Vascular Occlusion

Notwithstanding the conceptual simplicity of the sickling phenomenon, when acute microvascular occlusion causes an acute painful episode it is a complex and evolving process. It seems virtually certain that similar events, but of a less severe degree and remaining at a subclinical level, are a recurrent or even near-constant feature of sickle vascular pathobiology.

Insofar as sickling is responsible, risk factors include anything that can prolong microvascular transit time (e.g., inflammatory milieu, RBC stiffness), increase RBC dehydration and MCHC (e.g., clinical dehydration, injudicious use of diuretics), foster arterial oxygen desaturation (e.g., lung disease, sleep apnea), increase blood viscosity (e.g., transfusion, inflammation, clinical dehydration), right-shift the oxygen binding curve (e.g., acidosis), or disturb vascular dynamics (e.g., cold, neurochemical responses).

The extraordinary heterogeneity amongst sickle RBCs undoubtedly confers considerable behavioral variability as they lose oxygen while traversing the microcirculation single-file. Such heterogeneity is perhaps the most perplexing feature of sickle disease pathobiology.

RBC Deformability

The diminished deformability of dehydrated (high MCHC) sickle RBC undoubtedly contributes to the impairment of microvascular flow. Some dense cells (especially ISCs) can have difficulty entering the microvasculature, for example, at bifurcations. RBC with lower HbF content will transit with a higher risk of sickling, and HbF level is inversely related to the frequency of vasoocclusive painful crises.  Low HbF RBCs tend to become more dehydrated (have higher MCHC) and are less deformable.  They, therefore, pass within the microcirculation less easily. Nonetheless, among sickle patients vasoocclusive severity correlates positively with preserved deformability, rather than impairment thereof. This probably reflects the higher endothelial adhesivity of more deformable RBC. Whether RBC adhesivity and poor deformability exert synergistic effects within the smallest vessels has not been studied, nor has any role for dynamic change of rigidity during deoxygenation on the timescale of micro vascular transit.

Adhesive RBC

The tendency of sickle RBC to abnormally adhere to endothelium slows the microvascular flow. Indeed, in transgenic sickle mice, vascular occlusion is a two-step process: adhesion of less dense (reticulocyte-enriched) sickle RBC to endothelium in the postcapillary venule slows the flow and initiates vasoocclusion via retrograde log-jamming by dense, poorly deformable, and sickling cells (see Fig.1).  Consistent with this, among patients clinical vasoocclusive severity correlates positively with the endothelial adhesive ness displayed by sickle RBCs in vitro.  To be sure, participation of sickle RBC adhesion in pathophysiology is governed by endothelial activation states. In the sickle context, a multitude of biologic mediators can influence endothelial surface features (see box on The Complex Sickle Milieu ).

Fig1. SICKLE RBC ADHESION TO ENDOTHELIUM. RBCs adhere to the vascular wall endothelium under flowing conditions in the microcirculation of a rat infused with human sickle RBC. Immobile RBCs are on walls of the postcapillary venule that still is flowing (long arrow). The smaller feeder microvessels (small arrows) have no flow because of the log jam of RBC. (Reproduced with permission from Kaul DK, Fabry ME, Nagel RL. Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications. Proc Natl Acad Sci U S A. 1989;86:3356.)

Adhesive WBC

Consistent with their inflammatory endothelial activation state, sickle mice also exhibit abnormal leucoadhesion to endothelium even at baseline; and when they are exposed to hypoxia/reoxygenation (which triggers a sickling/unsickling response) this is enormously augmented.  Just as for adherent sickle RBC, leucoadhesion in post-capillary venules slows microvascular transit of RBC, and blocking this with antibody to P-selectin (but not to E-selectin) greatly improves microvascular flow. On the other hand, in sickle disease WBC, participate in intravascular heterocellular interactions, just as they do in another arteriopathy, atherosclerosis. Also, in sickle mice, it has been observed that when adherent WBC engages E selectin, an activating wave causes them to secondarily capture sickle RBC—but only after massive tumor necrosis factor (TNF) injections.

Hemolytic Anemia

RBC life span in HbSS averages about 15 days, but with marked interindividual variability (from ~7 to ~30 days); in HbSC disease, the average is about 30 days.  All four fundamental mechanisms that can underlie premature RBC removal in hematologic disease—erythrophagocytosis, fragmentation, trapping, and osmotic lysis—prob ably contribute ( Fig. 2, bottom). These mechanisms derive from the multiple aberrant properties of sickle RBC (see Fig. 2 , middle) that are consequences of the pathogenic molecular behaviors of the mutant HbS (see Fig. 2, top).

Fig2. MECHANISMS LEADING TO HEMOLYSIS IN SICKLE CELL DISEASE. This integrated synthesis proposes how the distinct molecular behaviors of HbS (top) cause the development of multiple sickle RBC abnormalities (middle) that, in turn, lead to the four mechanisms of accelerated RBC destruction (bottom). (Modified with permission from Hebbel RP: Reconstructing sickle cell disease: A data-based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence-based medicine. Am J Hematol. 2011:86:123−154.)

This model suggests that the routes to accelerated RBC removal resolve into two contributory mechanistic cascades. One flows from polymer formation and underlies RBC trapping, fragmentation, and osmotic lysis, causes of intravascular hemolysis. The other cascade flows from HbS instability and underlies erythrophagocytosis, the cause of extravascular hemolysis. Although speculative, the illustrated integrated synthesis of extant research data presents a plausible mechanistic blueprint.  The proportionate contributions of intravascular versus extravascular hemolysis to the overall hemolytic rate have never been determined. These may vary amongst individuals and with clinical context, just as the net hemolytic rate does. For example, sickle RBC survival drops substantially during acute painful episodes, but whether this precedes or follows vasoocclusion onset is not known.

The shortest survival is exhibited by sickle RBCs that are most dehydrated and that have the lowest amounts of HbF,  consistent with the polymerization-based abnormalities (see Fig. 2 , left side). Yet, it is not known whether these two RBC features fully explain the very wide range of hemolytic rates. Presumably, the sickle RBCs’ fragility is related, and sickled RBCs do lose Hb via microvesiculation. Improved RBC hydration caused by concurrent α -globin gene deletion improves RBC survival.

The only biomarkers so far documented to correlate significantly with measured RBC life span in HbSS are the (uncorrected) reticulocyte percentage and HbF level. As for lactate dehydrogenase (LDH) as a putative hemolysis severity biomarker, the only available data show that LDH level does not correlate with measured sickle RBC survival. Despite this, associations with LDH are what the “hyperhemolysis” hypothesis is based on.

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