Blood Coagulation: From Structure and Function to Therapeutics

The past two decades have seen major advances in the reactions of coagulation from the perspective of novel insights into mechanisms and the uncovering of new regulatory pathways or strategies. These advances bear on the next generation of approaches to modulate the reactions of coagulation for therapeutic gain. This session will focus on new insights into structure and function of the coagulation reactions as well as translation into novel therapeutic strategies.

Dr. Bruce Sullenger will describe how properties of nucleic acids can be employed to generate RNA aptamers that function as rapidly reversible inhibitors of coagulation factors and platelet proteins. He will discuss combinatorial chemistry methods that have been employed to generate nucleic acid ligands that can act as specific inhibitors of many proteins involved in hemostasis and thrombosis. The mechanism(s) of such inhibition will be addressed as well as how this understanding is guiding the development of the next generation of such inhibitors. Finally, Dr. Sullenger will present preclinical and clinical studies evaluating such therapeutics and their reversal agents.

Dr. Peter Lenting will discuss how the proteases that act in the coagulation cascade differ in catalytic capacity and how they frequently need cofactors to achieve physiologically relevant function. He will focus on factor IXa and the increased bleeding associated with the functional absence of its cofactor factor VIIIa. Whereas cofactor deficiency can be corrected via replacement therapy, the use of purified cofactor concentrates is associated with several limitations. Some of these limitations have been resolved by the development of alternate molecules with cofactor-like activities. Dr. Lenting will also discuss the similarities and dissimilarities between the original cofactor and cofactor-mimetics.

Dr. Nicola Mutch will focus on the relatively recent advances engendered by the discoveries of polyphosphate (polyP) as a modulator of the coagulation reactions. PolyP is a biopolymer of negatively charged phosphate residues that is ubiquitous in nature and varies in chain length according to the organism and tissue in which it is synthesized.  PolyP with a defined chain length of 80-100 phosphates is contained within the dense granules of platelets and is released following agonist stimulation. Dr. Mutch will discuss how platelet-derived polyP affects the coagulation cascade at several distinct points to promote clot formation. She will also discuss recent finding suggesting that polyP retained on the activated platelet membrane further modifies the function of this biopolymer in coagulation.