Sickle cell disease: selected aspects of pathophysiology

Abstract

Sickle cell disease (SCD), a genetically-determined pathology due to an amino acid substitution (i.e., valine for glutamic acid) on the beta-chain of hemoglobin, is characterized by abnormal blood rheology and periods of painful vascular occlusive crises. Sickle cell trait (SCT) is a typically benign variant in which only one beta chain is affected by the mutation. Although both SCD and SCT have been the subject of numerous studies, information related to neurological function and transfusion therapy is still incomplete: an overview of these areas is presented. An initial section provides pertinent background information on the pathology and clinical significance of these diseases. The roles of three factors in the clinical manifestations of the diseases are then discussed: hypoxia, autonomic nervous system regulation and blood rheology. The possibility of a causal relationship between these three factors and sudden death is also examined. It is concluded that further studies in these specific areas are warranted. It is anticipated that the outcome of such research is likely to provide valuable insights into the pathophysiology of SCD and SCT and will lead to improved clinical management and enhanced quality of life.

Fig. 1

Time course of the parasympathetic HRV indices. o Indicates significant difference between control and SCD subjects ( p < 0.05). ^* Indicates significant difference from the baseline of the same time-course ( p < 0.05). (a) High frequency power of HRV (HFP), (b) adjusted high frequency power (aHFP).

Fig. 2

Time course of the sympathovagal balance indices. o Indicates significant difference between control and SCD subjects ( p < 0.05). (a) Ratio between high frequency and low frequency powers (LHR), (b) adjusted ratio between high frequency and low frequency powers (aLHR).

Fig. 3

Left side: RR interval series. Time domain analysis allows the calculation of indices such as standard deviation of all normal RR intervals (SDNN), known to reflect global ANS activity. The proportion of adjacent normal RR intervals differing more than 50 ms from the preceding RR (PNN50) reflects the parasympathetic activity. Right side: Power spectrum density. Spectral analysis allows us to estimate sympathovagal balance with various calculated indices, such as: Total power of the spectrum (Ptot), High frequency of the spectrum (HF), Low frequency of the spectrum (LF) and LF/HF ratio. These reflect global ANS activity, parasympathetic activity, parasympathetic and sympathetic activities and sympathovagal balance, respectively.

Fig. 4

Hemorheological parameters and ANS activity in controls with HbA (CONT group, black bar) and in SCT carriers (SCT group, white bar); ^*difference between the two groups ( p < 0.05). (a): Blood viscosity at 225s⁻¹; (b): RBC rigidity index derived from viscometry data obtained at 225s⁻¹; (c): hematocrit-blood viscosity ratio calculated for a shear rate of 225s⁻¹; (d): SDNN; (e): HF. (f) Corresponds to the relationship between the hematocrit-blood viscosity ratio and SDNN. (Modified from Connes et al. [16].)

Fig. 5

Oxygen transport effectiveness (i.e., HVR) of samples at a selected high (300 s⁻¹) and a selected low (5 s⁻¹) shear rate. While at high shear all curves reached a maximum value representing an optimal Hct for HVR, no such optimum Hct could be determined at low shear rates. Arrows represent the influence of Hct and percent SS RBC on HVR for a typical, guideline-based transfusion protocol (i.e., increase Hct from 20% to 35% and reduce proportion of SS RBC from 100% to 50%). Figure modified from Alexy et al. [3].