Anemia – The overlooked factor in bleeding related to liver disease
Authors: Jecko Thachil
Journal: Journal of Hepatology (2010)

Hemostasis and thrombosis in patients with liver disease: The ups and downsJournal of HepatologyVol. 53Issue 2PreviewPatients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. Full-Text PDF Anemia as a potential contributor to bleeding in patients with liver disease – Neglected but not forgottenJournal of HepatologyVol. 54Issue 3PreviewWe appreciate the interest of Dr. Thachil in our recently published meeting report on coagulation disorders in patients with liver disease [1]. 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 [2,3]. Full-Text PDF Open Access Several 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]Lisman T. Caldwell S.H. Burroughs A.K. Northup P.G. Senzolo M. Stravitz R.T. et al.Coagulation in liver disease study group. 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 (276) Google Scholar]. 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. How anemia would worsen the bleeding tendency in these patients has not been directly studied but several factors are responsible. Firstly, anemia worsens the hyperdynamic circulation, the key pathogenetic feature of portal hypertension [[2]Cirera I. Elizalde J.I. Piqué J.M. Feu F. Casadevall M. Goldin E. et al.Anemia worsens hyperdynamic circulation of patients with cirrhosis and portal hypertension.Dig Dis Sci. 1997; 42: 1697-1702Crossref PubMed Scopus (32) Google Scholar]. This is possibly due to the reduction in blood viscosity but some evidence for the role of the vasodilator nitric oxide (NO) has also been suggested [[3]Anand I.S. Chandrashekhar Y. Wander G.S. Chawla L.S. Endothelium-derived relaxing factor is important in mediating the high output state in chronic severe anemia.J Am Coll Cardiol. 1995; 25: 1402-1407Abstract Full Text PDF PubMed Scopus (99) Google Scholar]. As demonstrated in experimental animals, NO may also play a central role in the systemic and splanchnic vasodilation associated with portal hypertension with increased vascular responses to specific inhibitors of NO biosynthesis [[2]Cirera I. Elizalde J.I. Piqué J.M. Feu F. Casadevall M. Goldin E. et al.Anemia worsens hyperdynamic circulation of patients with cirrhosis and portal hypertension.Dig Dis Sci. 1997; 42: 1697-1702Crossref PubMed Scopus (32) Google Scholar]. Secondly, there is evidence that red blood cells not only have passive, rheological effects on blood coagulation but also actively stimulate thrombin generation [[4]Horne III, M.K. Cullinane A.M. Merryman P.K. Hoddeson E.K. The effect of red blood cells on thrombin generation.Br J Haematol. 2006; 133: 403-408Crossref PubMed Scopus (104) Google Scholar]. The best example of the haemostatic role of red cells is represented by the increased thrombotic tendency of polycythemia and erythropoiesis-stimulating agents. Interestingly, a small prospective study of 42 patients with chronic anemia (unrelated to liver disease) shown an unexplained improvement in the activated partial thromboplastin time but not in the prothrombin time measured before and after the transfusion of packed red cells [[5]Ho C.H. The hemostatic effect of packed red cell transfusions in patients with anemia.Transfusion. 1998; 38: 1011-1014Crossref PubMed Scopus (63) Google Scholar]. By far, the most likely explanation for the bleeding tendency with anemia is the effect of red cells on platelet function. Red cells release adenosine diphosphate which promotes platelet aggregation and also stimulates platelet synthesis of thromboxane A2, a key platelet activator during vessel injury. Haemoglobin could also play an important role because of its high affinity for NO. The reduced NO scavenging, caused by the reduced level of haemoglobin in anemia, activates guanylyl cyclase and further impairs platelet aggregation. Moreover, in normal physiological states, red cells, being the largest cells, tend to occupy the central part of the vasculature, pushing the platelets nearer to the vessel wall, where they are poised to respond to injury. In anemic states, the concentration of platelets in proximity to the endothelium is reduced thus affecting the haemostatic process. The beneficial effect of red cells on platelet function was first reported by Duke in 1910 but was conclusively proved by Hellem who examined anemic patients with bleeding defects showing a decrease in bleeding time (BT) upon transfusion of washed red cells [[6]Hellem A.J. Borchgrevink C.F. Ames S.B. The role of red cells in haemostasis: the relation between haematocrit, bleeding time and platelet adhesiveness.Br J Haematol. 1961; 7: 42-50Crossref PubMed Scopus (167) Google Scholar]. This observation has been more recently confirmed, when improved BT after red cell transfusions were observed in experimental and clinical subjects with continued thrombocytopenia and in uremic patients with bleeding tendency and normal platelet counts [7Blajchman M.A. Bordin J.O. Bardossy L. Heddle N.M. The contribution of the haematocrit to thrombocytopenic bleeding in experimental animals.Br J Haematol. 1994; 86: 347-350Crossref PubMed Scopus (100) Google Scholar, 8Livio M. Marchesi D. Remuzzi G. Gotti E. Mecca G. deGaetano G. Uraemic bleeding: role of anaemia and beneficial effect of red cell transfusions.Lancet. 1982; 2: 1013-1015Abstract PubMed Scopus (302) Google Scholar]. One of the possible negative arguments for these studies would be the assessment of BT rather than further bleeding episodes, with red cell replacement. BT is prolonged in cirrhotics to variable extent, although the exact cause for this phenomenon has never been explained, especially when there was no negative correlation between platelet counts and BT, and an abnormal VonWillebrand factor was not seen in these patients [[9]Mannucci P.M. Vicente V. Vianello L. Cattaneo M. Alberca I. Coccato M.P. et al.Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time.Blood. 1986; 67: 1148-1153PubMed Google Scholar]. In this context, it is useful to remember that BT is not just a measure of platelet function but is also influenced by red cell volume, blood urea concentration, and strength of the vascular connective tissue. Although platelet dysfunction in liver disease has been experimentally shown to be balanced by increased highly active VonWillebrand factor multimers, the aforementioned remaining factors (especially correctable anemia), have not been considered [[1]Lisman T. Caldwell S.H. Burroughs A.K. Northup P.G. Senzolo M. Stravitz R.T. et al.Coagulation in liver disease study group. 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 (276) Google Scholar]. Studies on a favourable outcome on bleeding with treatment of anemia in liver disease are worthwhile, especially as similar measures have hugely benefited patients with renal impairment treated with erythropoietin and intravenous iron. Homoncik and colleagues have conducted a randomized, double-blind, placebo-controlled trial of erythropoietin in 22 thrombocytopenic patients with alcoholic liver cirrhosis and have found higher platelet counts and platelet reactivity by flow cytometry in these patients with a more pronounced effect in presence of lower platelet counts [[10]Homoncik M. Jilma-Stohlawetz P. Schmid M. Ferlitsch A. Peck-Radosavljevic M. Erythropoietin increases platelet reactivity and platelet counts in patients with alcoholic liver cirrhosis: a randomized, double-blind, placebo-controlled study.Aliment Pharmacol Ther. 2004; 20: 437-443Crossref PubMed Scopus (44) Google Scholar]. In summary, although “blood component” (plasma products) transfusion may indeed be harmful in liver patients with bleeding tendency, strong consideration should be made for “blood” transfusion, despite its rare adverse effects. It is also worthwhile assessing the response to iron replacement and/or erythropoietin administration in selected patients (bearing in mind thrombotic potential) on the bleeding risk associated with liver disease. 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.