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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 and dehydrated sickle RBCs

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].

RBC  rigidity & Impaired biorhelogy

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].

Sickle cell membrane abnormalities

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].

Increased blood viscosity

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].

Adhesion to  the  vascular  endothelium

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.