Spontaneous intracerebral hemorrhage (sICH) is the deadliest subtype of stroke. Despite being the cause of significant morbidity and mortality, no effective treatment for sICH exists. Hematoma volume is shown to correlate with the 30-day mortality rate. Continued cerebral bleeding leading to hematoma expansion is highest in the first 3 hours after symptom onset and may continue in ?40% of patients between 3 and 24 hours after the onset. The prevention of hematoma expansion in sICH has been an attractive therapeutic target. Dr. Jy (Co-investigator) and his group have studied red blood cell-derived micro particles (RMP) as hemostatic agents for over a decade. RMP have the potential to be used as a therapeutic agent in sICH since they promote clotting at sites of active bleeding, in part, by interaction with platelets and by amplifying activation of the contact pathway. The goals of this project are (R21 phase) to establish the purity, stability, in vitro efficacy, and pharmacokinetics of RMP prepared by the high pressure extrusion method, and (R33 phase) to establish the efficacy of RMP in reducing hematoma volume, as well as improving neurological outcome and mortality in clinically relevant sICH animal models. The ultimate goal is to translate these findings to clinical practice in order to reduce morbidity from sICH. We hypothesize that post-sICH RMP treatment will suppress hematoma growth and improve long-term neurological outcome and reduce post-sICH mortality. Preliminary results support this hypothesis in that RMP treatment (1 h post-collagenase injection) effectively prevented hematoma growth when measured at 24 h in a collagenase-induced sICH model.
Our specific aims addressing these goals are: R21 phase:
Aim 1 : To characterize the purity, in vitro coagulant activity and stability (shelf-life) of RMP.
Aim 2 : To establish the pharmacokinetic profile and bio-distribution of RMP in rats. R33 phase:
Aim 3 : To determine the optimum therapeutic dose of RMP in preventing hematoma growth following experimental sICH in rats.
Aim 4 : To determine the optimal (and maximal) therapeutic time window for RMP administration.
Aim 5 : To validate the efficacy of RMP therapy in in diseased spontaneously hypertensive rats, which simulate human sICH more closely. In this proposal the efficacy of RMP will be evaluated by examining hematoma volume (short-term experiments) or infarct volume (longer-term experiments) (primary outcome), and long-term neurological function and mortality (secondary outcomes). Based on preliminary results we are confident that RMP therapy will mitigate hematoma growth, as well as improve neurological outcome following sICH in our animal model. The results obtained will provide pre-clinical evidence demonstrating the efficacy of RMP in lowering post-sICH hematoma growth, and will also provide data for subsequent animal and, ultimately, human studies.
Despite being the cause of significant morbidity and mortality, spontaneous intracerebral hemorrhage (sICH) remains the least treatable stroke subtype. The prevention of hematoma expansion in sICH is an attractive therapeutic target. Our earlier studies demonstrated that red blood cell micro particles (RMP) have hemostatic properties. We propose to determine the efficacy of RMP in preventing hematoma growth after experimental sICH in rats.
| Jy, Wenche; Rehni, Ashish K; Bidot Jr, Carlos et al. (2018) Pharmacokinetics of Human Red Blood Cell Microparticles Prepared Using High-Pressure Extrusion Method. Front Pharmacol 9:599 |
