Hemoglobin interaction with GP1bα induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis.
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.
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India Biotechnology Department, Manipal University, Manipal, Karnataka, India.
Rashi
R
Singhal
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India Biotechnology Department, Manipal University, Manipal, Karnataka, India.
Gowtham K
GK
Annarapu
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India.
Ankita
A
Pandey
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India.
Sheetal
S
Chawla
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India.
Amrita
A
Ojha
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India.
Avinash
A
Gupta
Thrombosis Research Division, Baylor College of Medicine, Houston, TX, USA.
Miguel A
MA
Cruz
Hematology, All India Institute of Medical Sciences, New Delhi, India.
Tulika
T
Seth
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region, Biotech Science Cluster, Faridabad, India prasenjit@rcb.res.in.
Prasenjit
P
Guchhait
D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000473:pathology; D006461:Hemolysis; D006801:Humans; D008297:Male; D015539:Platelet Activation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*
D006454:Hemoglobins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor