Thrombosis is a pathological process in which, under certain conditions, an embolus is formed in a blood vessel by a component of the circulating blood, causing partial or complete blockage of the vessel and impairment of blood supply to the corresponding area. Acute clinical events caused by thrombosis include acute myocardial infarction, ischemic stroke, pulmonary embolism and disseminated intravascular coagulation (DIC), which are often life-threatening. The following will explain the mechanism of thrombosis and the progress of treatment respectively.
1.The formation process and classification of thrombus
Thrombus formation is the adhesion of platelets to the exposed collagen surface after endothelial injury, and the release of adenosine diphosphate (ADP) and thromboxane (TX) A2 from the adhering platelets to promote more platelet adhesion and aggregation to form platelet thrombus (thrombus head); endothelial injury activates the endogenous and exogenous coagulation system, forming fibrin precipitation between platelet trabeculae and a large number of red blood cells in the network between fibrin networks, forming the thrombus body and finally the thrombus body. The thrombus body is formed, and finally the local blood flow is stopped, the blood is coagulated, and the thrombus tail is formed. Depending on the location and thrombus components, thrombus can be divided into
(1) White thrombus: occurs at sites with fast blood flow (e.g. arteries, ventricles) and is mainly composed of platelets with relatively little fibrin and red blood cell content.
(2) Red thrombus: occurs after extremely slow or stopped blood flow and is composed of fibrin and red blood cells.
(3) Mixed thrombus: often manifests as a process of continuous thrombus formation. In mitral stenosis and atrial fibrillation, the thrombus formed in the left atrium is a mixed thrombus.
(4) Clear thrombus: mainly composed of fibrin, this thrombus occurs in small vessels of microcirculation and can only be seen under the microscope, so it is also called microthrombus. According to the type of vessels, it can be divided into arterial, venous and capillary thrombosis.
2.The specific mechanism of thrombus formation
(1) Arterial thrombosis
In arterial thrombosis, due to the high blood pressure and high flow rate of arteries, it is not easy for thrombin to accumulate to the effective concentration locally. Only when it adheres to the atherosclerotic plaque and gathers platelets to narrow the local arterial lumen, the thrombin accumulates to the effective concentration and transforms fibrinogen into fibrin, and the network blood cells form thrombus.
(2) Venous thrombosis
Venous thrombosis is due to blood hypercoagulation and stasis, so venous thrombosis is a mixed thrombus composed mainly of fibrin and blood cells. The hypercoagulable state of the blood is now also known as thrombophilia, and its causes can be classified as congenital or secondary. Congenital prone to thrombosis lacks antithrombin, protein C and protein S, and has features such as anti-activated protein C. Secondary hypercoagulation can be seen in malignancy, congenital heart disease, oral contraceptives, nephrotic syndrome and antiphospholipid antibody syndrome, etc. Long-term bed rest, post major surgery, obesity and varicose veins are also causative factors for venous thrombosis.
(3) Microvascular thrombosis
It is caused by the expression of tissue factor by microvascular endothelial cells or the appearance of procoagulant substances in blood circulation, such as DIC. It can also be caused by the activation of platelets to form aggregates, such as thrombotic thrombocytopenic violet scar, and heparin-induced thrombocytopenia, which forms transparent emboli in microvessels and leads to organ failure.
3.Coagulation and anticoagulation system
(1) Coagulation system
The coagulation system of the body includes two aspects of coagulation and anticoagulation, and the dynamic balance between them is the key to maintaining the flow of blood in the body and preventing blood loss in the normal body. The normal hemostasis (coagulation) of the body mainly depends on the intact blood vessel wall structure and function, the effective platelet quality and quantity, and the normal plasma coagulation factor activity. Among them, platelets and coagulation factors are important components of physiological hemostasis (coagulation). Tissue factor (tissuefactor, TF), or coagulation factor III (factor III), is the only coagulation factor that is not present in normal human plasma. It is present on vascular endothelial cells, monocytes, macrophages, and is abundant in brain, lung, and placenta. Inflammation, infection, endotoxin, and immune complexes can contribute to the synthesis and expression of tissue factor, which can be released into the plasma. In DIC, thrombophilia, endotoxemia, and malignancy, plasma tissue factor levels increase, reflecting the activation of the coagulation system. In other words, thrombus formation is a process in which the circulating TF continuously covers the surface of the thrombus, repeatedly initiating coagulation and eventually increasing the thrombus.
(2) Anticoagulation system
The anticoagulation system exists in the body, which negatively regulates the coagulation process. The most important anticoagulant system in human body includes: Tissue factor pathway inhibitor (TFPI), which belongs to Kunitz type serine protease inhibitor family of proteins, and is divided into Tissue factor pathway inhibitor-1 (TFPI-1) and Tissue factor pathway inhibitor-2 (TFPI-2). TFPI-1 has 276 amino acids and is composed of an N-terminal, three repeating Kunitz domains (K1, K2 and K3) and a c-terminal. Studies have shown that the Kl structural domain of TFPI-1 binds to factor VIIa, the K2 structural domain binds to factor (Xa), and the K3 structural domain has no direct protease inhibitory function, but it and the c-terminus are required for heparin and cell surface binding. the K2 structural domain of TFPI-1 binds to factor Xa, forming the TFPI-Xa complex; the TFPI-1K1 structural domain interacts with factor VII a interacts with factor VIIa to form the TF-FVIIa-TFPI-Xa tetramer, which interrupts the exogenous coagulation pathway cascade [3]. Golino et al. showed that transfection of arterial endothelial cells with reverse transcribed DNA (cDNA) of the TFPI gene effectively prevented intravascular thrombosis, suggesting that TFPI has a good therapeutic effect on thrombotic diseases. In recent years, the application of recombinant TFPI (rTFPI) treatment was found to reduce thrombosis, and good results were also obtained in phase II clinical trials of rTFPI for sepsis.
Tissue factor pathway inhibitor-2 (TFPI-2), also known as placentaprotein-5 (PP5) or matrix-associated serine protease inhibitor (MSPI), is a serine protease inhibitor with a relative molecular mass of 32,000 and is synthesized by cells of the vascular system (endothelial cells, smooth muscle cells, fibroblasts). TFPI-2 is a broad-spectrum serine protease inhibitor that effectively inhibits the activities of matrix metalloproteinases (MMP), fibrinolytic enzymes, trypsin, chymotrypsin, histoproteinases and other protein hydrolases, and plays an important role in maintaining the structural integrity of the extracellular matrix (ECM) and inhibiting tumor cell infiltration and metastasis. 2 gene is widely distributed and highly expressed in normal tissues such as human liver, kidney, heart and skeletal muscle, while its expression is reduced in tumor tissues. This is because the activation of oncogenes down-regulates the expression of TFPI-2.
The anticoagulant effect of TFPI-2: TFPI-2 reduces thrombin production by binding and inactivating the TF/VIIa complex and also inhibits factor Xa, and these effects can be greatly enhanced by heparin; TFPI-2 indirectly inhibits matrix metalloproteinases (MMPs) by inhibiting fibrinolytic enzymes. In turn, MMPs are involved in degrading ECM, promoting the process of atherosclerotic plaque destabilization and tending to rupture. tFPI-2 also has a protective effect against atherosclerosis. In addition to endothelial cells expressing TFPI2, in atherosclerotic tissues, TFPI-2 is also expressed in macrophages, T lymphocytes and smooth muscle cells. Apparently, TFPI-2 has a protective effect on atherosclerotic plaques.
Antithrombin III is a serine proteaseinhibitor in plasma. The active centers of factors IIa, VII, IXa, Xa, and Ⅻa all contain serine residues and all belong to serine protease (serineprotease). The arginine residues on the antithrombin III molecule can bind to the serine residues in the active centers of these enzymes, thus “closing” the active centers of these enzymes and making them inactive. In the blood, each molecule of antithrombin III can bind to one molecule of thrombin to form a complex, thereby inactivating the enzyme. Protein C system is another important physiological anticoagulant in the body, with a molecular weight of 62,000, which is synthesized by the liver and depends on the presence of vitamin K. Protein C is present in plasma in the form of zymogens and is activated by the binding of thrombin to thrombin regulatory proteins to become activated protein C (APC). Activated protein C has multiple anticoagulant and antithrombotic functions, the main effects include: inactivation of coagulation factors V and VIII, restriction of factor Χa binding to platelets, and enhancement of fibrinolysis.
4.Progress in thrombosis treatment
The aim of thrombotic disease prevention and treatment is to improve the hypercoagulable state, re-evacuate or reconstruct blood flow pathways to prevent tissue ischemia and necrosis. In developing antithrombotic treatment strategies, attention should first be paid to whether the site of involvement is the venous or arterial circulatory system; the extent and location of vascular involvement; the expansion of thrombosis, the risk of embolism or recurrence; and the relative advantages and disadvantages of antithrombotic therapy versus bleeding. Arterial thrombosis treatment focuses on antiplatelet therapy, and the application of antiplatelet agents such as aspirin and clopidogrel can reduce the occurrence of arterial thrombosis; whereas venous thrombosis is mainly caused by blood stasis and hypercoagulation, so activity should be increased and anticoagulants such as warfarin and heparin should be used, and attention should be paid to the presence of easy embolism. Since the thrombosis is transformed from fibrin to connective tissue with time, the earlier the thrombolytic drugs are used, the better.
(1) Anti-platelet agents
Antiplatelet agents can inhibit platelet adhesion and aggregation, thus producing an antithrombotic effect. According to their mechanism of action, they are divided into two categories: platelet metabolism inhibitors and platelet membrane glycoprotein (GP) IIb/IIIa receptor antagonists. Clinically used antiplatelet agents include aspirin, clopidogrel, and glycoprotein (GP) IIb/IIIa receptor inhibitors, which are by far the most potent class of antiplatelet agents, such as abciximab, etefibatide, and tirofiban. Cilostazol, a phosphodiesterase III inhibitor, inhibits platelet aggregation and vasodilatation by inhibiting phosphodiesterase activity and blocking cAMP degradation, preventing thrombosis and vascular obstruction.
(2) Anticoagulant
The treatment of venous thrombosis is mainly based on anticoagulants. Anticoagulants include heparin, low molecular heparin, warfarin, hirudin (direct inhibitor of thrombin), recombinant hirudin, dermatan sulfate, fondaparinuxsodium and Ximelagatran. Among them, recombinant hirudin, fondaparinux sodium and Ximelagatran are new anticoagulants developed in recent years. In vivo, fondaparinux selectively binds to the pentosan binding site on antithrombin III (ATIII), causing an irreversible change in the conformation of ATIII and a 300-fold increase in its anti-Factor Xa activity. Ximelagatran is a precursor drug that binds directly to the active site of thrombin and produces an inhibitory effect, and is rapidly converted to Melagatran after absorption in the small intestine, which binds to thrombin and prevents the conversion of fibrinogen into fibrin. The predictability of Ximelagatran anticoagulant response is good, and coagulation monitoring is not required.
(3) Thrombolytic agents
Thrombolytic agents can recanalize blood vessels by intravenous infusion or topical catheter administration. Its effect is to convert fibrinogen into fibrinolytic enzymes, which dissolve the formed fibrin in the thrombus, which is more direct and effective than anticoagulation. It is best used within 1 to 2 days of thrombosis. The clinical drugs used are streptokinase (SK), urokinase (UK), and tissue-type fibrinogen activator (t-PA). Third-generation thrombolytic agents: The advantages of these drugs allow for faster and more specific titration. These include: ralteplase, monteplase, tenecteplase, etc. There are also newly developed thrombolytic agents: Ankyrase, which was marketed in the UK in 1999, can reduce blood viscosity; DSPA-α1 is a natural thrombolytic agent with the same thrombolytic capacity as t-PA but with higher fibrin specificity, and is currently in phase II clinical trials.