Higher baseline whole blood viscosity is associated with chronic SCD complications Free

Background

Sickle cell disease (SCD) is an inherited group of hemoglobinopathies that result in the production of abnormal sickle hemoglobin (HbS), which polymerizes under low-oxygen conditions. Intracellular HbS polymers decrease the deformability and membrane health of red blood cells (RBCs), making them more likely to occlude and adhere to microvasculature and lyse. Pulmonary embolism (PE), cerebrovascular disease (CVD), and priapism are commonly thought to represent sub-phenotypes of SCD primarily driven by intravascular hemolysis and vascular dysfunction, which also tend to alter whole blood flow parameters at baseline.

Whole blood viscosity (WBV) can be measured with cone-and-plate viscometry set to shear rates that can capture flow in venous (45s-1) and arterial (225s-1) systems. At lower shear rates like those seen in venous flow, viscosity is primarily driven by RBC aggregation and plasma protein level, which are also implicated in these chronic complications.

On a pathophysiology level, increased WBV is known to contribute to pulmonary thrombosis and stroke risk, but these potentially clinically useful biomarkers are not used prospectively in patient management and risk assessment. Here we present the use of WBV in determination of chronic complication risk in SCD in a prospective study.

Methods

Peripheral blood samples from 540 steady-state adult individuals with SCD were collected in EDTA under an Emory University IRB approved protocol from August 2022 to February 2025. Blood samples were run on an ADVIA2120i hematology analyzer for complete blood counts and a Brookfield viscometer set at shear rates of 45s-1 and 225s-1 to assess whole blood viscosity at venous and arterial flow states, respectively. Viscosity readings were adjusted for hematocrit by taking the ratio of hematocrit to viscosity (HVR); a higher HVR is associated with better oxygen-carrying capacity. Acute and chronic complication information was obtained via a chart review of electronic health records. Individuals with a history of pain crises or acute chest syndrome in the past 30 days, or individuals with a recent transfusion history were excluded.

Nonparametric Mann-Whitney tests were used to compare viscosity values between cohorts. R (version 4.5.1) was used to analyze data and a p value < 0.05 was significant.

Results

Complication frequency was not significantly different by sex (p = 0.92), or age at sample collection (p = 0.65).

16 SCD individuals were diagnosed with either priapism, cerebrovascular disease, or pulmonary embolism a median of 105 days after the WBV measurements. The HVR at venous shear was 0.553cP-1 lower in individuals that developed either priapism, CVD, or PE compared to 202 individuals that were complication-free (p = 0.03). However, there was a reversal of this trend at arterial shear rates, where individuals that developed either priapism, CVD, or PE had 1.3cP-1 higher HVR (p = 0.01).

Reticulocyte and platelet counts were higher by 78 x106 cells/µL and 151 x103 cells/µL, respectively (p = 0.02, p = 0.0002) in individuals that developed priapism, CVD, or PE. Mean cell volume was also elevated by 4.2fL (p = 0.04), and overall hemoglobin was lower by -0.9 gm% in these individuals compared to those without the above diagnoses (p = 0.04).

Discussion

Individuals diagnosed with either priapism, CVD, or PE after sample collection had lower baseline HVR at 45s-1 shear rate, modeling venous circulation, compared to those without, signaling a reduced oxygen-carrying capacity. Individuals with priapism, CVD, or PE hemolysis exhibited elevated reticulocyte counts and decreased hemoglobin compared to those without, potentially due to poor RBC deformability leading to increased hemolysis. Venous shear viscosity is driven by RBC aggregation, a key component of thrombus formation. Given that the median follow-up period for our control group was 532 days greater than the follow-up period for individuals that developed a complication, and our small case size of 16 individuals, the interpretation of these results is subject to type I error. We are currently collecting additional samples from new subjects to increase our sample size and create a more balanced complication frequency among cohorts for future analyses. However, these results highlight the importance of WBV as a biomarker in predicting hemolysis-associated chronic complications of SCD, particularly those involving venous circulation.