Anemia as a potential contributor to bleeding in patients with liver disease – Neglected but not forgotten
Authors: Ton Lisman, Stephen H. Caldwell, Robert J. Porte
Journal: Journal of Hepatology (2010)

Anemia – The overlooked factor in bleeding related to liver diseaseJournal of HepatologyVol. 54Issue 3PreviewSeveral elegant studies, summarised in their review by the Coagulation in Liver Disease Study Group, have helped in changing the paradigm of bleeding related to liver disease, from abnormal coagulation profile to haemostatic alterations secondary to portal hypertension, endogenous heparinoids, sepsis, and renal failure [1]. However, one of the key omissions in this respect is the role of anemia in worsening the haemorrhagic tendency of liver dysfunction. Anemia is common in individuals with chronic liver disease and is likely to be of multifactorial etiology including folate deficiency, hypersplenism, hemodilution, haemolysis, bone marrow suppression due to viruses or ethanol, renal insufficiency, and, most importantly, variceal bleeding. Full-Text PDF Open Access We appreciate the interest of Dr. Thachil in our recently published meeting report on coagulation disorders in patients with liver disease [[1]Lisman T. Caldwell S.H. Burroughs A.K. Northup P.G. Senzolo M. Stravitz R.T. et al.Hemostasis and thrombosis in patients with liver disease: the ups and downs.J Hepatol. 2010; 53: 362-371Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. Dr. Thachil states that the anemia of liver disease may be important in the bleeding manifestations in these patients, with which we fully agree. The role of anemia was simply not discussed during the 3rd International Symposium on Coagulopathy and Liver disease, highlights of which were summarised in the meeting report. Whereas the omission of the role of anemia in the conference programme is the responsibility of us as conference organisers, we have made a case for the role of anemia in the coagulopathy of liver disease in previous publications [2Lisman T. Adelmeijer J. de Groot P.G. Janssen H.L. Leebeek F.W. No evidence for an intrinsic platelet defect in patients with liver cirrhosis-studies under flow conditions.J Thromb Haemost. 2006; 4: 2070-2072Crossref PubMed Scopus (47) Google Scholar, 3Lisman T. Leebeek F.W.G. de Groot P.G. Haemostatic abnormalities in patients with liver disease.J Hepatol. 2002; 37: 280-287Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. We fully agree that red cells are important in the hemostatic process, in particular due to the effects of red cells on platelet attachment to the damaged vasculature in flowing blood. In fact, experimental evidence from us and others has indicated that anemia is a key factor in platelet hypofunction studied in ex vivo experimental models [2Lisman T. Adelmeijer J. de Groot P.G. Janssen H.L. Leebeek F.W. No evidence for an intrinsic platelet defect in patients with liver cirrhosis-studies under flow conditions.J Thromb Haemost. 2006; 4: 2070-2072Crossref PubMed Scopus (47) Google Scholar, 4Escolar G. Cases A. Vinas M. Pino M. Calls J. Cirera I. et al.Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100): influence of hematocrit elevation.Haematologica. 1999; 84: 614-619PubMed Google Scholar]. Furthermore, as also mentioned by Dr. Thachil, correction of anemia in patients with renal disease by red cell transfusion or administration of erythropoietin appears to reduce uremic bleeding. Nevertheless, we do believe clinical evidence supports the concept of ‘rebalanced hemostasis’ in liver disease [[5]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 116: 878-885Crossref PubMed Scopus (413) Google Scholar]. More and more centers report that a large proportion of patients can undergo a liver transplantation without any requirements for blood product transfusion despite persistent perioperative anemia (reviewed in [[5]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 116: 878-885Crossref PubMed Scopus (413) Google Scholar]). The rebalanced hemostasis theory explains these observations by the presence of compensatory factors for thrombocytopenia (high levels of von Willebrand factor) and decreased levels of procoagulant and antifibrinolytic proteins (i.e., decreased levels of anticoagulant and profibrinolytic proteins). No compensatory factor for anemia appears present, although as mentioned in our meeting report, platelet function in vivo could be promoted by a reduced glycocalix on the vascular endothelium. To our knowledge experimental data on a possible role of reduced endothelial glycocalix in promoting platelet function in the anemic and the thrombocytopenic patient with cirrhosis are not available, but experiments testing this hypothesis would be of interest. As discussed in the meeting report, bleeding episodes do occur in patients with liver disease, and also during liver transplantation severe bleeding can on occasion be encountered. Reversal of anemia may thus be of benefit for the patient with liver disease by reducing bleeding risk, and we agree with Dr. Thachil that clinical studies on this issue are worthwhile. We have recently proposed outlines for clinical studies on the prevention of bleeding or thrombosis in patients with liver disease [[5]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 116: 878-885Crossref PubMed Scopus (413) Google Scholar] and agree that randomised controlled studies on reduction of bleeding during invasive procedures by red cell transfusion or administration of erythropoietin and intravenous iron would also be of interest. These studies, however, should carefully assess potential risks associated with these therapeutic strategies. We and others have recently demonstrated that transfusion of red cell concentrates during liver transplantation is associated with increased morbidity and mortality [[6]de Boer M.T. Christensen M.C. Asmussen M. van der Hilst C.S. Hendriks H.G. Slooff M.J. et al.The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation.Anesth Analg. 2008; 106: 32-44Crossref PubMed Scopus (261) Google Scholar]. Accumulating clinical and laboratory evidence suggests that a restrictive transfusion policy, which includes acceptance of a low hematocrit, during liver transplantation is safe and effective (reviewed in [[5]Lisman T. Porte R.J. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences.Blood. 2010; 116: 878-885Crossref PubMed Scopus (413) Google Scholar]). Transfusion of red cell concentrates to patients with liver failure may result in aggravation of portal hypertension, which may even paradoxically induce or facilitate bleeding. These effects demonstrated both experimentally and clinically (reviewed in [[7]Argo C.K. Balogun R.A. Blood products, volume control, and renal support in the coagulopathy of liver disease.Clin Liver Dis. 2009; 13: 73-85Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]) led to recommendations that red cell transfusions be limited in variceal bleeding with a target hemoglobin between 7 and 8 g/dl in the Baveno V criteria [[8]de Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol. 2010; 53: 762-768Abstract Full Text Full Text PDF PubMed Scopus (1096) Google Scholar]. One could argue that a slightly higher value or use of a hematocrit target of 25% might better balance between effective platelet rheology and portal pressure as the initial platelet plug probably plays some role in variceal bleeding cessation, although pressure effects dominate. The effects of red cell transfusion on hemostasis in the patient with liver failure and portal hypertension are thus complex, and clinical studies should, therefore, assess both efficacy and safety. In our opinion, current evidence suggest that a restrictive transfusion policy, which includes restrictive use of red cell concentrates should be standard of care until randomised clinical studies suggest otherwise. Administration of erythropoietin may be a more attractive therapeutic strategy in patients with liver disease, as an unwanted volume expansion is avoided. Moreover, erythropoietin has the advantage of also stimulating thrombopoiesis to some extent [[9]Stohlawetz P.J. Dzirlo L. Hergovich N. Lackner E. Mensik C. Eichler H.G. et al.Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans.Blood. 2000; 95: 2983-2989PubMed Google Scholar]. Nevertheless, erythropoietin has been associated with an increased risk of thrombosis in critically ill patients, which may be of concern [[10]Corwin H.L. Gettinger A. Fabian T.C. May A. Pearl R.G. Heard S. et al.Efficacy and safety of Epoetin Alfa in critically ill patients.N Engl J Med. 2007; 357: 965-976Crossref PubMed Scopus (426) Google Scholar]. In summary, we concur with Dr. Thachil that the anemia of cirrhosis may be linked to bleeding. We welcome clinical studies on anemia reversal to prevent bleeding in these patients, but these studies should take potential side effects into account. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.