Since the mid-1980s, my research has focused on biochemical mechanisms by which the blood clotting system is triggered, with a particular emphasis on studying protein-membrane interactions in clotting. In 2006, my lab discovered that inorganic polyphosphate, which is released from activated human platelets, is a potent modulator of blood clotting and inflammation. Work from my lab has led to a number of spin-offs with potential clinical applications, including new diagnostic assays. We are also working on novel hemostatic agents for treating bleeding, and anti-inflammatory/anti-thrombotic agents with potential for reduced bleeding side effects relative to conventional anticoagulant drugs.
We are investigating how the blood clotting cascade is regulated, with applications to thrombotic diseases, bleeding disorders, and inflammation. Many of our studies have focused on understanding the initiation phase of blood clotting, an event that takes place when the soluble plasma protein, factor VIIa (a serine protease), binds to the integral membrane protein, tissue factor (TF), on cell surfaces. We also discovered that polyphosphate (an inorganic polymer of phosphate present in many infectious microorganisms and secreted by activated human platelets) is a novel modulator of the blood clotting cascade and may represent the long-sought (patho)physiologic activator of the contact pathway of blood coagulation.
Our current research efforts focus primarily on: (1) Understanding, with atomic-scale resolution, how blood clotting proteins interact with membrane surfaces and how these membrane binding events contribute so profoundly to catalysis; and (2) Understanding the mechanisms by which polyphosphate modulates the clotting system in hemostasis, thrombosis and inflammation.
Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, and Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 124:3183-3190, 2014. PMCID: PMC4239329
Shenoi RA, Kalathottukaren MT, Travers RJ, Lai BFL, Creagh AL, Lange D, Yu K, Weinhart M, Chew BH, Du C, Brooks DE, Carter CJ, Morrissey JH, Haynes CA, and Kizhakkedathu JN. Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Sci Transl Med 6:260ra150, 2014. PMC Journal - In Process
Gajsiewicz JM, Smith SA, and Morrissey JH. Polyphosphate and RNA differentially modulate the contact pathway of blood clotting. J Biol Chem 292:1808-1814, 2017. PMCID: PMC5290954
Kalathottukaren MT, Abraham L, Kapopara PR, Lai BF, Shenoi RA, Rosell FI, Conway EM, Pryzdial EL, Morrissey JH, Haynes CA, and Kizhakkedathu JN. Alteration of blood clotting and lung damage by protamine are avoided using the heparin and polyphosphate inhibitor UHRA. Blood 129:1368-1379, 2017. PMCID: PMC5345737
Smith SA, Baker CJ, Gajsiewicz JM, and Morrissey JH. Silica particles contribute to the procoagulant activity of DNA and polyphosphate isolated using commercial kits. Blood 130:88-91, 2017. PMCID: PMC5501151
Muller MP Wang Y, Morrissey JH, and Tajkhorshid E. Lipid specificity of the membrane binding domain of coagulation factor X. J Thromb Haemost 15:2005-2016, 2017. PMCID: PMC5630516
Muehl EM, Gajsiewicz JM, Medfisch SM, Wiersma ZSB, Morrissey JH, and Bailey RC. Multiplexed silicon photonic sensor arrays enable facile characterization of coagulation protein binding to Nanodiscs with variable lipid content. J Biol Chem 292:16249-16256, 2017. PMCID: PMC5625054
Mafi A, Abbina S, Kalathottukaren MT, Morrissey JH, Haynes C, Kizhakkedathu JN, Pfaendtner J, Chou KC. Design of polyphosphate inhibitors: A molecular dynamics investigation on polyethylene-glycol-linked cationic binding groups. Biomacromolecules 19:1358-1367, 2018.
Slatter DA, Percy CL, Allen-Redpath K, Gajsiewicz JM, Brooks NJ, Clayton A, Tyrrell VJ, Rosas M, Lauder SN, Watson A, Dul M, Garcia-Diaz Y, Aldrovandi M, Heurich M, Hall J, Morrissey JH, Lacroix-Desmazes S, Delignat S, Vincent Jenkins P, Collins PW & O’Donnell VB. Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies. JCI Insight 3:e98459, 2018. PMCID: PMC5926910
Smith SA and Morrissey JH. 2013 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: Polyphosphate: a novel modulator of hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 35:1298-1305, 2015. PMCID: PMC4441552.
Smith SA and Morrissey JH. Inorganic polyphosphate in blood coagulation. In: Inorganic Polyphosphates in Eukaryotic Cells, chapter 11, T Kulakovskaya, E Pavlov and EN Dedkova, eds. (Springer International Publishing, Cham, Switzerland), pp. 159-176, 2016.
Smith SA and Morrissey JH. Interactions between platelets and the coagulation system. In: Platelets (4th Edition), chapter 21, Michelson AD, ed. (Elsevier/Academic Press, London), In Press.