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Van Walderveen M.C.,McMaster University | Berry L.R.,McMaster University | Chan A.K.C.,McMaster University | Chan A.K.C.,Thrombosis and Atherosclerosis Research Institute TaARI
Journal of Biochemistry | Year: 2010

Protein C in its activated form (APC) limits thrombin generation. Protein C inhibitor (PCI) readily neutralizes APC. Heparin accelerates this reaction, which may complicate anticoagulant treatment in patients with varying APC generation potential. A potent anticoagulant conjugate of antithrombin and heparin (ATH) was prepared, and its effect on APC+PCI reactions was tested. Second order rate constants for APC+PCI reactions were measured by discontinuous rate experiments in the presence of heparin or ATH. Similarly, low molecular weight fractions of heparin (LMWH) and ATH (LMWATH) were tested, as was high molecular weight ATH (HMWATH). Mechanisms of heparin or ATH binding to APC or PCI were assessed using electrophoresis. While heparin gave a higher maximal APC inhibition rate compared to ATH, peak inhibition rate was achieved at comparatively lower ATH concentrations. Since LMWH was ineffective at enhancing APC inhibition by PCI, unfractionated heparin likely acts by bridging APC and PCI. Unlike heparin, ATH may conformationally activate either APC or PCI since LMWATH significantly catalyses APC inhibition. Binding studies showed that ATH readily associates with APC. Thus, although a small fraction of ATH efficiently catalyses APC inhibition by PCI, complete ATH preparations induce a decreased maximal rate of APC-PCI formation compared to unfractionated heparin. © 2010 The Authors.

Paredes N.,Thrombosis and Atherosclerosis Research Institute TaARI | Mondal T.,McMaster University | Brandao L.R.,Hospital for Sick Children | Chan A.K.C.,McMaster University
Blood Coagulation and Fibrinolysis | Year: 2010

Kawasaki disease is an acute, systemic vasculitis of unknown cause affecting mainly neonates (infants) and young children. Despite treatment during the acute phase with intravenous immunoglobulin and aspirin, up to 5% of those affected will develop coronary aneurysms, predisposing them to thrombotic complications that could result in myocardial infarction and/or death. There are treatment protocols in place for the management of myocardial infarction in adults, but the practical nature of medication is unclear in children. To date, there are no clinical trials or specific recommendations on the dosing of thrombolytic therapy for the treatment of myocardial infarction in Kawasaki pediatric patients. However, there are reports of the use of thrombolytic agents, including streptokinase, urokinase and tissue plasminogen activator, as well as the monoclonal platelet glycoprotein (GP)IIb/IIIa receptor inhibitor, abciximab, that have been used to treat myocardial infarction in children with Kawasaki disease. The outcomes in these reports are varied. This review provides a summary of the available data on the management of children with Kawasaki disease suffering from myocardial infarction or thrombotic complications that can potentially lead to myocardial infarction. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Stevic I.,Thrombosis and Atherosclerosis Research Institute TaARI | Parmar N.,University of Toronto | Paredes N.,Thrombosis and Atherosclerosis Research Institute TaARI | Berry L.R.,Thrombosis and Atherosclerosis Research Institute TaARI | And 2 more authors.
Cell Biochemistry and Biophysics | Year: 2011

Heparin is a major prophylactic and treatment agent for thrombosis. Structurally, this anticoagulant is a polydisperse, highly negatively charged polysaccharide mixture that contains a variable density of sulfate group substituents per molecule. Previous study has shown that heparin molecules have a high affinity for a wide range of metal ions with varying oxidation states. However, reports in literature on binding of heparin to metals have investigated only a small sampling of heparin-metal ion interactions. Since interaction of heparin with fluid phase and cell surface macromolecules in vivo is dependent on the heparin structure when bound in a metal ion complex, a survey of the physical parameters for heparin binding to metals is imperative. Atomic absorption and spectrophotometry experiments were performed for metal quantification, and in this study, the relative values for affinity constants and number of binding sites for heparin binding to several alkaline, alkaline earth, main group, and transition metals in their most common oxidation states are reported. We found an overall trend for heparin-metal affinity to be Mn2+ > Cu2+ > Ca2+ > Zn2+ > Co2+ > Na+ > Mg2+ > Fe3+ > Ni2+ > Al3+> Sr2+, with the trend in Nb being opposite compared with the Ka. © 2010 Springer Science+Business Media, LLC.

Elit L.M.,McMaster University | Lee A.Y.,University of British Columbia | Parpia S.,McMaster University | Swystun L.L.,McMaster University | And 7 more authors.
Thrombosis Research | Year: 2012

Objective: Low molecular weight heparin reduces the risk of venous thromboembolism (VTE) and may have antineoplastic effects by interfering with angiogenesis and with tumor growth and metastasis. A multicentre phase II randomized trial was done to evaluate the antineoplastic potential of dalteparin in ovarian cancer (OC). Materials and Methods: Women with newly-diagnosed epithelial OC were randomized to receive standard chemotherapy (CT) and one of 3 doses of dalteparin (50 IU/kg, 100 IU/kg, or 150 IU/kg) subcutaneously once daily during the first 3 of 6 cycles of 3-weekly CT. Blood was drawn on day 1 of each cycle for CA125 and, in a substudy of randomized patients, for markers of coagulation activation and angiogenesis. The primary outcome was tumor response defined by ≥ 50% reduction in serum CA125 from baseline sustained for at least 28 days. Patients were followed until the end of CT. Results: The study was terminated early due to poor recruitment. Seventy-seven women were evaluable for the primary outcome. A 50% drop in CA125 at the end of cycle 3 was seen in 85% of the 50 IU/kg group, 92% of the100 IU/kg group, and 85% of the 150 IU/kg group. There were no symptomatic VTE or major bleeding events while on dalteparin. Two patients experienced VTE several days after discontinuing study drug. Women on dalteparin had lower levels of D-dimer and thrombin-antithrombin, and higher levels of tissue factor pathway inhibitor, relative to baseline. Conclusion: Dalteparin is safe and well tolerated in women receiving CT for newly-diagnosed epithelial OC. A dose-response effect was not identified. The lack of control group precluded any inference on the antineoplastic effect of dalteparin. © 2012 Elsevier Ltd. All rights reserved.

Swystun L.L.,McMaster University | Swystun L.L.,Thrombosis and Atherosclerosis Research Institute TaARI | Mukherjee S.,McMaster University | Liaw P.C.,Thrombosis and Atherosclerosis Research Institute TaARI | Liaw P.C.,McMaster University
Journal of Thrombosis and Haemostasis | Year: 2011

Background: Thrombosis is a common complication for breast cancer patients receiving chemotherapy. However, the mechanisms by which breast cancer chemotherapeutic agents increase this risk are largely uncharacterized. Nucleic acids released by injured cells may enhance coagulation via the activation of the contact pathway. Objectives: In this study, we examined the effects of breast cancer chemotherapy agents on the release ofcell-free DNA (CFDNA) and its relationship to thrombin generation using in vitro and in vivo methods. Methods: CFDNA release and thrombin-antithrombin (TAT) levels were measured in plasma of breast cancer patients and healthy mice receiving chemotherapy. Venous whole blood and cultured cells were exposed to chemotherapy and CFDNA release and levels of DNA-histone complexes were measured. The procoagulant activity of isolated CFDNA was measured with calibrated, automated thrombin generation. Results: Breast cancer patients receiving chemotherapy had elevated levels of CFDNA 24h post-chemotherapy, a time-point at which elevated thrombin-antithrombin levels have been previously reported. Treatment of healthy mice with doxorubicin, epirubicin and 5-fluorouracil increased CFDNA release, with a corresponding elevation in TAT complex formation. Venous whole blood and neutrophils incubated with chemotherapeutic agents had elevated CFDNA in plasma or cell supernatants. In addition, incubation of venous whole blood with chemotherapy decreased histone-DNA complex levels. CFDNA released from epirubicin-treated whole blood significantly elevated thrombin generation in a dose-dependent manner, and involved activation of the contact pathway. Conclusions: Release of CFDNA from chemotherapy-injured cells may represent a novel mechanism by which thrombosis is triggered in cancer patients. © 2011 International Society on Thrombosis and Haemostasis.

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