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Recombinant human activated protein C in a liver transplant recipient in the immediate postoperative period.

The use of recombinant human activated protein C (rhAPC) in patients who have severe sepsis and are at high risk of death has demonstrated a reduction in risk of death in a large randomised control trial (1). This study excluded patients with previous liver transplantation (LT) due to concerns about an increased risk of bleeding (1). rhAPC remains unlicensed for use in patients with previous liver transplantation. We present our experience with the use of rhAPC in a LT recipient who developed severe sepsis in the immediate postoperative period, when the risk of bleeding is higher due to underlying coagulopathy.

The patient was a 63-year-old man with a history of end-stage alcoholic liver disease and co-existing hepatocellular carcinoma, type 2 diabetes and previous spontaneous bacterial peritonitis. His transplant was complicated by extensive adhesions and associated massive haemorrhage. Unfortunately, over the next 12 hours he developed sepsis of unknown origin with associated multi-organ system failure. Treatment consisted of broad-spectrum antibiotics, fluid replacement, a very high level of inotropic support, mechanical ventilation and continuous renal replacement therapy. In the presence of severe circulatory failure along with progressive organ dysfunction unresponsiveness to standard therapy, it was decided to administer rhAPC. The patient's family was informed of the major risk of serious bleeding and consent was obtained.

At the initiation of the rhAPC infusion at 22 hours post-LT, the patient's coagulation profile was slightly abnormal (platelet count 57000 /[mciro]l, international normalised ratio 2.4, prothrombin time 28 seconds and activated prothrombin time 97 seconds). Fresh frozen plasma and platelets were administered to correct these values. Following the rhAPC infusion, the patient demonstrated progressive haemodynamic improvement and the inotropes were slowly weaned. In addition, the patient's oxygen requirements and lactate levels decreased steadily. As the patient's condition improved, he was weaned off the ventilator and renal function gradually returned to normal. He was discharged from the ICU on the 15th postoperative day and discharged from hospital on the 51st postoperative day.

Sepsis is the leading cause of early mortality during the postoperative period in LT recipients. This is usually due to the associated inflammatory cascade which can result in endovascular injury, microvascular thrombosis, organ failure and death1. PostLT patients with severe sepsis and multiorgan failure may benefit from the use of rhAPC, as it has the overall potential to markedly reduce the generalised inflammatory response. In vitro data suggest that rhAPC inhibits cytokine release from monocytes and reduces selectin-mediated 'rolling' of neutrophils on activated endothelium (2). rhAPC also inhibits factor VIIIa and factor Va, resulting in a reduction in thrombin levels (3). This directly results in decreased fibrin deposition and may limit microvascular thrombosis. In animal studies, rhAPC has been also shown to reduce liver and kidney injury by reducing renal endothelial and hepatocyte apoptosis as well as hepatic and renal tubular necrosis following reperfusion (4). This effect can provide an extra benefit in LT patients.

There are, however, few published reports on the use of rhAPC in this group of patients. Serious bleeding is a worrisome complication of rhAPC administration and is theoretically more likely to occur in patients predisposed to bleeding, such as septic post-LT patients. However, despite the perceived high risk of intracranial haemorrhage, we are aware of only one case report of a severe intracranial haemorrhage with a fatal outcome in a LT recipient treated with rhAPC (5). Furthermore, intra-cranial haemorrhage is a known complication of LT even in the absence of anticoagulant treatment (5).

A few reports in the literature discuss the use of rhAPC in the treatment of late onset sepsis in LT patients (6). In these reports, all the patients except one (who developed an intracranial haemorrhage and died), recovered from sepsis-induced circulatory failure (5).

We conclude that rhAPC can be considered for use in the management of septic shock in the immediate postoperative period of critically ill liver transplant patients who do not respond to standard treatment and are at high risk of death. However, there is a need to be vigilant to avoid bleeding complications in this group of patients, and the importance of this cannot be over-emphasised.


(1.) Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709.

(2.) Grinnel BW, Herman RB, Yas SB. Human protein C inhibits selectin-mediated cell adhesions: role of unique focosylated oligosaccharide. Glycobiology 1994; 4:221-225.

(3.) Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of human factor VII procoagulant by activated human protein C and its analogy to factor V. Blood 1984; 63:486-489.

(4.) Park SW, Chen SW, Kim M, D'Agati VD, Lee HT. Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice. Kidney Int al 2009; 76:739-750.

(5.) Hudcova J, Schumann R. Fatal outcome in a liver transplant recipient treated with activated protein C. Liver Transpl 2009;15:1901-1902.

(6.) Kulkarni S, Naureckas E, Cronin DC 2nd. Solid-organ transplant recipients treated with drotrecogin alfa (activated) for severe sepsis. Transplantation 2003; 75:899-901.

V. Rewari

Z. B. Milan

M. Attia

M. Davies

Leeds, United Kingdom
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Title Annotation:Correspondence
Author:Rewari, V.; Milan, Z.B.; Attia, M.; Davies, M.
Publication:Anaesthesia and Intensive Care
Article Type:Letter to the editor
Date:Jul 1, 2011
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