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578 Part V Red Blood Cells

that low-affinity adhesive mechanisms would gain relevance in that determinants of RBC adhesivity and endothelial activation play an
situation. Indeed, an unanswered question is whether or not RBC important role in vasoocclusion pathobiology. Consistent with this,
adhesion occurs via a single, dominant mechanism in vivo. To date, clinical vasoocclusive severity correlates with the endothelial adhesiv-
only RBC/endothelial adhesion mediated by α v β 3 and P-selectin have ity of sickle RBCs in vitro.
been verified in vivo in the sickle mouse, in which blockade of Impairment of microvascular flow also derives from the dimin-
P-selectin inhibits adhesion of both RBCs and white blood cells ished deformability of dehydrated sickle RBC. Dense cells (especially
(WBCs) to endothelium and effects improvement in blood flow. ISCs) can have difficulty entering the microvasculature, e.g., at
Participation of sickle RBC adhesion in pathophysiology is gov- bifurcations. Whether RBC adhesivity and poor deformability
erned, in part, by endothelial activation state. For example, adhesion perhaps exert combined or synergistic effects within the smallest
events mediated by endothelial vascular cell adhesion molecule 1 vessels has not been studied, nor has any role for dynamic change of
(VCAM-1), α v β 3 , and P-selectin are activated, respectively, by tumor rigidity as deoxygenation progresses during microvascular transit.
necrosis factor (TNF), platelet activating factor, and thrombin. Each Clinical vasoocclusive severity in humans correlates with preservation
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of these endothelial stimulants is elevated in sickle blood. However, of RBC deformability rather than with impairment thereof, perhaps
there is a multitude of biologic modifiers in the sickle context that because more dense cells tend to be misshapen and less able to make
can influence endothelial surface features (see Box on Complex Sickle close adhesive contacts with endothelium.
Milieu). Additional influencing factors would include: the reticulo-
cyte count; flow and shear rates; vessel diameter, geometry and
vasomotion; marginated WBCs; mixed blood cell interactions with Hemolytic Anemia
endothelium; concurrent processes (e.g., degree of platelet activation
or dehydration); and possibly even environmental exposure to endo- RBC life span in sickle cell anemia averages about 15 days but
thelial toxins such as tobacco smoke. with marked interindividual variability (from ~7 to ~30 days); in
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HbSC disease, the average is about 30 days. All four fundamental
mechanisms that can underlie RBC removal in hematologic
Macrophage Interaction disease—erythrophagocytosis, fragmentation, trapping, and osmotic
lysis—probably contribute (Fig. 41.9, bottom). These are conse-
Sickle RBCs are readily phagocytosed by macrophages because of quences of the proximate aberrancies of the sickle RBC discussed
RBC membrane modifications by malondialdehyde, PS externaliza- earlier (Fig. 41.9, middle) that result from the specific molecular
tion, and opsonization by immunoglobulin. The latter process is behaviors of the mutant HbS (Fig. 41.9, top). Although speculative,
triggered by abnormal clustering of membrane protein Band 3 (see the illustrated, integrated synthesis of extant research data presents a
Fig. 41.7) and possibly by modification induced by malondialdehyde. plausible mechanistic blueprint. 12
The most dense cells have the most surface immunoglobulin and Although complex, the routes to accelerated RBC removal seem-
higher PS externalization, and they exhibit the greatest interaction ingly resolve into two contributory mechanistic cascades: one from
with macrophages and potential for erythrophagocytosis. polymer formation that underlies three terminal processes (trapping,
fragmentation, osmotic lysis) that cause intravascular hemolysis; and
THE ROLE OF RED BLOOD CELLS IN one from HbS instability that leads to erythrophagocytosis and
extravascular hemolysis. Notably, intravascular hemolysis seems to
DISEASE PATHOGENESIS account for only one-third of overall hemolysis, while two-thirds
seemingly is explained by extravascular hemolysis. The influence of
Vascular Occlusion the instability-based cascade is most evident in enhanced erythropha-
gocytosis of sickle RBC, promoted by denatured Hb causing Band 3
Notwithstanding the conceptual simplicity of the sickling phenom- clumping causing attraction of immunoglobulin.
enon, when acute microvascular occlusion occurs, causing an acute The shortest survival is exhibited by the sickle RBCs that are most
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painful episode, it is a complex and evolving process. It seems prob- dehydrated and that have the lowest amounts of HbF, consistent
able that similar events, but of less severe degree and remaining at a with the polymerization-based abnormalities (see Fig. 41.9, left side).
subclinical level, are a recurrent or even near-constant feature of sickle Yet, it is not known whether these two RBC features fully explain
vascular pathobiology. The current understanding of microvascular the very wide range of hemolytic rates. Presumably, the sickle RBCs’
vasoocclusion in sickle cell anemia does carry lingering enigmas. 9 fragility is related, and sickled RBCs do lose Hb via microvesiculation
Insofar as sickling is responsible, risk factors would include any- when sickling is reversed. Improved RBC hydration caused by con-
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thing that would increase RBC dehydration and MCHC (e.g., current α-globin gene deletion improves RBC survival. Sickle RBC
insufficient clinical hydration, injudicious use of diuretics), foster survival drops substantially during acute painful episodes, but whether
arterial oxygen desaturation (e.g., lung disease, sleep-disordered this precedes or follows vasoocclusion onset is not known. The only
breathing), prolong microvascular transit time (e.g., inflammatory biomarkers so far documented to correlate strongly and quantitatively
milieu), increase blood viscosity (e.g., transfusion, clinical dehydra- with measured RBC lifespan in sickle cell anemia are the (uncor-
tion), right shift the oxygen binding curve (e.g., acidosis), or disturb rected) reticulocyte percentage and HbF level. 12
vascular dynamics (e.g., cold, aberrant neurochemical responses,
vasomotive rhythms). The extraordinary heterogeneity amongst
sickle RBC undoubtedly confers enormous variability in behavior of Consequences of Hemolysis
individual RBC as they lose oxygen while traversing the microcircula-
tion single-file. Although such behavioral heterogeneity is perhaps the Hemolysis exerts complex effects. Some are indirect, stemming from
dominant feature of sickle disease pathobiology, it currently is expanded erythropoiesis, such as enhanced production of highly
immeasurable at the level of microcirculatory physiology. At the adhesive reticulocytes and augmented elaboration of placental growth
sensitivity of epidemiology, HbF level is inversely related to frequency factor. This growth factor activates blood monocytes and promotes
of vasoocclusive painful crises. 10 augmented production of endothelin-1 (ET-1) that can exert multiple
Enabling vasoocclusion, adhesion of sickle RBC to endothelium effects relevant to sickle pathobiology: induce vasoconstriction, cause
allows greater deoxygenation by slowing microvascular flow. Indeed, nociceptive hypersensitization, activate RBC NADPH oxidase activ-
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in transgenic sickle mice, vascular occlusion is a two-step process. ity, and prompt release of inflammatory mediators. Other hemolysis
This model holds that adhesion of less dense (reticulocyte-enriched) effects derive directly from RBC components released into the blood.
sickle RBCs to endothelium in the postcapillary venule initiates Arginase diminishes plasma arginine, possibly impeding endothelial
vasoocclusion, after which logjamming by dense, poorly deformable, nitric oxide synthase (eNOS). A robust elaboration of PS-positive
and sickling cells creates retrograde propagation (Fig. 41.8). Thus, RBC microparticles exerts a signaling impact upon endothelial cells,