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Effect of irrigation on fibrinolytic rtPA therapy in a clot model of intracerebral haemorrhage: a systematic in vitro study

  • Original Article - Vascular
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A Correction to this article was published on 29 October 2020

This article has been updated

Abstract

Objective

Although fibrinolytic therapy is an upcoming treatment for intracerebral haemorrhage (ICH), standard guidelines are lacking, and some clinical issues persist. Here, we used our recently devised clot model of ICH to systematically analyse effects of irrigation and cerebrospinal fluid (CSF) on fibrinolysis.

Methods

In vitro clots of human blood (25 ml) were generated and a catheter irrigation system was applied to deliver fluid/treatment. Clots were weighed before and after treatment and compared to rtPA treatment alone. First various drainage periods (15, 30 and 60 min; n = 3 each) and irrigation rates (0, 15, 90 and 180 ml/h; n = 3–5 each) were tested, followed by rtPA administration (1 mg, 15 min incubation) at each irrigation rate. Potential fibrinolytic effect of CSF was examined by incubation with 5 ml healthy vs. haemorrhagic CSF (n = 3 each). To assess a washout effect treatment with saline (0.9%), rtPA (1 mg) and high-rate irrigation (180 ml/h) were compared with measuring plasminogen level before and after. Furthermore clots were treated with a combination of plasminogen (150% serum concentration) and rtPA (1 mg).

Results

Relative clot end weights after 60 min irrigation system treatments were 66.3 ± 3.8% (0 ml/h), 46.3 ± 9.5% (15 ml/h), 46.5 ± 7.1% (90 ml/h) and 53.3 ± 4.1% (180 ml/h). At a lower irrigation rate (15 ml/h), relative end weights were lowest (49.5 ± 4.6%) after 60 min (15 min: 62 ± 4.3%, p = 0.016; 30 min: 62.90 ± 1.88%, p = 0.012). The combination of rtPA and irrigation produced following relative end weights: 0 ml/h, 35 ± 3.2%; 15 ml/h, 32.1 ± 5.7%; 90 ml/h, 36.7 ± 6.3% and 180 ml/h, 41.9 ± 7.5%. No irrigation (0 ml/h) versus rtPA alone showed a significant difference (p < 0.0001) in higher clot weight reduction by rtPA. Similar rtPA+15 ml/h irrigation achieved a significant higher weight reduction compared to 15 ml/h irrigation alone (p = 0.0124). No differences were evident at 90 and 180 ml/h irrigation rates with and without rtPA. Healthy (55.1 ± 5%) or haemorrhagic (65.2 ± 6.2%) CSF showed no fibrinolytic activity. Plasminogen levels in clots declined dramatically (> 80% initially to < 10%) after 1 mg single rtPA dosing and high-rate (180 ml/h) irrigation. The fibrinolytic benefit of adding plasminogen to rtPA was marginal.

Conclusions

In our in vitro clot model, irrigation combined with rtPA (vs. rtPA alone) conferred no added lytic benefit. Likewise, exposure to haemorrhagic CSF did not increase clot lysis.

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Acknowledgments

We are grateful to all voluntary blood donors, who made this study possible. We thank Stefan Kindel and Thomas Bauer for the drawing of Fig. 1. We thank Dr. Yasar Luqman Ahmed and Mr. Mohammad Ahsan Sadiq for the proofreading.

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Authors and Affiliations

  1. Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Julia Masomi-Bornwassser, Fabio Freguia, Hendrik Müller-Werkmeister, Alf Giese & Naureen Keric

  2. Department of Neuropathology, University- and Knappschaft- Hospital Bochum, Bochum, Germany

    Fabio Freguia

  3. Department of Anaesthesiology, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Asklepios Klinikum Harburg, Hamburg, Germany

    Hendrik Müller-Werkmeister

  4. Institute of Neurosurgical Pathophysiology, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Oliver Kempski

  5. OrthoCentrum Hamburg, Hansastr. 1-3, Hamburg, Germany

    Alf Giese

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  1. Julia Masomi-Bornwassser
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Correspondence to Naureen Keric.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The ethics committee of Rhineland-Palatinate approved this study. All blood samples were collected from healthy volunteers who granted informed consent. All CSF samples were obtained through informed patient consent.

Additional information

This work has been presented as a conference paper in May 2017 at the annual meeting of the Germany Society of Neurosurgery (DGNC) held in Magdeburg, Germany.

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Masomi-Bornwassser, J., Freguia, F., Müller-Werkmeister, H. et al. Effect of irrigation on fibrinolytic rtPA therapy in a clot model of intracerebral haemorrhage: a systematic in vitro study. Acta Neurochir 160, 1159–1165 (2018). https://doi.org/10.1007/s00701-018-3517-9

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  • DOI: https://doi.org/10.1007/s00701-018-3517-9

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