Just anticoagulate, don't bleed ! It's all in the genes.

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Atherosclerosis, the buildup of cholesterol and fatty substances in the lining of the arteries, raises the risk of blood clots (clumps in the blood vessels, usually made up of cholesterol, fats, fibrous material, and clotted blood).

Studies have shown that atherosclerosis occurs in about 30% of adults over the age of 30, and in more than half of those over the age of 40. This means that a significant number of adults are at risk of thrombosis at any time. When a thrombus is present in a deep vein, it can cause a deep vein thrombosis (deep vein thrombosis, DVT); when a thrombus is formed in the lungs, it can cause a pulmonary embolism (pulmonary emboli *** , PE); and when a thrombus is present in the cerebral vasculature or the coronary arteries, it can lead to stroke and myocardial infarction, respectively. and myocardial infarction, respectively. Thrombophilia is a generalized term for a body that is prone to developing blood clots, which may be caused by congenital genetic variations, or by changes in clotting mechanisms that occur later in life as a result of surgery, cancer, pregnancy, or the use of specific medications, or by the interaction of both congenital and acquired factors [Note 1]. The mechanisms that cause congenital thrombophilia include [Note 2, 3]:

I. Overactivation of active factors that promote coagulation, for example, mutation of the G1691A gene in the fifth coagulation factor (the mutated gene produces a protein called factor V Leiden), which is essential for the activation of protein C (also called factor XIV, which is an important anticoagulant), and for the activation of protein C (also called factor XIV, which is an important anticoagulant). factor XIV, an important anticoagulant factor. Prothrombin has a mutation in the G20210A gene.

Both of these mutations occur mainly in Western populations.

II. Deficiencies in the anticoagulant system, e.g., protein C deficiency. Protein S (which assists protein C in anticoagulation) deficiency. antithrombin deficiency.

These three deficiencies are the main culprits for congenital thrombophilia in Asian populations.

Thrombosis prevention is an overkill

Thrombosis is one of the top 10 leading causes of cardiovascular and cerebrovascular deaths worldwide, and is associated with significant healthcare expenditures and caregiving burdens. To prevent thrombosis, antithrombotic drugs are used by millions of patients each year. The mechanism of action of antithrombotic drugs currently used in clinical practice is categorized as either antiplatelet or anticoagulant drugs [Note 4]. Platelets are an important part of the thrombus development process, therefore, all active factors or receptors involved in platelet attachment, activation, aggregation, and finally thrombus formation can theoretically be used as the therapeutic targets of antiplatelet drugs. Anti-coagulant drugs, which act on the endogenous and exogenous pathways of the coagulation system, as well as thrombin, are also common therapeutic choices. However, even with the newer oral anticoagulants (NOACs), the feared side effect of bleeding can still occur. Imagine if the body's clotting mechanism is suppressed to reduce the formation of blood clots, and if internal blood vessels leak or bleed due to external forces or aging, the suppressed clotting mechanism may not be able to be controlled in a timely manner, and problems such as gastrointestinal hemorrhage, internal bleeding, or hemorrhagic stroke may occur. It is difficult for current antithrombotic drugs to achieve the ideal balance of preventing blood clots without causing bleeding at the same time. However, if you can selectively block one of the pathways in the clotting chain, you may be able to inhibit clotting without causing bleeding.

Genetic studies help identify appropriate antithrombotic sites

Genetic and molecular biology studies have shown that the endogenous coagulation pathway is less important for hemostasis than the exogenous pathway and the ****analogous pathway. In addition, studies have shown that the endogenous pathway has an important protein, Factor XI, which, if defective, can help reduce venous thrombosis and stroke if the gene is defective so that the expression or function of the protein is limited.

Various animal studies have shown that antibodies, small molecules, or antisense inhibitors that act on Factor XI are effective in combating thrombosis, and that knocking out the Factor XI gene in mice has been found to help combat arterial embolism [Note 5, 6]. What's more, lack of Factor XI did not appear to increase the risk of bleeding, so the researchers hypothesized that inhibiting Factor XI effectively might actually prevent thrombosis, but at a lower risk of bleeding than traditional antithrombotic drugs.

Anti-clotting without bleeding - a dream come true

UCSF and Pfizer recently announced a new human IgG1 antibody, DEF, that selectively binds to the active region of activated Factor XI without affecting the Factor XI zymogen. DEF selectively binds to the active region of activated Factor XI, but does not affect the zymogen of Factor XI or other coagulation proteases [Note 7]. Since DEF acts only after activation of the Factor XI coagulation system and does not destroy zymogen, there is no need to calculate the dosage of DEF with special regard to the time of coagulation factor synthesis. Animal studies have shown that DEF is effective in inhibiting blood clotting and preventing arterial blockage and venous embolism, but does not cause bleeding. However, as a precaution, the research team has developed a second antibody, revC4, which can rapidly reverse the activity of DEF and restore normal clotting in emergency situations. These results show that the use of Factor XI in antithrombotic drugs is worth exploring, and the results of the animal studies raise the expectation that the development of DEF, other similar anti-Factor XI drugs, and the reversal agent revC4 will improve the current limitations of antithrombotic therapy and achieve safer and more effective therapeutic qualities.

References: 1. Rosendaal FR. Lancet 1999; 353:1167-73. 2. De Stefano V et al. Blood 1996; 87:3531-44. 3. Seligsohn U et al. N Engl J Med 2001; 344:1222-31. 4. 2001; 344:1222-31. 4. Mega JL et al. Lancet. 2015; 386:281-91. 5. Gailani D et al. J Thromb Haemost 2015; 13:1383-95. 6. Müller F et al. Curr Opin Hematol 2011; 18:349-55. 7. David T et al. Sci Transl Med 2016; 8:353ra112.

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Topics: Genetic Research, Cholesterol