Microclots and Neutrophil Activation as Potential Indicators for Stroke Risk and Reperfusion Failure

Официальное название

Micro-clots and Neutrophil Activation as Potential Indicators for Stroke Risk and Reperfusion Failure The CLOTSAFE - Study (Micro-CLOTs, Stroke Risk, Activated Neutrophils, Reperfusion FailurE)

Обзор

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

Подробное описание

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.

Вмешательства

• Диагностический тест 3D rotational digital tomography
  DHTM is label-free and records the phase shift of low-energy light passing through the specimen on a transparent surface with minimal perturbation. DHTM measures the refractive index (RI) and computes the refractive index gradient (RIG), unveiling optical heterogeneity in cells. We will analyze blood samples for the detection of altered neutrophil phenotypes and microclots.
• Диагностический тест Atomic Force Microscopy
  The atomic force microscope (AFM) is widely used in materials science and has found many applications in biological sciences but has been limited in use in vision science. The AFM can be used to image the topography of soft biological materials in their native environments. We will analyze blood samples for the detection of altered neutrophil phenotypes and microclots
• Диагностический тест Micro-Computertomography
  Micro-CT is a 3D imaging technique utilizing X-rays to see inside an object, slice by slice. Micro-CT, also called microtomography or micro computed tomography, is similar to hospital CT or "CAT" scan imaging but on a small scale with greatly increased resolution. Samples can be imaged with pixel sizes as small as 100 nanometers and objects can be scanned as large as 200 millimeters in diameter. We will use micro-CT to analyze blood clots from patients with large vessel occlusion.

Первичные конечные точки

• Quantification and characterization of microclots [Срок оценки: First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year]
• Quantification and characterization of neutrophils [Срок оценки: First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year]
• Evaluation of reperfusion failure in patients with large vessel occlusion and mechanical thrombectomy [Срок оценки: <24 hours in patients with mechanical thrombectomy]

Вторичные конечные точки (5)

• Change in National Institute of Health Score Scale (NIHSS) [Срок оценки: First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year]
• Degree of disability or dependence assessed by the modified ranking scale (mRS) [Срок оценки: First Visit/Admission and patients with acute stroke after 24 hours, 3 months and 1 year]
• Assessment Quality of Life using European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) [Срок оценки: 365 days]
• Incidence of new cardiovascular disease [Срок оценки: 365 days]
• All-cause mortality [Срок оценки: 365 days]

Критерии участия

Критерии включения

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

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Швейцария · 1 центр

• University Hospital Zurich — Zurich

Идентификаторы

NCT: NCT06530927 · 2024-01353

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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