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Characterization of the plasma and blood anticoagulant potential of structurally and mechanistically novel oligomers of 4-hydroxycinnamic acids

Henry, Brian La,c; Thakkar, Jay Na,c; Martin, Erika Jd; Brophy, Donald Fb; Desai, Umesh Ra,c

Blood Coagulation & Fibrinolysis: January 2009 - Volume 20 - Issue 1 - p 27–34
doi: 10.1097/MBC.0b013e328304e077
ORIGINAL ARTICLES
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Recently, we designed sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids that displayed interesting anticoagulant properties. Structurally and mechanistically, sulfated DHPs are radically different from all the anticoagulants studied to date. To assess whether their unique mechanism and structure is worth exploiting for further rational design of homogeneous DHP-based molecules, we investigated their anticoagulant potential in human plasma and blood using a range of clotting assays. Sulfated DHPs prolong plasma clotting times, prothrombin and activated partial thromboplastin times at concentrations comparable to the clinically used low-molecular-weight heparin, enoxaparin. Fibrin formation studies on human plasma show that there is a structural dependence of anticoagulant action. Human whole blood studies using thromboelastography and hemostasis analysis system indicate that they are 17–140-fold less potent than enoxaparin. These results demonstrate that sulfated DHPs possess good in-vitro and ex-vivo activity, which will likely be improved through a rational design.

aDepartments of Medicinal Chemistry, USA

bPharmacy, USA

cInstitute for Structural Biology and Drug Discovery, USA

dCoagulation Special Studies Laboratory, Virginia Commonwealth University, Richmond, Virginia, USA

Received 11 January, 2008

Revised 8 April, 2008

Accepted 15 April, 2008

Correspondence to Umesh R. Desai, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23219, USA Tel: +1 804 828 7328; fax: +1 804 827 3664; e-mail: urdesai@vcu.edu

© 2009 Lippincott Williams & Wilkins, Inc.