The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend

• Published in: Blood Vol. 112; no. 8; pp. 3011 - 3025
• Main Authors: Coller, Barry S., Shattil, Sanford J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.10.2008; Americain Society of Hematology; American Society of Hematology
• Series: ASH 50th Anniversary Review
• Subjects: Animals; ASH 50th Anniversary Review; Biological and medical sciences; Fibrinogen - metabolism; Hematologic and hematopoietic diseases; Hematology - history; Hematology - methods; History, 20th Century; History, 21st Century; Humans; Medical Laboratory Science; Medical sciences; Platelet Aggregation; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - chemistry; Platelet Glycoprotein GPIIb-IIIa Complex - genetics; Thrombasthenia - diagnosis; Thrombasthenia - genetics; Glycoprotein IIbIIIa; Platelet; Hematology; Technology; C-Onc gene; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-06-077891

Starting 90 years ago with a clinical description by Glanzmann of a bleeding disorder associated with a defect in platelet function, technologic advances helped investigators identify the defect as a mutation(s) in the integrin family receptor, αIIbβ3, which has the capacity to bind fibrinogen (and other ligands) and support platelet-platelet interactions (aggregation). The receptor's activation state was found to be under exquisite control, with activators, inhibitors, and elaborate inside-out signaling mechanisms controlling its conformation. Structural biology has produced high-resolution images defining the ligand binding site at the atomic level. Research on αIIbβ3 has been bidirectional, with basic insights resulting in improved Glanzmann thrombasthenia carrier detection and prenatal diagnosis, assays to identify single nucleotide polymorphisms responsible for alloimmune neonatal thrombocytopenia, and the development of αIIbβ3 antagonists, the first rationally designed antiplatelet agents, to prevent and treat thrombotic cardiovascular disease. The future looks equally bright, with the potential for improved drugs and the application of gene therapy and stem cell biology to address the genetic abnormalities. The αIIbβ3 saga serves as a paradigm of rigorous science growing out of careful clinical observations of a rare disorder yielding both important new scientific information and improved diagnosis, therapy, and prevention of other disorders.