Rational Design of an Ex Vivo Model of Thrombosis

Berny, Michelle A.; Patel, Ishan; White-Adams, Tara C.; Simonson, Patrick; Gruber, Andrá S.; Rugonyi, Sandra; McCarty, Owen J. T.

doi:10.1007/s12195-010-0103-5

Cited by 13 publications

(15 citation statements)

References 13 publications

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“…Occlusion assays were performed as previously described (2). Briefly, treated whole blood was recalcified by the addition of Ca 2ϩ and Mg 2ϩ and then driven by a constant-pressure gradient through collagen-coated capillaries at an initial shear rate of 285 s Ϫ1 , with the time required for flow to cease recorded as the occlusion time.…”

Section: Methodsmentioning

confidence: 99%

Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation

Larson

Tormoen

Weaver

et al. 2013

American Journal of Physiology-Cell Physiology

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Several studies have implicated the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in inhibition of normal platelet function, suggesting a role for platelets in EPA- and DHA-mediated cardioprotection. However, it is unclear whether the cardioprotective mechanisms arise from alterations to platelet-platelet, platelet-matrix, or platelet-coagulation factor interactions. Our previous results led us to hypothesize that EPA and DHA alter the ability of platelets to catalyze the generation of thrombin. We tested this hypothesis by exogenously modifying platelet membranes with EPA and DHA, which resulted in compositional changes analogous to increased dietary EPA and DHA intake. Platelets treated with EPA and DHA showed reductions in the rate of thrombin generation and exposure of platelet phosphatidylserine. In addition, treatment of platelets with EPA and DHA decreased thrombus formation and altered the processing of thrombin precursor proteins. Furthermore, treatment of whole blood with EPA and DHA resulted in increased occlusion time and a sharply reduced accumulation of fibrin under flow conditions. These results demonstrate that EPA and DHA inhibit, but do not eliminate, the ability of platelets to catalyze thrombin generation in vitro. The ability of EPA and DHA to reduce the procoagulant function of platelets provides a possible mechanism behind the cardioprotective phenotype in individuals consuming high levels of EPA and DHA.

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Section: Methodsmentioning

confidence: 99%

Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation

Larson

Tormoen

Weaver

et al. 2013

American Journal of Physiology-Cell Physiology

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“…35 A 0.02 × 0.2 × 30 mm collagen-coated glass capillary tube (Vitrotube; Vitrocom, Mountain Lakes, NJ) was vertically mounted below a reservoir (ID = 0.75 cm) and immersed in a PBS bath. Whole blood samples (0.5 mL) were mixed with 0.1 mL of 0.9% NaCl and 0.15% CaCl 2 solution containing 50 U thrombin to produce a 0.8 cm height blood clot at the bottom of the reservoir.…”

Section: Blood Clot Lysis and Micro-ct Analysismentioning

confidence: 99%

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Chen¹,

Yang²,

Ma³

et al. 2012

IJN

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Background and methods: Silica-coated magnetic nanoparticle (SiO 2 -MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO 2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO 2 surface, which provides abundant -NH 2 functional groups for conjugating with tPA. Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO 2 -MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO 2 -MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO 2 -MNP (SiO 2 -MNP-tPA) did not alter blood component concentrations. After conjugating to SiO 2 -MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO 2 -MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO 2 -MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis. Conclusion: Biocompatible SiO 2 -MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.

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“…An ex vivo intravascular thrombolysis model driven by a constant pressure gradient, which is similar to the condition that maintains blood circulation in vivo, was used to determine blood clot lysis induced by tPA or chitosan-MNP-tPA (Berny et al, 2010) (Fig. 1).…”

Section: Ex Vivo Thrombolysis Model and In Vivo Rat Embolic Modelmentioning

confidence: 99%

Characterization of chitosan magnetic nanoparticles for in situ delivery of tissue plasminogen activator

Chen

Yang

et al. 2011

Carbohydrate Polymers

150

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Rational Design of an Ex Vivo Model of Thrombosis

Cited by 13 publications

References 13 publications

Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation

Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle

Characterization of chitosan magnetic nanoparticles for in situ delivery of tissue plasminogen activator

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