ÌÇÐÄvlogÃÛÌÒ the Lab
The major emphasis of the Thiagarajan Lab is to elucidate the mechanism of the hypercoagulable state associated with the presence of antiphospholipid antibodies. Patients with systemic lupus erythematosus and allied autoimmune disorder have antibodies that react with anionic phospholipid such as cardiolipin in immunological assays.
Some of these antibodies also interfere with phospholipid-dependent coagulation tests and these inhibitors are called lupus anticoagulant. The immunological specificity of these antibodies is complex and it ranges from phospholipid binding proteins, a complex of phospholipid proteins and anionic phospholipid to anionic phospholipid alone. A number of phospholipid binding protein such as b 2 glycoprotein I, prothrombin, annexin V or oxidized LDL have been identified as an integral component of the complex epitope for these antibodies.
The clinical significance of these antibodies lies in the fact that their presence of is a strong risk factor for thrombosis: arterial, venous, microvascular and embolic. We have developed epitope libraries by phage-display from lymphocytes of patients with these antibodies and thrombosis. We are isolating recombinant scFv fragments to determine their epitope specificity. We utilize several in vitro coagulation assays and in vivo animal models of thrombosis to elucidate the mechanism of hypercoagulable state.
We are also exploring the cause and consequences of anionic phospholipid exposure in blood cells. Anionic phospholipids, such as phosphatidylserine, are normally present in the inner leaflet of membrane bilayer. Transbilayer movement of phosphatidylserine occurs during apoptosis, cellular senescence and during platelet activation. Exposure of phosphatidylserine in platelets is accompanied by the generation of platelet-derived microvesicles.
Microvesicles are also generated from other blood cells such as macrophages and endothelial cells during apoptosis and they are present in normal plasma. Deficiency of anionic phospholipid exposure and microvesiculation in platelets leads to an inherited bleeding disorder (Scot syndrome). Increased microvesicles have been detected in the circulation in patients with disseminated intravascular coagulation, heparin-induced thrombocytopenia, the antiphospholipid antibody syndrome, transient ischemic attacks, and thrombotic thrombocytopenic purpura, all conditions associated with either arterial or venous thrombosis. These associations suggest that, while they may be necessary for normal hemostasis, elevated microvesicles concentrations could predispose to thrombosis.
Clearly, a homeostatic mechanism must exist to balance the generation of anionic phospholipids by providing for their clearance, which when perturbed will enhance the risk of thrombosis. We are investigating defects in the clearance of microvesicles as a cause of hypercoagulable state.
Dasgupta SK, Le A, Haudek SB, Entman ML, Rumbaut RE, Thiagarajan P. Rho associated coiled-coil kinase-1 regulates collagen-induced phosphatidylserine exposure in platelets. PLoS One. 2013; 8(12):e84649. View in:
Pongas G, Dasgupta SK, Thiagarajan P. Antiplatelet factor 4/heparin antibodies in patients with gram negative bacteremia. Thromb Res. 2013 Aug; 132(2):217-20. View in:
Thiagarajan P, Afshar-Kharghan V. Platelet transfusion therapy. Hematol Oncol Clin North Am. 2013 Jun; 27(3):629-43. View in:
Mediwala SN, Sun H, Szafran AT, Hartig SM, Sonpavde G, Hayes TG, Thiagarajan P, Mancini MA, Marcelli M. The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. Prostate. 2013 Feb 15; 73(3):267-77. View in:
Dasgupta SK, Le A, Chavakis T, Rumbaut RE, Thiagarajan P. Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium. Circulation. 2012 Apr 3; 125(13):1664-72. View in:
Zhou Z, Thiagarajan P, Udden M, Lòpez JA, Guchhait P. Erythrocyte membrane sulfatide plays a crucial role in the adhesion of sickle erythrocytes to endothelium. Thromb Haemost. 2011 Jun; 105(6):1046-52. View in:
Dasgupta SK, Argaiz ER, Mercado JE, Maul HO, Garza J, Enriquez AB, Abdel-Monem H, Prakasam A, Andreeff M, Thiagarajan P. Platelet senescence and phosphatidylserine exposure. Transfusion. 2010 Oct; 50(10):2167-75. View in:
Mandava P, Dalmeida W, Anderson JA, Thiagarajan P, Fabian RH, Weir RU, Kent TA. A Pilot Trial of Low-Dose Intravenous Abciximab and Unfractionated Heparin for Acute Ischemic Stroke: Translating GP IIb/IIIa Receptor Inhibition to Clinical Practice. Transl Stroke Res. 2010 Sep; 1(3):170-7. View in:
Abdel-Monem H, Dasgupta SK, Le A, Prakasam A, Thiagarajan P. Phagocytosis of platelet microvesicles and beta2- glycoprotein I. Thromb Haemost. 2010 Aug; 104(2):335-41. View in:
Abdel-Monem H, Prakasam A, Thiagarajan P. Howell-jolly body-like inclusions in neutrophils of a transplant recipient in association with ganciclovir therapy. Arch Pathol Lab Med. 2010 Jun; 134(6):809-10. View in:
The Perumal Thiagarajan Lab is exploring the cause and consequences of anionic phospholipid exposure in blood cells.
Anionic phospholipids, such as phosphatidylserine, are normally present in the inner leaflet of membrane bilayer. Transbilayer movement of phosphatidylserine occurs during apoptosis, cellular senescence and during platelet activation. Exposure of phosphatidylserine in platelets is accompanied by the generation of platelet-derived microvesicles.
Microvesicles are also generated from other blood cells such as macrophages and endothelial cells during apoptosis and they are present in normal plasma. Deficiency of anionic phospholipid exposure and microvesiculation in platelets leads to an inherited bleeding disorder (Scot syndrome). Increased microvesicles have been detected in the circulation in patients with disseminated intravascular coagulation, heparin-induced thrombocytopenia, the antiphospholipid antibody syndrome, transient ischemic attacks, and thrombotic thrombocytopenic purpura, all conditions associated with either arterial or venous thrombosis.
These associations suggest that, while they may be necessary for normal hemostasis, elevated microvesicles concentrations could predispose to thrombosis. Clearly, a homeostatic mechanism must exist to balance the generation of anionic phospholipids by providing for their clearance, which when perturbed will enhance the risk of thrombosis.
We are investigating defects in the clearance of microvesicles as a cause of hypercoagulable state.