Intraoperative administration of 4-factor prothrombin complex concentrate reduces blood requirements in cardiac transplantation

Patients waiting for an OHT have often received a left ventricular assist device (LVAD), a device attached to the left ventricle and aorta to assist in pumping blood out of the heart – as part of this regimen warfarin is typically administered to avoid thromboembolic events. However, when a donor match is found, rapid reversal of anticoagulation needs to be achieved in order to carry out the transplant surgery. Reversal of warfarin can be achieved by administration of vitamin K and fresh frozen plasma (FFP), or a combination of the two. These methods are commonly used in the reversal of anticoagulation, however, they have their limitations. For instance, both methods have significant time limitations – vitamin K to antagonise the effects of warfarin, and FFP to thaw before administration. There is also a risk of transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRIAL) with FFP.

So, what is the alternative? Prothrombin complex concentrate (PCC) has also been approved for warfarin reversal. There are various forms of PCC available, one being the non-activated 4F-PCC which contains high concentrations of vitamin K-dependant clotting factors which have been depleted by warfarin, in addition to low levels of antithrombin III and heparin. A few studies have reported reversal strategies for pre-operative administration in OHT operations (Marthia et al., 2012; Kantorovich et al., 2015; Nuckles et al., 2015; Cleary et al., 2016). One strategy is split dosing, whereby a fraction of the dose is administered pre-operation and the remaining dose is given post-operation, the idea behind this is to minimise bleeding during the operation. The efficacy of split dosing 4F-PCC has been demonstrated through a randomised comparison to FFP, giving half the 4F-PCC dose pre-bypass and the remaining half post-bypass (Demeyere et al., 2010).

Despite the different split dosing strategies for anticoagulation reversal with PCC, the data on its use in cardiac surgery is limited, particularly in the much smaller population of patients undergoing OHT operations. This study by Sun et al., sought to address this retrospectively analysing 74 patients with a pre-existing LVAD undergoing OHT between 2013–2016 and comparing 4F-PCC-mediated and alternative anticoagulation reversal, by measuring blood product utilisation, time to chest closure, Intensive Care Unit (ICU) length of stay, overall length of hospital stay, thrombotic complications, kidney injury, and 30-day mortality rate.

Patients were categorised as being in the 4F-PCC group or no 4F-PCC group. No significant differences were observed in the baseline characteristics of these two groups, including international normalised ratio (INR), heart failure aetiology, and platelet count.

After baseline blood measurements were taken patients received 10 mg of intravenous (IV) vitamin K. A loading dose of 5000 mg aminocaproic acid was then administered followed by an infusion at 1 g/hour. A secondary 5000 mg bolus dose was administered when surgery commenced.

Initiation of heparin anticoagulation began with a 400 unit/kg IV bolus and was closely monitored via activated clotting time (ACT). Finally, protamine sulphate was administered at a dose of 1:1 to the heparin loading dose.

A total of 32 patients received 4F-PCC, with one-third of the dose administered pre-operatively and the remaining two-thirds administered post-operatively after protamine was given. The 4F-PCC dose administered was dependent on the pre-operative INR, rounded to the nearest vial.

• INR 2–4 = 25 units 4F-PCC/kg actual body weight
• INR 4–<6 = 35 units 4F-PCC/kg actual body weight
• INR >6 = 50 units 4F-PCC/kg actual body weight

Interestingly, there was a significant difference in blood product utilisation between the 4F-PCC group and no 4F-PCC groups. Those receiving 4F-PCC required fewer units of cryoprecipitate, FFP, and packed red blood cells compared to those not receiving 4F-PCC (figure 1). This could be of benefit to the patient as there is an increased risk of allosensitisation when administering blood products due to the introduction of antibodies which can lead to transplant organ rejection (Holt et al., 2004).

The time taken to chest closure was also significantly different between the two groups (no 4F-PCC 618.80 ± 11.41 vs. 4F-PCC 547.91 ± 110.08 minutes, p=0.008). Time to chest closure has been a substitute measure for intra-operative bleeding in previous literature (Yan et al., 2014; Dyke et al., 2006), therefore the quicker time may indicate improved patient outcomes in terms of bleeding.

Despite the reduction in time to chest closure and blood product utilisation, no significant differences were seen in ICU length of stay, post-operative length of stay in hospital, 30-day mortality rate, kidney injury, or thrombotic complications – which was predicted to be improved through the administration of 4F-PCC.

The study has demonstrated some hopeful results for the future of 4F-PCC in OHT, no differences were seen in the longer-term outcomes such as length of stay or mortality and therefore further studies are needed to expand upon this research. In addition, the single institution methodology and sample size limits the ability to make safety claims and generalise the results for a wider population. Furthermore, there was no set transfusion algorithm and blood transfusion was at the discretion of the patient care team; this should be developed in future studies to be tailored to individual patient needs.