Recent in vivo studies from several laboratories have challenged the paradigm that tissue factor is solely responsible for triggering blood clotting in thrombotic disease, by showing that blocking the function of coagulation factor XII (which is essential for the contact pathway of blood clotting) significantly decreases thrombosis in animal models. However, for many years it has been unclear how the contact pathway is initiated in vivo. Recent work from our laboratory has identified inorganic polyphosphate as the long-sought (patho) physiologic activator of the contact pathway. Polyphosphate is secreted from activated platelets and accumulates in infectious microorganisms;we propose that it is an important triggering agent at the nexus of prothrombotic and pro-inflammatory pathways. Our studies have now shown that, in addition to being an extremely potent initiator of the contact pathway, polyphosphate also accelerates factor V activation and enhances fibrin clot structure, leading to thicker fibrin fibrils that are more resistant to fibrinolysis. Because the ability of polyphosphate to modulate blood clotting has only recently been discovered, we still do not understand mechanistically how polyphosphate exerts its effects on coagulation. Similarly, many questions remain regarding where, when and how if functions in vivo. These questions will be addressed in three aims, which focus on: understanding how polyphosphate triggers the contact pathway of clotting;understanding how polyphosphate accelerates factor V activation;and understanding how polyphosphate functions in vivo. The work outlined in this grant proposal will therefore provide a mechanistic understanding of how polyphosphate functions in hemostasis, thrombosis and inflammation. These studies are designed to identify novel drug targets for interrupting thrombotic and inflammatory pathways with minimized risk of bleeding side effects. They are also designed to develop novel hemostatic agents for treating bleeding.
Our laboratory has recently identified a substance - polyphosphate - which is released by certain human cells, and which regulates the blood clotting system. We are investigating how polyphosphate accomplishes this, which can lead to new insights into thrombotic diseases such as heart attack and stroke. These studies may also allow us to develop new methods that could eventually be used to treat bleeding episodes in patients.
|Shenoi, Rajesh A; Kalathottukaren, Manu Thomas; Travers, Richard J et al. (2014) Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Sci Transl Med 6:260ra150|
|Wat, Jovian M; Foley, Jonathan H; Krisinger, Michael J et al. (2014) Polyphosphate suppresses complement via the terminal pathway. Blood 123:768-76|
|Matafonov, Anton; Leung, Philberta Y; Gailani, Adam E et al. (2014) Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 123:1739-46|
|Hebbard, Carleigh F F; Wang, Yan; Baker, Catherine J et al. (2014) Synthesis and evaluation of chromogenic and fluorogenic substrates for high-throughput detection of enzymes that hydrolyze inorganic polyphosphate. Biomacromolecules 15:3190-6|
|Smith, Stephanie A; Morrissey, James H (2014) Polyphosphate: a new player in the field of hemostasis. Curr Opin Hematol 21:388-94|
|Morrissey, James H; Choi, Sharon H; Smith, Stephanie A (2012) Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 119:5972-9|
|Morrissey, James H (2012) Polyphosphate: a link between platelets, coagulation and inflammation. Int J Hematol 95:346-52|
|Boettcher, John M; Davis-Harrison, Rebecca L; Clay, Mary C et al. (2011) Atomic view of calcium-induced clustering of phosphatidylserine in mixed lipid bilayers. Biochemistry 50:2264-73|
|Semeraro, Fabrizio; Ammollo, Concetta T; Morrissey, James H et al. (2011) Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118:1952-61|
|Morrissey, J H; Tajkhorshid, E; Rienstra, C M (2011) Nanoscale studies of protein-membrane interactions in blood clotting. J Thromb Haemost 9 Suppl 1:162-7|
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