作者：王乐民
出版社：人民卫生出版社
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血栓病的起源与发生:免疫细胞平衡功能崩溃与启动机制试读：
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血栓病的起源与发生：免疫细胞平衡功能崩溃与启动机制=The Origin and Onset of Thrombus Disease：collapsed balancing function of immune cells and triggering factors：英文/王乐民著．—北京：人民卫生出版社，2017
ISBN 978-7-117-25335-2
Ⅰ．①血… Ⅱ．①王… Ⅲ．①血栓栓塞-研究-英文 Ⅳ．①R543
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版权所有，侵权必究！The Origin and Onset of Thrombus Disease Collapsed balancing function of immune cells and triggering factors
著 者：王乐民
出版发行：人民卫生出版社有限公司 人民卫生电子音像出版社有限公司
地 址：北京市朝阳区潘家园南里19号
邮 编：100021
E - mail：ipmph@pmph.com
制作单位：人民卫生电子音像出版社有限公司
排 版：人民卫生电子音像出版社有限公司
制作时间：2019年4月
版 本 号：V1.0
格 式：mobi
标准书号：ISBN 978-7-117-25335-2
策划编辑：李江
责任编辑：李江打击盗版举报电话：010-59787491 E-mail：WQ@pmph.com注：本电子书不包含增值服务内容，如需阅览，可购买正版纸质图书。About the AuthorLeMin Wang, MD, PhDProfessor of Department of Cardiology Tongji Hospital of Tongji University Shanghai, China
Treatises as the editor
1.Acute pulmonary embolism. Helongjiang: Helongjiang science and technology publishing house, 1999.
2.Pathophysiology of cardiovascular disease(Tranlsation). Helongjiang: Helongjiang science and technology publishing house, 2000.
3.Pulmonary embolism and deep venous thrombosis. Beijing: People's Medical Publishing House, 2001.
4.Coronary heart disease. Beijing:People's Medical Publishing House, 2003.
5.Pulmonary circulation diseases. Beijing: People's Medical Publishing House, 2007.
6.Pulmonary embolism and deep venous thrombosis. second edition. Beijing: People's Medical Publishing House, 2008.Preface
The aim of this book is to summarize research data, which support a central role of alterations in immune functions in thrombosis development. Whilst venous (red) and arterial (white) thrombi differ histologically, their upstream initiating factors are similar.Venous thrombi, whether familial or acquired, result from a defensive mechanism to prevent the passage of intravenous microorganisms or malignant cells by the formation of biological filters. Such filters then also trap red blood cells, hence resulting in typical venous red thrombosis. Arterial thrombosis results from endothelial damage leading to platelet adhesion. The rupture of the atherosclerosis soft plaque cap and superficial anabrotic damage to the endothelium may result from the effects of reactive oxygen species or cytokines released from neutrophils activated in response to the microorganisms that have entered the bloodstream following the collapse of the immune cell balance function. Thus venous thrombosis results from activation of the body's new defensive mechanism, whilst arterial thrombosis results from a failure of defensive mechanism to clear pathogens.
This book brings together extensive studies of the author conducted over the past couple of decades into the origins and pathogenesis of thrombosis with publications in a range of leading international journals. We have conducted studies in a variety of clinical groups and on different experimental models, using a range of technical approaches including genomics, proteomics, immunology, microbiology and cytology. We also analyzed internal and external causes of acquired and familiar venous thrombosis and proposed origin and onset of venous thrombus diseases and its triggering factors. Based on genomics and immunocytological research findings, we proposed collapsed immune cell balance function as the origin of arterial thrombus diseases and concluded that exogenous microorganisms may be the triggering factor of arterial thrombosis.
The recognition of natural phenomena originates from curiosity and observation,gradually from shallower to the deeper and from the surface to the center, rising spirally.It is the same with recognizing diseases. However, it is the development of the times that provides the possibility to understand the micro structures and functions of diseases.“The origin and onset of thrombus Diseases” welcomes any comments, suggestions or criticisms from readers with common interest in research or clinical areas.
This book is dedicated to all graduate students of our thrombosis research team. Their multi-dimensional perspective work verifies the origin and onset of thromboembolic disease and its immune mechanism. The team members includes: Dr.Fan Yang, Dr. Qianglin Duan, Dr. Wei Lv, Dr. Zhu Gong, Dr. Haoming Song, Dr. Lin Zhou, Dr. Yanli Song, Dr. Wenwen Yan, Dr. Hao Wang, Dr. Qiang Wang, Dr. Guiyuan Li, Dr. Yun Jin, Dr. Siwan Wen, Dr. Zhiru Ge, Dr. Kebin Cheng, Dr.Mei Fu, Dr. Xiaoyu Zhang, Dr. Chunyu Huang, Dr. Yuan Xie, Dr.Jinghua Tan, Dr. Qi Yu, Dr. Yixin Chen,Dr. Chuanrong Li.Acknowledgment
I greatly appreciate Profs. Jinfa Jiang, Wenju Xu, Xianghua Yi, Haiying Wan from Tongji Hospital of Tongji University for data collection and detection. I also give thanks to Prof.Yu Zhang from electron microscopy center of Fudan Univserity, Profs. Hengjun Gao and Xiaoying Shen from South Gene Chip Center for their platform. Profs. Huikang Zhao and Jing Chen made great effort in image production. Guanghe Li helped to edit the draft. Many thanks should also be given to my parents, my wife and friends. Finally,I specially appreciate Dr. Qianglin Duan, Prof. Shulin Liu and Prof. Anthony Dart.Monash University, Australia.for their kind help in English usage.Introduction
Thrombosis, in arterial or venous vessels, is a common disease with a high morbidity worldwide. Since all the organs and tissues are supported by the blood circulation system, thrombus can occur in any part of the body and is related to a diverse range of clinical disciplines. Additionally, the presence of arterial or venous thrombosis is indicative of a subversive imbalance in the body defense system.
In 1856, the German pathologist Rudolf Virchow first identified 3 main factors responsible for thrombosis, subsequently known as Virchow's triad, including hypercoagulability of the blood, damage of the vessel wall and hemodynamic alterations such as stasis. Virchow's triad remains the paradigm guiding clinical practice today.For decades, there have been many international guidelines on the prevention, clinic diagnosis and treatment of arterial and venous thrombi, proposing risk factors and risk stratification of arterial or venous thrombus. Thrombosis in the coronary, cerebral,peripheral arteries and pulmonary arteries and in deep vein still remains at a high incidence worldwide, so different interventions and prevention measures have been adopted. Patients with thrombotic diseases may suffer from the sequelae and young patients often die from thrombosis.
The advantages of the refinement of the clinical branches for the convenience of intensive work are self-evident. However, for the specifics of the refinement, the viewpoints of the practitioners are limited: they tend to focus on the divided parts, so the human body integrality is often cut into pieces. As a result, the knowledge is often fragmentary and the internal integrity of science is split, largely owing to the limitation of recognition about the disease, which, whether in the arterial or venous system, is usually a local expression of a systemic disease instead of abnormities in one particular organ or a single vessel branch. Therefore, it should be analyzed in a holistic view rather than at the specif i c thrombotic organ or location to search for the leakage.
For the evidence-based medicine of thrombotic diseases, risk factors could be evaluated based on the observed clinical manifestations. However, they are not the essence of the genesis of the disease and so may not reveal the causality of the disease.Statistical data may suggest the causality but may not be correct. In order to comprehend the thrombosis correctly, the underlying mechanisms should be explored.
Much about thrombosis is still a mystery, such as its origins. A full picture of the thrombosis should be obtained with a holographic thinking instead of the linear or planar thinking. Meanwhile, the mechanisms behind the development of the thrombotic disease should be revealed, and the processes of pathogenesis from the clinical manifestation to the nature of the disease should be explored. There are needs of evidence, epitomization of medical knowledge, integration of multiple disciplines,as well as vertical and horizontal fusions. Not only a deep understanding of the clinical practices should be established to raise query in clinics, but also the advanced methods in modern medicine should be adopted to deal with the massive data acquired. In the meanwhile, rational thinking and hierarchical analysis on a philosophical level are indispensable, which is just like exploring the unknown mysteries of the universe.
Venous thrombosis is triggered by infected cells or malignant cells, while arterial thrombosis may be triggered by pathogenic microorganisms. However, the underlying condition of both venous and arterial thrombosis is the same. Both thrombosis occur under the collapse of the immune cell balance function, which is the common kernel of the origin of thrombus disease. The venous thrombosis results from the substitution of own new defense morphology, but the arterial thrombosis results from the self repair of the injured endarterium. The dif f erent expressing ways both follow common law of biology, which benef i ts self stabilization and continuity of living bodies. However, the local benef i cial defense and repair lead eventually to harmful thrombotic clogging, and the activation of blood coagulation factors only makes the defense and repair firmer.
The immune system, consisting of a variety of organs, tissues, cells and their products, which is to timely and ef f ectively remove deleterious factors from the body.Collapsed immune cell balance function refers to non-function or signif i cant dysfunction of immune cells. There are short-term inhibition of immune cell function and long-term signif i cant dysfunction of immune cell function. Systemic immnune cell balance function collapse inevitably results in subversive disease, including thrombotic diseases. Even in the presence of thrombus risk factors, thrombosis will not occur in an individual with a healthy immune cell balance function.
The nervous, endocrine and immune systems paly important roles in regulating internal physiological activities and self equilibrium as a whole. The neuro-endocrineimmune regulation is a huge development of the macro-control theory of modern medicine. The innate and adaptive immune functions are both under the mediation of the vegetative nerve and endocrine systems. Thus, immune cell balancing function collapse is associated with the state of over stress, in which transmitters secreted by excessively activated sympathetic nerves can decrease the number of lymphocytes,inhibit the receptors of lymphocytes, increase the number of phagocytes, and activate the receptors of phagocytes. This phenomenon is obvious in middle-aged patients with thrombotic diseases. The immune function can be influenced by many factors such as advanced age, infection, temperature, barometric pressure, drugs as well as food balance, with which thrombotic diseases in elder people are often related. It should be extended to the upstream of the disease from the middle and lower reaches to prevent the thrombotic disease, to decrease the incidence and to increase the cure rate. Hence,it is needed to lower the stress level inside human body and restore the balance of neuroendocrine functions, which is the new content of prevention, treatment and rehabilitation of thrombotic diseases.Part I Venous thrombusChapter 1 The origin and onset of acute venous thrombus
Immune cell balancing function collapse refers to no function or significant dysfunction of immune cells, involving mostly T lymphocytes. Under the condition of immune cell balancing function collapse, acute venous thrombosis originates from intravenous immune adhesive inflammatory reactions triggered by infected cells/malignant tumor cells, which happens throughout the whole process of genesis of venous thrombosis.
Thrombotic inflammation, including infectious inflammation (by pathogenic microorganism) and non-infectious inflammation (by malignant tumor cells), is a defensive response. The outcome of inflammation depends on the strength of immune cell balancing function. With the condition of immune cell balancing function collapse, the human body loses the function of eliminating intravenous infected cells/malignant tumor cells timely and effectively. Thus, integrin subunits β1, β2 and β3 on the membrane of platelets and white blood cells are activated to combine with the ligand fibrinogen into a reversible mesh-like structure, which is like the intravenous biological filter and acts as physical defense of the human body to prevent the infected cells/malignant tumor cells in the distal veins from flowing back. During the process of defense, blood cells, mainly red blood cells, stagnate and fulfill the filter, which stops the blood flow in the local veins and thus results in venous thrombotic diseases.
The process, in which integrin β2 and β3 receptors on white blood cells or platelets membrane combine with their ligands fibrinogen, is reversible and easy to be disintegrated. Thus, only under the condition of stasis can the biological filter form.Otherwise, the combinations will be impacted into pieces by the quick blood flow.Integrin β2 on the membrane of neutrophils combines with its ligand Factor X to Factor Xa, activates coagulation factors and converts fibrinogen in the filamentous sieve into fibrin, which makes the intravenous biological filter firm. Fibrinoid inflammation is the pathological manifestation of venous thrombosis.
In people with a sound immune function, infected cells/malignant tumor cells can be removed timely and ef f ectively, which makes it unnecessary to start the intravenous biological filter to act as a compensatory physical defense. Thus, acute venous thrombotic events will not take place under such circumstances. Patients with collapsed immune cell balancing functions are a group of people,who have particularly high risks of venous thrombosis. Meanwhile, anyone who has venous thromboembolism may have infected cells/malignant tumor cells in veins, which may trigger the genesis of venous thrombosis. Only under the condition of immune cell balancing function collapse, the risk factors, such as advanced age, infection, trauma, surgery, autoimmune disease, longtime bedding, pregnancy, delivery as well as long trip syndrome, may cause venous thrombosis. However, even with definable risk factors, venous thromboembolism usually does not form in people with sound immune functions.
(Published: Int J Clin Exp Med 2015;8(11):19804-19814)Chapter 2 The answer to the onset of acute venous thrombus1.Questions from clinics
Venous thromboembolism (VTE) includes pulmonary thromboembolism (PE) and deep venous thrombosis (DVT). Venous thromboembolisms that could be diagnosed in clinics are called dominant VTE. The clinical spectrum of VTE is relatively wide, because VTE can occur in different organs and tissues. However, dormant VTE that is hard to be diagnosed in clinics is often found in autopsy. VTE, including cerebral cortical vein, cerebral venous sinus thrombosis, acute PE, chronic thromboembolic pulmonary hypertension (CTEPH), hepatic venular occlusive disease, Butchart's syndrome,mesenteric venous thrombosis, pelvic venous thrombosis, DVT and PE after surgeries as well as clinically common lower limb DVTs, distributes in diverse clinical disciplines and is a disease faced by almost all the clinical disciplines. Among them, PE has become a global medical care problem due to its high morbidity, misdiagnosis rate and mortality[1, 2]. VTE can be divided into two categories, genetic VTE and acquired VTE. According to the results of epidemiological investigations, the incidence of genetic VTE is relatively low, while most of the VTEs are acquired VTEs. Both of them can be called symptomatic VTE (Figure 2-1-1,2,3) and are hard to be distinguished.Figure 2-1-1 Simulation diagram of pulmonary thromboembolismFigure 2-1-2 Simulation diagram of Iliac vein thrombosis
Figure 2-1-3 Simulation diagram of lower extremity deep venous thrombosis
Many risk factors of VTE have been identified by organizations such as the American College of Chest Physicians (ACCP), which has published nine editions of guidelines for VTE diagnosis [3], treatment and prevention from 1995 to 2012. Proposed VTE risk factors include advanced age, infection, malignancy, autoimmune disease,surgery, trauma, pregnancy, long trip syndrome, family history and so on. ACCP has raised the risk stratification of surgical patients. Different measures should be taken in patients with different stratification to prevent VTE. Actually, only a small part of the patients with same risk stratification and same external environment have had VTE. In 2008, Shackfore [4] reported that 84% of the 37619 surgical patients were partly or totally treated and prevented according to the guideline. From 1995, when the first ACCP was published, to 2004, the numbers of symptomatic VTE increased rather than decreased,and there was segregation between preventing risk factors and VTE occurrence.
Thus, here the questions come. Why does the incidence of VTE increase as the age increases? Why does the incidence of VTE stay high in patients with malignancies? Why does only a small part of patients with the same infection develop VTE? Sudden death caused by acute PE resulting from surgeries, pregnancy, delivery or long trip syndrome is always hard to prevent. However, the vast majority of the population will not develop VTE under the same conditions. Both being thrombus, acute arterial thrombus is white thrombus but acute venous thrombus is red thrombus. What does the pathological difference mean? Thrombolytic therapy is effective for arterial thrombosis within several hours after onset, but venous thrombosis, with a wide thrombolytic time window, can be delayed to several days, 2 weeks, or even longer. What causes the difference in the thrombolytic time window between acute venous and acute arterial thrombus? Acute venous thrombus can autolyze, while arterial thrombus cannot. For VTE patients, oral anticoagulants are usually recommended for 3, 6 or 12 months and occasionally lifelong. Currently, there are no objective criteria for individual evaluation that complicates the selection of anti-coagulation therapy by physicians. Furthermore, even with standard anti-coagulation therapy and international normalized ratio (INR), some patients still develop CTEPH. Thus, the physicians are extremely puzzled about anticoagulant usage.
Query raised in clinics usually originates from clinical practices. The risk factors of VTE are only the clinical phenomenon of incident VTEs and the summary of evidencebased medicine, not the essence of this disease. So far, the medical resources put into the global prevention of VTE have not had the predicted effects. The reasonable explanation of this separation phenomenon between clinical prevention and treatment guidelines of VTE and clinical practices is that the etiology and pathogenesis of VTE are still unclear.2.Protein components analysis of acute venous thrombus
The acute venous thrombosis freshly taken out from the body is red to the naked eyes and is fragile. It is composed of red blood cells, platelets, white blood cells and plasma proteins under microscope.
Mass spectrographic analyses have shown that a majority of the proteins in the thrombus are fibrinogen, the the remaining being mainly serum albumin and cytoskeletal proteins [5]. The reversible combinations between the receptor and their ligand-- fibrinogens suggest that acute venous thrombus is easy to autolyze and delayed thrombolysis is effective, so it should be easy to lyse the thrombus through interventional fragmentation.
Acute venous thrombus is red and is composed of red blood cells, platelets, white blood cells and fibrinogen. But how does fibrinogen bind to blood cells in the formation of thrombus? MS/MS and bioinformatics analyses of thrombus in patients with acute PE have shown that subunits β1, β2 and β3 in integrins are the core proteins of acute venous thrombus.
Integrins, important members in cell adhesion molecule family, mediate the adhesion between cells and between cells and extracellular matrix (ECM) and are involved in the bidirectional
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