Stroke therapy and diagnosis

Stroke affects between 15-20 million people worldwide, a third of which result in death and a third in disability. 

X-ray of the skull of a patient suffering from stroke, affected area colored red

Illustration: Colourbox

About the project

The incidence of stroke is predicted to increase with the aging population. It is estimated that the economic costs of this disease, in the USA, in 2030 will be 240 billion USD per year. 87% of these are caused by a clot in the brain and are called ischemic stroke and the rest are due to rupture of brain vessels and are called hemorrhagic stroke. 

One exisiting treatment for ischemic stroke is tPA but this has many shortcomings:

  1. There is a short time window in which tPA can be applied (< 4.5 h) after which the clot properties change and tPA is not effective.
  2. tPA causes severe bleeding in the brain of 10% of the patients which receive this drug (hemorrhagic transformation).
  3. tPA is ineffective against clots in larger vessels and these are treated with surgery to remove the clot.
  4. Only 3-10 % of patients receive tPA treatment and only 50% of these actually benefit from it.
  5. Surgical removal of the clots is becoming an increasingly viable option but this is only possible if clots are in large vessels.

Treatment of ischemic stroke is one of the most intensively researched topics with many promising developments in designing new generation of thrombolytic, neuroprotective and neuroREgenerative factors as well as surgical techniques.

We have discovered a factor that helps to dissolve clots faster and protects the brain in stroke.

Outcomes

In an ageing population the incremental impact of diseases such as stroke will increase. This project addresses issues related to the treatment of stroke patients in the acute situation.

The current treatments are not satisfactory and need significant improvement. We have demonstrated that a circulating blood protease, Factor FVII Activating Protease (FSAP) speeds up lysis of blood clots by tPA in vitro and has neuroprotective effects on cultured brain cells. Thus, FSAP represents a novel treatment and our ambition is to develop this concept further.

To consolidate this idea the influence of FSAP on stroke is being investigated in terms of the molecular mechanisms of action in animal models in vivo as well as at a biochemical level.

Financing

NFR: 2016-2020
Cooperation Stiftelsen Norsk Luftambulance (SNLA)

Cooperation

Stiftelsen Norsk Luftambulanse

Publications

  • Kara, Emrah; Nielsen, Nis Valentin; Eggertsdottir, Bergrun; Thiede, Bernd; Kanse, Sandip & Løset, Geir Åge (2020). Design and characterization of a new pVII combinatorial phage display peptide library for protease substrate mining using Factor VII activating protease (FSAP) as model. ChemBioChem. ISSN 1439-4227. 21(13), p. 1875–1884. doi: 10.1002/cbic.201900705. Full text in Research Archive
  • Byskov, Kristina; Etscheid, Michael & Kanse, Sandip (2020). Cellular effects of factor VII activating protease (FSAP). Thrombosis Research. ISSN 0049-3848. 188, p. 74–78. doi: 10.1016/j.thromres.2020.02.010. Full text in Research Archive
  • Parahuleva, Mariana S; Worsch, M; Euler, Gerhild; Choukeir, Maryana; Mardini, Amar & Parviz, Behnoush [Show all 11 contributors for this article] (2020). Factor VII Activating Protease Expression in Human Platelets and Accumulation in Symptomatic Carotid Plaque. . Journal of the American Heart Association (JAHA). ISSN 2047-9980. 9. doi: 10.1161/JAHA.120.016445. Full text in Research Archive
  • Zuchtriegel, G.; Uhl, B; Ramsauer, Michaela; Dominik, Julian; Mittmann, L & Canis, Martin [Show all 10 contributors for this article] (2020). Vitronectin stabilizes intravascular adhesion of neutrophils by coordinating beta2 integrin clustering. . Haematologica. ISSN 0390-6078. doi: 10.3324/haematol.2019.226241. Full text in Research Archive
  • Ueslue, Ouezguer; Herold, Joerg & Kanse, Sandip (2019). VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization. Cells. ISSN 2073-4409. doi: 10.3390/cells8111396. Full text in Research Archive
  • Rut, Wioletta; Nielsen, Nis Valentin; Czarna, Justyna; Poreba, Marcin; Kanse, Sandip & Drag, Marcin (2019). Fluorescent Activity-Based Probe for the Selective Detection of Factor VII Activating Protease (FSAP) in Human Plasma. Thrombosis Research. ISSN 0049-3848. 182, p. 124–132. doi: 10.1016/j.thromres.2019.08.016. Full text in Research Archive
  • Bohnert, Bernhard; Daiminger, Sophie; Woern, Matthias; Sure, Florian; Staudner, Tobias & Ilyaskin, Alexandr [Show all 14 contributors for this article] (2019). Urokinase-type Plasminogen Activator (uPA) Is Not Essential for Epithelial Sodium Channel (ENaC)-mediated Sodium Retention in Experimental Nephrotic Syndrome . Acta Physiologica. ISSN 1748-1708. 227(4). doi: 10.1111/apha.13286.
  • Dahm, Anders Erik A; Jacobsen, Eva-Marie; Wik, Hilde Skuterud; Jacobsen, Anne Flem; Mollnes, Tom Eirik & Kanse, Sandip [Show all 7 contributors for this article] (2019). Elevated complement C3 and C4 levels are associated with postnatal pregnancy-related venous thrombosis. Thrombosis and Haemostasis. ISSN 0340-6245. 119(9), p. 1481–1488. doi: 10.1055/s-0039-1692426. Full text in Research Archive
  • Nielsen, Nis Valentin; Roedel, Elfie; Manna, Dipankar; Etscheid, Michael; Morth, Jens Preben & Kanse, Sandip (2019). Characterization of the enzymatic activity of the serine protease domain of Factor VII activating protease (FSAP). Scientific Reports. ISSN 2045-2322. 9(1). doi: 10.1038/s41598-019-55531-x. Full text in Research Archive
  • Praetner, M; Zuchtriegel, G; Holzer, M; Uhl, B; Schaubaecher, J & Mittmann, L [Show all 16 contributors for this article] (2018). Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion. Arteriosclerosis, Thrombosis and Vascular Biology. ISSN 1079-5642. 38(4), p. 829–842. doi: 10.1161/ATVBAHA.117.309760.
  • Olsson, Maja; Stanne, Tara M.; Pedersén, Annie; Lorentzen, Erik; Kara, Emrah & Martinez-Palaciàn, Adoraciòn [Show all 14 contributors for this article] (2018). Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. Journal of Thrombosis and Haemostasis. ISSN 1538-7933. 16(10), p. 2024–2034. doi: 10.1111/jth.14258. Full text in Research Archive
  • Etscheid, Michael; Subramaniam, Saravanan; Lochnit, Guenter; Zabczyk, Michał; Undas, Anetta & Lang, Irene M. [Show all 8 contributors for this article] (2018). Altered structure and function of fibrinogen after cleavage by Factor VII Activating Protease (FSAP). Biochimica et Biophysica Acta. ISSN 0006-3002. 1864(10), p. 3397–3406. doi: 10.1016/j.bbadis.2018.07.030.
  • Cole, John W.; Kanse, Sandip; Authors, Other & Mitchell, Braxton (2018). Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. PLOS ONE. ISSN 1932-6203. doi: 10.1371/journal.pone.0206554. Full text in Research Archive
  • Subramaniam, Saravanan; Kanse, Sandip; Kothari, Hema; Reinhardt, Christoph & Craig, Fletcher (2018). Post-transcriptional, post-translational and pharmacological regulation of tissue factor pathway inhibitor. Blood Coagulation and Fibrinolysis. ISSN 0957-5235. 29(8), p. 668–682. doi: 10.1097/MBC.0000000000000775.
  • Kara, Emrah; Manna, Dipankar; Løset, Geir Åge; Schneider, E L; Craik, C S & Kanse, Sandip (2017). Analysis of the substrate specificity of Factor VII activating protease (FSAP) and design of specific and sensitive peptide substrates. Thrombosis and Haemostasis. ISSN 0340-6245. doi: 10.1160/TH17-02-0081. Full text in Research Archive
  • Grasso, Simona; Neumann, A; Lang, IM; Etscheid, Michael; von Köckritz-Blickwede, M & Kanse, Sandip (2017). Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs). Thrombosis Research. ISSN 0049-3848. 161, p. 36–42. doi: 10.1016/j.thromres.2017.11.012. Full text in Research Archive
  • Sperling, C; Maitz, MF; Grasso, Simona; Werner, C & Kanse, Sandip (2017). A Positively Charged Surface Triggers Coagulation Activation Through Factor VII Activating Protease (FSAP). ACS Applied Materials & Interfaces. ISSN 1944-8244. 9(46), p. 40107–40116. doi: 10.1021/acsami.7b14281. Full text in Research Archive
  • Byskov, Kristina; Boettger, Thomas; Ruehle, Paul F.; Nielsen, Nis Valentin; Etscheid, Michael & Kanse, Sandip (2017). Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells. Atherosclerosis. ISSN 0021-9150. 265, p. 133–139. doi: 10.1016/j.atherosclerosis.2017.08.029. Full text in Research Archive
  • Reiterer-Farhan, Veronika; Figueras‐Puig, Cristina; Le Guerroue,, Francois; Confalonieri, Stefano; Vecchi, Manuela & Jalapothu, Dasaradha [Show all 11 contributors for this article] (2017). The pseudophosphatase STYX targets the F‐box of FBXW7 and inhibits SCFFBXW7 function. EMBO Journal. ISSN 0261-4189. 36(3), p. 260–273. doi: 10.15252/embj.201694795.
  • Espada Serrano, Sandra; Stavik, Benedicte; Holm, Sverre; Sagen, Ellen Lund; Bjerkeli, Vigdis & Skjelland, Mona [Show all 12 contributors for this article] (2017). Tissue factor pathway inhibitor attenuates ER stress-induced inflammation in human M2-polarized macrophages. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 491(2), p. 442–448. doi: 10.1016/j.bbrc.2017.07.070.
  • Herold, Joerg; Nowak, Steven; Kostin, Sawa; Daniel, Jan-Marcus; Francke, Alexander & Subramaniam, Saravanan [Show all 8 contributors for this article] (2017). Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model. American journal of translational research. ISSN 1943-8141. 9(6), p. 3084–3095.
  • Leiting, Silke; Seidl, Sebastian; Martinez-Palaciàn, Adoraciòn; Muhl, Lars & Kanse, Sandip (2016). Transforming growth factor-β (TGF-β) inhibits the expression of factor VII-activating protease (FSAP) in hepatocytes. Journal of Biological Chemistry. ISSN 0021-9258. 291(40), p. 21020–21028. doi: 10.1074/jbc.M116.744631.

View all works in Cristin

  • Bohnert, Bernhard; Kanse, Sandip; Haerteis, Silke; Korbmacher, Christoph & Artunc, Ferruh (2019). Rebuttal to Editorial: Sodium Retention by uPA in Nephrotic Syndrome? Acta Physiologica. ISSN 1748-1708. doi: 10.1111/apha.13427.

View all works in Cristin

Published Feb. 28, 2019 3:28 PM - Last modified Dec. 12, 2019 1:13 PM