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Sickle Cell Disease

Dhananjay K Kaul

10.1002/cphy.cp020417

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Introduction
2 Erythrocytic Factors
2.1 HbS polymerization and microvascular transit times
2.2 Generation of dense sickle red cells
3 Microvascular Factors
4 Hemodynamic Behavior of Sickle red Cells
4.1 Ex vivo studies
4.2 In vivo studies in transgenic sickle mice
4.3 Intravital studies in sickle patients
5 Sickle Red Cell Interaction with Vascular Endothelium
5.1 Sites and characteristics of sickle red cell adhesion in the microcirculation
5.2 Adhesion molecules
6 Inflammation
7 The Role of Red Cell and Leukocyte Adhesion in Vaso‐Occlusion
8 Vascular Tone
8.1 Red cell rheological factors in vascular reactivity
8.2 NO bioavailability
8.3 Peroxynitrite, tetrahydrobiopterin, and eNOS
8.4 Nitrite pool
8.5 Non‐NO vasodilators
9 Anti‐Sickling Therapeutic Strategies
9.1 Fetal hemoglobin
9.2 Experimental modulation of red cell density
9.3 Gene therapy
9.4 Conclusions and future directions
Figure 1. Figure 1.

In hemoglobin S, single nucleotide substitution (GTG for GAG) in the 6th codon of the β‐globin gene results in the replacement of a glutamic acid residue by a valine residue. Deoxygenation results in polymerization of hemoglobin S (HbS) and shape changes (sickling) of HbS‐polymer‐containing red cells. Figure modified from reference 15, by permission of M.H. Steinberg. (See page 20 in colour section at the back of the book)
Figure 2. Figure 2.

Among red cell subpopulations, discocytes form the largest component of sickle blood and transform to typical sickled forms upon deoxygenation. On the other hand, dense sickle red cells (e.g. ISCs) show minimal transformation with deoxygenation. Figure modified from reference 20.
Figure 3. Figure 3.

(A–C) Arteriovenous Vrbc, wall shear rates and volumetric flow rate (Q) profiles in the arteriolar and venular branching orders (A2–A4 and V4–V2, respectively) in the resting cremaster muscle microcirculation of C57BL, BERK, BERK + γ mice 54. Microvascular blood flow in the BERK mice is characterized by a pronounced decline in arteriolar wall shear rates, and by a greater Q in A2 and V2 vessels. Note the normalization of wall shear rates and Q in BERK + γ (mice to control values. *P < 0.05 vs. C57BL and BERK mice (Kruskal‐Wallis test for ANOVA).

Reproduced with permission from Ref. 54
Figure 4. Figure 4.

Adhesion of sickle red cells in venules of the ex vivo mesocecum vasculature infused with a bolus of human sickle red cells during perfusion with Ringer‐albumin. (A) Adherent sickle red cells of discocyte morphology are seen deformed in the direction of the flow (arrow). (B) Increased adhesion of sickle red cells at venular bending and at junctions of small‐diameter immediate postcapillary venules. In this instance, the immediate postcapillary venules are completely blocked (arrows). (C) The inverse relationship between vessel diameter and sickle redcells adhesion in venules of the ex vivo mesocecum vasculature. The regression fits the equation y = aX−b, r = −0.81, p = < 0.001). Figure modified from reference 35.
Figure 5. Figure 5.

Ex vivo mesoceum microvasculature. (A) A clear vessel lumen (a, arteriole; v, venule is seen during perfusion with Ringer‐albumin solution. (B) The same area under epifluorescence illumination after a bolus infusion of SS1 reticulocytes (fluorescein isothiocyanate (FITC)‐labeled) and SS2 discocytes mixed in 1:1 ratio depicts preferential adhesion of SS1 red cells (small arrows) in the venule during flow (Large arrows indicates the flow direction). (C) Adherent SS1 and SS2 red cells in a venule. (D) The same area under epifluorescence illumination shows that the majority of adherent red cells are from SS1 fraction. Modified from Ref. 35.
Figure 6. Figure 6.

Selective trapping of dense SS4 red cells in postcapillary venules after a bolus infusion of a mixture of SS2 (discocytes) and FITC‐labeled SS4 cells (ISCs and dense discocytes) (3:1 ratio). (A) Areas of venular obstruction. Arrows indicate unobstructed areas showing only adherent sickle redcells. (B) The same area under epifluorescence illumination showing localization of FITC‐labeled dense SS4 red cells trapped in the obstructed venules and their absence in the areas with adhesion (arrows). Modified from Ref. 35.
Figure 7. Figure 7.

Videomicrographs showing in vivo adhesion of red cells in cremasteric venules of transgenic (S + S‐Antilles) sickle mice. (A) Adherent red cells (small arrows) in the venular flow (large arrow). (B) A rolling leukocyte (L) is distinguished from adherent red cells (small arrows) by its larger diameter. (C) A sickled cell with distinct spicules (small arrow) in the venular flow (large arrow). Bar in each case = 10 μm.

Reproduced with permission from Ref. 53
Figure 8. Figure 8.

Schematic representation of adhesion molecules involved in SS cell (RBC)‐endothelium interactions. EC matrix = extracellular matrix; IAP = integrin‐associated protein; ICAM‐4 = intercellular adhesion molecule‐4; Sulf. glycolipids = sulfated glycolipids. (See page 21 in colour section at the back of the book)
Figure 9. Figure 9.

A model for vaso‐occlusion in sickle cell disease. (A) Adhesion of deformable sickle red cells (arrows) and leukocytes (light colored) in postcapillary venules. (B) Adhesion of these cells is followed by reduction in local wall shear rates and selective trapping of dense sickle red cells, which could result in HbS polymerization in the trapped (dark red) and adhered sickle cells, and obstruction of the affected vessels. (See page 21 in colour section at the back of the book)
Figure 10. Figure 10.

Immunoperoxidase staining for eNOS in the cremaster muscle microvasculature of C57BL, BERK and BERK + γ mice. (A) Negative control. (B) The same vessels in an adjacent section from control C57BL cremaster muscle showing positive reaction for eNOS in the vessel wall (arrow heads). (C) BERK mice show a strongly positive reaction in the vessel wall (arrow heads), (d) In contrast to BERK mice, BERK + γ (mice show a distinct decrease in the intensity of staining for eNOS in vessels (arrow heads).

Reproduced with permission from 54. (See page 21 in colour section at the back of the book)
Figure 11. Figure 11.

Arteriolar diameter (% increase) responses to topical application of Ach (10−6 M) and SNP (10−6 M) in C57BL. BERK‐trait. BERK and BERK + γ mice. Note the attenuated response of arterioles in BERK mice to Ach (A) and SNP (B). Ach and SNP caused significant increases in arteriolar diameters of BERK + γ (mice as compared with that in BERK mice (∼33 and ∼50% increases, respectively). *p < 0.005–0.000001 compared with C57BL and BERK‐trait mice. + p < 0.00–0.002 compared with the diameter increase in BERK mice.

Reproduced with permission from 54
Figure 12. Figure 12.

Plasma heme and its effect on NO consumption and microvascular response to SNP. (A) Arterial plasma in human patients with sickle cell disease contains an average of 4.2 + 1.1 μmol heme compared with 0.2 + 0.1 μmol heme in the plasma of normal human volunteers. (B) Heme concentration within plasma of sickle cell patients shows a significant correlation with NO consumption (orange circles; line represents the best fit, r = 0.9, P < 0.0001). (C) Relationship between plasma heme levels and the arteriolar diameter response to SNP in the cremaster microcirculation of C57BL (control), BERK, BERK‐trait and BERK + y mice. A strong correlation is observed between the percent arteriolar diameter increase in response to SNP and the extent of hemolysis (plasma heme). With a greater hemolysis in sickle (BERK) mice the diameter response was blunted. Low plasma heme levels in controls were associated with maximal arteriolar dilation, while BERK mice expressing 20% fetal hemoglobin showed a lower plasma heme and an improved diameter response compared with BERK mice.

Figures A and B are reproduced from reference 120 by permission. Figure C is based on the published data in reference 54. (See page 22 in colour section at the back of the book)
Figure 13. Figure 13.

Elevated nitrotyrosine levels and eNOS monomerization in sickle (BERK) mice. (A) Western blot analysis of cremaster muscle lysates for the expression of nitrotyrosine. Two prominent bands of nitrated proteins (66 and 26 kDa) were detected by the antibody to nitrotyrosine. BERK mice showed increased tyrosine nitration of both 66 and 26 kDa proteins (i.e. average increase: 5‐fold and ∼2‐fold respectively), while the BERK + γ mouse showed a smaller increase as compared with C57BL controls. The nitrotyrosine levels in BERK‐trait and β – thal mice showed no increase as compared with C57BL controls. Control lane depicts positive nitrotyrosine controls provided by the antibody manufacturer. Equal loading of the samples was ascertained using anti‐actin antibody. (B) Western blots of lung homogenates under nondenaturing conditions demonstrate 280 kDa dimer (active form) and 140 kDa eNOS monomer. Wild‐type (WT) and hemizygous (Hemi) sickle mice had more eNOS dimer than monomer, but sickle mice showed almost a complete lack of dimerized eNOS. Positive monomer controls show eNOS dissociated completely to monomeric form by boiling. (C) Lung nitrotyrosine, evidence of NO scavenging by superoxide, was elevated in sickle mice.

Figure A is reproduced with permission from reference 54. Figures B and C are reproduced from reference 117, by permission
Figure 14. Figure 14.

Immunoperoxidase staining for COX‐2 in the cremaster muscle microvasculature of C57BL, BERK and BERK + γ mice. (A) Negative control. (B) The same vessels in an adjacent section from the control C57BL cremaster muscle show negative to weakly positive reaction (arrow heads). (C) and (D) Strongly positive reaction for COX‐2 in vascular endothelium of blood vessels in BERK mice (arrow heads). (e) BERK (γ mice show negative or weakly positive reaction for COX‐2 in vessel walls (arrow heads).

Reproduced with permission from 54. (See page 22 in colour section at the back of the book)


Figure 1.

In hemoglobin S, single nucleotide substitution (GTG for GAG) in the 6th codon of the β‐globin gene results in the replacement of a glutamic acid residue by a valine residue. Deoxygenation results in polymerization of hemoglobin S (HbS) and shape changes (sickling) of HbS‐polymer‐containing red cells. Figure modified from reference 15, by permission of M.H. Steinberg. (See page 20 in colour section at the back of the book)



Figure 2.

Among red cell subpopulations, discocytes form the largest component of sickle blood and transform to typical sickled forms upon deoxygenation. On the other hand, dense sickle red cells (e.g. ISCs) show minimal transformation with deoxygenation. Figure modified from reference 20.



Figure 3.

(A–C) Arteriovenous Vrbc, wall shear rates and volumetric flow rate (Q) profiles in the arteriolar and venular branching orders (A2–A4 and V4–V2, respectively) in the resting cremaster muscle microcirculation of C57BL, BERK, BERK + γ mice 54. Microvascular blood flow in the BERK mice is characterized by a pronounced decline in arteriolar wall shear rates, and by a greater Q in A2 and V2 vessels. Note the normalization of wall shear rates and Q in BERK + γ (mice to control values. *P < 0.05 vs. C57BL and BERK mice (Kruskal‐Wallis test for ANOVA).

Reproduced with permission from Ref. 54


Figure 4.

Adhesion of sickle red cells in venules of the ex vivo mesocecum vasculature infused with a bolus of human sickle red cells during perfusion with Ringer‐albumin. (A) Adherent sickle red cells of discocyte morphology are seen deformed in the direction of the flow (arrow). (B) Increased adhesion of sickle red cells at venular bending and at junctions of small‐diameter immediate postcapillary venules. In this instance, the immediate postcapillary venules are completely blocked (arrows). (C) The inverse relationship between vessel diameter and sickle redcells adhesion in venules of the ex vivo mesocecum vasculature. The regression fits the equation y = aX−b, r = −0.81, p = < 0.001). Figure modified from reference 35.



Figure 5.

Ex vivo mesoceum microvasculature. (A) A clear vessel lumen (a, arteriole; v, venule is seen during perfusion with Ringer‐albumin solution. (B) The same area under epifluorescence illumination after a bolus infusion of SS1 reticulocytes (fluorescein isothiocyanate (FITC)‐labeled) and SS2 discocytes mixed in 1:1 ratio depicts preferential adhesion of SS1 red cells (small arrows) in the venule during flow (Large arrows indicates the flow direction). (C) Adherent SS1 and SS2 red cells in a venule. (D) The same area under epifluorescence illumination shows that the majority of adherent red cells are from SS1 fraction. Modified from Ref. 35.



Figure 6.

Selective trapping of dense SS4 red cells in postcapillary venules after a bolus infusion of a mixture of SS2 (discocytes) and FITC‐labeled SS4 cells (ISCs and dense discocytes) (3:1 ratio). (A) Areas of venular obstruction. Arrows indicate unobstructed areas showing only adherent sickle redcells. (B) The same area under epifluorescence illumination showing localization of FITC‐labeled dense SS4 red cells trapped in the obstructed venules and their absence in the areas with adhesion (arrows). Modified from Ref. 35.



Figure 7.

Videomicrographs showing in vivo adhesion of red cells in cremasteric venules of transgenic (S + S‐Antilles) sickle mice. (A) Adherent red cells (small arrows) in the venular flow (large arrow). (B) A rolling leukocyte (L) is distinguished from adherent red cells (small arrows) by its larger diameter. (C) A sickled cell with distinct spicules (small arrow) in the venular flow (large arrow). Bar in each case = 10 μm.

Reproduced with permission from Ref. 53


Figure 8.

Schematic representation of adhesion molecules involved in SS cell (RBC)‐endothelium interactions. EC matrix = extracellular matrix; IAP = integrin‐associated protein; ICAM‐4 = intercellular adhesion molecule‐4; Sulf. glycolipids = sulfated glycolipids. (See page 21 in colour section at the back of the book)



Figure 9.

A model for vaso‐occlusion in sickle cell disease. (A) Adhesion of deformable sickle red cells (arrows) and leukocytes (light colored) in postcapillary venules. (B) Adhesion of these cells is followed by reduction in local wall shear rates and selective trapping of dense sickle red cells, which could result in HbS polymerization in the trapped (dark red) and adhered sickle cells, and obstruction of the affected vessels. (See page 21 in colour section at the back of the book)



Figure 10.

Immunoperoxidase staining for eNOS in the cremaster muscle microvasculature of C57BL, BERK and BERK + γ mice. (A) Negative control. (B) The same vessels in an adjacent section from control C57BL cremaster muscle showing positive reaction for eNOS in the vessel wall (arrow heads). (C) BERK mice show a strongly positive reaction in the vessel wall (arrow heads), (d) In contrast to BERK mice, BERK + γ (mice show a distinct decrease in the intensity of staining for eNOS in vessels (arrow heads).

Reproduced with permission from 54. (See page 21 in colour section at the back of the book)


Figure 11.

Arteriolar diameter (% increase) responses to topical application of Ach (10−6 M) and SNP (10−6 M) in C57BL. BERK‐trait. BERK and BERK + γ mice. Note the attenuated response of arterioles in BERK mice to Ach (A) and SNP (B). Ach and SNP caused significant increases in arteriolar diameters of BERK + γ (mice as compared with that in BERK mice (∼33 and ∼50% increases, respectively). *p < 0.005–0.000001 compared with C57BL and BERK‐trait mice. + p < 0.00–0.002 compared with the diameter increase in BERK mice.

Reproduced with permission from 54


Figure 12.

Plasma heme and its effect on NO consumption and microvascular response to SNP. (A) Arterial plasma in human patients with sickle cell disease contains an average of 4.2 + 1.1 μmol heme compared with 0.2 + 0.1 μmol heme in the plasma of normal human volunteers. (B) Heme concentration within plasma of sickle cell patients shows a significant correlation with NO consumption (orange circles; line represents the best fit, r = 0.9, P < 0.0001). (C) Relationship between plasma heme levels and the arteriolar diameter response to SNP in the cremaster microcirculation of C57BL (control), BERK, BERK‐trait and BERK + y mice. A strong correlation is observed between the percent arteriolar diameter increase in response to SNP and the extent of hemolysis (plasma heme). With a greater hemolysis in sickle (BERK) mice the diameter response was blunted. Low plasma heme levels in controls were associated with maximal arteriolar dilation, while BERK mice expressing 20% fetal hemoglobin showed a lower plasma heme and an improved diameter response compared with BERK mice.

Figures A and B are reproduced from reference 120 by permission. Figure C is based on the published data in reference 54. (See page 22 in colour section at the back of the book)


Figure 13.

Elevated nitrotyrosine levels and eNOS monomerization in sickle (BERK) mice. (A) Western blot analysis of cremaster muscle lysates for the expression of nitrotyrosine. Two prominent bands of nitrated proteins (66 and 26 kDa) were detected by the antibody to nitrotyrosine. BERK mice showed increased tyrosine nitration of both 66 and 26 kDa proteins (i.e. average increase: 5‐fold and ∼2‐fold respectively), while the BERK + γ mouse showed a smaller increase as compared with C57BL controls. The nitrotyrosine levels in BERK‐trait and β – thal mice showed no increase as compared with C57BL controls. Control lane depicts positive nitrotyrosine controls provided by the antibody manufacturer. Equal loading of the samples was ascertained using anti‐actin antibody. (B) Western blots of lung homogenates under nondenaturing conditions demonstrate 280 kDa dimer (active form) and 140 kDa eNOS monomer. Wild‐type (WT) and hemizygous (Hemi) sickle mice had more eNOS dimer than monomer, but sickle mice showed almost a complete lack of dimerized eNOS. Positive monomer controls show eNOS dissociated completely to monomeric form by boiling. (C) Lung nitrotyrosine, evidence of NO scavenging by superoxide, was elevated in sickle mice.

Figure A is reproduced with permission from reference 54. Figures B and C are reproduced from reference 117, by permission


Figure 14.

Immunoperoxidase staining for COX‐2 in the cremaster muscle microvasculature of C57BL, BERK and BERK + γ mice. (A) Negative control. (B) The same vessels in an adjacent section from the control C57BL cremaster muscle show negative to weakly positive reaction (arrow heads). (C) and (D) Strongly positive reaction for COX‐2 in vascular endothelium of blood vessels in BERK mice (arrow heads). (e) BERK (γ mice show negative or weakly positive reaction for COX‐2 in vessel walls (arrow heads).

Reproduced with permission from 54. (See page 22 in colour section at the back of the book)
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Article Title: Sickle Cell Disease
 

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Dhananjay K Kaul. Sickle Cell Disease. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 769-793. First published in print 2008. doi: 10.1002/cphy.cp020417