Inhibition of plasmin generation in plasma by heparin, low molecular weight heparin, and a covalent antithrombin–heparin complex
Blood Coagulation and Fibrinolysis
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are commonly used anticoagulants to treat thrombotic diseases. However, these anticoagulants are associated with some limitations such as increased bleeding, variable dose response, and the necessity for frequent monitoring. This led to the development of the antithrombin-heparin covalent complex (ATH) which has been shown to overcome many of these limitations. Numerous past studies have proven ATH to be a better anticoagulant
... in comparison to UFH. More recent studies aimed at studying its interaction with the fibrinolytic pathway. It was observed that ATH inhibited free and fibrin bound plasmin (Pn), the main serine protease of fibrinolysis. As well, the rates of Pn generation on fibrin clots decreased in the presence of ATH. These studies were conducted in purified systems and did not elucidate the interaction of ATH with Pn in the presence of its natural inhibitors, α 2 -macroglobulin (α 2 -M) and α 2 -antiplasmin (α 2 -AP). Thus, this study focuses on analyzing the effects of ATH in comparison to UFH and LMWH on Pn generation in plasma, to allow for a better understanding of such mechanisms under more physiological conditions. In comparison to the absence of anticoagulants, total Pn generated decreased in the presence of 0.7 U/ml of UFH or ATH and 2.1 U/ml of ATH. This confirms previous in vitro studies in which UFH + AT and ATH can inhibit Pn activity. In addition, quantified Pn bound α 2 -M complexes showed a reduction at 0.7 U/ml of ATH suggesting that ATH may be able to compete with α 2 -M for Pn. However, the amount of quantified Pn bound α 2 -AP complexes were not affected as α 2 -AP is a much faster inhibitor of Pn. It was noted that LMWH did not affect Pn generation. As a result, this study adds to our understanding of ATH mechanisms of action and aids in its development for clinical use. iii express my gratitude to Helen Atkinson and Leslie Berry for always going above and beyond to provide advice and guidance. In addition, I would like to thank Dr. Howard Chan for all the invaluable guidance on my research and future career. Lastly, I am thankful to Dr. Paul Kim for agreeing to be on my committee and providing unlimited advice on my research.