Low-shear red blood cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy

Abstract

Background: Simple chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen-carrying capacity, reducing demands for high cardiac output. While transfusion decreases factors associated with vasoocclusion, including percent hemoglobin (Hb)S, reticulocyte count, and circulating cell-free Hb, it increases blood viscosity, which reduces microvascular flow. The hematocrit-to-viscosity ratio (HVR) is an index of red blood cell oxygen transport effectiveness that varies with shear stress and balances the benefits of improved oxygen capacity to viscosity-mediated impairment of microvascular flow. We hypothesized that transfusion would improve HVR at high shear despite increased blood viscosity, but would decrease HVR at low shear.

Study design and methods: To test this hypothesis, we examined oxygenated and deoxygenated blood samples from 15 sickle cell patients on CTT immediately before transfusion and again 12 to 120 hours after transfusion.

Results: Comparable changes in Hb, hematocrit (Hct), reticulocyte count, and HbS with transfusion were observed in all subjects. Viscosity, Hct, and high-shear HVR increased with transfusion while low-shear HVR decreased significantly.

Conclusion: Decreased low-shear HVR suggests impaired oxygen transport to low-flow regions and may explain why some complications of sickle cell anemia are ameliorated by CTT and others may be made worse.

Figure 1

Schematic representation of the effects of hematocrit on blood viscosity and the hematocrit to blood viscosity ratio (HVR). The HVR is less than maximal in area A due to low hemoglobin level and in area C due to elevated blood viscosity; a maximal HVR is achieved at an “optimal hematocrit”.

Figure 2

Effects of transfusion on whole blood viscosity-shear rate relations. All blood samples behaved as non-Newtonian fluids with viscosity increasing as shear rate is decreased. Blood viscosity also increases with hematocrit (see Figure 1) and thus post-transfusion levels are higher than those for pre-transfusion blood regardless of oxygenation status. (p<0.001 at all shear rates for both deoxygenated and oxygenated blood)

Figure 3

Effects of deoxygenation on whole blood viscosity-shear rate relations. Viscosity increased over the entire shear rate range subsequent to deoxygenation (p<0.002), with the effects most prominent at lower shear rates. Pre-transfusion, deoxygenation increased viscosity by 19% at 1 s⁻¹ and 13% at 1,000 s⁻¹; post-transfusion increases due to deoxygenation were somewhat greater at 1 s⁻¹ (27%) but identical at the highest shear.

Figure 4

Effects of deoxygenation on the hematocrit to blood viscosity ratio (HVR) for pre-transfusion (Panel A) and post-transfusion (Panel B) blood samples. Regardless of oxygenation status, HVR increased with shear rate owing to the non-Newtonian behavior of blood and the decrease of viscosity with increasing shear rate (Figure 2). Both pre- and post-transfusion blood samples exhibit a shear rate dependent decrease of HVR with deoxygenation.

Figure 5

The effects of shear rate on HVR for the range used in the present study, with results expressed as percent change from appropriate pre-transfusion values; negative percent changes indicate a worsening of HVR. Note that transfusion significantly impaired HVR at low shear (1, 2, and 5 s⁻¹) under both oxygenated and deoxygenated conditions, with an effect size ranging from 17.6% (1 s⁻¹) to 8.2% (5 s⁻¹) (* = p<0.05). HVR tended to be lower at 10 s⁻¹ (** = 0.05<P<0.1); no significant effects were observed at higher rates of shear.