Page 691 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 41 Pathobiology of Sickle Cell Disease 583

macrovascular vasculopathy, hemolysis, and specific complications 11. Kaul DK, Fabry ME: In vivo studies of sickle red blood cells. Sickle red
highlight the certainty that phenotypic heterogeneity will be influ- cell-endothelium interactions. Microcirculation 11:153, 2004.
enced by underlying genetic variations affecting adhesion biology, 12. Hebbel RP: Reconstructing sickle cell disease: a data-based analysis of
cation homeostasis, inflammatory signaling, vasoregulation, and so the “hyperhemolysis paradigm” for pulmonary hypertension from the
on. Indeed, the spectrum of potential foci at which genetic variation perspective of evidence-based medicine. Am J Hematol 86:123, 2011.
might exert effects and be relevant to sickle disease phenotypic 13. Franco RS, Yasin Z, Palascak MB, et al: The effect of fetal hemoglobin
diversity is as vast and complex as human biology itself. on the survival characteristics of sickle cells. Blood 108:1073, 2006.
The single-nucleotide polymorphisms (SNPs) that have been 14. Embury SH, Clark MR, Monroy G, et al: Concurrent sickle cell anemia
detected in association with specific clinical complications are far too and alpha-thalassemia. Effect on pathological properties of sickle erythro-
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numerous to describe here. Of course, much work is still needed to cytes. J Clin Invest 73:116, 1984.
discern whether such associations are actually informative vis à vis 15. Reiter CD, Wang X, Tanus-Santos JE, et al: Cell-free hemoglobin
pathogenic specifics. Several SNPs seem particularly interesting. A limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8:1383,
TNF (-308) promoter polymorphism is associated with large vessel 2002.
stroke in children. Polymorphisms affecting the HO-1 promoter 16. Taylor JG, 6th, Nolan VG, Mendelsohn L, et al: Chronic hyper-hemolysis
create heterogeneity in GT repeat lengths (the shorter of which enable in sickle cell anemia: association of vascular complications and mortality
greater HO-1 responsiveness, e.g., to heme) are described as being with less frequent vasoocclusive pain. PLoS ONE 3:e2095, 2008.
associated with lower hospitalization rate for ACS in children. Inter- 17. Belcher JD, Chen C, Nguyen J, et al: Heme triggers TLR4 signaling
estingly, a TLR4 polymorphism prevalent only in sub-Saharan Africa leading to endothelial cell activation and vasoocclusion in murine sickle
leads to a greater inflammatory TNF-α responsiveness to TLR4 cell disease. Blood 123:377, 2014.
ligands that is protective in malaria, and could well impact sickle 18. Hebbel RP: Ischemia-reperfusion injury in sickle cell anemia: relationship
biology. A wholly different approach to this general problem was to acute chest syndrome, endothelial dysfunction, arterial vasculopathy,
provided by examination of gene expression by, and inflammatory and inflammatory pain. Hematol Oncol Clin North Am 28:181, 2014.
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response of, endothelial cells derived from sickle children. Those 19. Kaul DK, Hebbel RP: Hypoxia/reoxygenation causes inflammatory
from children with circle of Willis disease exhibited suggestive inflam- response in transgenic sickle mice but not normal mice. J Clin Invest
matory gene expression, plus an actual exaggerated NFκB response 106:411, 2000.
to stimulation with inflammatory mediators. Certainly, the contribu- 20. Gladwin MT, Schechter AN, Ognibene FP, et al: Divergent nitric oxide
tion of various nonglobin genetic influences will continue to be bioavailability in men and women with sickle cell disease. Circulation
identified as modern and creative approaches are being applied to the 107:271, 2003.
problem of phenotypic diversity in sickle cell anemia. 21. Nath KA, Katusic ZS, Gladwin MT: The perfusion paradox and vascular
instability in sickle cell disease. Microcirculation 11:117, 2004.
22. Sangkatumvong S, Khoo MC, Kato R, et al: Peripheral vasoconstriction
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