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Sriram Krishnaswamy, PhD
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.
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
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
PubMed:
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
Bradford HN, Krishnaswamy S. The Fragment 1 Region of Prothrombin Facilitates the Favored Binding of Fragment 12 to Zymogen and Enforces Zymogen-like Character in the Proteinase. J Biol Chem. 2016 May; 291(21):11114-23. PMID: 27013660
Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Hemostas. 2013 Jun; 11 Suppl 1:265-76. PMID: 23809130
Links of Interest
Multidisciplinary investigation of thrombosis and hemostasis (Cornerstone blog, December 21, 2018)
Oligonucleotide Therapeutics Society Paper of the Month
ISTH Congress to be held in Philadelphia in 2021
CHOP Thrombosis Expert’s Work to Be Honored (Cornerstone blog, June 3, 2015)