There are several inter-related factors that impact on vaso-occlusion in SCD, these include the following: RBC density, RBC rigidity, membrane anomalies, blood viscosity and endothelial cell adhesion.
Dense,
dehydrated RBCs are typically present in the blood of SCD patients[26]. Cellular
water balance is altered due to changes in cation homeostasis resulting from a
number of "leaky" membrane channels[75,84]. The two main systems
implicated include the Ca+2-activated K+ efflux (Gardos)
channel and K+/Cl- cotransport system, which are activated
by sickling (increase intracellular Ca+2) and plasma acidosis in
reticulocytes, respectively[26,84]. The result is a tendency towards a dense,
dehydrated state with an increase in Hb concentration in RBCs. The high mean
cellular Hb concentration (MCHC) and low mean cellular volume (MCV) are
indicative of increased density and cellular dehydration;
both are typically of patients with Hb SC disease[85].
Blood
rheology studies have shown that adequate RBC flexibility is crucial to
microvascular circulatory function[86,87,89]. RBC shape and deformability impact
on blood flow properties[86-88]. Sickled cells, and ISCs in particular, are
stiff and rigid and do not deform easily [86] because they have lost the
fluidity of the normal cell membrane[75,87,88]. Also, problems might arise
because the RBC has a mean diameter (
~
8
m
m) that is more than twice
that of the mean diameter of the capillaries in the microcirculation (
~
3
m
m). This is relevant because
non-deformable RBCs have been shown to have difficulty to traverse the
microcirculation[87,89].
In
addition, there are various abnormalities of the sickle RBC membrane. Hb S-(auto)oxidation
can damage the membrane[26]. However, most membrane damage is reported to result
from the instability of Hb S and its interaction with the membrane[26]. These
membrane changes include the following: (1) abnormal cation homeostasis (K+
efflux, Na+/K+ ATPase,
Na+/H+ exchanger, Ca+2 ATPase and Ca+2
channel)[75]; (2) dysfunctional lipid bilayer (externalization of
phosphatidylserine); (3) membrane iron deposits; and (4) abnormal membrane
protein defects, including C3b, IgG and Band 3 clusters[75].
An
increase in plasma or membrane
viscosity in SCD patients can cause a decrease in blood flow[27]. Increased
plasma viscosity is attributed to increased plasma proteins in individuals with
SCD[83]. Also, RBC sickling causes increased membrane viscosity[75,83,88]. Given
the kinetic considerations of Hb S polymerization, a reduced flow rate in vivo may bring capillary transit time above the critical delay
time for polymerization. It is also noteworthy that an increase in Hct
(increased RBC numbers) in SCD patients typically leads to higher whole blood
viscosity[83], and increased frequency of painful crises in clinical
reports[83].
The sickle cell interaction with the endothelial lining[90-93] is another factor which can impact on the blood flow by increasing the vascular transit time[93] of SCD RBCs. Endothelial interactions are most apparent in SCD patient subpopulations that do not show clinical correlation with dense cells, ISCs or deformability[94,95]. Proposed interactions of endothelial cell (EC) adhesion include a VCAM-l-to-VLA-4 ( a 4 b 1) integrin pathway on sickle reticulocytes[27]; a plasma TSP-to-CD36 (gpIV) surface receptor mechanism on reticulocytes[27]; and adhesogenic protein (e.g., vonWillebrand Factor) attachment to the endothelial cell lining[27]. Furthermore, a number of acute phase reactants have been shown to stimulate or initiate EC-RBC interactions. This suggests that there is a role for WBCs[27,83] and/or immune stimulation[27,83] in SCD pathophysiology.