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
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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:
diamone1@mskcc.org.
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 gkato@nhlbi.nih.gov.
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.