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E-mail
krishnaswamy [at] email.chop.edu
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Location - People View
Room 310A

3615 Civic Center Blvd
Philadelphia, PA 19104
United States

Sriram Krishnaswamy, PhD
Sriram Krishnaswamy
Investigator

Dr. Krishnaswamy studies molecular mechanisms underlying the reactions of blood coagulation. His laboratory investigates how the proteins of blood coagulation interact with each other and with membranes to yield a regulated clotting response to vascular injury or an unregulated response in thrombotic or bleeding disease.

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Bio

Dr. Krishnaswamy studies molecular mechanisms of blood coagulation, and his lab investigates how the proteins of blood coagulation interact with each other and membranes to yield a regulated clotting response to vascular injury or an unregulated response in thrombotic or bleeding disease.

A regulated blood coagulation response to vascular injury is essential for life. Excessive bleeding is associated with a range of genetic or acquired conditions that impair the clotting response. Thrombotic diseases result from exuberant or dysregulated clotting. Together, diseases associated with excessive clotting or bleeding represent one of the major causes of morbidity and mortality in the developed world.

Dr. Krishnaswamy's research focuses on understanding the proteolytic activation steps in coagulation that are catalyzed by membrane complexes assembled from the reversible binding of a serine protease to a protein cofactor on a membrane surface. A combination of biophysical, mutagenesis, and functional studies are used by the lab team to relate these binding steps to large increases in the function of the serine protease towards its biological substrate, and to understand how cofactors and membranes function in greatly enhancing the catalytic power of the enzyme complex.

His lab also studies how the biological substrate is recognized by the enzyme complex and the mechanisms by which substrate cleavage imparts biological activity in the product.

Dr. Krishnaswamy and his team also use X-ray crystallography, small angle X-ray scattering, single molecule reconstruction using high-resolution cryo-electron microscopy and hydrogen-deuterium exchange to provide structural insights into how the interactions between the components relate to function. His goal is to use mechanistic insights resulting from this work to reveal novel strategies to modulate the coagulation reactions for treatment of disease.

Education and Training

BS, Syracuse University (Biology), 1979

PhD, Syracuse University (Biochemistry), 1984

Fellowship, University of Vermont (Biochemistry), 1987

Titles and Academic Titles

Investigator

Associate Professor of Pediatrics

Professional Memberships

Kenneth Brinkhous Young Investigator Prize in Thrombosis, American Heart Association, 1989

ATVB Special Recognition Award in Thrombosis, American Heart Association, 2013

Children’s Hospital of Philadelphia Faculty Mentor Award, 2014

Sol Sherry Distinguished Lecture in Thrombosis, American Heart Association, 2014

Publication Highlights

Bradford HN, Krishnaswamy S. Occlusion of anion-binding exosite 2 in meizothrombin explains its impaired ability to activate factor V. J Biol Chem. 2019 Feb; 294(7):2422-2435. PMID: 30578302
Gunaratne R, Kumar S, Frederiksen JW, Stayrook S, Lohrmann JL, Perry K, Bompiani KM, Chabata CV, Thalji NK, Ho MD, Arepally G, Camire RM, Krishnaswamy S, Sullenger BA. Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass. Nat Biotechnol. 2018 Aug; 36(7):606-613. PMID: 29863725
Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med. 2016 Aug; 22(8):924-32. PMID: 27455511
Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Hemostas. 2013 Jun; 11 Suppl 1:265-76. PMID: 23809130

Links of Interest