Reconstructing sickle cell disease: A data‐based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence‐based medicine

Abstract

The ''hyperhemolytic paradigm'' (HHP) posits that hemolysis in sickle disease sequentially and causally establishes increased cell-free plasma Hb, consumption of NO, a state of NO biodeficiency, endothelial dysfunction, and a high prevalence of pulmonary hypertension. The basic science underpinning this concept has added an important facet to the complexity of vascular pathobiology in sickle disease, and clinical research has identified worrisome clinical issues. However, this critique identifies and explains a number of significant concerns about the various HHP component tenets. In addressing these issues, this report presents: a very brief history of the HHP, an integrated synthesis of mechanisms underlying sickle hemolysis, a review of the evidentiary value of hemolysis biomarkers, an examination of evidence bearing on existence of a hyperhemolytic subgroup, and a series of questions that should naturally be applied to the HHP if it is examined using critical thinking skills, the fundamental basis of evidence-based medicine. The veracity of different HHP tenets is found to vary from true, to weakly supported, to demonstrably false. The thesis is developed that the HHP has misidentified the mechanism and clinical significance of its findings. The extant research questions identified by these analyses are delineated, and a conservative, evidence-based approach is suggested for application in clinical medicine. Am. J. Hematol. 86:123-154, 2011. V

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

“…The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet velocity (TRV) of >2.5 m/s by echocardiography has been shown to be an independent risk factor for early mortality (odds ratio 8-15) (5,(15)(16)(17)(18)(19)(20). This finding was initially considered to be consistent with pulmonary arterial hypertension (PH) (5,17,(21)(22)(23)(24)(25).…”

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…It was therefore concluded that pulmonary hypertension in sickle cell patients is caused by a complex, multifactorial pathophysiology that may involve NO depletion, vasoconstriction, thromboembolic vascular occlusion, left ventricular impairment, chronic vascular remodeling, and secondary hemodynamic effects caused by the hyperdynamic circulation that occurs in many patients with more severe or chronic anemia. 64,65 The quantitative contributions of these individual factors and the specific role of free Hb and hemin in the pathophysiology of vascular complication in sickle cell disease remain an important area for further mechanistic evaluation in clinical settings.…”

Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: Current Practice and Emerging Trends

“…The widely variable severity of symptoms and target organ damage even within similar phenotypes depends on the extent of vascular inflammation/injury, cellular/ chemokine changes, and the induction of a hypercoagulable state that is blamed on inflammatory pathways spurred by nitric oxide depletion, C-reactive protein, inflammatory cytokines such as IL-6, and adhesion molecules. 1,2 However, the level of contribution of individual pathways is unclear, making targeted pharmacologic intervention complicated. 3 Although not curative, there have been significant advances in supportive care for SCD in the last decade.…”