Treatment
Depending on the strategy of volume resuscitation, it is often further diluted. Fibrinogen is also reduced (hypofibrinogenaemia), not detectable (afibrinogenaemia) and/or non-functional (dysfibrinogenaemia) in patients with congenital fibrinogen deficiencies. Since fibrinogen deficiencies are known to be associated with an increased risk of excessive bleeding and mortality, treatment involves fibrinogen replacement. Fibrinogen replacement therapies include fresh frozen plasma (FFP), cryoprecipitate and fibrinogen concentrate (FCH), which has been shown to be at least as effective as cryoprecipitate.
Fibrinogen concentrate is at least as effective as cryoprecipitate for treating fibrinogen deficiency; however, practical and safety differences exist.
Here, we highlight clinical trial data on fibrinogen replacement therapies for different clinical settings and introduce practical considerations comparing safety, storage and speed of delivery.
Fresh frozen plasma
Fresh frozen plasma (FFP) is the most commonly used source of coagulation factor replenishment. FFP is prepared by centrifugation of carefully obtained whole blood and contains fibrinogen at a variable concentration of 0.6 g/300mL unit or 2.0 g/L (range = 0.9 to 3.2 g/L), as well as albumin, protein C, protein S antithrombin and tissue factor pathway inhibitor (Theusinger et al., 2011; Kelley & Guzman, 2018). It is stored by freezing to less than -25°C within 8 hours of collection (Stanworth & Tinmouth, 2009).
FFP can be used to treat fibrinogen deficiencies; however, it has several limitations including a low fibrinogen concentration (Theusinger et al., 2011). Large volumes would therefore need to be administered in the case of severe hypofibrinogenemia, increasing the risk of transfusion related complications such as TRALI (transfusion-related acute lung injury) (Benson et al., 2009). It is therefore not recommended as a treatment option for fibrinogen replenishment and should only be used in the absence of cryoprecipitate or fibrinogen concentrate (Franchini & Lippi, 2012; McDonnell, 2018; Spahn et al., 2019).
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Cryoprecipitate
Cryoprecipitate is a standard treatment in many countries to replenish fibrinogen in cases of acquired fibrinogen deficiency experienced during trauma involving excessive bleeding, PPH and surgery (Nascimento et al., 2014). Like fresh frozen plasma (FFP), standard preparation of cryoprecipitate does not involve pathogen inactivation. Whilst cryoprecipitate is a standard treatment in the UK, USA, Australia and Canada, most European countries have withdrawn cryoprecipitate as a standard treatment due to the risk of transmitting pathogens and the availability of fibrinogen concentrate as an effective and pathogen-free alternative (Sørensen & Bevan, 2010; Nascimento et al., 2014).
Cryoprecipitate is prepared by the controlled thawing of pooled and frozen FFP at a temperature between 1 and 6 °C (Nascimento et al., 2014). In this process, higher molecular weight proteins precipitate and the remaining soluble proteins are removed as supernatant following centrifugation. The precipitate (cryoprecipitate) is resuspended in a small amount (10 to 20 mL) of remaining supernatant to form a concentrated mixture of fibrinogen, von Willebrand factor, factor VIII, factor XIII and fibronectin (Sørensen & Bevan, 2010). The UK guidelines specify that a minimum of 140 mg of fibrinogen is present in each unit of cryoprecipitate (NICE guideline NG24, 2015), however variations in unit volume exist due to differences in donor fibrinogen levels and cryoprecipitate preparation (Nascimento et al., 2014). Adults are commonly given 200 mL of cryoprecipitate which equates to 2 pools of 5 units each, with an average fibrinogen concentration of 15–17 g/L (Wong & Curry, 2018). This is enough to raise plasma fibrinogen levels by approximately 1 g/L.
Learn more on how cryoprecipitate compares to fibrinogen concentrate for treating fibrinogen deficiency and the associated practical considerations for both treatments in the next sections.
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Fibrinogen concentrate (FCH)
Fibrinogen concentrate is a single-factor treatment purified from pools of human plasma and processed further into a powder that allows for easy storage and reconstitution at administration. It is approved for the treatment and prophylaxis of congenital fibrinogen deficiencies such as afibrinogenaemia and hypofibrinogenaemia in many countries including the UK, USA, Canada, Australia and many other European countries (Costa-Filho et al., 2016). It is also approved in Brazil, Uruguay, Taiwan and some European countries such as Germany and Austria as the standard treatment for acquired fibrinogen deficiency experienced during trauma, surgery and postpartum haemorrhage (PPH) (Costa-Filho et al., 2016).
Human fibrinogen concentrate (FCH) is obtained through Cohn fractionation of pooled human plasma. The resulting fraction has high purity and allows for accurate dosing since a defined dose is filled per vial. Reconstitution with sterile water to the desired final concentration for infusion is fast and allows for lower infusion volumes compared to FFP and cryoprecipitate. This latter characteristic reduces the risk of complications related to high transfusion volumes. An additional routine step in the manufacture of fibrinogen concentrate is viral inactivation using techniques such as heat treatment, pasteurisation, nanofiltration, treatment with solvent detergents or a combination of these techniques. This ensures that the risk of viral contamination during treatment remains minimal. The half-life of fibrinogen concentrate was determined as approximately 77 hours in patients of congenital fibrinogen deficiency (Idris et al., 2014). A requirement for repeated doses therefore indicates high levels of fibrinogen consumption or limited production.
There has been recent interest in better understanding the usefulness for fibrinogen concentrate, both for the prevention and treatment of severe bleeding episodes. Also, more comprehensive studies to compare fibrinogen concentrate against the standard cryoprecipitate treatment are underway.
FCH for treatment of congenital deficiency
FCH is the approved standard treatment for acute bleeds and as a prophylactic treatment for congenital fibrinogen deficiencies in the UK, USA, Canada, Australia and many European countries (Costa-Filho et al., 2016). This is because FCH is proven to be safe due to viral inactivation and due to the lower volumes required for infusion (Casini et al., 2016). FCH has been shown to be effective and well tolerated for patients of afibrinogenaemia, hypofibrinogenaemia and dysfibrinogenaemia (Kreuz et al., 2005; Manco-Johnson et al., 2009; Peyvandi, 2009; Casini et al., 2016). FCH has also been shown to improve outcomes when used as a prophylactic treatment prior to surgery for congenital fibrinogen deficiency (Bornikova et al., 2011). This benefit needs to be balanced with the risk of thrombolytic complications and supplementation and is therefore restricted to scenarios where bleeding is expected.
FCH for treatment of acquired fibrinogen deficiency
Fibrinogen concentrate is approved for acquired fibrinogen deficiency in Brazil, Uruguay, Taiwan and some European countries such as Germany and Austria (Costa-Filho et al., 2016). Various studies indicate that fibrinogen concentrate may be useful for treating patients with acquired fibrinogen deficiencies experienced during cardiac and other surgeries, postpartum haemorrhage (PPH), trauma, as well as during liver transplantation and more specifically, for dilutional and consumptive coagulopathies.
FCH in cardiac patients
Low plasma fibrinogen is a predictor for excessive bleeding and mortality risk in cardiac surgery patients (Kozek-Langenecker et al., 2017). Whilst the European Society of Anaesthesiology (ESA) guidelines on management of severe perioperative bleeding recommend a trigger level for fibrinogen supplementation of <1.5–2.0 g/L, there is no consensus on the trigger value specifically in a cardiac setting (Kozek-Langnecker et al., 2017). Studies on the management of perioperative bleeding identified a possible trigger value of 2.15 g/L (2–2.2 g/L) fibrinogen for patients experiencing a severe bleed versus 1.15 g/L as a predictive value for developing a severe bleed (Karkouti et al., 2013; Kindo et al., 2014; Ranucci et al., 2016). Target values in a perioperative setting have not been formally assessed, however studies have aimed to achieve ROTEM-FIBTEM values of 22 mm that corresponds to 3.75 g/L (Rahe-Meyer et al., 2009; Ranucci et al., 2011; Solomon et al., 2011; Rahe-Meyer et al., 2013a). These studies were double-blind randomised trials that assumed either that 4 g fibrinogen should increase plasma concentrations by 1 g/L, or that 1 g of fibrinogen should increase FIBTEM by 2 mm in an average weight person. Ranucci and colleagues identified target values of 2.8 g/L for non-bleeding patients and 3.75 g/L for patients with severe bleeds (Ranucci et al., 2016). They further confirmed that the expected dose to raise fibrinogen levels from 1.15 to 2.80 g/L or from 2.15 to 3.75 g/L is 6.8 g of fibrinogen concentrate or 22 units of cryoprecipitate.
The ESA guidelines on management of severe perioperative bleeding further recommend fibrinogen concentrate (FCH) infusion guided by viscoelastic haemostatic assay monitoring to reduce perioperative blood loss (Kozek-Langnecker et al., 2017). The recommendation is based mainly on the clinical trial and study data, outlined below, which indicate that FCH may reduce the need for allogeneic blood transfusion and is generally safe in a cardiac surgery setting.
A retrospective study to assess fibrinogen recovery parameters after administration of FCH to 39 patients with diffuse bleeding after weaning from cardiopulmonary bypass (CPB) during cardiac surgery found that FCH (mean dose = 6.5 g) increased plasma fibrinogen concentration to more than baseline levels (3.3 g/L, maximum clot firmness [MCF] of 15.5 mm), both on the day of infusion (1.9 to 3.6 g/L, MCF from 10.1 to 20.7 mm) and the following day (1.9 to 4.5 g/L, MCF from 10.1 to 22.3 mm) (Figure 13) (Solomon et al., 2010). Furthermore 90% of patients received no intraoperative transfusion of allogeneic blood products after administration of FCH, suggesting that FCH contributed to the correction of bleeding.
Figure 13. Increase in mean fibrinogen levels in patients (n = 39) after fibrinogen concentrate (FCH) infusion following weaning from cardiopulmonary bypass (CPB) (adapted from Solomon et al., 2010).
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Practical considerations for fibrinogen replenishment: a comparison
Unlike FFP and cryoprecipitate, fibrinogen concentrate is a single-factor agent. Despite this, fibrinogen concentrate has been shown to be as effective as FFP and cryoprecipitate, indicating that additional coagulation factors present in FFP and cryoprecipitate are unlikely to impact on treatment outcome for most cases. In terms of replenishment, there appears to be no additional clinical benefit of using fibrinogen concentrate over FFP or cryoprecipitate. The major differentiating factors to consider in the clinic is therefore cost, speed of preparation, storage and safety (Table 5).
Table 5: Comparison of fresh frozen plasma (FFP), cryoprecipitate and fibrinogen concentrate (FCH) (adapted from Wong & Curry, 2018).
FFP and cryoprecipitate are more widely available and cheaper to source than fibrinogen concentrate; however, indirect costs for preparation, transportation, storage and associated wastage are often overlooked and need to be considered in evaluating real-term cost-effectiveness (Sørensen & Bevan, 2010; Nascimento et al., 2014; Wong & Curry, 2018). A recent study calculated that after considering 28% wastage for cryoprecipitate, a further 44% reduction in cost of fibrinogen concentrate or a significant reduction in time spent at ICU would be needed to match the cost of cryoprecipitate (Okerberg et al., 2016). More recently, a cost analysis in the Netherlands found that fibrinogen concentrate is a cost-saving option for the management of bleeding during cardiac surgery when compared to fresh frozen plasma (Kelly et al., 2019). While the acquisition cost was higher for fibrinogen concentrate, other hospital-based costs were found to be lower, leading to a 21.1% reduction in overall cost of FCH compared to FFP (Kelly et al., 2019).
Significant benefits in safety and effectiveness are required to make fibrinogen concentrate economically viable (Wong & Curry, 2018). Product preparation and time to administer impact on the safety of use. The amount of fibrinogen in fibrinogen concentrate is standardised whereas the amount of fibrinogen in cryoprecipitate varies on average between 15–17 g/L but has also been shown to vary drastically from 3–30 g/L (Nascimento et al., 2014; Wong & Curry, 2018). Unlike with FFP and cryoprecipitate, the preparation of fibrinogen concentrate involves viral inactivation and removal of antibodies and antigens that can trigger an allergic response. The former means that fibrinogen concentrate carries a significantly reduced risk of viral infection and the latter eliminates the need for blood group matching. In terms of preparation, FFP and cryoprecipitate require blood group matching and approximately 17–20 minutes for thawing at 30–37°C. Fibrinogen concentrate takes approximately 10 minutes to reconstitute and is administered faster and at lower volumes (100 mL) compared to FFP and cryoprecipitate, thereby reducing the risk of transfusion volume-related complications. Reported adverse events are similar (Wong and Curry, 2018). There are clear advantages for using fibrinogen concentrate over standard cryoprecipitate therapy, however, further studies are needed to ascertain true costs, safety and effectiveness of fibrinogen concentrate compared to cryoprecipitate.
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