Microclots and Neutrophil Activation as Potential Indicators for Stroke Risk and Reperfusion Failure
- Conditions
- Ischemic Stroke
- Interventions
- Diagnostic Test: 3D rotational digital tomographyDiagnostic Test: Atomic Force MicroscopyDiagnostic Test: Micro-Computertomography
- Registration Number
- NCT06530927
- Lead Sponsor
- University of Zurich
- Brief Summary
Stroke remains a major health burden worldwide. Many patients are severely disabled and stay in need of care. Mechanical thrombectomy has dramatically improved outcomes for stroke patients with large vessel occlusions, yet 40-50% of patients with successful recanalization remain severely disabled despite successful recanalization, a scenario called "futile recanalization". One of the causes for this lack of treatment effect is capillary obstruction, or "no reflow", potentially resulting from activated neutrophils and micrometer-sized blood clots. To address this issue, we employ digital holotomographic and atomic force microscopy to investigate the structural and chemical characteristics of blood and clot material in stroke patients and individuals at high risk of developing a stroke. Our study elucidates the association of activated neutrophils and microclots with stroke risk, and may be associated with clinical outcome, stroke ethology and reperfusion failure in patients with stroke. Leveraging label-free microscopy tools, could potentially lead to the discovery of new biomarkers for individualized stroke treatment and prevention, ultimately offering rapid identification of at risk patients and improving clinical outcomes
- Detailed Description
Background:
Stroke remains a major health burden worldwide. Many patients are severely disabled and stay in need of care. Since introducing mechanical thrombectomy as a therapeutic option, clinical outcome has drastically improved over the last few years. However, despite successful macrovascular reperfusion (recanalization), patients with stroke still have a significant risk (about 40-50%) of remaining severely disabled, a scenario called "futile recanalization". One of the causes for this lack of treatment effect is capillary obstruction, or "no reflow", potentially resulting from activated neutrophils and micrometer-sized blood clots. Previous work in rodent stroke models demonstrated that removal of these capillary stalls indeed improves reperfusion and recovery after stroke. However, there is a lack of knowledge regarding the role of neutrophils or microclots in patients with stroke, and their potential to indicate reperfusion failure.
Aim:
The goal of our study is to search for activated neutrophils and microclots in peripheral blood samples from patients with stroke. We anticipate that neutrophil and microclot characteristics such as size, shape, or surface structure may indicate stroke risk, and may be associated with clinical outcome, stroke ethology and reperfusion failure in patients with stroke. Our goal is to improve the prediction of stroke risk and treatment success.
Methodology:
We plan to prospectively include 500 patients with acute and chronic stroke, as well as a control group. We have teamed up with biophysicists from the Swiss Federal Laboratories for Materials Science (EMPA) using the novel microscopic tools 3D rotational digital tomography (DHTM) to achieve an unprecedented resolution of less than 10 μm for detection of altered neutrophil phenotypes and microclots in peripheral blood samples. Furthermore, in patients undergoing mechanical thrombectomy, retrieved clots will be analyzed with high-density micro-computertomography (micro-CT). Quantity, mechanical and structural properties of microclots and neutrophils will be correlated with risk of reperfusion failure, stroke recurrence and clinical recovery. Analyses of clots from patients with large vessel occlusion will be used to derive risk of reperfusion failure along with most likely source of the clot, and thus, most likely stroke etiology.
Potential Significance:
Current diagnostic tools are insufficient to predict response to treatment, clot source or stroke recurrence risk. Our project has the potential to discover new, clinically applicable biomarkers identifying patients at risk within a few hours, enabling individualized stroke treatment and prevention.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 500
Patients without acute stroke CS or CSG
- No previous stroke or previous stroke ≥ 1 year ago
- Signed informed consent
Patients with acute stroke (AS-noTx, AS-IVT, AS-MT):
- Patients admitted with high suspicion of acute ischemic stroke
- Time of onset of stroke symptoms ≤ 12 hours
- Consent according to the regulations of research in an emergency situation
- Ischemic stroke later confirmed
All groups:
- Pregnancy
- Age under 18 years
Acute Stroke no Therapy
• Acute treatment with IVT or with MT
Acute Stroke IVT-Group • Acute treatment with MT or without IVT
Acute Stroke MT-Group
• Acute treatment without MT
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Acute Stroke No Therapy Group Atomic Force Microscopy Patients with acute stroke, but without intravenous thrombolysis or mechanical thrombectomy Control Group 3D rotational digital tomography Patients without previous documented stroke Acute Stroke MT-Group Atomic Force Microscopy Patients with acute stroke and mechanical thrombectomy Acute Stroke MT-Group Micro-Computertomography Patients with acute stroke and mechanical thrombectomy Control Group Atomic Force Microscopy Patients without previous documented stroke Chronic Stroke Group 3D rotational digital tomography Patients with previous stroke ≥1year ago Acute Stroke IVT only Group 3D rotational digital tomography Patients with acute stroke and intravenous thrombolysis Acute Stroke MT-Group 3D rotational digital tomography Patients with acute stroke and mechanical thrombectomy Chronic Stroke Group Atomic Force Microscopy Patients with previous stroke ≥1year ago Acute Stroke No Therapy Group 3D rotational digital tomography Patients with acute stroke, but without intravenous thrombolysis or mechanical thrombectomy Acute Stroke IVT only Group Atomic Force Microscopy Patients with acute stroke and intravenous thrombolysis
- Primary Outcome Measures
Name Time Method Quantification and characterization of neutrophils First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year 3D rotational digital tomography and atomic force microscopy
image morphological outcome measurements:
* size: diameter (µm), surface area (µm2), volume (fl), thickness (µm), sphericity
* dry mass (g/dl)
* praevalence (count in numbers)
* activation state (activated vs. not activated vs. dead)Evaluation of reperfusion failure in patients with large vessel occlusion and mechanical thrombectomy <24 hours in patients with mechanical thrombectomy Defined by successfull macrovascular reperfusion (TICI \>=2c) and insufficient microvascular reperfusion with the outcome measurment (yes/no)
Successfull macrovasular reperfusion is defined according to the mTICI score 2c or 3.
Microvascular reperfusion success will be evaluated with thresholds were used to discriminate between microvascular hypoperfusion and reperfusion, calculated from perfusion images obtained on computed tomography (CTP) or magnetic resonance perfusion imaging (MRP).Quantification and characterization of microclots First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year 3D rotational digital tomography and atomic force microscopy
imaging outcome measurements:
* size: length (µm), width (µm)
* dry mass (g/dl)
* praevalence (count in numbers)
* composition (platelet aggregate vs. fibrin-rich microclots vs. microclot composite)
- Secondary Outcome Measures
Name Time Method Change in National Institute of Health Score Scale (NIHSS) First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year will be assessed using National Institutes of Health Stroke Scale (NIHSS)
NIHSS
13 assessed functional domains Range 0-42, higher score indicates severe impairmentAll-cause mortality 365 days Mortality
Degree of disability or dependence assessed by the modified ranking scale (mRS) First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year will be assessed using modified Rankin Scale (mRS)
mRS
Range: (0-6) 0 = no symptoms, 6 = death, higher score indicates severe impairmentAssessment Quality of Life using European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) 365 days EQ-5D-5L
Evaluation of 5 different aspects of health with likert scale (1-5)
MOBILITY SELF-CARE USUAL ACTIVITIES PAIN / DISCOMFORT ANXIETY / DEPRESSION Each domain is scored individually, higher values indicate higher impairment of quality of lifeIncidence of new cardiovascular disease 365 days Stroke, heart attack, brain bleeding