Interpretation of the Pathological Mechanism of Blood Stasis in Traditional Chinese Medicine in Light of Understanding of Hypercoagulable States in Modern Medicine

Abstract

In both Traditional Chinese Medicine (TCM) and modern medicine, they agree that the integrity and healthy structure of the vascular endothelium are essential for normal hemodynamics. Damage to the vascular endothelium can quickly activate the extrinsic coagulation pathway by triggering the tissue factor (TF) and lead to coagulation. This damage, along with a loss of anticoagulant properties through antithrombin III (AT III), TF pathway inhibitors, and the protein C system, can result in a hypercoagulable state and even thrombosis. Hypercoagulability is not only a common feature of many cancers but also an important factor promoting tumor development and metastasis, which corresponds to the TCM theory of “blood stasis leading to tumors.” The pharmacological effects of heparin and aspirin have similarities with TCM's “activating blood circulation and removing blood stasis” theory in improving blood circulation, treating related diseases, and their anti-inflammatory effects.

Keywords

blood stasis - hypercoagulable state - thrombosis - heparin - aspirin - Traditional Chinese Medicine - modern medicine

Blood stasis is an important concept in Traditional Chinese Medicine (TCM), which refers to a state in which blood circulation is impaired, leading to stagnation and accumulation. It is often closely related to the onset and development of various diseases.[1] With the in-depth research in modern medicine on hemodynamics and hypercoagulable states, it has been found that blood stasis and hypercoagulable state share many similarities in their pathological mechanism and clinical manifestations. A hypercoagulable state refers to a pathological condition in which the blood's coagulation ability is enhanced and the anticoagulant system's function is weakened, leading to an increased tendency for thrombosis.[2] This corresponds to the blood circulation disorders and blood stasis accumulation described in TCM theory.

This article analyzes the basic concept, pathological mechanism, and manifestations of blood stasis in various diseases, revealing the mapping relationship between blood stasis and hypercoagulable state in modern medicine. Heparin and aspirin, as representative drugs for “activating blood circulation and removing blood stasis,” have been widely used in modern medicine, further validating the intersection and complementarity of TCM and Western medical theories. These analyses provide a modern medical basis for TCM's blood stasis syndrome, and offer new perspectives and methods for the treatment of related diseases in modern medicine.

Basic Concept of Blood Stasis

Blood stasis refers to the impaired flow of blood, resulting in stagnation and accumulation, either due to blood being trapped within the body or conditions like prolonged illness affecting the collaterals. In the circulatory system, the vessels are considered the house of blood. The integrity and smoothness of the vessels are the primary factors in ensuring the normal circulation of blood. The movement of blood is also related to the quality of the blood itself. If the blood is thickened or becomes more viscous due to phlegm and dampness, it can lead to poor circulation and blood stagnation. Additionally, the movement of blood is influenced by pathogenic factors. Invasion of yang pathogens or internal generation of heat may lead to pathological changes of the excessive heat, which forces the blood to flow irregularly and can result in bleeding or blood stasis. On the other hand, when external cold invades or cold develops internally, it can lead to excessive yin, causing the obstruction of channels and retarded blood flow and even blood stasis.[1]

The heart qi promotes blood movement, the lung qi disperses and sends down, the liver qi ensures smooth flow, the spleen governs blood, and the liver stores blood. These functions work synergistically to maintain normal blood circulation. For example, if the heart qi is insufficient, blood circulation may become weak; if the lung qi is insufficient, it may fail to regulate the dispersing and descent; if the spleen qi is weak, it may not effectively govern blood, leading to qi deficiency and blood stasis; if the liver qi is obstructed, or if liver qi ascends inappropriately, bleeding may occur; if liver qi stagnates, it can result in qi and blood stasis.[1] Therefore, the pathogenesis of blood stasis involves multiple aspects of the body, including the meridians, qi, blood, and organs.

Understanding Blood Stasis in Traditional Chinese Medicine from the Pathological Mechanism of Hypercoagulable States

Maintaining normal coagulation function, including the process of forming stable blood clots, is an inherent characteristic of the blood system. Normal blood flow is maintained by the balance between procoagulants and anticoagulants, and it is a process where coagulation factors are activated in a certain sequence to ultimately convert fibrinogen into fibrin via thrombin. This process includes the formation of prothrombin activator, thrombin formation, and fibrin formation, which are the three basic steps. The prothrombin activator is a complex of Xa, V, Ca²⁺, and platelet factor 3, and its formation requires the activation of FX. According to the different initiation pathways and involved factors in the formation of the prothrombin activator, coagulation is divided into intrinsic and extrinsic coagulation pathways. Protein C and its cofactor protein S are vitamin K-dependent proteins synthesized by the liver. Protein C exists in the body in its proenzyme form in the blood circulation. When activated by the complex of thrombin and thrombomodulin on the vascular endothelium, activated protein C, with the help of protein S, inactivates FVa and FVIIIa on platelet membranes, prevents FV and FVIII from binding to the platelet surface, and enhances the binding of thrombin III to thrombin, thereby reducing platelet activity and exerting an anticoagulant effect.[3] Hypercoagulability is a modern medical diagnosis where the blood tends to form thrombi. Hypercoagulability describes the pathological state of excessive coagulation or coagulation without bleeding.

Consistent with the basic theory of TCM, modern medicine also believes that the integrity and good structure of the vascular endothelium are essential for normal hemodynamics. Factors such as infections and smoking can damage the vascular endothelium, which can quickly activate the extrinsic coagulation pathway through the tissue factor (TF), triggering coagulation, and damage to anticoagulants such as antithrombin III (AT III), TF pathway inhibitors, and the protein C system can lead to the loss of anticoagulant properties, resulting in hypercoagulability or even thrombosis. Endothelial plasminogen activator inhibitor is crucial for regulating fibrinolysis, and damage to endothelial function causes an imbalance in fibrinolysis, leading to a procoagulant state.[4] [5]

Based on in-depth research on cardiovascular diseases in TCM, a preliminary understanding of “phlegm turbidity” has emerged, with its corresponding material foundation in modern medicine, particularly in the context of blood lipid components. Dyslipidemia, especially hyperlipidemia, is a key factor in the development of atherosclerosis.[6] During atherosclerosis, lipids deposit on the vascular wall, forming plaques that not only narrow the blood vessels but may also become unstable and rupture, triggering coagulation. Coagulation activates platelets and coagulation factors, forming clots. Hyperlipidemia promotes a hypercoagulable state and thrombosis formation through mechanisms such as increased oxidative stress, endothelial cell damage, enhanced platelet aggregation, activation of coagulation factors, and inhibition of fibrinolysis.[7] The case of amniotic fluid embolism is a typical example of blood “phlegm turbidity” components. After amniotic fluid components enter the bloodstream, they can activate FXII, initiating the intrinsic coagulation pathway. They can also directly stimulate platelet activation and aggregation, enhancing the coagulation response, and promote coagulation and thrombosis through the activation of inflammatory factors and the complement system.[8]

TCM, through its syndrome differentiation methods, can reflect pathological conditions at an early stage.[9] For example, heart failure can be linked to the TCM concept of “insufficient heart qi and weak blood circulation.” In heart failure patients, reduced cardiac output leads to insufficient tissue perfusion, promoting thrombosis formation. Reduced cardiac output causes slower venous return, blood stasis, and an increased risk of venous thrombosis. Cardiac dysfunction causes endothelial cell dysfunction, which reduces nitric oxide production, increases reactive oxygen species, and promotes platelet activation and coagulation factor activation. Cardiac dysfunction leading to high shear stress in blood vessels can cause endothelial cell damage and platelet aggregation. In heart failure patients, activation of the renin–angiotensin–aldosterone system and excitation of the sympathetic nervous system increase levels of angiotensin II, aldosterone, and catecholamines, promote vasoconstriction and water–sodium retention, increase blood volume and blood viscosity, and facilitate thrombosis formation.[10]

Understanding Blood Stasis from the Hypercoagulable State Promoted by Tumors and Autoimmune Diseases

Armand Trousseau first described superficial thrombophlebitis as a precursor to visceral malignancies.[11] Hypercoagulable state is a common feature of many cancers, such as pancreatic cancer, lung cancer, breast cancer, and gastric cancer, which all display hypercoagulability and thrombosis.[12] [13] Venous thrombosis is also the most common cancer-associated complication.[2] Studies have shown that hypercoagulability is not merely a secondary effect caused by the presence of tumors; it is also an important factor in promoting tumor development and metastasis. For example, the complement cascade and hypercoagulability mutually induce the formation of neutrophil extracellular traps in a vicious cycle, and in this feedback loop, they can jointly promote the tumorigenic phenotype of immune cells and protect tumor cells from immune attack, ultimately promoting tumor development and metastasis.[14] The “blood stasis leading to tumors” theory in TCM refers to the impaired flow of blood in the body, leading to blood stasis accumulation, which then triggers or promotes the formation of tumors.[15] As stated in the Collected Insights on Diseases of the Surgery Department (Yang Ke Xin De Ji): “Due to anxiety and overthinking, unfulfilled desires, liver and spleen qi reversal, leading to obstruction of the meridians and collaterals, and the formation of nodules,” pointing out that breast cancer is caused by emotional anxiety leading to the obstruction of qi and blood, and meridians, ultimately forming tumors. These theories align with current oncological research results, and the term “blood stasis leading to tumors” has been incorporated into multiple editions of the Pathology textbook published by the People's Medical Publishing House.[16]

Among patients with various autoimmune diseases, there is often a tendency towards hypercoagulability. The most typical disease in this category is antiphospholipid antibody syndrome, characterized by thrombosis or recurrent miscarriage (placental vascular thrombosis), with the main treatments being heparin and aspirin.[17] Rheumatoid arthritis (RA) is a typical representative of “bi” syndrome in TCM, where the pathogenic factors correspond to inflammatory cells and the inflammatory factors they secrete. Inflammation leads to joint fibrosis and symptoms in the joints and muscles, which can be seen as “qi and blood blockage.”[18] In thrombodynamic measurements, RA patients show increased clot growth rate, size, and plasma clot optical density, indicating a chronic hypercoagulable state. The rate and extent of clot retraction in RA patients is significantly reduced and is associated with platelet dysfunction, presenting as impaired activation responses. Changes in clot growth and retraction parameters are related to the level of systemic inflammation. These findings confirm the pathogenic role of hypercoagulability in RA.[19] Clinically, the risk of lower extremity deep vein thrombosis in RA patients is 1.9 times that of the general population.[20] Other autoimmune diseases, such as systemic lupus erythematosus (excluding those with thrombocytopenia), Behçet's disease, and Sjögren's syndrome, also often present with hypercoagulability or even inflammatory thrombosis.

The Blood-Activating and Blood Stasis-Resolving Effects of Heparin

Heparin is a classic first-line anticoagulant, discovered by Jay McLean and William Henry Howell in 1916, and has been in use for over a hundred years. Heparin is a heterogeneous, linear, highly sulfated anionic glycosaminoglycan. This structural characteristic allows heparin to interact selectively with various proteins. Among the heparin-binding proteins, the most important is the serine protease inhibitor AT III, which imparts anticoagulant properties to heparin and is clinically used in the prevention and treatment of deep vein thrombosis, pulmonary embolism, etc. In addition to binding AT III, numerous biologically active heparin-binding proteins have been found to interact with each other. Studies have also revealed other pharmacological activities of heparin, including antiviral, antitumor, anti-inflammatory, and lipid-lowering effects.[21] [22]

Research indicates that heparin can activate lipoprotein lipase, thereby reducing plasma triglyceride and other lipid levels.[23] Heparin combined with insulin has been widely confirmed through clinical studies as a safe and effective treatment for hypertriglyceridemia-related pancreatitis.[24] [25] Low-molecular-weight heparin is used not only as an anticoagulant for cancer-related thrombosis treatment[26] but also, along with its derivatives, can directly influence tumor cell signaling, inflammation, angiogenesis, and metastasis through mechanisms involving growth factors, adhesion molecules, chemokines, and heparinase, thus demonstrating antitumor effects.[27] [28] Heparin also has anti-inflammatory properties. Studies show that heparin can inhibit neutrophil activity,[29] suppress macrophage polarization (showing bidirectional regulation, exhibiting an M2 phenotype in lipopolysaccharide-induced macrophage cell line RAW264.7),[30] and inhibit the release of inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1, etc.[31] These properties enable heparin to show potential therapeutic value in various inflammatory diseases and autoimmune conditions such as inflammatory bowel disease,[32] bronchial asthma,[33] and RA.[34] Research indicates that after viral, bacterial, or fungal infection of the host, pathogens first bind to the host cell's heparin sulfate, facilitating pathogen adhesion and invasion.[35] Heparin, as a competitive inhibitor of heparin sulfate, can block the binding of pathogen proteins to heparin sulfate on the surface of host cells, suggesting its clinical potential in treating or preventing pathogen infections.[27] Studies have shown that low-molecular-weight heparin or standard heparin can reduce the mortality rate in critically ill COVID-19 patients.[36] A retrospective report on 449 COVID-19 patients from Wuhan first proposed practical evidence for heparin as an anticoagulant in the treatment of COVID-19.[37] In a cohort study of 4,297 COVID-19 patients in the United States, the preventive use of heparin within 24 hours of hospitalization significantly reduced the risk of death.[38] Additionally, heparin has shown potential applications in degenerative diseases such as Alzheimer's disease and diabetic neuropathy.[22] Therefore, heparin, as a drug with “blood-activating and blood stasis-resolving” effects, demonstrates therapeutic value in a variety of internal diseases through both its anticoagulant and non-anticoagulant actions.

The Blood-Activating and Blood Stasis-Resolving Effects of Aspirin

Aspirin is an extremely widely used non-steroidal anti-inflammatory, antipyretic, and analgesic drug, and it also has antiplatelet aggregation effects. By inhibiting platelet aggregation and exerting anti-inflammatory actions, aspirin can improve blood circulation and reduce the risk of thrombosis, which aligns with the concept of “activating blood” in TCM. Aspirin has shown potential value in the treatment of various cancers, with the most substantial evidence for colorectal cancer. Aspirin can reduce the incidence of colorectal cancer by 29%.[39] Its mechanisms include directly affecting vascular endothelial growth factor receptors or mediating paracrine effects by inhibiting the synthesis of thromboxane (TXA2) through prostaglandin-endoperoxide synthase 1 (PTGS1) in platelets, as well as inhibiting the PTGS-mediated conversion of arachidonic acid into prostaglandin E2 (PGE2). Aspirin may also directly or indirectly suppress Wnt signaling by downregulating PGE2.[40]

Additionally, aspirin stimulates the production of endogenous anti-inflammatory regulators, such as lipoxins, thereby inhibiting inflammatory responses and reducing inflammatory markers such as C-reactive protein, TNF-α, IL-6, etc.[41] Studies have confirmed that aspirin is effective in treating various neuropsychiatric disorders. Mental illnesses can also lead to an increase in the secretion of β-thromboglobulin, platelet ATP, ADP, and increased release of serotonin, which reflects the correctness of the TCM theory of liver qi stagnation leading to blood stasis.[42]

The pharmacological effects of aspirin are in alignment with the TCM theory of “activating blood and resolving blood stasis” in terms of improving blood circulation, treating related diseases, and exerting anti-inflammatory effects.

Inspiration from Traditional Chinese Medicine's Blood Stasis Theory

The theory of blood stasis in TCM and modern medicine's research on hypercoagulable states exhibit profound mutual validation and complementarity in terms of pathological mechanisms, clinical manifestations, and treatment strategies. By comparing the basic concepts and pathological mechanism of blood stasis with a hypercoagulable state in detail, it becomes evident that there are commonalities between the two on multiple levels. The blood stasis theory not only provides a solid theoretical foundation for TCM's treatment of various diseases but also offers valuable perspectives for modern medicine in interpreting and addressing hypercoagulable states and related diseases.[9] For instance, the specific material basis of the relationship between TCM organs and blood stasis cannot yet be fully explained by modern medicine, which seems to guide future research directions in modern medicine. Additionally, hypercoagulable state and the early stages of thrombosis in tumor and autoimmune disease populations are often overlooked by clinicians, yet managing hypercoagulable state can have a significant impact.

Heparin and aspirin, as modern “blood-activating and blood stasis-resolving” drugs, align with the TCM concept of “when the flow is smooth, there is no pain; when there is pain, the flow is blocked.” Integrative medicine has demonstrated enormous potential in multidisciplinary research. For example, the application of heparin and aspirin in cancer treatment not only confirms their direct antitumor effects and improvement of survival but also suggests that they regulate the tumor microenvironment, inhibit tumor development and metastasis, and offer new ideas for cancer treatment. In research on autoimmune diseases, cardiovascular diseases, and neuropsychiatric disorders, the “blood-activating and blood stasis-resolving” effects of these drugs have also brought significant clinical benefits to patients. “Blood-activating and blood stasis-resolving” is an important therapeutic principle in TCM. With a wide range of medicinal herbs used to activate blood and resolve blood stasis, TCM offers foundation for the modern development of medicinal materials.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Yong Chen: Conceptualization, project administration, funding acquisition, and writing—review and editing. Yujie Zhang: Writing—original draft.

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Publication History

Received: 12 November 2024

Accepted: 20 January 2025

Article published online:
08 April 2025