The impact of thrombo‐inflammation on the cerebral microcirculation

Abstract

Cerebrovascular diseases include a number of conditions that involve thrombosis and inflammation, including stroke, intracranial stenosis, aneurysms, carotid and vertebral stenosis, and vascular malformations. Ischemic stroke is one of the leading causes of morbidity and mortality worldwide, and the leading cause of adult disability, resulting in a significant socioeconomic burden. 1,2 Rapid recanalization with intravenous thrombolysis or endovascular thrombectomy is the mainstay of current and evolving acute ischemic stroke management. 3 However, there is limited indication of rapid recanalization therapies due to a shorter time window and availability of stroke centers, and a large number of patients with ischemic stroke receive no acute therapy resulting in significant residual neurological damage, a long-term recovery period, and further risk of recurrent events and complications. 4 Therefore, there is a rapidly growing clinical need of additional therapies which may not be time-sensitive and can be given to a wider number of stroke patients and in nonspecialty centers. In recent years, there has been a considerable advancement in the research and development of neuroprotective and anti-inflammatory agents as potential adjunctive therapies in both pre-clinical clinical models. 5,6 In our own work, we have shown that pharmacologically targeting the Annexin A1/formyl peptide receptor (FPR)-2 pathway can significantly attenuate cerebrovascular thrombo-inflammation by modifying neutrophil-platelet phenotype from pro-inflammatory to pro-resolutory. 7,8 The cerebral microcirculation (comprising of neurovasculature within the brain <100 μm in diameter) is the most critical part of neurovascular bed, providing all metabolic needs to the cerebral parenchyma.

Thromboinflammatory challenges in stroke pathophysiology

“…Brain microvasculature (<100μm of diameter) includes the vast majority of the endothelial cells (EC) present in the central nervous system (CNS) providing all metabolic and nutrition requirements to the brain parenchyma, also supporting several neurovascular physiological functions [ 28 ]. Under physiological conditions, Ecs maintain vascular integrity by exerting an anti-platelet, anti-coagulant, and anti-inflammatory role.…”

The Pathophysiological Aspects of Cerebral Diseases

“…This is the basis of the glutamate excitotoxicity theory and may explain why pyramidal neurons in the hippocampus and Purkinje cells in the cerebellum that rely on glutamate neurotransmission are particularly vulnerable to ischemia [20]. The center of the irrigated tissue area, when receiving less than 10 ml/100 g of brain tissue, after 4-5 minutes, cannot maintain the sodium and potassium transporter working, generating a cytotoxic edema that will evolve to cell apoptosis, a process mediated by calcium and the glutamate (Figure 3) [21].…”

Neutrophils and Platelets: Immune Soldiers Fighting Together in Stroke Pathophysiology

“…NETosis describes a physiological response of neutrophils, when activated, to produce and extrude complexes of decondensed DNA, termed NETs [ 37 , 38 ]. These NETs are known to not only play a protective role in the immune response against invading pathogens, but they have also been shown to possess pro-inflammatory properties that can promote coagulation and thrombosis leading to and further exacerbating IS [ 5 , 39 ]. NETs are laden with prothrombotic mediators such as H3cit + (citrullinated histone H3), CatG, NE and myeloperoxidase (MPO) [ 4 , 34 ].…”

“…Neutrophils and platelets are key players in ischemic brain injury and its resolution [ 4 , 5 , 6 , 7 ]. Resolution is the physiological ability of the body to achieve homeostasis after infection or inflammation.…”

“…In vivo, NPAs are also facilitated by margination of platelets and neutrophils to the periphery of blood vessels as a consequence of displacement of erythrocytes to the central part of the vessels [ 17 ]. Ischemia-reperfusion injury (I/RI), which is one of the main underlying causes of IS pathogenesis [ 5 , 18 , 19 ], further enables NPA formation and amplifies thromboinflammatory responses in IS [ 7 , 20 ] ( Figure 2 ).…”