Thrombo-Haemorheological Coupling in Haemoglobinopathies: Mechanistic Insights into the Bidirectional Interplay between Coagulation Activation and Erythrocyte Flow Properties

Abstract

Hemoglobinopathies (e.g., HbS, HbC, HbF) are the most common single-gene disorders worldwide, especially in sub-Saharan Africa. Beyond affecting red blood cells and oxygen transport, they significantly disrupt blood clotting (hemostasis) and blood flow properties (haemorheology). This review synthesizes current evidence from molecular biology, cellular hematology, and clinical hemostasis research to construct a mechanistically integrated framework for thrombo-haemorheological coupling in hemoglobinopathies. We examine how hemoglobin structural variants alter erythrocyte membrane phospholipid topology, intracellular viscosity, and cytoskeletal integrity to produce downstream procoagulant signaling, and conversely, how activated coagulation factors, fibrin deposition, and platelet-mediated networks feed back to impair erythrocyte flow properties. Specific genotype-phenotype relationships are examined across HbAA, HbAS, HbSS, HbSC, HbCC, HbAC, and elevated HbF phenotypes. The role of the vascular endothelium, neutrophil extracellular traps (NETs), and the thrombo-inflammatory axis is critically evaluated. We propose the Thrombo-Haemorheological Coupling Axis (THCA) as a framework for future research and therapeutic targeting.