Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes

Kato, Gregory J.; Gladwin, Mark T.; Steinberg, Martin H.

doi:10.1016/j.blre.2006.07.001

Cited by 737 publications

(725 citation statements)

References 113 publications

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“…The association of SCD leg ulcers with biomarkers of vascular dysfunction and pulmonary hypertension has been a recurrent theme [30,32,33]. Both conditions are associated with elevated plasma level of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide (NO) synthase [34,35].…”

Section: Pathophysiologymentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience. Am. J. Hematol. 91:22-30, 2016. V C 2015 Wiley Periodicals, Inc. Clinical CasesCase 1. A 49 year old African American woman with sickle cell anemia, bilateral hip replacements for avascular necrosis of the femoral head, pulmonary arterial hypertension documented by pulmonary artery catheterization, and history of laser treatment and vitrectomy for proliferative retinopathy and vitreous hemorrhage, presented with a very painful ulcer at the right malleolus. She has had three previous ulcers, on both legs, the first at age 32 years, attributed to excessive standing at her job, no trauma, which had responded to topical care and healed within few months of presentation. At that time she was not taking hydroxyurea, but has been taking it now for longer than 10 years with good fetal hemoglobin response: 17%. This current ulcer developed while she was experiencing high personal stress but no physical trauma. She rarely experiences vaso-occlusive pain crisis and has very infrequent hospitalizations. She was referred to the wound care service and after 7 months of unfruitful therapies, including surgical debridement, MIST ultrasound therapy, antibiotics, and compressions, she was started on monthly transfusions and her ulcer healed 5 months later. She has had consistently elevated serum lactate dehydrogenase (LDH) (>600 IU/L), serum dire...

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Section: Pathophysiologymentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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“…NO also modulates vascular permeability [6][7][8], angiogenesis [9,10], platelet adhesion and aggregation [11][12][13], and leukocyte adhesion [14][15][16]. Thus, NO bioavailabilty is important in maintaining several aspects of homeostasis and its dysfunction contributes to a large variety of diseased states [17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

Azarov

Jeffers

et al. 2008

Free Radical Biology and Medicine

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Release of hemoglobin from the erythrocyte during intravascular hemolysis contributes to the pathology of a variety of diseased states. This effect is partially due to the enhanced ability of cellfree plasma hemoglobin, which is primarily found in the ferrous, oxygenated state, to scavenge nitric oxide. Oxidation of the cell-free hemoglobin to methemoglobin, which does not effectively scavenge nitric oxide, using inhaled nitric oxide has been shown to be effective in limiting pulmonary and systemic vasoconstriction. However, the ferric heme species may be reduced back to ferrous hemoglobin in plasma and has the potential to drive injurious redox chemistry. We propose that compounds that selectively convert cell-free hemoglobin to ferric, and ideally iron-nitrosylated heme species that do not actively scavenge nitric oxide would effectively treat intravascular hemolysis. We show here that nitroxyl, generated by Angeli's salt (Sodium α-oxyhyponitrite, Na 2 N 2 O 3 ), preferentially reacts with cell-free hemoglobin compared to that encapsulated in the red blood cell under physiologically relevant conditions. Nitroxyl oxidizes oxygenated ferrous hemoglobin to methemoglobin and can convert the methemoglobin to a more stable, less toxic species, iron-nitrosyl hemoglobin. These results support the notion that Angeli's salt or a similar compound could be used to effectively treat conditions associated with intravascular hemolysis.

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“…To date, genetic factors have not been shown to contribute to the development of SCD pulmonary hypertension, although some have speculated that mutations known to affect the rate of SCD related hemolysis like a-thalassemia might influence susceptibility to this complication [14,15]. In anticipation of an emerging era of low cost whole genome resequencing and personalized medicine [16,17], we have performed targeted sequencing and genotyping of globin genes containing hemoglobin mutations on 2 chromosomes to determine their role in susceptibility to pulmonary hypertension in a well-characterized adult SCD cohort.…”

Section: Introductionmentioning

confidence: 99%

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

et al. 2007

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Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident a-thalassemia (Odds Ratio [OR] 5 0.95, 95% CI 5 0.46-1.94, P 5 NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (OR 5 0.18, 95% confidence interval [CI] 5 0.06-0.51, P 5 0.0005) or Sb 1 thalassemia (OR 5 0.25, 95% CI 5 0.06-1.16, P 5 0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of followup (Hazard Ratio 5 8.20, P 5 0.0057). Am.

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Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes

Cited by 737 publications

References 113 publications

Critical Reviews: How we treat sickle cell patients with leg ulcers

Critical Reviews: How we treat sickle cell patients with leg ulcers

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

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