To the editor:

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 catheter-drawn specimens processed at bedside to decrease artifactual hemolysis, serum LDH correlated with plasma hemoglobin, a well-accepted marker of intravascular hemolysis (r = 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 = 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 = .0004).

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.

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.

Close modal

LDH also strongly correlates with another product of hemolyzing red cells, erythrocyte-derived microparticles, in a study from Amsterdam (r = 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 = 0.36, P = .006, n = 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 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.

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.

1
Ballas
 
SK
Lactate dehydrogenase and hemolysis in sickle cell disease.
Blood
2013
, vol. 
121
 
1
(pg. 
243
-
244
)
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
, vol. 
107
 
6
(pg. 
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
, vol. 
52
 
2
(pg. 
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
, vol. 
94
 
11
(pg. 
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
, vol. 
98
 
3
(pg. 
464
-
472
)
7
Ballas
 
SK
Marcolina
 
MJ
Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia.
Transfusion
2006
, vol. 
46
 
1
(pg. 
105
-
110
)
8
White
 
JM
Billimoria
 
F
Muller
 
MA
Davis
 
LR
Stroud
 
CE
Serum-α-hydroxybutyrate dehydrogenase levels in sickle-cell disease and sickle-cell crisis.
Lancet
1978
, vol. 
1
 
8063
(pg. 
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
, vol. 
95
 
9
(pg. 
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
, vol. 
45
 
18
(pg. 
1578
-
1582
)
Sign in via your Institution