Hemoglobin interaction with GP1bα induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis

• Published in: Haematologica (Roma) 2015-12, Vol.100 (12), p.1526-1533
• Main Authors: Singhal, Rashi, Annarapu, Gowtham K, Pandey, Ankita, Chawla, Sheetal, Ojha, Amrita, Gupta, Avinash, Cruz, Miguel A, Seth, Tulika, Guchhait, Prasenjit
• Format: Article
• Language: English
• Subjects: Apoptosis; Blood Platelets - metabolism; Blood Platelets - pathology; Female; Hemoglobins - metabolism; Hemoglobinuria, Paroxysmal - pathology; Hemolysis; Humans; Male; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex - metabolism
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2015.132183

Intravascular hemolysis increases the risk of hypercoagulation and thrombosis in hemolytic disorders. Our study shows a novel mechanism by which extracellular hemoglobin directly affects platelet activation. The binding of Hb to glycoprotein1bα activates platelets. Lower concentrations of Hb (0.37-3 μM) significantly increase the phosphorylation of signaling adapter proteins, such as Lyn, PI3K, AKT, and ERK, and promote platelet aggregation in vitro. Higher concentrations of Hb (3-6 μM) activate the pro-apoptotic proteins Bak, Bax, cytochrome c, caspase-9 and caspase-3, and increase platelet clot formation. Increased plasma Hb activates platelets and promotes their apoptosis, and plays a crucial role in the pathogenesis of aggregation and development of the procoagulant state in hemolytic disorders. Furthermore, we show that in patients with paroxysmal nocturnal hemoglobinuria, a chronic hemolytic disease characterized by recurrent events of intravascular thrombosis and thromboembolism, it is the elevated plasma Hb or platelet surface bound Hb that positively correlates with platelet activation.