Subscribe to RSS
DOI: 10.1160/TH17-02-0132
Amino-Fucoidan as a Vector for rtPA-Induced Fibrinolysis in Experimental Thrombotic Events
Publication History
24 February 2017
22 August 2017
Publication Date:
05 January 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201801/lookinside/thumbnails/10-1160-th17-02-0132_170132-1.jpg)
Abstract
Acute ischaemic stroke, myocardial infarction and pulmonary embolism are the main causes of mortality and morbidity worldwide. Thrombolysis by intravenous injection of recombinant tissue plasminogen activator (rtPA) remains the most common non-interventional treatment to recanalize occluded vessels. However, this procedure is limited by significant drawbacks, including high doses and bleeding complications. Recent studies showed that fucoidan targets the intraluminal thrombus in vivo. We have developed a chimaera covalently linking fucoidan, able to target platelets within the thrombus, to dilysine, able to non-covalently bind rtPA. We hypothesize that this construct should vectorize rtPA to the thrombus, thus increasing its fibrinolytic efficacy and avoiding its deleterious effects. In vitro, rtPA mixed to dilysine fucoidan (DLF) shows a greater fibrinolytic effect than rtPA alone, both on platelet-rich thrombus and in whole blood. In vivo, occluded mesenteric vessels, carotid artery and vena cava were more efficiently recanalized by DLF complexed to rtPA than by rtPA alone. This study thus provides evidence that DLF may be a promising therapeutic tool to fight against acute thrombosis by enhancing rtPA fibrinolytic efficiency.
* Radouane Ghebouli and Stephane Loyau contributed equally to this study.
-
References
- 1 Finegold JA, Asaria P, Francis DP. Mortality from ischaemic heart disease by country, region, and age: statistics from World Health Organisation and United Nations. Int J Cardiol 2013; 168 (02) 934-945
- 2 Go AS, Mozaffarian D, Roger VL. , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129 (03) 399-410
- 3 National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333 (24) 1581-1587
- 4 Chapman KM, Woolfenden AR, Graeb D. , et al. Intravenous tissue plasminogen activator for acute ischemic stroke: A Canadian hospital's experience. Stroke 2000; 31 (12) 2920-2924
- 5 Collen D, Lijnen HR. The tissue-type plasminogen activator story. Arterioscler Thromb Vasc Biol 2009; 29 (08) 1151-1155
- 6 Docagne F, Parcq J, Lijnen R, Ali C, Vivien D. Understanding the functions of endogenous and exogenous tissue-type plasminogen activator during stroke. Stroke 2015; 46 (01) 314-320
- 7 Hacke W, Kaste M, Bluhmki E. , et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359 (13) 1317-1329
- 8 Sussman ES, Connolly Jr ES. Hemorrhagic transformation: a review of the rate of hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol 2013; 4: 69
- 9 Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129 (03) 307-321
- 10 Medcalf RL. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost 2007; 5 (Suppl. 01) 132-142
- 11 Mutch NJ, Thomas L, Moore NR, Lisiak KM, Booth NA. TAFIa, PAI-1 and alpha-antiplasmin: complementary roles in regulating lysis of thrombi and plasma clots. J Thromb Haemost 2007; 5 (04) 812-817
- 12 Longstaff C, Thelwell C, Williams SC, Silva MM, Szabó L, Kolev K. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117 (02) 661-668
- 13 Silva MM, Thelwell C, Williams SC, Longstaff C. Regulation of fibrinolysis by C-terminal lysines operates through plasminogen and plasmin but not tissue-type plasminogen activator. J Thromb Haemost 2012; 10 (11) 2354-2360
- 14 Kaneko M, Sakata Y, Matsuda M, Mimuro J. Interactions between the finger and kringle-2 domains of tissue-type plasminogen activator and plasminogen activator inhibitor-1. J Biochem 1992; 111 (02) 244-248
- 15 Foxall C, Watson SR, Dowbenko D. , et al. The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide. J Cell Biol 1992; 117 (04) 895-902
- 16 Polley MJ, Phillips ML, Wayner E. , et al. CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x. Proc Natl Acad Sci U S A 1991; 88 (14) 6224-6228
- 17 Bachelet L, Bertholon I, Lavigne D. , et al. Affinity of low molecular weight fucoidan for P-selectin triggers its binding to activated human platelets. Biochim Biophys Acta 2009; 1790 (02) 141-146
- 18 Rouzet F, Bachelet-Violette L, Alsac JM. , et al. Radiolabeled fucoidan as a p-selectin targeting agent for in vivo imaging of platelet-rich thrombus and endothelial activation. J Nucl Med 2011; 52 (09) 1433-1440
- 19 Bonnard T, Yang G, Petiet A. , et al. Abdominal aortic aneurysms targeted by functionalized polysaccharide microparticles: a new tool for SPECT imaging. Theranostics 2014; 4 (06) 592-603
- 20 Suzuki M, Bachelet-Violette L, Rouzet F. , et al. Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus. Nanomedicine (Lond) 2015; 10 (01) 73-87
- 21 Dische Z. New color reactions for determination of sugars in polysaccharides. Methods Biochem Anal 1955; 2: 313-358
- 22 Roth M. Fluorescence reaction for amino acids. Anal Chem 1971; 43 (07) 880-882
- 23 Schoergenhofer C, Buchtele N, Schwameis M, Bartko J, Jilma B, Jilma-Stohlawetz P. The use of frozen plasma samples in thromboelastometry. Clin Exp Med 2017
- 24 Dekker SE, Viersen VA, Duvekot A. , et al. Lysis onset time as diagnostic rotational thromboelastometry parameter for fast detection of hyperfibrinolysis. Anesthesiology 2014; 121 (01) 89-97
- 25 Boulaftali Y, Ho-Tin-Noe B, Pena A. , et al. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis. Circulation 2011; 123 (12) 1326-1334
- 26 Li W, McIntyre TM, Silverstein RL. Ferric chloride-induced murine carotid arterial injury: a model of redox pathology. Redox Biol 2013; 1: 50-55
- 27 von Brühl ML, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
- 28 Clauss A. [Rapid physiological coagulation method in determination of fibrinogen]. Acta Haematol 1957; 17 (04) 237-246
- 29 Sun X, Berthiller J, Trouillas P, Derex L, Diallo L, Hanss M. Early fibrinogen degradation coagulopathy: a predictive factor of parenchymal hematomas in cerebral rt-PA thrombolysis. J Neurol Sci 2015; 351 (1-2): 109-114
- 30 Trouillas P, Derex L, Philippeau F. , et al. Early fibrinogen degradation coagulopathy is predictive of parenchymal hematomas in cerebral rt-PA thrombolysis: a study of 157 cases. Stroke 2004; 35 (06) 1323-1328
- 31 El Amki M, Lerouet D, Coqueran B. , et al. Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke. Exp Neurol 2012; 238 (02) 138-144
- 32 Francis CW, Kornberg A. Fibrinogen- and fibrin-degradation products during fibrinolytic therapy. Ann N Y Acad Sci 1992; 667: 310-323
- 33 Loscalzo J, Vaughan DE. Tissue plasminogen activator promotes platelet disaggregation in plasma. J Clin Invest 1987; 79 (06) 1749-1755
- 34 Terres W, Umnus S, Mathey DG, Bleifeld W. Effects of streptokinase, urokinase, and recombinant tissue plasminogen activator on platelet aggregability and stability of platelet aggregates. Cardiovasc Res 1990; 24 (06) 471-477
- 35 Desilles JP, Loyau S, Syvannarath V. , et al. Alteplase reduces downstream microvascular thrombosis and improves the benefit of large artery recanalization in stroke. Stroke 2015; 46 (11) 3241-3248
- 36 Runge MS, Bode C, Matsueda GR, Haber E. Antibody-enhanced thrombolysis: capture of tissue plasminogen activator by a bispecific antibody and direct targeting by an antifibrin-tissue plasminogen activator conjugate in vivo. Trans Assoc Am Physicians 1987; 100: 250-255
- 37 Ma YH, Wu SY, Wu T, Chang YJ, Hua MY, Chen JP. Magnetically targeted thrombolysis with recombinant tissue plasminogen activator bound to polyacrylic acid-coated nanoparticles. Biomaterials 2009; 30 (19) 3343-3351
- 38 McCarthy JR, Sazonova IY, Erdem SS. , et al. Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy. Nanomedicine (Lond) 2012; 7 (07) 1017-1028
- 39 Absar S, Gupta N, Nahar K, Ahsan F. Engineering of plasminogen activators for targeting to thrombus and heightening thrombolytic efficacy. J Thromb Haemost 2015; 13 (09) 1545-1556
- 40 Zhu H, Fan X, Yu Z. , et al. Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke. J Cereb Blood Flow Metab 2010; 30 (06) 1137-1146
- 41 Zhang B, Jiang T, She X. , et al. Fibrin degradation by rtPA enhances the delivery of nanotherapeutics to A549 tumors in nude mice. Biomaterials 2016; 96: 63-71