Ischemia, Thrombosis, and Embolism

Ischemia, thrombosis, and embolism are important processes that can lead to the occurrence of ischemic stroke. 1 

Ischemia is the condition of restricted or reduced blood flow in the body. Thrombosis will lead to the formation of a clot in the affected blood vessels, otherwise known as a thrombus, which will eventually cause ischemia. The thrombus could undergo many mechanisms, including propagation, dissolution, organization, and recanalization. But the most damaging mechanism is embolization, where the thrombi detach from their origin and travel to distant body areas, resulting in infarction. This is also known as thromboembolism, embolism resulted from the product of thrombosis. Another possible method of embolism would be the process of cholesterol embolization, where blood cholesterol contents.5 

Once infarction has begun, the process would lead to cell death in affected areas. If the infarct occurs in the brain, this would be known as a stroke, specifically an ischemic stroke if the origin-concerned condition is from ischemia.5 

Further Development of Ischemic Stroke

Location of Infarction

Ischemic stroke could be present in many vessels in the brain. Some of the major occlusions and infarctions occur at1:

1. Middle cerebral artery (MCA) 

2. Anterior cerebral artery (ACA)

3. Posterior cerebral artery (PCA)

4. Vertebral arteries 

5. Basilar artery

6. Cerebellar arteries

7. Lacunar arteries

Some of these locations could be visualized in the 3D activity below which shows the Circle of Willis. Take your time to familiarize yourself with these locations to help you better understand the development of ischemic stroke. 6 

Molecular Mechanisms

Aside from embolizations and infarctions, there remain molecular mechanisms that underlie future stroke development. They are categorized into 3 main aspects: 7 , 8  

1. Excitotoxicity 

2. Oxidative stress 

3. Neuroinflammation

Excitotoxicity

Excitotoxicity and calcium overload are two closely related mechanisms that are present in conditions caused by ischemic stroke and are often caused by excessive activation of glutamate receptors. Following the occurrence of ischemic stroke, energy deficits (ATP depletion) are common, and as a result, ion pump failure begins in affected areas. Oxygen deprivation due to ischemia would prevent oxidative phosphorylation at affected areas, causing a rapid drop in ATP levels. The resultant ion disturbances also affect Na⁺/K⁺ and Ca²⁺ ATPases, disturbing ionic gradients. 8  This process in turn increases intracellular Na⁺ and Cl⁻ ion content, causing further water influx, swelling, edema, and cell lysis.7

Glutamate, an important neurotransmitter, would accumulate and be released into intracellular space. This excess glutamate would cause the hyperactivation of NMDA and AMPA receptors, causing calcium influx into neurons. This leads to activation of destructive enzymes, mitochondrial dysfunction, and cell death in neurons.7

Mitochondrial dysfunction is also present in these cases. The increase in intracellular calcium triggers the opening of the mitochondrial membrane transition pore at mitochondria. This results in loss of mitochondrial membrane potential, ATP depletion, mitochondrial swelling, and the release of cytochrome C. This further activates apoptotic and necrotic pathways, leading to mitochondrial and neuronal cell death. 8 

Oxidative Stress

During ischemia and the following reperfusion, reactive oxygen species (ROS) would be produced in excessive amounts. Major sources of ROS are the mitochondria and NADPH oxidases. Because of the high intracellular calcium content caused by oxygen deprivation (above section), calcium ions activate calcium-dependent nitric oxide synthase (NOS), which produces ROS species as well as peroxynitrite. ROS damages cellular DNA, lipids, and proteins and leads to cellular dysfunction, activation of apoptotic pathways, and extensive tissue damage. 7

Neuroinflammation

Neuroinflammation is prominent in ischemic stroke patients. Neuronal injury resulted from ischemic-caused cell death, activation of glial cells, and infiltration of leukocytes and monocytes. Neuroinflammation can have either neuroprotective or neurotoxic effects.7 During these inflammatory responses, pro-inflammatory signaling involving platelets, adhesion molecules (ICAM-1 and VCAM-1), cytokines (IL-1, 6, 10, 17, 29, TNF-alpha), matrix metalloproteinases, and prostaglandins amplifies inflammation and neuronal injury. 8  

Nitrogen oxide, NO, is a vasodillator present in our bodies. During a stroke, NO production decreases, resulting in reduced vasodilation and increased intravascular clot formation, worsening the already present ischemia. 8  

Resultant inflammation and oxidative stress increase the permeability of the blood-brain barrier. The release of proteases and downregulation of endothelial junction proteins cause the breakdown of endothelial tight junctions, resulting in protein leaks into the affected brain tissue and the presence of immune cells infiltrating the brain. Immune cells such as mast cells and macrophages are activated and lead to the release of histamine, proteases, and pro-inflammatory cytokines. This produces further neuronal damage and cerebral edema, enhancing inflammation and blood brain barrier damage. 8 

Review Questions

ANSWER KEY

1. B

2. B

3. D