I. Mechanism of action Warfarin (coumadin) prevents the circulating application of vitamin K by inhibiting hepatic epoxide reductase, which prevents the inactive oxidized (epoxide type) vitamin K from being reduced to the active reduced (hydroquinone type) vitamin K. It interferes with the carboxylation of vitamin K-dependent coagulation factors II, VII, IX and X, so that these coagulation factors cannot be activated and remain only in the precursor phase ( antigenic, inactive), and achieve the purpose of anticoagulation. II. Pharmacodynamics and pharmacokinetics Warfarin has good oral bioavailability, predictable onset and duration of action, and in healthy individuals, the blood concentration peaks after 90 minutes of oral administration. The half-life of warfarin in achromosomes is 36-42 hours, and it is mainly bound to albumin in plasma. Fetal blood concentrations were close to maternal values, but warfarin was not found in human breast milk. Warfarin is almost completely cleared by metabolism and the metabolites have a weak anticoagulant effect. Warfarin is excreted mainly by the kidneys, rarely into the bile, and only a very small amount is excreted in the urine as a prototype, so there is no need to adjust the warfarin dose in patients with renal insufficiency. The dose-response relationship of warfarin is highly variable and is influenced by many factors and therefore needs to be monitored closely. Anticoagulation generally occurs within 24 hours of administration, but the peak anticoagulant effect may extend up to 72-96 hours; therefore, warfarin alone should not be used in acute antithrombotic situations. Heparin or low-molecular heparin should be used first for acute antithrombosis, and the heparinoids should be discontinued only after at least 4 days of crossover (maintaining INR above therapeutic range for more than two days) so that warfarin can achieve effective antithrombotic levels after stopping heparin. Warfarin must be monitored to adjust the dose by the International Normalized Ratio (INR), where INR=PTRISI, where ISI is the International Sensitivity Index, representing the procoagulant activity (sensitivity) of prothrombin, and PTR is the ratio of the subject’s PT to normal plasma PT. The antithrombotic effect of warfarin depends on the decrease of prothrombin (II), which has a half-life of about 72 hours. Due to the short half-life of factor VII and protein C (6-8 hours), the levels of factor VII and protein C drop quickly after the application of warfarin, and the PT (INR) measured early after the administration of the drug mainly reflects the level of plasma factor VII, which at this time does not reflect the true antithrombotic level in the body. In other words, even if the INR reaches the target range, the antithrombotic effect of warfarin has not yet reached the standard because the level of factor II has not yet been reduced to the effective level. （The initial dose of warfarin for Chinese is recommended to be 3 mg; elderly people older than 75 years old and patients at high risk of bleeding should start with 2 mg orally once a day, with a target INR of 2.O to 3.0 depending on the condition. The initial shock dose is not recommended. If the INR is below 1.5, the dose should be increased by 0.5 mg/d; if the INR is above 1.5, the dose can be temporarily not increased and wait for the result of INR measurement after 7 days; if the INR does not change much compared with the basal level, the dose can be increased by 1 mg/d. Our observation proves that the starting dose of 2 mg is too small, which will increase the time needed to reach the standard and increase the number of INR determinations. If the INR value is too high or too low, or if the warfarin dose is changed for some reason, the next INR should be determined according to the INR value and dose adjustment. time to observe INR. Dose adjustment should be based on the INR value, with each increase or decrease in the amount of O.5-1 mg/d. Before each dose adjustment, the reason for the change in INR should be carefully sought and reference should be made to INR values measured over a previous period of time. If the INR has been stable in the past and there is an occasional increase in INR, the dose can be temporarily left unadjusted and the INR rechecked after 3-7 days as long as the INR does not exceed 3.5-4.0. INR measurement should also not be done too often. Many factors, including travel, diet, environment, physical condition, having other diseases and medication use, can cause changes in the INR. When factors affecting the response to medication are present, such as aspirin for patients with colds, discontinuation of medication for any reason or irregular medication, additional INR should be done several times so that the medication dose can be adjusted in a timely manner to maintain the INR within the target range of treatment. (ii) Some factors affecting INR Certain drugs can affect the pharmacokinetics of warfarin by inhibiting the synthesis of vitamin K-dependent coagulation factors, increasing metabolic clearance, and interfering with other hemostatic pathways. Fluctuations in the uptake and absorption of vitamin K in food affect the efficacy of warfarin. Hepatic insufficiency impairs vitamin K-dependent clotting factor synthesis and enhances the response to warfarin. Hypermetabolic states such as hyperthyroidism increase the metabolism of clotting factors and enhance the efficacy of warfarin. Vitamin K antagonizes the anticoagulant effect of warfarin, thereby reducing the anticoagulant effect. In order to maintain the stable anticoagulant strength of warfarin, it is necessary for patients to maintain a relatively balanced diet, especially a relatively balanced intake of vitamin K-rich green vegetables. 1. Disease factors Endogenous factors such as disease directly contribute to the hypercoagulable or hypocoagulable state of the blood, which in turn has possible antagonistic or synergistic effects with warfarin. Table l lists some of the diseases that enhance and diminish the anticoagulant effect of warfarin. (c) Prevention of adverse reactions to bleeding should be done by: 1) careful history taking, thorough physical examination and corresponding physical and laboratory tests to find and pay attention to the high-risk factors causing bleeding; 2) monitoring INR as required and adjusting the dose of medication according to INR; 3) strengthening training of medical staff on medication use and monitoring. Strengthen the responsibility and service level of medical staff, register and regularly follow up each patient taking medication and treatment. Antithrombotic treatment should preferably be in the specialized outpatient clinic for antithrombotic treatment, where patients are uniformly treated, managed and followed up by specialized doctors; 4. Provide patients with manuals about medication and monitoring, initial treatment advice for bleeding and other adverse reactions and communication links between patients and the responsible doctors. 5.Strengthen the publicity and education for patients and their families to improve patients’ compliance with medication and avoid taking the wrong medication, misuse and omission; 6.Inform patients in detail about the precautions of medication, notify or consult the responsible physician promptly in case of obvious changes in diet or environment, illness, medication or discontinuation of a certain medication, travel, accidental injury, etc., and follow medical advice to consult and arrange medical treatment in a timely manner; 7.Educate patients in daily life to avoid trauma and other factors that cause bleeding, such as skin incisions caused by shaving; 8. In case of serious bleeding complications or bleeding that cannot be easily stopped, patients should contact their own physician or go to the hospital for timely medical treatment. In patients at high risk of thrombosis, the ratio of benefit (reduction of embolism) to risk (severe bleeding) after taking the drug should be evaluated in a comprehensive manner. It should be clear that thromboembolism and bleeding events (except cerebral hemorrhage) are not of equal importance, and mild to moderate bleeding should cause less harm to the patient overall than thromboembolism. Not all bleeding should result in a reduction in warfarin dose or discontinuation, and the timing of discontinuation should be weighed against the benefits and risks. IV. Surgery in patients on long-term oral anticoagulation If the patient is undergoing elective or emergency surgery, the INR should be reduced to 1.0 to 1.5 levels at the time of surgery if possible. Dearon et al. found that it takes about 4 days to discontinue warfarin until the INR is 1.5, and the INR can reach 2.0 after 3 days of resuming medication. if anticoagulants are discontinued 4 days before surgery and resumed the same day after surgery, there will be at least 4 days of high risk for thrombosis in the perioperative period. Four management options are available before surgery: first, stop warfarin for 4-5 days preoperatively and resume postoperatively with low-dose heparin (5000 U subcutaneously); second, stop warfarin for 4-5 days preoperatively and replace it with preoperative low-dose heparin 5000 U subcutaneously or a prophylactic dose of low-molecular heparin, and postoperatively with low-dose heparin (or low-molecular heparin) and warfarin; third, stop warfarin 4-5 days preoperatively and replace it with full-dose heparin or low-molecular heparin, or in the case of intravenous heparin, stop it 5 hours preoperatively; fourth, start reducing the warfarin dose to INR 1.3-1.5, 4-5 days preoperatively Warfarin is resumed postoperatively and may be supplemented with low-dose heparin. The management of pre- and postoperative anticoagulation is based on the patient’s risk of thromboembolism. In patients with chronic atrial fibrillation, the risk of thromboembolism is low, and a period of preoperative warfarin discontinuation is acceptable; in patients with mechanical valve replacement and combined atrial fibrillation, the patient is not allowed to have an anticoagulation “vacuum” and must be supplemented with low molecular heparin (heparin). In elective noncardiac surgery in patients with mechanical valve replacement, warfarin is discontinued 5 days prior to surgery and low molecular heparin is used until the early morning of the day of surgery, and low molecular heparin is resumed on the evening of the surgery, along with oral warfarin, and low molecular heparin is discontinued after the target INR is achieved. Emergency surgical anesthesia in patients being treated with warfarin is very controversial, and some have reported 950 patients being treated with oral anticoagulants and regional blocks up to 1000 times, with no problems as a result; Wu reported 180 patients being treated with oral anticoagulants and receiving epidural or lumbar anesthesia, again without any complications, but most scholars have reservations, as the consequences would be very detrimental. The administration of the warfarin antagonist vitamin K1 intravenously may be considered in patients who are expected to be anesthetized and operated on. After intravenous administration of vitamin K1, the prothrombin time or INR decreases significantly within 6-8 hours and is not corrected until 12-24 hours, so the INR or prothrombin time should be monitored again before anesthesia. The use of vitamin K1 to antagonize the effects of warfarin should be accompanied by the application of low-molecular heparin in patients with a high thrombotic group. Unless there is a clear and indisputable advantage of intralesional anesthesia over general anesthesia for a particular patient, the possibility of medically induced intralesional hemorrhage should be avoided for safety reasons and general anesthesia should be used. When warfarin administration is resumed after surgery, low-dose intravenous or subcutaneous heparin should be added at the same time for at least 4-5 days, because it takes 3-7 days for the anticoagulant effect to appear after oral administration of warfarin, and the dose of oral anticoagulants should be adjusted by monitoring the INR.