Novel Therapies for Stroke Under the Microscope

Ingrid Hein

July 05, 2019

Two enzymes — ADAMTS13 and DNase 1 — might be key to breaking up blood clots in patients with ischemic stroke, new research is showing.

"It's amazing how little we've known about thrombi," said Simon De Meyer, PhD, from the laboratory of thrombosis research at KU Leuven, Kulak Kortrijk Campus, in Belgium. "We've just been thinking there's a clot in a blood vessel in the brain, get rid of it."

But understanding that not all thrombi are identical, as previously reported by Medscape Medical News, and knowing which parts of the clot are causing acute ischemic stroke have opened avenues for research into possible treatment.

Currently, alteplase, a tissue plasminogen activator (tPA), is the only medication approved for the treatment of ischemic stroke by the US Food and Drug Administration. But only about 10% of patients are eligible for it, and it is successful in less than half of those.

Another treatment option — mechanical removal of the clot with endovascular thrombectomy — is also out of reach for many patients but does give researchers the opportunity to examine removed thrombi.

"All of a sudden we've got all these thrombi in our hands. That's why new research has been made possible," De Meyer told Medscape Medical News.

He will be describing some of the insights gained after investigation of removed thrombi by his and other labs, and emerging novel therapies for stroke, at the upcoming International Society on Thrombosis and Haemostasis 2019 Congress in Melbourne, Australia.

De Meyer's group has been zoning in on the von Willebrand factor, a blood protein known to be a crucial player in the formation of arterial thrombus. "Some thrombi contain large amounts of it," he noted.

von Willebrand factor works with fibrin(ogen) to link platelets and stabilize the platelet plug. In fact, "if your thrombus contains enough von Willebrand factor, tPA is not effective; your thrombus will not be lysed or even discovered by tPA," he explained.

The ADAMTS13 enzyme is known for its ability to cleave von Willebrand factor. In a study of acute ischemic stroke induced in tPA-resistant mice, 5 minutes after the enzyme was administered, the improvement in blood flow was striking; at 25 minutes, blood flow was at 75% of baseline; and at 60 minutes, it was stable (Blood. 2016;127:2337-2345). Even when the injection of ADAMTS13 was delayed for 60 minutes, blood flow was restored to 43.9% of baseline in the subsequent 60 minutes.

"The ADAMTS13 enzyme cuts the von Willebrand factor into smaller pieces," which prevents it from triggering the formation of unnecessary blood clots, De Meyer said. His lab is seeing the same results in ex vitro human thrombi that have been removed with mechanical thrombectomy, he reported.

Although the enzyme has not yet been approved for use in clinical trials of stroke, "ADAMTS13 looks safe for bleeding," he said. This will likely provide another element in the arsenal of tools for the quick dissolution of thrombi after stroke, he added.

The composition of 188 human thrombi collected after endovascular thrombectomy is described in a recent study by De Meyer and his colleagues, which confirms the importance of von Willebrand factor (Haematologica. Published online May 2, 2019).

In that study, histologic examination showed that the stroke thrombi were composed of two main areas: those rich in red blood cells entangled with a mesh of thin fibrin fibers; and those rich in platelets, in which dense fibrin structures are aligned with von Willebrand factor. Abundant amounts of leukocytes and DNA accumulate in and around the platelet-rich areas, which make them resistant to thrombolysis and difficult to retrieve with thrombectomy.

Targeting NETs With DNase 1

De Meyer was also involved in a study that showed that the combination of tPA and DNAse 1 had a significant effect on 68 thrombi mechanically extracted from patients with ischemic stroke (Ann Neurol. 2017;82:223-232).

That team looked at the neutrophil extracellular traps (NETs) that promote thrombus formation. NET formation is driven by the release of decondensed chromatin, and DNase 1 degrades DNA when extracellular chromatin is targeted.

When tPA alone was administered, the thrombi weighed 63% of their original weight after 120 minutes. However, with the combination cocktail, the thrombi weighed just 41% of their original weight at 120 minutes (P < .01).

It's a research field where we can think about what I like to call 'making a thrombolytic cocktail'.

"This is all new. It's a research field where we can think about what I like to call 'making a thrombolytic cocktail'," De Meyer explained. "Instead of just tPA, we can potentially add DNase 1 or ADAMTS13."

"It opens up new opportunities that could be relevant given the enormous limitations we have at the moment," although research has only been done in mouse models to date, he acknowledged.

"It offers promise, but it's not yet approved to go into clinical trials." The results are too early to change current treatment, he noted.

Minimizing Danger From Stroke

Only about 10% to 20% of patients in the most active centers are treated with acute therapies like tPA and clot extraction, said Mitchell Elkind, MD, from Columbia University in New York City. "There's a need for other ways of minimizing danger from stroke."

"People have tried to add clot-busting medications to see if two drugs are better than one. We're all excited to see if there are other meds that would improve outcomes without increasing the risk of bleeding," he told Medscape Medical News.

"We also need to work on neuroprotection or salvaging the brain tissue" to restore function to the injured brain once the ischemic process has set in, Elkind added.

De Meyer and Elkin disclosed no relevant financial relationships.

International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress. To be presented July 8, 2019.

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