“Is targeting thrombosis without affecting haemostasis possible?
Every treatment for thrombotic conditions comes at a price – a risk of bleeding. With DOACs, the risk of major bleeding is 3-7% per year. Holy grail is to find therapies that treat thrombosis w/o bleeding. Is this possible or just a pipe dream? Let’s look at recent progress.
Factor XI inhibitors. FXI is a part of the intrinsic pathway of coagulation and activates factor IX. People with FXI deficiency do bleed but rarely spontaneously – usually from major haemostatic challenges such as childbirth or surgery.
Lots of studies have shown that bleeding risk is low on FXI inhibitors but are they effective at preventing / treating clots? This infographic from Harrington et al. JACC 2023 shows the completed / on-going trials.
However, the OCEANIC-AF trial of oral FXI inhibitor asundexian was stopped early due to lack of efficacy – more patients were having strokes on asundexian than in the comparator arm – apixaban.
Thoughts on FIX inhibitors: seem effective for VTE prevention? effective for treatment of VTE or as secondary prevention? Seem ineffective for AF but may not be class effect. Might be useful as adjunct therapy in stroke and MI – results of efficacy trials awaited.
Platelet inhibition. Platelets are very important haemostatic cells. Targeting with GpIIbIIIa blocker eptifibatide is effective but –> bleeding +++ Other targets on platelets are intriguing though.
GPVI, the plt collagen receptor is a promising target. Stimulation –> robust plt activation. However, has limited role in haemostasis. People deficient in GPVI are either asymptomatic or have only a minor bleeding.
Glenzocimab is a monoclonal antibody that inhibits platelet activation through GPVI. Several trials are planned / on-going. (Image from Billiald et al. 2023, Blood Advances)
ACTIMIS – randomised, phase 1a/2a trial of glenzocimab as add on therapy in ischaemic stroke undergoing thrombolysis or thrombectomy. Reported at ESOC 2022. Glenzocimab –>haemorrhagic events + mortality but small study + needs confirming.
Other on-ongoing trials: ACTISAVE study – phase 2/3: RCT assessing effect of thrombolysis +/- thrombectomy vs thrombolysis +/- thrombectomy + glenzocimab (a continuation of ACTIMIS).
GREEN study – phase 2b/3: RCT assessing effect of thrombectomy (EVT) + glenzocimab v. EVT alone on 90-day functional outcome (mRS). Interim analysis expected this year.LIBERATE study – randomised phase 2b – add on therapy in MI just starting up now.
There’s ++ interest in targeting thromboinflammation – shouldn’t affect haemostasis. CANTOS study randomised pts with prev MI + CRP >2 to anti IL-1β, anakinra or placebo. Led to recurrent cardiovasc events but fatal infection – no effect on OS.
CANTOS shows proof of principle that targeting inflammation can reduce thrombosis but with risk of infection. What else could be done?
Targeting leukocyte-platelet interactions by inhibiting the MAC-1/Gp1ba interaction is a promising strategy. Preclinical models show blockade with an antibody or glucosamine –> delayed thrombosis after carotid artery injury.
An observational study using UK biobank showed a decreased risk of cardiovascular disease in people taking glucosamine supplements: usual caveats of observational data apply here! Other mechanisms of action probably at play as well.
Finally, neutrophil extracellular traps (NETs) are found in clots. Excitingly, these can be targeted using DNase which does not increase risk of bleeding. De Meyer et al. found that treatment of mice with DNase –> better outcomes
Modulation of NETs has also been found to reverse resistance to tPA in a mouse model of thrombotic stroke (Image: Peña-Martínez et al. 2019, Stroke).
The NETs-TARGET study is a pilot phase 2 trial of Dornase Alfa, recombinant DNase, now recruiting patients with ischaemic stroke post-thrombectomy and looking at rates of arterial recanalization.
DNase as a therapy is potentially very exciting as it could possibly be used in patients with acute stroke symptoms before CT head has ruled out a bleed – could be given by paramedics! Good review of thromboinflammation in brain ischaemia here.
There are obviously loads more studies and targets out there, I’ve just picked out a few that I am aware of and am excited about. Apologies for any errors / misrepresentation. Intended as educational only. Feel free to comment with your own thoughts and perspectives.”