Severe Acute Anemia After Liver Transplantation in an Elderly
Jehovah
’
s Witness Treated With High-dose Erythropoietin and Ferric
Carboxymaltose: A Case Report
D.M. Brunettaa,*, J. Kaufmana, G.C. De Santisb, D.F.G. Mesquitac, F.N.O.A. Souzac, and J.H.P. Garciac
aWalter Cantidio University Hospital, Federal University of Ceara, Hematology Division, Fortaleza, Ceará, Brazil;bCenter for Cell Based Therapy, Medical School of Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; andcWalter Cantidio University Hospital, Federal University of Ceara, Liver Transplantation Division, Fortaleza, Ceará, Brazil
ABSTRACT
Background. There is no standard treatment for patients with severe anemia who refuse blood transfusion or cannot receive red blood cells.
Case report. After an orthotopic liver transplantation, an elderly Jehovah’s Witness who refused blood transfusion presented with severe acute anemia with hemorrhagic shock. The calculated red blood cell loss was near 70%. Associated with surgical treatment and sup-portive measures, the patient was treated with high-dose erythropoietin and ferric carboxymaltose.
Results. The patient presented a rapid increase in hemoglobin concentration and retic-ulocyte count with resolution of hemorrhagic shock after the proposed pharmacologic treatment combined with local hemostatic measures. She was transferred to a low-risk unit 4 days after transplantation and was discharged from the hospital on day 10. The hemoglobin concentration was normal 35 days after the bleeding event.
Conclusion. This case demonstrated that a protocol with high-dose erythropoietin and ferric carboxymaltose may be an option for patients with severe anemia who refuse blood transfusion or cannot receive red blood cells.
O
NLY a few patients are reported to have survived great losses of blood without transfusion, and most pub-lished cases refer to Jehovah’s Witnesses [1e5]. The chal-lenge posed by treating Jehovah’s Witnesses has provided major information in the medical literature on bloodless medicine[3,4,6]. The odds of death increase 2.5 times for each gram decrement in postoperative hemoglobin con-centration (Hb), with mortality becoming extremely high among individuals with an Hb below 5 g/dL[3].A retrospective cohort study of surgical patients who declined red blood cell (RBC) transfusions for religious reasons and died with an Hb concentration of 6 g/dL or less revealed that most patients with an Hb of 3 g/dL or greater had a median of 4.5 days from lowest Hb to time of death [7]. This study concluded that it is imperative that in-dividuals with Hb below 5 or 6 g/dL receive immediate support. Here we report a case of acute severe anemia after liver transplantation in an elderly Jehovah’s Witness.
CASE REPORT
A 62-year-old female Jehovah’s Witness underwent a liver trans-plantation due to autoimmune cirrhosis. Her Child-Pugh score was C10 and her Meld score was 21. Her preoperative Hb was 13.2 g/dL and her INR was 1.78. Before the operation the patient and her family stated that, even in life-threatening circumstances, treatment with blood and any blood-related products, including coagulation factors, was unacceptable. However, she accepted a cell-saver system. She received an ABO-identical liver from a deceased donor. The cava-sparing piggyback technique was used[8]. The transplantation was performed without great losses of blood, with a cell saver recovery of 126 mL. During the operation and her stay in the intensive care unit (ICU), the patient was monitored by use of a three-lead ECG, central venous catheter, oxygen saturation, and urinary catheter.
*Address correspondence to Denise Menezes Brunetta, Rua Capitão Francisco Pedro, 1290, Rodolfo Teofilo, Fortaleza, Ceará 60.430-270, Brazil. E-mail:[email protected]
0041-1345/15
http://dx.doi.org/10.1016/j.transproceed.2015.09.014
ª2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Fig 1. Large arrows denote use of erythropoietin 40,000 UI. Small arrows denote use of erythropoietin 12,000 UI. The stars mean use of ferric carboxymaltose. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase.
After an initially uneventful liver transplantation, the patient was admitted to the ICU in a stable hemodynamic condition. She had been extubated promptly. Her Hb fell from a preoperative level of 13.2 g/dL to 11.1 g/dL after surgery.
Two hours after her admission in ICU, her blood pressure dropped and norepinephrine was started, along withfluids. After approximately 8 hours, life-threatening hemorrhage was detected. Hb fell from 11.1 g/dL to 4.6 g/dL. Hemodynamic stability was achieved by fluid resuscitation and norepinephrine infused at a maximum of 10.2mg/min. During subsequent emergency laparot-omy, a small lesion in the hepatic artery and a leak in the cava anastomosis were identified as the bleeding sources.
The patient was readmitted in ICU with Hb 4.3 g/dL still needing furtherfluid resuscitation. Twenty-four hours after the operation, Hb fell to 3.9 g/dL. She received oxygen by nasal cannula, which was sufficient to maintain her oxygen saturation above 95%. For the next 2 days the norepinephrine infusion was continued in decreasing doses. The calculated red blood cell loss was approxi-mately 70%. Despite the significant drop of Hb, there was no evi-dence of ischemic liver lesion.
Erythropoietic therapy with recombinant human erythropoietin IV (rhEPO) (Eprex; Janssen Inc., Titusville, N.J., United States) 40,000 IU was started on the day after the transplantation and maintained until day 10. After day 10, rhEPO was reduced to 12,000 IU s.c. every other day for 8 more days. In addition to rhEPO, the patient received cobalamin, folic acid, and 2 doses of ferric car-boxymaltose (Ferinject, Vifor Pharma, Zurich, Switzerland) (1 g on day 1 and 500 mg on day 8).
There was a rapid increase in Hb and reticulocyte count (Fig 1). Four days after the hemorrhagic shock, the patient was transferred to a low-risk unit and was discharged from the hospital 10 days after the transplantation, with a Hb of 5.3 g/dL. The patient presented with a normal Hb concentration (12.3 g/dL) 35 days after the bleeding event.
DISCUSSION
RBC transfusion in the context of liver transplantation is subject of many studies [9e12]. The patient in this case report had a classic high-risk profile for transfusion, such as elevated INR and high CTP score[9e12].
Liver transplantation can successfully be performed in Jehovah Witnesses as long as (1) the medical team has extensive expertise in thatfield; (2) the Hb concentration, platelet count, and INR are within appropriate levels; and (3) there is availability of cell saver to minimize blood loss and avoid transfusion [13]. Despite that, how to manage perioperative anemia always must be addressed in this population.
Erythropoietin (EPO) is an essential factor for the sur-vival, proliferation, and differentiation of erythroid pro-genitor cells. Upon binding of EPO to the cell surface receptors, the cells acquire antiapoptotic properties and grow into matured red blood cells [14]. Tissue hypoxemia represents the main cause of and maximum stimulus for increased EPO release[15].
In critically ill patients, the release of proinflammatory mediators results in decreased EPO release, leading to an inadequate erythropoietic response [16]. This might have been diminished or avoided by the use of intravenous
rhEPO. The optimal dose of EPO is still unclear, especially when treating critically ill patients with life-threatening acute blood loss[16].
Besides stimulating erythropoiesis, research in rhEPO has focused on cellular protection against hypoxic and ischemic injury in different tissues[15,17e19]. Erythropoi-etin can provide cellular protection against apoptosis by inhibiting specific cellular protein kinase cascades and plays a specific role in repair and regeneration, including the recruitment of stem cells into the region of damage [17]. The molecular effects of erythropoietin in different tissues may explain why, despite the severe acute anemia, no evident cellular damage occurred. Conversely, one pro-spective trial found no renoprotective effect of rhEPO (1 single of high-dose - 400 U/kg) in patients at risk of developing acute kidney injury after undergoing coronary artery bypass grafting [18], and a review of the published studies concluded that evidence is sparse to support a tissue-protective benefit of rHuEPO in humans [20]. Further clinical trials of EPO, both for the induction of hematopoiesis and in cellular protection in hypoxic condi-tions, are required.
A different approach in this case was the use of ferric carboxymaltose (FCM), a new IV iron formulation with iron content of 24% to 32% [21]. Iron supplied as FCM is quickly provided to different tissues, mainly to the bone marrow, liver, and spleen. FCM is a robust and stable molecule with similar characteristics to ferritin, which min-imizes the release of free iron during its administration, allowing greater iron delivery to tissues and a faster reple-tion of iron stores by a single infusion[21]. Compared with oral iron, the use of FCM increases EPO response and prevents the depletion of iron stores induced by EPO[22]. A meta-analysis of efficacy and safety of FCM stated that it is effective in treating iron deficiency anemia in many chronic conditions, although there is little information about acute blood losses. The review increases the evidence available to support recommendations given for IV iron treatment, but there are limited trial data comparing different IV iron preparations[23].
We believe this protocol may be a good option for the patients who refuse or cannot receive RBC transfusion.
REFERENCES
[1] de Araujo Azi LM, Lopes FM, Garcia LV. Postoperative management of severe acute anemia in a Jehovah’s Witness. Transfusion 2014;54:1153e7.
[2] Shander A, Javidroozi M, Naqvi S, Aregbeyen O, Caylan M, Demir S, et al. An update on mortality and morbidity in patients with very low postoperative hemoglobin levels who decline blood transfusion (CME). Transfusion 2014;54:2688e95.
quiz 2687.
[3] Carson JL, Noveck H, Berlin JA, Gould SA. Mortality and morbidity in patients with very low postoperative Hb levels who decline blood transfusion. Transfusion 2002;42:812e8.
[4] Posluszny Jr JA, Napolitano LM. How do we treat life-threatening anemia in a Jehovah’s Witness patient? Transfusion 2014;54:3026e34.
[5] McCartney S, Guinn N, Roberson R, Broomer B, White W, Hill S. Jehovah’s Witnesses and cardiac surgery: a single in-stitution’s experience. Transfusion 2014;54:2745e52.
[6] Rogers DM, Crookston KP. The approach to the patient who refuses blood transfusion. Transfusion 2006;46:1471e7.
[7] Tobian AA, Ness PM, Noveck H, Carson JL. Time course and etiology of death in patients with severe anemia. Transfusion 2009;49:1395e9.
[8] Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989;210: 649e52.
[9] De Santis GC, Brunetta DM, Nardo M, Oliveira LC, Souza FF, Cagnolati D, et al. Preoperative variables associated with transfusion requirements in orthotopic liver transplantation. Transfus Apher Sci 2014;50:99e105.
[10] Xia VW, Du Braunfeld M, Neelakanta G, Hu KQ, Nourmand H, et al. Preoperative characteristics and intraoperative transfusion and vasopressor requirements in patients with low vs. high MELD scores. Liver Transpl 2006;12:614e20.
[11] Massicotte L, Beaulieu D, Roy JD, Marleau D, Vandenbroucke F, Dagenais M, et al. MELD score and blood product requirements during liver transplantation: no link. Trans-plantation 2009;87:1689e94.
[12] Mangus RS, Kinsella SB, Nobari MM, Fridell JA, Vianna RM, Ward ES, et al. Predictors of blood product use in orthotopic liver transplantation using the piggyback hepatectomy technique. Transplant Proc 2007;39:3207e13.
[13] Garcia JH, Coelho GR, Feitosa Neto BA, Nogueira EA, Teixeira CC, Mesquita DF. Liver transplantation in Jehovah’s Witnesses patients in a center of northeastern Brazil. Arq Gastro-enterol 2013;50:138e40.
[14] Tanaka T, Nangaku M. Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents. Exp Cell Res 2012;318:1068e73.
[15] Nangaku M. Tissue protection by erythropoietin: newfi nd-ings in a movingfield. Kidney Int 2013;84:427e9.
[16] Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:965e76.
[17] Wang L, Di L, Noguchi CT. Erythropoietin, a novel versa-tile player regulating energy metabolism beyond the erythroid sys-tem. Int J Biol Sci 2014;10:921e39.
[18] Dardashti A, Ederoth P, Algotsson L, Bronden B, Grins E, Larsson M, et al. Erythropoietin and protection of renal function in cardiac surgery (the EPRICS Trial). Anesthesiology 2014;121:582e90. [19] Cassis P, Gallon L, Benigni A, Mister M, Pezzotta A, Solini S, et al. Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury. Kidney Int 2012;81:903e18.
[20] Lund A, Lundby C, Olsen NV. High-dose erythropoietin for tissue protection. Eur J Clin Invest 2014;44:1230e8.
[21] Toblli JE, Angerosa M. Optimizing iron delivery in the management of anemia: patient considerations and the role of ferric carboxymaltose. Drug Des Devel Ther 2014;8:2475e91.
[22] Rineau E, Chaudet A, Carlier L, Bizot P, Lasocki S. Ferric carboxymaltose increases epoetin-alpha response and prevents iron deficiency before elective orthopaedic surgery. Br J Anaesth 2014;113:296e8.
[23] Moore RA, Gaskell H, Rose P, Allan J. Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data. BMC Blood Disord 2011;11:4.
