Sickle cell anemia pathophysiology: Back to the data
Authors: James R. Eckman, Stephen H. Embury
Journal: American Journal of Hematology (2010)

Dr. Hebbel in his comprehensive and objective analysis of the complex pathophysiology in sickle cell disease [1] as it pertains to the "hyperhemolysis paradigm" (HHP) [2,3], published in this issue of the American Journal of Hematology, provides the field with a number of insights, hypotheses, and experimental approaches that could guide basic and clinical research in the second century of knowledge of the disease in the West [1]. The review emphasizes the occupational responsibility for clinicians and researchers to apply critical thinking to interpretation of biomedical information. Hebbel employed an immense body of knowledge in "reconstructing" the "new understanding of sickle cell disease" that has evolved from the HHP, choosing to outline the considerable remaining work that would have to be done to validate the hypotheses rather than simply declaring the validity of his analysis. Dr. Hebbel has focused his review on the relationship between hemolysis, nitric oxide consumption, and pulmonary hypertension in sickle cell disease [1]. He articulates major concerns regarding the HHP [2, 3], many of which have also been articulated by other respected leaders in the fields of sickle cell disease and pulmonary hypertension [4, 5]. In his consideration of the underpinnings of this widely accepted version of sickle cell pathophysiology, HHP has not stood up well at all. Dr. Hebbel provided critical analysis of existing data to conclude the tools used by HHP proponents for diagnosing hemolytic rate and pulmonary hypertension, which are neither adequate nor appropriate for the purposes to which they have been applied. He makes two major points about these diagnostic tools that must be considered carefully in future directions in sickle cell research and clinical management. The first is the validity of the "hemolytic index" and existence of two distinct phenotypes based on hemolytic rates. He clearly identifies the need for the hemolytic index to be validated by comparison with direct measurements of red cell survival and presents compelling data, using analysis of existing data, which suggests that the present hemolytic index likely does not directly reflect rate of hemolysis. The use of the hemolytic rate in the HHP is predicated on the assumption that lactate dehydrogenase (LDH) is a quantitative biomarker of hemolysis in sickle cell disease [3]. There is no evidence that LDH levels correlate strongly with the rate of hemolysis in patients with sickle cell anemia. Indeed, Hebbel's analysis of the Cooperative Study of Sickle Cell Disease (CSSCD) database indicated that in patients with sickle cell anemia (HbSS), the LDH levels correlate poorly with the reticulocyte percentage, a much more robust index of hemolysis. The inclusion of patients with sickle cell genotypes/phenotypes having lower reticulocyte counts, LDH levels, and hemolytic rates [6] in the HHPs analysis creates the artifactual illusion of LDH as a quantitative marker of hemolytic rate. Hebbel's comprehensive evidence-based assessment revisits the mechanisms of hemolysis in sickle disease and illustrates that these are better defined but more complicated than many appreciate and that fundamental questions about these processes remain unanswered. He has elucidated that a presently undefined but significant degree of the anemia in sickle cell disease is due to extravascular destruction of red blood cells, rather than to peripheral hemolysis. He also reminds us that levels of LDH, aspartate transaminase, and total bilirubin are influenced by liver disease and damage to a number of tissues affected in sickle cell disease. Dr. Hebbel also provides considerable support that hemolysis is a continuous variable, perhaps with a skewed distribution. A recent preliminary report of the results of a principle component analysis on data from 203 patients using 10 subphenotype variables revealed that complications of sickle cell disease do not cluster into two distinct subphenotypes [7]. The authors concluded that the clear-cut distinctions in the HHP are not applicable in clinical practice. The second area that Dr. Hebbel cogently evaluates in the relationship of the tricuspid jet velocity (TJV) to true elevation in pulmonary artery pressures and the relationship of true elevation in pulmonary artery pressure in sickle cell disease to primary pulmonary hypertension. After thoughtful review based on available data he concludes that a TJV value of ≥2.5 is an overly sensitive and nonspecific indicator of pulmonary hypertension, the basis of which he has provided in his review. In brief, Hebbel does not dismiss the HHP outright but, rather, reinterprets it. He submits that among sickle cell disease patients TJV screening identifies three distinct pathophysiologies: real pulmonary hypertension (the smallest group), frank false-positives because of the hyperdynamism associated with chronic anemia (the largest group), and "dynamic pulmonary hypertension," as he refers to it. He persuasively argues that the last group probably has dynamic fluctuations in pulmonary vasoconstriction but not the pathology of true pulmonary hypertension. He explains how this concept may play out in the "dynamic pulmonary hypertension" of sickle disease, with the pulmonary vascular wall responding abnormally to germane processes, such as hypoxia during sleep, decreased NO bioavailability, or a proposed unique vulnerability of the pulmonary vascular endothelium to products from sickle erythrocytes. Dr. Hebbel correctly concludes that the use of TJV ≥ 2.5 for diagnosing pulmonary hypertension in patients with sickle cell disease will result in unacceptably high number of false positive diagnoses both for research and clinical applications, especially in children [8]. A recent preliminary report by the HHP proponents themselves concedes that catheterization documentation pulmonary hypertension is absent in 35% of adult patients with sickle cell disease with TJV ≥ 2.5 [9]. Others had determined the false positive rate to be 75% [10]. Most importantly in this consideration, reliance on a diagnostic method that results in 35–75% false positive diagnoses would result in providing patients with misleading and potentially alarming information, which is not in their best interest. At the time of this writing, TJV ≥ 2.5 has been used as the diagnostic criterion for pulmonary hypertension in sickle cell disease in at least 74 publications. The increased mortality rate reported for patients with TJV ≥ 2.5 is a very important observation that must be considered in future research. Is this association real? Does it result from true pulmonary hypertension? Because Dr. Hebbel shows that the etiologies of elevation in pulmonary pressure in sickle cell disease are very complex, what are the true determinants of mortality? Should this be a target for clinical intervention or do underlying pathophysiologic mechanisms exist that are more important in improving prognosis? Truly this is a very complex and potentially important area of future investigation that requires thoughtful study. Throughout his review Dr. Hebbel provides a number of hypothesis developing questions that should keep young investigators occupied for the next 100 years of sickle cell investigation. A particularly fertile area for research derives from Hebbel's vision that sickle cell disease patients diagnosed with pulmonary hypertension includes a subset who have "dynamic pulmonary hypertension" with transient fluctuations of pulmonary vasoconstriction as the result of the enduring endothelial dysfunction resultant from inflammation or other endothelial perturbants, which in turn causes exaggerated responses to vasoconstrictive stimuli such as hypoxemia or low NO levels. Hebbel cautions that this condition is not the primary result of NO consumption and that, lacking substantive evidence for NO as a cause of real pulmonary hypertension, the suggestion of this mechanism for pulmonary hypertension in sickle cell disease is illusory. He further posits that this may explain some of the cases of sudden death that occur during pain episodes and other complications in patients with sickle cell disease. Hebbel has identified a possible cause of overdiagnosis of pulmonary hypertension as "incautious" use of the language. The shift in language by HHP proponents to include all patients having TJV ≥ 2.5 as having true pulmonary "arterial" hypertension [11] might have been incautious, or it could be an example of force drift—an executive statement intended to allow excesses in practice. Such inaccuracies facilitate the use of advocacy rather than science to influence opinion, compound the problems of false positive diagnoses, and create unnecessary anxiety among our patients. Dr. Hebbel has conducted a careful analysis of the recent directions in sickle cell research that focus primarily on HHP and elevated TJV. His comprehensive review should become a framework for future research in sickle cell disease. However, his most important contribution is his demonstration of the rigor in thought required to make real progress in scientific investigation. He cites many pitfalls that may have plagued recent work in our field and has articulated the need for a higher level of scientific rigor going forward. Everyone working in this field should study Dr. Hebbel's thoughtful analysis, both in terms of the hypotheses and questions he has developed and of the careful approach he suggests for applying the principles of the scientific method. Finally, for our patients, it is critical that we consider a number of Dr. Hebbel's concerns. The clinical use of TJV in sickle cell disease as a clinical tool appears premature. The test has a significantly high false positive rate, and therefore has the potential to generate considerable unnecessary diagnostic testing. Clearly, more clinical research is indicated to establish its validity, provide diagnostic algorithms, and determine the validity of the measure as a predictor and cause of increased mortality. It would also appear that therapeutic intervention trials are premature given our present understanding of the pathophysiology of the elevated TJV. What is the impact of pulmonary hypertension on the psychological health of our patients? In preparing this commentary, we could find no literature on this topic. Many individuals with sickle cell disease are being told they have pulmonary hypertension based on TJV. A considerable amount of information readily available to patients suggests that pulmonary hypertension is associated with a very poor prognosis. At this time, there is no established treatment or even promising therapeutic approaches. Studies that address this concern should be considered, and all clinical investigative protocols should define and address the burden of this subject. Primum non nocere! (Above all, do no harm!) From Hippocrates, Latin translation.