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.
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).
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.
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).
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.
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