.5 seconds (or international normalised ratio, INR, of 0.8–1.1), is used to estimate fibrinogen levels (Chernecky & Berger, 2013). Note that this normal range is dependent on the presence of vitamin K antagonists such as warfarin and phenprocoumon, which if present, produces an average INR range of 2–3. Like the Clauss assay, a calibration curve is generated using a standard plasma of known fibrinogen concentration measured by optical density. The key difference in this assay is the addition of thromboplastin to the reaction instead of thrombin. Thromboplastin converts prothrombin into thrombin which in turn impacts on fibrinogen conversion to fibrin. This assay is therefore an indirect measure of fibrinogen activity and a key limitation is that the results could be due to either low fibrinogen levels/function, or reduced levels of prothrombin.
Activated partial thromboplastin time (aPTT)-derived fibrinogen assay
Similar to the PT-derived fibrinogen assay, the aPTT-derived fibrinogen assay is an indirect measure of fibrinogen activity (Sobas et al., 2002). For the aPTT assay, platelet poor plasma that has undergone chelation to remove calcium is incubated at 37°C with phospholipid (cephalin), a contact activator (such as kaolin or micronised silica), and calcium in molar excess. Clotting time is measured from the addition of calcium and the aPTT is the time taken to form a fibrin clot with a normal range of 30–40 seconds, measured using optical density. The patient aPTT is used against a fibrinogen standard for estimating fibrinogen levels.
Other traditional methods
Other methods that can give an indication of fibrinogen activity include thrombin time (TT) and reptilase time (RT). Similar to the PT-derived fibrinogen assay, thrombin time is the time it takes for a plasma sample to create a clot when thrombin is added to the reaction, with a normal range of between 12 to 14 seconds (Hoffbrand, 2002; Lillicrap et al., 2009). Prolonged clotting time equates to either a quantitative or qualitative defect in fibrinogen (Hatton, 2008). This assay is particularly sensitive to the presence of heparin. If heparin is present, reptilase is instead added to the reaction in the place of thrombin, effectively giving a readout of reptilase time (RT), the normal range for which is 15 to 20 seconds (Lillicrap et al., 2009).
It is important to note that tests which focus solely on measuring fibrinogen function provide only a fraction of information on the overall haemostatic condition of a patient. To get an overall picture of coagulopathy in the clinic, particularly for cases of acquired fibrinogen deficiency, multiple tests may be needed in conjunction with fibrinogen testing. Decisions on which tests are needed should be influenced by the individual patient circumstance and their comorbidities.
Learn about point-of-care viscoelastic devices such as rotational thromboelastometry (ROTEM) and thromboeslastography (TEG) that can provide a better overview of coagulation, including fibrinogen function and fibrinolysis.
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Point-of-care functional assays
Viscoelastic devices such as rotational thromboelastometry (ROTEM) and thromboeslastography (TEG) measure overall coagulation ability by indicating clotting time, time to maximum clot strength and clot degradation (fibrinolysis) (Peng et al., 2018). They also provide a sensitive readout for the diagnosis of hyperfibrinolysis compared to other techniques such as immunochemical techniques that lack total biomarker specificity.
Since whole bloods can be tested quickly and in real-time with TEG and ROTEM devices, they are increasingly being used as point-of-care tools at the bedside for directing treatment choices made during surgical procedures (Peng et al., 2018). A study on perioperative samples taken from major paediatric surgery patients indicated no significant difference in readings for ROTEM testing carried out at the bedside versus in a laboratory setting, however bedside testing saved an average of 11 minutes compared to laboratory-based ROTEM testing (p<0.001) (Haas et al., 2012). Further, various studies covering cardiac surgery, trauma, postpartum haemorrhage (PPH) and liver transplantation have indicated that point-of-care coagulation testing leads to a reduced need for transfusions, reduced mortality and increased cost-effectiveness (Görlinger et al., 2011; Schöchl et al., 2011; Weber et al., 2012; Kirchner et al., 2014; Spahn et al., 2014; Leon-Justel et al., 2015; Mallaiah et al., 2015; Nardi et al., 2015; Roullet et al., 2015; Whiting et al., 2015; Solomon et al., 2016).
Despite recognition of the potential for the use of viscoelastic devices in the clinic, earlier limitations included ease of use as well as variability and accuracy concerns that were based on limited clinical data (Chitlur et al., 2011, Spahn et al., 2013). Full automation as well as more recent studies indicating improved reliability means that these devices, particularly ROTEM, are increasingly used to guide treatment decisions during medical procedures involving cardiac surgery, liver transplantation and PPH. To reflect this progress, the European Society of Anaesthesiology recommends viscoelastic assays for monitoring coagulation status in cases of peri-operative bleeding (Kozek-Langenecker et al., 2017). The 2019 European guidelines on management of major bleeding and coagulopathy following trauma recommends that resuscitation measures be continued using a goal-directed strategy, guided by the standard laboratory coagulation values and/or viscoelastic methods (Spahn et al., 2019).
Rotational thromboelastometry (ROTEM)
Rotational thromboelastometry (ROTEM) plots multiple aspects of the clotting cascade on to a trace in real-time. Initial indications of clot formation can be read as soon as 7 to 10 minutes following sampling, with full qualitative results available within 20 minutes (Collins et al., 2014). For the reaction, blood is mixed with reagents in a disposable container that has an oscillating sensor pin which detects changes in resistance as the reaction progresses. Greater resistance correlates with clot firmness. The changes in resistance are plotted on to a trace, the shape of which is used to determine readouts for both clot formation and degradation (Figure 2). ROTEM offers multiple channels for reactions that analyse different coagulation components (Crochemore et al., 2017):
- INTEM: activation of intrinsic pathway (contact phase) using ellagic acid (evaluates factors XII, XI, IX, VIII, X, V, II, I and von Willebrand)
- EXTEM: activation of extrinsic pathway using thromboplastin or tissue factor (evaluates factors II, VII, IX, X)
- HEPTEM: like INTEM but with neutralisation of heparin, using heparinase
- FIBTEM (fibrin-based extrinsically activated test): like EXTEM but with addition of cytochalasin D to inhibit platelet function, allowing for the analysis of fibrinogen on clot formation
- APTEM: activation like EXTEM but with addition of aprotinin to inhibit fibrinolysis. APTEM relative to EXTEM gives a true indication of hyperfibrinolysis
The resulting ROTEM trace provides the following values (Figure 2):
- CT (clotting time): time from mixing reagents to clot initiation detected as 2 mm amplitude
- CFT (clot formation time): time from CT to clot firmness of 20 mm amplitude
- alpha angle (α-angle): indication of how fast clot is forming
- A5/A10/A20: amplitude 5/10/20 minutes following CT
- MCF (maximum clot firmness): the maximum amplitude measured on trace
- LI30/LI60: clot lysis index 30/60 minutes following CT
- ML (maximum lysis): fibrinolysis is measured by ML > 15%
Figure 11. Features of plots for rotational thromboelastometry, ROTEM (top half) and thromboelastography, TEG (bottom half) (Adapted from Winearls et al., 2016).
For ROTEM: CT, clotting time; CFT, clot formation time; MCF, maximum clot firmness; LI60, lysis index 60 minutes following CT; ML, maximum lysis. For TEG: R, reaction time; K, clot formation time; MA, maximum amplitude; LY30, percentage lysis 30 minutes following maximum amplitude.
The FIBTEM and the EXTEM/APTEM ratio give an indication of fibrinogen deficiency and hyperfibrinolysis, respectively (Figure 3). The FIBTEM protocol assesses the impact of fibrinogen on clot formation with a readout of maximum clot firmness (MCF). In this reaction, a platelet inhibitor (cytocholasin D) is added to the reaction to remove the effect of platelet variation on the MCF readout (Bolliger et al., 2012). Correlation studies indicate that MCF readouts correlate positively with Clauss measurements for fibrinogen levels during cardiac surgery (Mace et al., 2016; Tirotta et al., 2019; ) liver transplantation (Roullet et al., 2010; Song et al., 2014; Hashir et al., 2019) and postpartum haemorrhage (Huissoud et al., 2009; Solomon et al., 2012; van Rheenan-Flach et al., 2013; Collins et al., 2014; Gillisen et al., 2019).
Figure 12. ROTEM and TEG traces for normal patient, patient with fibrinogen deficiency or fibrinolysis. (Adapted from Zostautiene et al., 2017; ROTEM, 2019).
The ROTEM EXTEM and APTEM protocols were found to be comparable to the standard euglobulin lysis time in accurately indicating ongoing hyperfibrinolysis in less than 15 minutes (Levrat et al., 2008). The APTEM reaction uses aprotinin to inhibit fibrinolysis whereas the EXTEM reaction does not. EXTEM viewed in the context of APTEM allows for accurate assessment of changes in EXTEM that can be attributed to hyperfibrinolysis. Roullet et al concluded that ROTEM EXTEM was useful for understanding overall coagulation during liver transplantation, and that the A10 value could guide platelet and fibrinogen transfusion (Roullet et al., 2010).
Despite the promise of these devices, some studies have highlighted both variability and accuracy issues in some contexts (Hunt et al., 2015; Seo et al. 2015; Blasi et al., 2017). For instance, Blasi et al indicate that FIBTEM MCF is not a good indicator of plasma fibrinogen after graft reperfusion during liver transplantation (Blasi et al., 2017). Whilst there have been recent improvements in the devices, such as full automation to remove user variability, more studies are required to understand the full potential for ROTEM in assessing fibrinogen and hyperfibrinolysis in specific clinical contexts.
Thromboelastography (TEG)
Similar to ROTEM, a thromboelastograph (TEG) depicts clot time, clot formation, clot stability and clot degradation, effectively plotting the interaction between fibrinogen, platelets and other clotting factors (Curry & Pierce, 2007; Hunt et al., 2015) (Figure 2). The functional fibrinogen (FF) assay of TEG measures the stability of polymerised fibrin. Platelets also contribute to clot strength and is a factor that varies depending on the individual patient situations. For this reason, the FF reaction is treated with the glycoprotein IIb/IIIa platelet inhibitor abciximab to eliminate the effect of platelet variation on the FF readout.
ROTEM is based on TEG, however unlike ROTEM which uses an optical detector, a torsion wire is used to measure clot formation in TEG. TEG also initiates movement through rotation of the cuvette, rather than the pin. The interpretation for ROTEM and TEG results is similar but they are not interchangeable, and there is evidence that they can yield differing results, particularly for fibrin clotting ability (Solomon et al., 2012; Rizoli et al., 2016) (Table 1). The outcome for TEG is a trace that is directly related to clot strength and allows for the assessment of different coagulation states; however, the nomenclature is somewhat different to that of ROTEM.
- R value (reaction time): The time taken from start until TEG amplitude reaches 2 mm, which corresponds to fibrin formation. Note that this time is prolonged in severe hypofibrinogenaemia.
- K value (clot formation time): The time taken from R-time until TEG amplitude reaches 20 mm, which corresponds to clot firmness. Note that this time is prolonged in cases of hypofibrinogenaemia.
- α-angle: Angle formed between the middle of the trace and a line drawn between the R and K-values. This is a function of the rate of fibrin polymerisation and is decreased in hypofibrinogenaemia.
- MA (maximum amplitude): Highest amplitude achieved which is representative of maximum clot strength. This is decreased in the case of hyperfibrinolysis.
- LY30/A30: a measurement of the percentage lysis 30 minutes following the maximum amplitude.
Table 1: Reference values for rotational thromboelastometry, ROTEM and thromboelastography, TEG (adapted from Walsh et al., 2011; ROTEM, 2019).
TEG MA readings for fibrinogen have been positively correlated to fibrinogen levels measured using the standard Clauss assay in a trauma (Harr et al., 2013; Kornblith et al., 2014; Meyer et al., 2014; Meyer et al., 2015; Peng et al., 2018) and liver transplantation setting (Yang et al., 2014). For cardiac surgery patients, the correlation is less clear. Some studies indicate a moderate correlation between TEG MA and Clauss fibrinogen levels (Fluger et al., 2011; Fluger et al., 2012; Gautam et al., 2017) whereas at least one study indicated that there is no correlation (Agarwal et al., 2015).
Whilst functional fibrinogen assays provide an indication of how much active fibrinogen is present in a patient sample, quantitative fibrinogen assays provide a better indication of the levels of fibrinogen present.
Other point-of-care devices
The latest point-of-care devices are being designed with the emergency setting in mind. One such device is the HemoSonics Quantra® which uses novel patented ultrasound technology (sonic estimation of elasticity via resonance, SEER) to measure clot stiffness. This new technology means that readings supposedly remain accurate even in the presence of vibration. The device is small, performs automatic quality checks every 8 hours, and uses a blood collection cartridge that negates the need for sample handling. New devices such as the HemoSonics Quantra® also aim to minimise decision-making and simplify display, both time-saving measures.
Learn about traditional functional assays such as the Clauss assay and the PT-derived assay in the traditional functional assays tab of this section. For more on quantitative fibrinogen assays, such as ELISA and clottable protein assay that are used to confirm congenital fibrinogen deficiencies, see the quantitive fibrinogen assays in the next tab in this section.
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Quantitative fibrinogen assays
Quantitative measurement of fibrinogen can be carried out using various immunological assays and the clottable protein assay (Mackie et al., 2003). It is important to note that whilst these assays give an indication of how much fibrinogen is present, they do not give an indication of the functional activity of fibrinogen. They are therefore used alongside functional assays to determine fibrinogen levels and activity, and are most often used to confirm suspected cases of congenital fibrinogen deficiency alongside genetic analysis.
Immunological assays
Immunological assays allow for quantitative measurements since they detect antigen, however it is not possible to distinguish between functional and non-functional protein. They are also time consuming and can take many hours to complete. They are therefore not regularly used to diagnose fibrinogen deficiency in acute settings; however, they are often used to confirm congenital fibrinogen deficiency. The enzyme-linked immunosorbent assay (ELISA) is the most accurate and widely used immunological assay compared to other techniques such as electrophoretic techniques, radial immunodiffusion, rapid latex agglutination, immune turbidimetry and nephelometry (Mackie et al., 2003; Chen et al., 2010). Polyclonal antibodies are generally utilised for these assays to ensure full coverage of fibrinogen protein; however, monoclonal antibodies that are specific to non-proteolysed fibrinogen are also available. The latter allows for the identification of fibrinogen that has not been processed through plasmin digestion and gives a better indication of functional fibrinogen levels.
Clottable protein assay
A clottable protein assay can be used to determine clot weight. In this assay, thrombin is added to patient sample plasma in the absence of calcium ions. The resulting clot is washed and treated with alkaline urea for protein measurement by spectrophotometry (Ratnoff & Menzie, 1951; Jacobsson et al., 1955, Blomback & Blomback, 1956). Since fibrin is the only protein in the clot structure, the protein concentration achieved is related directly to the amount of fibrin present in clots. This diagnostic test is therefore highly accurate and is often used to confirm congenital fibrinogen deficiencies; however, it is not used as a standard diagnostic test since it is a time-consuming and laborious technique (Mackie et al., 2003).
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