Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease

Abstract

Summary In sickle cell disease (SCD), vigorous reticulocytosis is required to partially compensate for chronic hemolytic anaemia. Consequently, early renal damage, insufficient to cause azotemia but sufficient to cause erythropoietin deficiency and chronic relative reticulocytopenia (chRR), could have severe clinical consequences. chRR was defined as reticulocytes <250 × 109/l despite haemoglobin <9 g/dl on ≥ two occasions ≥4 weeks apart. The influence of multiple variables including chRR on time from first clinic visit to death was evaluated in 306 SCD patients. In univariate analyses, fetal haemoglobin, indices of renal damage (serum creatinine, proteinuria), chRR and age, were associated with rate of death. In multivariate analysis, only age and chRR (Hazard ratio 3·6, 95% CI 2·049–6·327, P < 0·0001) were significant, underlining that chRR could be an early and important clinical consequence of renal damage. Even in chRR patients with normal serum creatinine levels, low haemoglobin and low reticulocyte counts were associated with low erythropoietin levels. In the general population, evaluation of erythropoietin levels is prompted by the combination of anaemia and abnormal serum creatinine. In SCD patients, this standard approach can miss a substantial risk factor for early death. chRR could be a practical and important criterion for diagnosis of erythropoietin deficiency in SCD.

Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe

“…Nine studies 11,21,24,29–34 met our inclusion criteria and were analyzed together with the UNC cohort for a total of 3257 participants. The quality of individual studies was assessed using the Newcastle-Ottawa Scale (Table 3).…”

Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study

“…Another risk is that high concentrations of decitabine can be DNA damaging and mutagenic and hence potentially pro-oncogenic. DNA damage can also be cytotoxic; this is a concern independent of potential oncogenicity because of the extraordinary demands on SCD bone marrow to compensate for severe hemolytic anemia—dwindling of such compensation by vaso-occlusive damage and age contributes to early death [ 8 , 23 , 31 , 32 , 98 ]. A major rationale for oral THU-decitabine, therefore, is creating decitabine pharmacology that reduces off-target anti-metabolite effects, DNA-damage, and cytotoxicity.…”

“…Cumulative attrition of these reserves occurs via vaso-occlusion in the marrow and to the kidneys [ 23 , 25 , 28 , 29 ]. This is a problem even separate from considerations of sustainable HbF induction via cytotoxicity: in SCD, erythropoiesis has to operate at >10-fold the normal rate to barely sustain hemoglobin levels compatible with life, and dwindling compensatory capacity is a major cause of early death [ 8 , 23 , 31 , 32 ]. Therefore, new, non-cytotoxic, durable, and more potent methods of inducing HbF are needed.…”

Targeting sickle cell disease root-cause pathophysiology with small molecules

“…31,33,37,38 A declining capacity to compensate for hemolytic anemia is a problem even separate from considerations of sustainable HbF induction via cytotoxicity: SCD patients require erythropoiesis at >10-fold the normal rate simply to sustain hemoglobin levels compatible with life, and dwindling compensatory reticulocytosis is a major cause of early death. 2,15,31,40 Therefore, alternative, non-cytotoxic, durable, and more potent methods of inducing HbF are needed.…”

“…The hemolytic anemia is frequently severe, and is only partially and non-sustainably compensated by >10-fold increases in erythropoiesis. 2 The net consequence of this anemia and vaso-occlusion is decreased oxygen delivery and hypoxic injury to potentially all tissues of the body, manifest clinically as episodic pain, chronic pain, avascular necrosis of bones, infections, overt and silent strokes, renal/respiratory/cardiac/hepatic failure, and early death. In the USA >$1 billion in annual health care costs is attributed to SCD, and even so, the median life expectancy of affected individuals is shortened by two or more decades on average.…”