Progress in pathological research and application of cerebral artery thrombosis in ischemic stroke

The incidence of stroke in China has exceeded 379 per 100,000, ranking first in the world. About 1.9 million people die from stroke each year. Stroke has surpassed tumors and coronary heart disease, becoming the first cause of death among Chinese residents. The high disability rate, high fatality rate and increasing incidence rate of stroke are important public health issues that affect the national economy and people's livelihood.

Ischemic stroke is damage to brain function caused by cerebrovascular blockage or blood supply disorder. It is the most common type of stroke, accounting for 69.6%-70.8% of strokes in my country. Cerebral artery thrombosis is the direct cause of ischemic stroke, and the characteristics of thrombus can directly affect the symptoms and prognosis of patients; intravenous thrombolysis and endovascular treatment are currently the most effective treatments for ischemic stroke, which can significantly reduce ischemic stroke The mortality and disability rate of stroke patients can improve life function. Studies have shown that different pathological types of thrombosis in cerebral arteries can affect the effect and prognosis of intravenous thrombolysis and endovascular treatment.

Therefore, studying the histopathological characteristics of thrombosis can better understand the etiology and disease progression of ischemic stroke, and effectively guide the treatment of ischemic stroke. In recent years, the pathology of cerebral artery thrombosis in ischemic stroke Review of the research and application progress of.

1. Histopathological research methods of cerebral artery thrombosis

At present, there is no uniform standard for the research methods of thrombus specimens. Paraffin section is the most commonly used method. Only a few scholars use electron microscopes to study thrombus. Hematoxylin-Eosin staining is the most commonly used staining method for paraffin sections. Some scholars also advocate the use of Matthew yellow scarlet blue staining, elastic fiber Van Giesen stain, Mallory phosphotungstic acid hematoxylin staining and other special staining methods. Fibrin, red blood cells and white blood cells are stained in different colors.

In addition, staining for calcium and lipids can also be performed to help clarify whether the emboli originated from atherosclerotic plaque. Studies have shown that inflammatory cell activity may be one of the causes of cerebral arterial thrombosis. Immunohistochemical staining techniques can be used to identify specific cells to clarify the cause and source of thrombosis, such as the use of CD61 labeled platelets and CD3 markers T cells, CD34-labeled endothelial cells, CD68-labeled macrophages, etc., but the results of different studies are quite different.

2. Classification and source of cerebral artery thrombosis

2.1 Classification of cerebral artery thrombosis

There are various types of emboli that cause cerebral artery obstruction. It can be thrombus, tumor thrombus, air thrombus, bacterial thrombus, atheroma, etc. Among them, thrombus is the most common embolism. There is currently no classification of cerebral artery thrombosis. The unified standard can be divided into four categories according to the pathophysiology and composition of thrombosis: white thrombus, red thrombus, mixed thrombus, and hyaline thrombus.

Some scholars believe that according to the proportion of red blood cells, thrombus can be divided into thrombus rich in red blood cells (red blood cell ratio>=70%), mixed thrombus (red blood cell ratio 31%~69%), and fibrin-rich platelet thrombus (red blood cell ratio<=30 %). Niesten et al. believe that thrombus can be classified according to the difference between the content of red blood cells and non-red blood cells. If the number of red blood cells exceeds 15% of the total amount of platelets and fibrin, it is called red thrombus. If the total amount of platelets and fibrin exceeds red blood cells 15 % Is a white thrombus, and there is a mixed thrombus between the two.

With the development of quantitative pathology, image analysis software can now be used to quantitatively analyze the blood cells, white blood cells and fibrin in thrombus, which can more accurately study the composition and nature of thrombus, and better analyze thrombus and its etiology, clinical manifestations and The relationship between treatment effect.

2.2 The source of cerebral artery thrombosis

There are many sources of cerebral artery thrombosis:

(1) Cardiac embolism. There are many causes of cardiogenic embolism. Atrial fibrillation is the most common cause. In addition, heart surgery, congenital heart disease, rheumatic heart disease, non-primitive heart valve, myxoma, etc. Can cause cardiogenic embolism.

(2) Arterial embolism usually originates from unstable atherosclerotic plaques on the carotid artery or thoracic aorta and the thrombus formed from falling off.

(3) Local cerebral artery thrombosis, in situ thrombosis caused by atherosclerotic plaque, inflammation or endothelial injury.

(4) Venous thrombosis, venous thrombosis caused cerebral artery embolism through abnormal shunt from right to left of the heart (patent foramen ovale, ventricular septal defect, etc.).

(5) Embolism from other sources (separation of tumors, vascular wall fragments, catheters, biological valves and other devices).

(6) The source of thrombus is not the cause. After a full and comprehensive examination, there are still more than 35% of ischemic stroke patients who cannot determine the source of thrombus. Venous-derived thrombus usually consists of a small amount of fibrin structure and a large number of red blood cells, while arterial-derived thrombosis usually contains a large number of platelets and fibrin, with less red blood cells, and may also contain atherosclerotic plaques and other components that cause cardiogenic thrombosis. The mechanism is complicated, including hemodynamic disorders, platelet activation, endothelial injury, and inflammatory cell activation may also be the cause of thrombosis. The pathological characteristics of cardiogenic thrombosis are currently unclear.

Studies by Niesten et al. showed that there is no significant difference in pathological characteristics between cardiogenic thrombosis and arterial thrombosis; Kim et al. believe that the content of red blood cells in cardiogenic thrombosis is significantly higher than that in arterial thrombosis; while Boeckh-Behrens et al. Compared with cardiogenic thrombus, cardiogenic thrombus has higher content of fibrin, platelets and white blood cells, and less red blood cell content; there is currently a lack of relevant studies on the pathology of cerebral artery thrombosis in ischemic stroke after cardiac surgery to understand the pathological characteristics of its thrombosis It is helpful to prevent the occurrence of stroke after cardiac surgery, and guide the treatment plan to choose the biomarker of cerebral artery thrombosis. Early related markers of thrombosis mainly include thrombin-antithrombin complex, plasmin alpha plasmin inhibitor Complexes, thrombomodulin, tissue plasminogen activator/plasminogen activator inhibitor complex, fibroblast degradation products, von Willebrand etiology, etc., but these markers are found in all thrombotic diseases Can be raised. Cerebral artery thrombosis-specific biomarkers have important guiding significance for clarifying the source and generation mechanism of cerebral artery thrombosis.

At present, there are very few positive results related to specific cerebral artery thrombosis markers. Dargazan et al. performed immunohistochemical staining of cerebral artery thrombosis in 54 patients with ischemic stroke, quantitatively analyzed cD3 positive T cells on the thrombus, and compared arterial thrombosis. The content of T cells in atherosclerotic thrombosis, cardiogenic thrombus and other causes of thrombus, the results showed that the number of T cells in atherosclerotic thrombus was significantly higher than other causes of thrombus and cardiogenic thrombus, suggesting that CD3 may be arterial origin The results of thrombosis biomarkers need to be further confirmed.

Macrophage migration inhibitory factor (MF) was first found in the activated T cell culture medium and is related to the activity of a variety of inflammatory cells, such as Parkinson’s disease, stroke and Alzheimer’s disease. MF can be observed in the blood and brain tissues of neurological diseases. Recent studies have shown that MF may be a key mediator in the formation of atherosclerotic lesions. 1 This suggests that MF may be related to cerebral arterial thrombosis, but currently there is no The study of MF in cerebral artery thrombosis. Cerebral artery thrombosis-specific markers may be an important direction for future research.

3. Pathological types and imaging manifestations of cerebral artery thrombosis

Head CT examination is the most basic examination for acute stroke. The composition of cerebral artery thrombus is different, and there can be different manifestations on CT. Studies have shown that thrombus rich in red blood cells are more likely to show high signal on CT, forming a high-density sign that is typical of acute aortic occlusion, while thrombus dominated by platelets and fibrin are shown as low-density cranial MR. Brain tissue and cerebral artery pathology, high-resolution MR of cerebral artery can distinguish the cause of cerebral artery stenosis or occlusion, such as atherosclerosis, arterial dissection, embolism, etc. However, the current research on the correlation between cranial MR and cerebral artery thrombosis pathology Less ischemic stroke is a dynamic development process. With the development and evolution of stroke, the imaging manifestations of cerebral arterial thrombosis will also change, but there is currently a lack of research on the dynamic changes of imaging of different types of thrombus.

4. Pathological types of cerebral artery thrombosis and thrombolytic treatment

Intravenous thrombolytic therapy is one of the most important treatments for acute ischemic stroke. It has been proven to significantly improve the prognosis of patients and reduce the mortality and disability rate of patients with ischemic stroke. At present, the most commonly used thrombolytic drug is recombinant tissue plasminogen activator (rt-PA). Animal experiments and in vitro studies on the effect of rt-PA on different types of thrombosis have shown that it is rich in fiber. Protein thrombus has a poor therapeutic effect on rt-PA, while thrombus rich in red blood cells shows better responsiveness. The study by Santos et al. also showed similar results through a comparative analysis of the thrombolytic effect of 308 patients. The reason may be that the nature of fibrin and fibrin that needs to be lysed may reduce rt-PA in thrombus rich in fibrin. Thrombus with high permeability and rich in red blood cells, the internal fibrin matrix content is less, the combination is sparse, and it is easier to break, the permeability of rt-PA is better, and the amount of rt-PA required to dissolve the thrombus is less. But rt-PA has no obvious effect on other types of thrombus, such as atherosclerotic plaque, leukocyte-based thrombus, and tumor thrombus.

5. Pathological types of cerebral artery thrombosis and endovascular treatment

Cerebral arterial endovascular treatment includes intra-arterial thrombolysis, mechanical thrombolysis, lambda stent placement, thrombus aspiration and retrievable scaffold thrombectomy, etc. Since the 1980s, people have begun to explore endovascular treatment. Open and occlude blood vessels to treat acute ischemic stroke, but the effect has not been confirmed by high-level clinical trials.

Until 2015, the release of 5 multi-center, follow-up controlled studies on endovascular treatment completely changed the status of endovascular treatment. The Lancet magazine published an editorial specifically calling endovascular treatment a revolution in stroke treatment. ". Studies have shown that the success rate of endovascular treatment and the number of operations directly affect the prognosis of patients, while the success rate of endovascular treatment and the number of operations are related to the nature of the thrombus. Maekawa and other studies have found that the success rate of thrombosis surgery with rich red blood cells is higher. , Fewer operations are required to complete recanalization.

Duy et al. analyzed the differences in the removal of thrombi from different operations in the same patient and found that the red blood cell content of the thrombus removed first was significantly higher than that of the thrombus removed later, suggesting that the thrombus with high red blood cell content is easier to remove. Retrievable thrombectomy stent thrombectomy is currently the most commonly used surgical method. Observing the interaction between thrombus and thrombus retrieval stent through an electron microscope revealed that the force between thrombus and thrombus retrieval stent is both mechanical and adhesion. Sexually, thrombus with high red blood cell content has stronger adhesion to the thrombus removal stent. However, some in vitro studies and animal experiments have shown the opposite results. The friction coefficient of fibrin-rich thrombus is significantly higher than that of thrombus with high red blood cell content.

The time of thrombus formation is also related to the success rate of endovascular treatment. Freshly formed thrombus is easier to remove through endovascular treatment than chronic thrombus. The physical characteristics of thrombus depend on the composition of the thrombus. Thrombuses of different nature will affect the operation method. Fresh thrombi rich in red blood cells are relatively soft, easily deformed and broken, and can be easily removed by catheter suction, while fibrin-based thrombus and old thrombus are harder. Large, the success rate of extraction through the catheter is low, and it is more suitable to use the retrievable embolization stent for treatment. Although thrombus rich in red blood cells is easy to recanalize, it is more likely to fragment and escape, leading to second embolism, and there is a higher risk of distal embolism.

Therefore, relevant precautions must be taken during the operation. Cerebral artery thrombosis is a direct target of endovascular treatment. There are limited studies on the influence of thrombus properties on surgical procedures. Some studies have shown conflicting results. Further research on the pathology of cerebral artery thrombosis can help better guide endovascular treatment.

6. Summary and Outlook

Cerebral artery thrombosis is the direct cause and treatment target of ischemic stroke. Studying the pathology of cerebral artery thrombosis can help to better guide the treatment of ischemic stroke. At present, the pathological classification and research methods of cerebral arterial thrombosis lack integration and standardization. Most research focuses on the red blood cells and fibrinous white blood in the thrombus. The research on white blood cells and other components is limited, and the white blood cells and other components are not clear. The source of thrombus may be more instructive.

Ischemic stroke is a dynamic development process. The study of the relationship and dynamic changes between thrombosis pathology and the image of rhizome is helpful for the early diagnosis of ischemic stroke and the evaluation of brain damage. treatment effect. There have been studies in the country to find specific biomarkers related to cerebral arterial thrombosis, to clarify the cause of thrombosis, but the results are limited; there are very few studies on the ultrastructure of thrombus, and it is helpful to understand the ultrastructure of thrombus. The mechanism and source of thrombosis can better guide the prevention and treatment of ischemic stroke. Thrombus-specific biomarkers and ultra-microscopic knots may be the direction of future cerebral arterial thrombosis research.

In terms of thrombolytic drugs, currently commonly used thrombolytic drugs on the market include urokinase (UK), streptokinase (SK), alteplase (rt-PA), pro-uk (Pro-UK), reteplase ( r-PA) and tenecteplase (TNK-Tpa), etc. In addition, some emerging biotechnology companies have also begun to deploy in the field of cardiovascular therapy, especially the market segment of thrombolytic therapy, and Hong Kong medicine oncolysis is one of them.

The company has developed and deployed 3 innovative thrombolytic drug product pipelines. Our core technology product YB1 can be combined with a variety of thrombolytic drugs to treat various thrombotic diseases. The three existing thrombolytic drug products under development are respectively It is YB1-rt-PA, YB1-rt-DE and YB1-rt-PL, and the future clinical effects are worth looking forward to.

The current period of high incidence of cardiovascular diseases in winter is at the height of the health threats caused by cardiovascular diseases caused by arrhythmia such as atrial fibrillation that continue to occur. The enthusiasm of innovative biotechnology companies in the field of new drug research and development has also increased the number of people in the country to a certain extent. A little optimistic, we hope that with the joint efforts of the whole society, the health of the people can be effectively improved, and the prevention and treatment of atrial fibrillation and other arrhythmic diseases can be done well, and the troubles of cardiovascular diseases can be avoided.