Coagulation management during liver transplantation: use of fibrinogen concentrate, recombinant activated Factor VII, prothrombin complex concentrate, and antifibrinolytics
Patients with ESLD, and those undergoing liver transplantation, typically have coagulation abnormalities as a consequence of the liver being the main source of most coagulation factors and inhibitors. In the past, this frequently resulted in haemorrhage and substantial transfusion of allogenic blood components to achieve haemostatic resuscitation.
Improvements in surgical techniques and transfusion protocols have significantly reduced transfusion levels in many liver transplantation centres, however, complications associated with plasma transfusion persist.
Problems with plasma and platelet transfusion
Transfusion of fresh frozen plasma (FFP) has typically been used during liver transplantation. However, pre-thawed plasma units are frequently only available at large medical centres and the additional time required to thaw leads to delays. Furthermore, substantial amounts of plasma are needed to achieve clinically significant increases in procoagulant factors with a resultant increase in the risk of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO). Large transfusion volumes may even increase the risk of bleeding through elevation of capillary and venous pressures, while they can also induce hypocalcaemia and hypothermia leading to impairment of thrombin generation. Meanwhile, the efficacy of plasma transfusion is limited in acidaemia, a condition observed in liver transplant patients due to reduced lactic acid elimination during the anhepatic phase.
While moderate thrombocytopenia (50–75 x 103/μL) is relatively common in ESLD patients (64–84%), severe thrombocytopenia (<50 x 103/μL) is found in only 1% of patients. Platelet transfusion offers limited efficacy, but was associated with a significant increase in early mortality and reduced 1-year graft survival versus non-treatment (Pereboom et al., 2009; Chin et al., 2016). Therefore, platelet transfusion should be reserved for actively bleeding patients during liver transplantation.
The limitations and risks associated with plasma and platelet transfusions mean alternatives should be considered for haemostatic resuscitation in patients undergoing liver transplantation and with moderate-to-severe coagulopathy.
Cryoprecipitates and fibrinogen-rich components
Intraoperative fibrinogen levels can rapidly drop if a patient experiences haemorrhage and is resuscitated with fibrinogen-poor fluids and components such as packed red blood cells (PRBC). Cryoprecipitates, derived from partially thawed FFP, are the conventional means for fibrinogen replacement. However, they are only clinically available in the United Kingdom and North America, and the need to thaw and ABO blood-type match delays their rapid administration during major haemorrhage and large transfusions.
Two fibrinogen concentrates (FC) are commercially available and indicated for the treatment of actively bleeding patients with congenital fibrinogen deficiency. Use of FC is simpler than cryoprecipitates as it can be reconstituted in distilled water and doesn’t require blood-type matching. It has also been shown to offer a more predictable increase in fibrin polymerisation and plasma fibrinogen levels than cryoprecipitates. One study exploring haemostasis in liver transplant patients used FC in patients with a reduced maximal clot firmness (FIBTEM <8 mm). This resulted in 57.5% of patients (n/N = 153/266) receiving FC. In addition, 34.9% of patients (93/266) received prothrombin complex concentrate (PCC) due to having a prolonged clotting time (EXTEM >80 seconds), while plasma transfusion was limited to patients with suspected Factor V and or Factor XI deficiency. Interestingly, in this patient population 85.3% and 71.4% of transplantations were performed without plasma and platelet transfusions, respectively, highlighting the usefulness of factor concentrates when used with pre-defined viscoelastic coagulation testing criteria (Kirchner et al., 2014).
Prothrombin complex concentrates
Purification of vitamin-K dependent clotting factors from plasma allows the preparation of 3-factor (factors II, IX and X) and 4-factor (factors II, VII, IX, and X) PCC. The higher concentration of factors in PCC than plasma allow rapid recovery of vitamin-K dependent factors in warfarin-treated patients. However, with reduced production of factors II, V, VII, IX and X being hallmarks of ESLD, the use of 4-factor PCC may warrant investigation. While the PROTON study is currently assessing the use of PCC in liver transplantation (Arshad et al., 2013) there is currently little efficacy or safety data in this population. However, a case series reported 22 patients with severe liver damage suffering from active bleeding or undergoing invasive procedures who received PCC infusion. Administration of PCC saw normal haemostasis restored in 76% of patients after the first dose, with the remaining patients achieving mildly delayed but sufficient haemostasis and normal haemostasis after the second dose. No PCC-related adverse events including thrombosis were observed (Lorenz et al., 2003). While the incidence of thrombosis with PCC is estimated to be 1.4% in warfarin-treated patients, no difference in thromboembolic events was observed between FC/PCC-treated and nontreated liver transplant patients (Kirchner et al., 2014).
Recombinant Factor VIIa
Recombinant factor VIIa (rFVIIa) promotes the activation of factor IX and X and is indicated for congenital bleeding disorders, such as haemophilia, with inhibitors and factor VII deficiency.
The use of rFVIIa for warfarin reversal is ineffective as thrombin generation is not restored. This is important for patients with ESLD or undergoing liver transplant where bleeding may be due to vitamin K-dependent clotting factor deficiencies. The use of preoperative rVIIa in patients undergoing liver transplantation has shown no (20, 40 or 80 μg/kg) or minimal (60 and 120 μg/kg repeated every 2 hours) benefit on transfusion rates, indicating that rVIIa should not be routinely used in liver transplantation. In addition, prothrombin time/international normalised ratio are not useful measures for its indication or efficacy in ESLD patients (Planinsic et al., 2005; Lodge et al., 2005).
Unlike trauma-associated disease, systemic fibrinolysis during liver transplantation is often transient and not a major predictor of mortality. It is typically observed during the late anhepatic stage and postreperfusion period and the use of antifibrinolytics is supported.
Since the withdrawal of aprotonin from the market, tranexamic acid (TXA) has typically been used, although ε-aminocaproic acid (EACA) is used in North America. While the use of TXA was shown in a meta-analysis and a study of 200 liver transplant patients to reduce the need for transfusions/blood products (Molenaar et al., 2007; Massicote et al., 2012), the use of antifibrinolytic therapy is frequently used sparingly due to fears of intravascular or graft thrombosis. However, a recent propensity-matched, cohort study revealed that TXA-treated patients had reduced PRBC and plasma requirements than non-treated patients without increased incidence of venous thromboses (Badenoch et al., 2017).
A significant number of patients undergoing liver transplantation require plasma transfusion. This review argues that point-of-care-guided FC and PCC administration can restore haemostasis in the majority of liver transplant patients and suggests that antifibrinolytic agents are a valuable adjunct therapy for the stabilisation of fibrin clots. Although these therapies offer a convenient alternative to plasma with a reduced risk of complications such as TRALI and TACO, they have been associated with thromboembolic complications and careful monitoring is required. While the use of FC and PCC offers an interesting alternative to plasma transfusion, randomised clinical trials would provide further clarity on their efficacy and safety profile in this patient population.
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