Lactate dehydrogenase and hemolysis in sickle cell disease
Lactate dehydrogenase and hemolysis in sickle cell disease
From www.bloodjournal.org by guest on October 28, 2014. For personal use only. 2013 122: 1091-1092 doi:10.1182/blood-2013-05-505016 Lactate dehydrogenase and hemolysis in sickle cell disease Gregory J. Kato, Seyed Mehdi Nouraie and Mark T. Gladwin Updated information and services can be found at: http://www.bloodjournal.org/content/122/6/1091.full.html Articles on similar topics can be found in the following Blood collections Red Cells, Iron, and Erythropoiesis (593 articles) Sickle Cell Disease (93 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org by guest on October 28, 2014. For personal use only. BLOOD, 8 AUGUST 2013 x VOLUME 122, NUMBER 6 Laetitia Borsu Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY April Chiu Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY Julie Teruya-Feldstein Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY David M. Hyman Developmental Therapeutics Center, Memorial Sloan-Kettering Cancer Center, New York, NY Marc Rosenblum Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY Contribution: E.L.D., E.P., and M.R. collected the data; E.L.D., O.A.-W., L.B., A.C., J.T.-F., D.M.H., and M.R. analyzed and interpreted the data; E.L.D., O.A.-W., E.P., L.B., J.T.-F., D.M.H., and M.R. wrote the manuscript; and all authors approved the final manuscript. CORRESPONDENCE 1091 Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Eli L. Diamond, Department of Neurology, Memorial SloanKettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: [email protected] References 1. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013;121(9): 1495-1500. 2. Haroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 2012;120(13):2700-2703. 3. Emile JF, Charlotte F, Amoura Z, Haroche J. BRAF mutations in ErdheimChester disease. J Clin Oncol. 2013;31(3):398. 4. Colombino M, Capone M, Lissia A, et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30(20):2522-2529. 5. Wang Y, Velho S, Vakiani E, et al. Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression. Cancer Discov. 2013;3(3):294-307. © 2013 by The American Society of Hematology To the editor: Lactate dehydrogenase and hemolysis in sickle cell disease Dr Ballas has provided a thoughtful perspective on the meaning of elevated serum lactate dehydrogenase (LDH) in sickle cell disease.1 He is clearly correct that serum LDH is generally high at steady state in sickle cell disease and comes from multiple sources, representing damage to cells from several different organs, but this is not the entire story. There are several lines of published data that address the questions he raises concerning the relationship of serum LDH to lysis of red cells. Our publication in Blood 7 years ago clearly documented the LDH isoenzyme data he requests. It showed at steady state an average of 71% of total LDH was derived from a combination of LD1 and LD2, reﬂecting disproportionate elevation of isoenzymes that are consistent with red cell origin.2 In fact, 96% of the specimens had LD1 levels above the expected range; isoforms of liver, muscle, lymphocytes, and platelets were underrepresented in total LDH.2 We also showed that in catheterdrawn specimens processed at bedside to decrease artifactual hemolysis, serum LDH correlated with plasma hemoglobin, a wellaccepted marker of intravascular hemolysis (r 5 0.73, P , .01).2 Although Neely et al carefully measured serum LDH and plasma hemoglobin released during hemolysis and did not assert their correlation,3 current analysis of their original data supports precisely such an association. Using the open-source digitizing software Enguage4 to convert Neely et al’s Figure 2 to digital values for LDH and free hemoglobin, statistical analysis of log-transformed data in GraphPad Prism 5.0 software shows a statistically signiﬁcant Pearson correlation (r 5 0.615, P , .001; Figure 1). Linear regression analysis of log-transformed data suggests that variations in plasma hemoglobin account for approximately 38% of the variation in LDH (P 5 .0004). LDH also strongly correlates with another product of hemolyzing red cells, erythrocyte-derived microparticles, in a study from Amsterdam (r 5 0.59, P , .001).5 A parallel result emerges from our analysis from a transcontinental multicenter trial in which LDH (adjusted for different LDH assays by site) from untransfused sickle cell anemia patients in the highest quartile of hemolytic component correlates with the count of erythrocyte-derived microparticles (r 5 0.36, P 5 .006, n 5 57) and other hemolytic markers.6 Our conclusion from these publications and our own data is that at steady state in adults with sickle cell disease, hemolysis contributes signiﬁcantly but nonexclusively to the serum LDH value. During vaso-occlusive crisis, LDH rises at least in part due to lysis of red cells, as shown by Dr Ballas in deﬁnitive chromium radiolabeling red cell survival studies7 and by several others in which LDH rises as hemoglobin levels fall,7-10 undoubtedly accompanied by variably increased LDH due to lysis of cells from other organs. We all should freely acknowledge the diversity of Figure 1. Correlation of serum LDH with plasma hemoglobin. Plot of data points derived from Neely and colleagues,3 with the solid line representing linear regression and the dashed lines indicating 95% confidence interval. Significance was calculated by Pearson correlation analysis of log-transformed data. From www.bloodjournal.org by guest on October 28, 2014. For personal use only. 1092 CORRESPONDENCE contributory organ LDH sources and prominent variability during transition from steady state to vaso-occlusive crisis, but we should not overlook the disproportionate contribution of red cells during steady state and that serum LDH in part represents intravascular hemolysis and release of plasma hemoglobin. Gregory J. Kato Sickle Cell Vascular Disease Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD Seyed Mehdi Nouraie Center for Sickle Cell Disease and Department of Internal Medicine, Howard University College of Medicine, Washington, DC Mark T. Gladwin Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Vascular Medicine Institute of the University of Pittsburgh, Pittsburgh, PA Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Gregory J. Kato, National Institutes of Health, 9000 Rockville Pike, MSC 1476, Building 10-CRC, Room 5-5140, Bethesda, MD 20892-1476; e-mail [email protected] References 1. Ballas SK. Lactate dehydrogenase and hemolysis in sickle cell disease. Blood. 2013;121(1):243-244. BLOOD, 8 AUGUST 2013 x VOLUME 122, NUMBER 6 2. Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006;107(6):2279-2285. 3. Neely CL, Wajima T, Kraus AP, Diggs LW, Barreras L. Lactic acid dehydrogenase activity and plasma hemoglobin elevations in sickle cell disease. Am J Clin Pathol. 1969;52(2):167-169. 4. Engauge Digitizer - Digitizing software. Open source digitizing software. Available at: digitizer.sourceforge.net. Accessed January 10, 2013. 5. van Beers EJ, Schaap MC, Berckmans RJ, et al; CURAMA study group. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica. 2009;94(11): 1513-1519. 6. Nouraie M, Lee JS, Zhang Y, et al; Walk-PHASST Investigators and Patients. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica. 2013;98(3):464-472. 7. Ballas SK, Marcolina MJ. Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia. Transfusion. 2006; 46(1):105-110. 8. White JM, Billimoria F, Muller MA, Davis LR, Stroud CE. Seruma-hydroxybutyrate dehydrogenase levels in sickle-cell disease and sickle-cell crisis. Lancet. 1978;1(8063):532-533. 9. Tumblin A, Tailor A, Hoehn GT, et al. Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease. Haematologica. 2010;95(9): 1467-1472. 10. Stankovic Stojanovic K, Steichen O, Lefevre G, et al. High lactate dehydrogenase levels at admission for painful vaso-occlusive crisis is associated with severe outcome in adult SCD patients. Clin Biochem. 2012; 45(18):1578-1582.