Research Article: Doppler sonography enhances rtPA-induced fibrinolysis in an in vitro clot model of spontaneous intracerebral hemorrhages

Date Published: January 17, 2019

Publisher: Public Library of Science

Author(s): Julia Masomi-Bornwasser, Philipp Winter, Axel Neulen, Sven R. Kantelhardt, Jochem König, Oliver Kempski, Florian Ringel, Naureen Keric, Juan TU.


Transcranial Doppler (TCD) was shown to enhance intravascular fibrinolysis by rtPA in ischemic stroke. Studies revealed that catheter-based administration of rtPA induces lysis of intracerebral hemorrhages (ICH). However, it is unknown whether TCD would be suitable to enhance rtPA-induced fibrinolysis in patients with ICH. The aim of this study was to assess the potential of TCD to enhance rtPA-induced fibrinolysis in an in vitro clot system.

Reproducible human blood clots of 25 ml were incubated in a water bath at 37°C during treatments. They were weighed before and after 6 different treatments: (I) control (incubation only), (II) rtPA only, (III) one Doppler probe, (IV) two Doppler probes placed vis-à-vis, (V) one probe and rtPA and (VI) two probes and rtPA. To quantify lysis of the blood clots and attenuation of the Doppler through a temporal squama acoustic peak rarefaction pressure (APRP) was measured in the field of the probes. Temperature was assessed to evaluate possible side effects.

Clot weight was reduced in all groups. The control group had the highest relative end weight of 70.2%±7.2% compared to all other groups (p<0,0001). Most efficient lysis was achieved using (VI) 2 probes and rtPA 36.3%±4.4% compared to (II, III, IV) (p<0.0001; p = 0.0002; p = 0.048). APRP was above lysis threshold (535.5±7.2 kPa) using 2 probes even through the temporal squama (731.6±32.5 kPa) (p = 0.0043). There was a maximal temperature elevation of 0.17±0.07°C using both probes. TCD significantly enhances rtPA-induced lysis of blood clots, and the effect is amplified by using multiple probes. Our results indicate that bitemporal TCD insonation of hematomas could be a new and safe approach to enhance fibrinolysis of ICH´s treated with intralesional catheter and rtPA.

Partial Text

Spontaneous intracerebral hemorrhage (ICH) occurs with an incidence of 10–30 / 100 000 per year in western countries [1,2]. Cerebral damage is caused directly by the bleeding and by second-line injury, which is induced by perihematomal edema (PHE) [3] and neuropathic products which appear during the inflammatory process [1].

Several studies have reported the efficacy of catheter-based treatment of ICH with rtPA [11,12,27–29]. One clinical trial showed an enhancement of rtPA-induced hematoma lysis by additional use of an intralesional 2 MHz ultrasound catheter [2]. Here we demonstrate, to the best of our knowledge for the first time, a significant sonothrombolysis with transcranial 2 MHz Doppler probes commonly used for diagnostic transcranial Doppler sonography in an in vitro clot system of ICH. In clinical use, the greatest advantages compared to intralesional ultrasound catheters would be the non-invasive nature of transcranial ultrasound and lower costs. The typical localization of the intracerebral hemorrhage are the basal ganglia [30]. These can be reached easily by TCD through the acoustic temporal window [31].

In this study we could demonstrate the effective lysis of blood clots by Doppler ultrasound, which can be enhanced by using two Doppler probes realized by our reproducible in vitro ICH clot system. Best results were achieved using two Doppler probes and rtPA. Attenuated through the temporal bone Doppler ultrasound is just marginally above lysis threshold. The bilateral Doppler alignment leads to a safe enhancement above lysis threshold.




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