Pyruvate Kinase Function Correlates With Red Blood Cell Properties and Clinical Manifestations in Sickle Cell Disease

Area of Science:

• Biochemistry
• Hematology
• Genetics

Background:

• Pyruvate kinase (PK) is crucial for glycolysis and ATP production.
• Reduced red blood cell (RBC) PK activity and thermostability are implicated in sickle cell disease (SCD) pathophysiology.
• The PK/hexokinase (HK) ratio and PK thermostability are key indicators of PK function.

Purpose of the Study:

• To investigate the association between impaired PK function and sickle RBC properties.
• To determine if reduced PK function correlates with SCD-related clinical manifestations.
• To explore the potential of PK activation therapy for SCD.

Main Methods:

• Studied 97 non-transfused patients with SCD (HbSS and HbS/β0 thalassemia).
• Assessed PK thermostability and PK/HK ratio.
• Correlated PK function parameters with RBC properties (reticulocyte count, HbF, point of sickling, oxygen affinity, RBC deformability, adhesion) and clinical complications using multivariate Poisson regression.

Main Results:

• PK thermostability correlated with reticulocyte count, HbF, point of sickling, oxygen affinity, and RBC adhesion to laminin.
• A low PK/HK ratio was associated with decreased PK thermostability, reduced RBC deformability, and elevated 2,3-diphosphoglycerate.
• Reduced PK thermostability and PK/HK ratio were independently associated with a higher incidence of SCD clinical complications.

Conclusions:

• Impaired PK function is linked to compromised sickle RBC properties.
• Reduced PK activity and stability are significant risk factors for SCD clinical manifestations.
• These findings support the therapeutic potential of targeting PK in SCD management.