Reader Comments

Post a new comment on this article

TRV, LDH and Hemolysis in Sickle Cell Disease

Posted by gregkato on 21 Sep 2015 at 14:58 GMT

This is one of many studies that continue to reproduce our findings from 2004 that elevated TRV is a risk factor for mortality in 195 adults with sickle cell disease (SCD), and that elevated TRV is linked to anemia, serum LDH and age (http://www.ncbi.nlm.nih.g...). Furthermore, steady state LDH level is well-documented to be a biomarker of increased severity of hemolytic anemia in SCD, associated significantly in a cohort of 213 patients with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor (http://www.ncbi.nlm.nih.g...). Our right heart catheterization studies in 81 patients with SCD further documented the association of LDH and other clinical markers of hemolysis with definitive PH in 55 patients (http://www.ncbi.nlm.nih.g...). Although often portrayed as a contradicting study, the results of SCD right heart catheterization in Paris also documented and association of definitive PH with high LDH and early mortality (http://www.ncbi.nlm.nih.g...). Both the Bethesda and Paris cohorts showed that the risk of PH rises as the TRV rises, especially 3 m/s and above; and they show that the positive predictive value is increased by a six-minute walk distance <500m or serum NT-proBNP level higher than 160 – 164.5 pg/mL. The results of this Brazilian study are consistent with high TRV as a risk factor for death, associated with low hemoglobin, high LDH, and bilirubin, the traditional and documented clinical laboratory markers of severity of hemolytic anemia.

No competing interests declared.

RE: TRV, LDH and Hemolysis in Sickle Cell Disease

Samir8391 replied to gregkato on 02 Oct 2015 at 01:02 GMT

To the Editor,
We greatly appreciate the comments by Dr. Kato who is a well-known authority on sickle cell disease (SCD) and its complications. We are also aware of the seminal study by Dr. Kato’s group in 2004 about the elevated levels of TRV and its diagnostic and prognostic implications. We think we are in agreement on most of the comments by Dr. Kato. There are two subtle differences, however, in our perception of certain details as follows.
We are very pleased that Dr. Kato did not use the word “Hyperhemolysis” in his comment and used hemolysis or hemolytic anemia instead. There is no doubt that hemolysis is a major component of the anemia of SCD. This ongoing low level hemolysis is associated with absence of plasma/serum haptoglobin and low levels of free plasma hemoglobin (Hb). In the early days of our sickle center we routinely determined the level of serum haptoglobin on our patients with SCD and it was always absent or extremely low. After determining serum haptoglobin in hundreds of patients in the steady state and during crises we discontinued using this test and instructed our house staff not to order this test on patients known to have SCD and we saved the hospital unnecessary expense. As far as plasma Hb, the story is more complex. Specifically, about one third of hemolysis in SCD is intravascular and two-thirds is extravascular. Plasma Hb may be detected in some patients especially in those with abnormal renal function. In addition, we have no data about the relation between intravascular and extravascular compartments of hemolysis and whether there is a mass action between the two types of hemolysis. Moreover, plasma Hb levels may be falsely high in the presence of high bilirubin level, lipidemia if the sample is postprandial, traumatic venipuncture, thrombosis, and stored blood sample for several hour before testing, history of blood transfusion within four weeks before testing and co-existent infection. Moreover with hyperhemolysis the sclerae become intensely icteric. As far as lactate dehydrogenase (LDH), we asked many of our hematology colleagues who teach hematology courses to medical student how they define hemolysis. All of them stressed that the clinical diagnosis of hemolysis is based on examination of the peripheral smear, reticulocyte count, the level of indirect serum bilirubin and haptoglobin level. Lactate dehydrogenase is a ubiquitous enzyme in all tissues. Damage of any tissue is associated with elevated LDH levels. We agree that LDH is elevated in pulmonary hypertension but most of this elevation is probably from damaged tissues including the damaged lung tissue with subsequent release of LDH. Thus, the reticulocyte count and the indirect bilirubin levels are by far much better surrogate markers of hemolysis than LDH.
The second difference pertains to the definition of pulmonary hypertension. In his comment, Dr. Kato addressed pulmonary hypertension (PH). In our paper we were trying to identify risk factors of pulmonary arterial hypertension (PAH) versus pulmonary venous hypertension (PVH). Although the title of our paper did not specify PAH, the objectives and discussion of the paper were to determine those patients who should have right heart catheterization (RHC) to rule out or rule in PAH. It is not unusual for novel ideas by leaders and visionaries to be misinterpreted by subsequent followers. In our review of the literature we were disappointed to find some investigators think that abnormal TRV is diagnostic of PH and that any elevation of the LDH is diagnostic of hyperhemolysis. In reference number 34 of our paper we referred to a study in which hyperhemolysis was diagnosed based on elevated levels of LDH although the reticulocyte counts and bilirubin levels were not statistically different between the study and control groups.
In summary, our study is in agreement with the findings of Drs. Kato, Gladwin and their associates provided we state without further descriptors that “abnormal TRV, severe anemia (in comparison to steady state values), older age (>32 years) and elevated levels of LDH are risk factors for death in adult patients with sickle cell anemia”. Patients with these abnormities should have RHC to establish further specific diagnoses.
Samir K. Ballas MD FACP
Maria Ana Mach Queiroz MD
Clarisse Lopes de Castro Lobo MD

No competing interests declared.