Warfarin is a very important drug that is often applied after cardiac surgery. The proper use of this drug is extremely closely related to whether the treatment of the disease achieves its ultimate goal (prolonging life expectancy and improving quality of life). Below, common questions about anticoagulation therapy with warfarin are answered one by one in layman’s terms as concisely as possible based on my own knowledge and experience. What is warfarin? In the 1920s, livestock farmers in North America discovered that some livestock would get a bleeding disorder. The disease seemed to be epidemic, and affected livestock would die from minor traumatic injuries that bled profusely or from internal bleeding. In 1929, it was discovered that the diseased animals were bleeding more than once because of thrombin dysfunction, and in 1940, the substance was purified, tested for chemical structure, and synthesized as coumarin. The molecular structure of coumarin was similar to that of vitamin K, and it was able to compete with vitamin K and interfere with the latter’s role in the synthesis of clotting factors in the liver. 1948 saw the use of this drug as a rodenticide, and in 1948, warfarin (chemically known as benzylacetone coumarin, a derivative of coumarin) was synthesized. The drug was approved by the U.S. Federal Food and Drug Administration in 1954 for use in humans. In 1953, Stalin, the leader of the Soviet Union, died after a long illness. Based on the symptoms of bleeding prior to his death, U.S. intelligence agencies believe that Beria and Khrushchev may have poisoned Stalin with warfarin. Pure warfarin is a white, odorless powder that is ideal for poisoning, and was used to anticoagulate U.S. President Dwight D. Eisenhower, who suffered an acute myocardial infarction in 1955. Why warfarin anticoagulation therapy? Warfarin is used to prevent the formation of blood clots in the body because of its anticoagulant effect. Under normal conditions, blood flows smoothly and continuously through the heart and blood vessels, and everywhere it touches is covered by a layer of endothelial cells. There is no direct contact between blood and extravascular tissue, no direct contact between blood and foreign bodies, and no obstruction or stagnation of blood flow. When any of these three “no’s” occur, the clotting process is activated and a thrombus is formed. After cardiovascular surgery, direct contact of a foreign body with the blood, trauma, exposure of tissue without endothelial cell coverage in the lumen of the vessel or in the heart, atrial fibrillation or ventricular wall tumors resulting in slow or even stagnant local blood flow can lead to thrombosis in the heart or blood vessels. In addition, a hypercoagulable state of the blood due to physical causes or surgical stimulation can also lead to thrombosis. Common conditions requiring warfarin treatment include: implantation of mechanical heart valves, atrial fibrillation, deep vein thrombosis, pulmonary artery embolism, implantation of artificial vessels in the venous system (e.g. total vena cava-pulmonary artery anastomosis), implantation of artificial vessels in peripheral arteries, myocardial infarction combined with large ventricular wall tumors with intraventricular thrombosis, and antiphospholipid antibody syndrome. At Fulbright Hospital, warfarin is applied most often in patients after valve surgery. Patients with persistent atrial fibrillation. Anticoagulation with aspirin alone is less effective than with warfarin. If the patient also has a prosthetic heart valve, warfarin anticoagulation should be used regardless of whether it is a bioprosthetic valve or not. How can I check the strength of warfarin therapy? The history of warfarin shows that its anticoagulant therapy is a double-edged sword; used well, it can effectively prevent thrombosis, used poorly, either the thrombus still forms or it triggers fatal bleeding. The anticoagulant strength of warfarin can be measured by an indicator known as Prothrombin Time (PT). There are 3 ways to report PT in the laboratory: Prothrombin Time in seconds, Prothrombin Time Activity Percentage (PTA) in percent, and International Normalized Ratio (INR). The INR is now referred to in anticoagulation therapy for the prevention of thrombosis after cardiac surgery, and it eliminates the variation in the activity of different batches of tests. This test is not complicated and is one of the basic clinical tests in hospitals, and should be available in any hospital that can perform surgery. As for the accuracy of the value of the test, it is not easy to evaluate. Generally speaking, the more this test is performed in a hospital every day, the more standardized and experienced the laboratory technician should be, and the smaller the error of the test value. This test does not require fasting before the blood is drawn, and eating has no effect on the test results. What is the appropriate anticoagulation level for me? This is a question that is asked by almost all patients taking warfarin. Answer: It varies from person to person. There is only one criterion for anticoagulation therapy, which is to minimize the risk of bleeding while ensuring that no thrombosis occurs. The likelihood of thrombosis varies from patient to patient. Patients with mechanical prosthetic heart valves are more likely to thrombose than patients with pure atrial fibrillation without valve disease; the incidence of thrombosis is higher with mechanical valves in the mitral position than in the aortic position. The degree of anticoagulation in the event of thrombosis and hemorrhage may also be different in different patients. Compared to whites and blacks, Asians are less likely to have thrombosis at lower levels of anticoagulation and more likely to have bleeding at slightly higher levels of anticoagulation. Therefore, the appropriate anticoagulation value depends first on the target of anticoagulation therapy. The American Heart Association, in its guidelines for the surgical management of valve disease, recommends that the INR be maintained at 2.0-3.0 in patients with bileaflet or Medtronic-Hall tilting disc valves in the aortic position and at 2.5-3.5 in patients with other tilting disc valves or ball cage valves (older valves that have long been unused in this country.) All patients with mechanical valves in the mitral position Patients with mechanical valves in the aortic position should also have an INR of 2.5-3.5 if they have high-risk factors, such as a history of thrombosis, atrial fibrillation, hypercoagulability, or left ventricular dysfunction. The situation is different domestically. Doctors found that the incidence of bleeding complications was high in patients when the above criteria were used, while the incidence of thrombosis did not increase when they were slightly lower; more bleeding than thrombosis were complications of anticoagulation in the Chinese. Japanese and Taiwanese physicians have also found a significantly higher incidence of bleeding in their own patients (of the same ethnicity as the Chinese) when anticoagulation is administered at the recommended values of the American Heart Association. Based on my personal knowledge and experience, the following is recommended for warfarin anticoagulation in cardiac surgery-related patients: except for patients from Xinjiang minorities with distinctly white features (e.g., Kazakhs, Uyghurs, etc.), Chinese with prosthetic mechanical valves should maintain an INR of 1.8-2.3 for simple aortic valves; for simple mitral valves or aortic valves plus mitral valves, the INR should Patients with a bioprosthetic valve with atrial fibrillation or without valvular disease with atrial fibrillation alone should maintain an INR of 1.8-2.3. Patients without atrial fibrillation with a bioprosthetic valve or with a valvuloplasty ring implanted in the mitral or tricuspid position must be treated with warfarin anticoagulation within 6 months after the procedure, and the INR should be maintained at 1.8-2.5. Patients who undergo total cavopulmonary anastomosis should be treated with warfarin anticoagulation for the first three months after surgery and should maintain an INR of 1.8-2.3. For Xinjiang minority, white, and black patients, anticoagulation criteria should refer to the relevant guidelines of the American Heart Association. There are now such websites abroad (e.g., www.warfarindosing.org) that can help patients calculate warfarin doses. Of course, it relies on a large amount of statistics from Europe and the United States, and the calculated results are based on their anticoagulation intensity, which is not adapted to us Chinese. However, from this online calculator, you can see which factors should be taken into account in the warfarin dose calculation and how much weight is given to each factor. We should have something similar for the Chinese ourselves, but we don’t have it yet. These are the things that we medical professionals should try to do. How should patients do their own anticoagulation therapy? Patients who require warfarin anticoagulation are started on oral warfarin with an initial dose of 5-6 mg as soon as the tracheal tube is removed after surgery and they are able to drink. from then until discharge, the patient’s blood is drawn daily during the postoperative recovery period to check the INR and the doctor adjusts the warfarin dosage according to the daily test results in order to achieve the desired anticoagulation strength as early as possible and to bring the warfarin dosage to A relatively stable level of warfarin dose is achieved before the patient is discharged. The INR values and daily warfarin doses during this period are recorded on an anticoagulation record. This record is given to the patient at the time of discharge and serves as an important reference for future anticoagulation therapy. So, don’t forget to take this record sheet when you are discharged from the hospital. Once discharged, the patient will need to start taking the medication on his or her own according to the warfarin dose a day or two before discharge. We recommend that patients take their medication at night every day on a regular basis. There are two advantages to doing this. One is that the INR is checked in the morning and the results may be available by noon, so you may have to consult with your doctor if you have questions, and it is possible that the final decision on the dose will be made by afternoon. If you take the medication in the morning or morning, the dose is not appropriate, but has been taken, can only be adjusted the next day, inconvenient. Secondly, if you take the medication at a fixed time, you will develop a habit in the long run and will not miss a dose. When you are in the hospital, INR is checked every day, and when you are discharged from the hospital, the ward doctor will give the patient 3 lab sheets. These 3 lab sheets are to facilitate the patient’s post-operative review. Patients can also go to the hospital’s simple outpatient clinic to have their labs ordered. After discharge from the hospital, laboratory tests are usually performed once every 2-3 days. That anticoagulation record sheet from the discharge should come into play at this time. The patient should record the daily warfarin dose and the results of each INR on that anticoagulation sheet. If the INR is within the appropriate range, maintain the current dose; if it is out of range, the medication needs to be adjusted. Generally, warfarin is increased or decreased by 1/4 tablet, and it is rare to need to increase or decrease by half or one tablet per day. An important dose adjustment tip is to pay attention to the trend of INR changes. If the assay value continues to rise or fall, the dose should be adjusted even though it is still in the desired range. If the INR value is greater than 3.0, the dose must be stopped the same day and the assay continued the next day. A rule of thumb is that if the INR value differs significantly from the target value, be sure to test daily on subsequent days until your INR test value is at the required anticoagulation strength. It is important to emphasize that the “normal range” (usually 0.8-1.2) on the test sheet is the normal value for people who are not taking anticoagulant medication, not the normal value after taking medication. The anticoagulation strength that should be achieved after taking the medication (as I have clearly explained above) is the “normal value” for patients taking the medication. After being discharged from the hospital and living in the vicinity of the hospital for a week or so, the patient can return home after 3 laboratory tests, when the INR value has stabilized, the warfarin dose has been roughly fixed, and the anticoagulation therapy and blood tests have been basically mastered, so there is no need to consult with the surgeon or ward doctor anymore. After returning home, it is usually necessary to have weekly laboratory tests, and if after one month, the laboratory values are stable and the warfarin dose does not need to change much, then it is possible to have biweekly laboratory tests. If the INR and warfarin dose remain stable after an extended interval of testing, then monthly testing is acceptable. We strongly recommend that patients have monthly tests and strongly criticize those who only have tests once every six months or even once a year. That is irresponsible to life, no matter who the life belongs to. There are three types of commercial warfarin available in China. The most widely used is the domestic warfarin, white sugar-coated tablets, each tablet 2.5 mg. Its advantages are stable sources, low prices (80 tablets per box, 20 yuan), the disadvantage is the accurate division of the difficulties, the drug is once a little worse. The second type is the imported Warfarin from Orion, Finland. This brand is available in a variety of doses, with the blue 3 mg tablets currently on the Chinese market. The advantages of this drug are that it is easy to be divided accurately and the homogeneity of the drug is good, but the disadvantages are that the source is unstable, it is not available in many cities in China, and the price is slightly higher (100 tablets per box, 50 yuan). The third is the American-made Coumadin. The advantage of this drug is that there are 9 dosage forms from 1 mg per tablet to 10 mg per tablet, and the color is different, so it is easy to distinguish and adjust the dose. The disadvantage is that it is expensive and rarely available in China. If a patient is taking a particular type of warfarin, it is best not to change it easily. Changing medications may result in large changes in anticoagulation strength, and anticoagulation complications due to medication changes are not uncommon in clinical practice. If a switch is necessary, the INR should be tested daily for one to two weeks after the switch until the values are in the therapeutic range and the warfarin dose is stable. What if I miss a dose of warfarin? It does not matter. Simply take the missed dose of warfarin the next day along with the regular dose for that day. Of course, if the missed dose is missed for several days, it must be treated as if the dose was restarted after discontinuation. In addition to increasing the dose for the first few days as appropriate, the most important thing is to review the INR immediately and daily for the next few days until the INR reaches the appropriate range. In fact, buy a divider box with Monday to Sunday marked on it, divide the warfarin for a week, and check the previous day’s box for any leftover medication each day when you take the medication, so that you do not miss a dose. What should I do if I have a warfarin overdose? Symptoms of a warfarin overdose are a variety of bleeding manifestations. Symptoms of bleeding, such as continuous bleeding from a wound, vomiting blood, tarry stools, muscle hematomas, bruising under the skin, hemiplegia or coma, should be seen immediately regardless of the INR value. The management of warfarin overdose is a matter for the physician, and all the patient or family has to do is to inform the physician of the purpose of warfarin therapy and the recent dosing of the patient. Generally, if the INR is below 4.0, if there is no bleeding, simply stop the medication and test the INR daily. Also, intravenous vitamin K1 can neutralize the anticoagulant effect of warfarin. It is important to remember that the higher the dose of vitamin K1 used, the more vitamin K1 will be stored in the patient’s body and the more difficult it will be to achieve therapeutic intensity with re-anticoagulation, which the patient will need after the bleeding is controlled. It is generally recommended that the dose of vitamin K1 should not exceed 10 mg. What factors can alter the anticoagulant effect of warfarin? First, the amount of the drug is influenced by the patient’s height and weight. To maintain the same anticoagulant strength, patients who are heavier will generally require more warfarin maintenance dose than those who are smaller. Some patients with improved cardiac function, increased appetite and reduced consumption after surgery start to gain weight gradually within one or two months after surgery, and plasma albumin concentration also increases significantly, so it is important to check INR and adjust the warfarin dose that needs to be increased due to weight gain. The second major factor is the difference in the metabolism of warfarin in humans, which, to put it plainly, means that people have different sensitivity to warfarin. As we mentioned above, there is a large difference in the intensity of warfarin anticoagulation between whites and our yellow counterparts. There are two important enzymes in the drug action of warfarin (VKORC1 and CYP29C), and different genetic types and combinations of types can lead to significant differences in the sensitivity and metabolic rate of warfarin, which in turn can lead to differences in the maintenance dose of warfarin and the target anticoagulation strength of patients. Testing of patients for the relevant genotypes is currently being performed on a small scale at Fu Wai Hospital, which will be very helpful in pre-screening those patients who are extremely sensitive and insensitive to warfarin. Food can have an impact on the effect of warfarin anticoagulation therapy. In reducing the anticoagulant effect of warfarin, food acts mainly through the vitamin K it contains. There are two sources of vitamin K in the body, the primary one being food sources (chlorophyll quinone) and the secondary one being produced by bacteria in the human intestine (menaquinone). Eating large amounts of vitamin K-rich foods will certainly affect the efficacy of warfarin, which is a vitamin K antagonist. I have not listed those vitamin K-rich foods here because they are inevitable and consumed daily in your daily life, and your maintenance dose of warfarin already includes a dose of these vitamin K. The key to the problem is to keep the variety of foods constant; you can’t eat a lot of fruits and vegetables one period of time and then eat a lot of fish and meat every day the next. Green vegetables and fruits in general people consume every day, but we should be careful about fruits and vegetables that we do not eat regularly. Nori, ginseng, avocados (consumed in large quantities) can reduce the anticoagulant effect of warfarin. In clinical work, we most often encounter problems not due to food, but due to the use of multivitamin preparations containing vitamin K as a supplement (Centrum, Silcon, etc.). After a patient’s surgery, relatives, friends, and family members think that the surgery has hurt the body and that it needs to be replenished, and often these are among the gifts given or supplements intentionally purchased. After taking these preparations, the patient’s warfarin dosage is high, and the INR rises rapidly to dangerous levels after discontinuation. In addition, mangoes, fish oil, grapefruit, cranberries (cranberries), salvia, turtle berry, and fenugreek seeds can enhance the anticoagulant effect of warfarin. There are a number of drugs that affect the anticoagulant effect of warfarin, and their mechanisms are complex. For the sake of simplicity, we have divided these drugs into two categories. One category is the drugs that can enhance the anticoagulant effect of warfarin, the most common of which is acetaminophen, including Benadryl and Tylenol, which are commonly used to reduce the symptoms of colds, and many cold medicines contain such ingredients. Therefore, patients taking warfarin should use these drugs or compounded preparations containing such ingredients with caution when they have a cold. Aspirin is a drug commonly used by heart patients, which can enhance the anticoagulant effect of warfarin (firstly, its anti-platelet aggregation effect is superimposed on the anticoagulant effect of warfarin, and secondly, it competes with warfarin for plasma protein binding in the blood, which increases the free degree of warfarin and indirectly increases the dose of warfarin). If aspirin is taken concurrently with warfarin, patients are advised to keep the dose of aspirin constant and to monitor the INR at the beginning of the coadministration until it stabilizes. Broad-spectrum antibiotics can enhance the anticoagulant effect of warfarin. In addition to factors such as affecting the metabolism of warfarin, antibiotics can inhibit intestinal flora, reducing the production of vitamin K by intestinal bacteria and reducing the source of vitamin K in the body. Among the commonly used cardiovascular drugs, diltiazem (Hersinol), etanercept (cortolone), and statin lipid-lowering drugs increase the anticoagulant effect of warfarin. The antimycotic drug fluconazole (Daifukang) can also enhance the anticoagulant effect of warfarin. The second group of drugs that can diminish the anticoagulant effect of warfarin is less common, except for preparations containing vitamin K. Commonly used are ribavirin, rifampin, abciximide, carbamazepine, barbiturates, and mesalazine. In conclusion, the instructions of other drugs should be read carefully before taking them and, if needed, the INR should be tested repeatedly during the course of administration to avoid undetected changes in anticoagulation strength brought about by drug interactions. Elderly people over 65 years of age, especially those over 75 years of age, have decreased coagulation function, increased vascular fragility and permeability, and in some cases, combined cerebrovascular pathology (e.g., cerebrovascular amyloidosis). Such patients are prone to cerebral hemorrhage and must be treated with caution with anticoagulation. The former Prime Minister of Israel, Sharon, suffered from cerebrovascular lesions and over-anticoagulation, and suffered a massive cerebral hemorrhage. Patients with valve replacement are prone to complications from anticoagulation therapy in the first two years of postoperative anticoagulation therapy, especially in the first year of initiation, with thrombosis or bleeding. Early after the patient’s surgery, the surface of the foreign body in the heart is not yet fibrinous and does not cover the vascular endothelium, and the area of exposed foreign body that can trigger a coagulation response is relatively large. Patients start to detect anticoagulation therapy by themselves and are not experienced enough to detect the problem and adjust the warfarin dose in time. Therefore, in the early post-surgical period, patients must have more laboratory tests, pay attention to the adjustment of warfarin dose, and must consult more doctors who have experience in anticoagulation therapy when they are not sure. What should I do if I need surgery on other parts of my body during warfarin anticoagulation therapy? If a patient needs surgery while on warfarin anticoagulation therapy, it is a relatively problematic issue because anticoagulation therapy may lead to increased bleeding at the surgical site. The solution is to discontinue warfarin for a few days prior to surgery while substituting heparin for treatment. Because of the short half-life of heparin, the patient’s coagulation function is completely normal when heparin is discontinued before surgery, eliminating the risk of post-surgical bleeding. However, the risk of doing so is that it leaves the patient with a period of time without warfarin anticoagulation, which cannot be fully replaced by the anticoagulant effect of heparin. Therefore, it is important to carefully assess before surgery whether post-operative bleeding poses a greater risk to the patient or whether the absence of warfarin anticoagulation poses a greater risk to the patient. The degree of tolerance for post-operative bleeding varies from site to site, as well as the ease of stopping bleeding after surgery. For example, if a tooth is extracted, the operation is small and the surgical site is well exposed, so effective pressure can be applied to stop the bleeding, even if the postoperative bleeding is slightly more, it will not be a big problem. Intracranial surgery is different. The brain tissue is rich in blood vessels, the surgical field is poorly exposed, and it is relatively difficult to stop bleeding. If there is still bleeding at the surgical site after surgery, it will lead to intracranial hematoma and compression of the brain tissue. Therefore, heparin replacement therapy is not required at all for minor surgeries (especially outpatient surgeries) in areas such as tooth extraction, skin, and fingers, whereas caution must be exercised for surgeries in critical areas such as the cranium and spine. If heparin replacement therapy is performed, the first important thing is to check INR daily from the time warfarin is discontinued until the time warfarin is taken after surgery to bring the anticoagulation strength up to the required level. warfarin is usually discontinued 4-5 days before surgery, and during this time 5,000 units of low molecular heparin are injected subcutaneously once every 12 hours, and heparin is discontinued 12 hours before surgery. Immediately after the wound bleeding stops after surgery, low molecular heparin is started at the same dose and in the same way as before, and warfarin is started until the INR reaches the prescribed anticoagulant strength and the heparin is stopped. If the patient is at high risk of thrombosis, the dosage of low molecular heparin can be increased to 100 U/Kg body weight. After stopping warfarin, the coagulation function is normal when the INR reaches 1.2 or less. In case of emergency surgery, vitamin K1 can be given intravenously as early as possible before surgery and INR values can reach normal range within 12-24 hours. The appropriate dose of vitamin K1 is one that will rapidly lower the INR to the normal range without causing resistance to postoperative warfarin anticoagulation (if the patient has excess vitamin K in the body, the INR will not rise immediately after taking warfarin). Intraoperative hemostasis should be done very carefully. In our clinical work, we often have patients who undergo emergency surgery due to prosthetic mechanical valve dysfunction without preoperative warfarin discontinuation, and the surgery is a secondary operation requiring sawing of the sternum, with severe tissue adhesions and large trauma. However, as long as the hemostasis is complete, the postoperative bleeding is not more severe than that of a routine first operation. In some patients with a lot of bleeding, it was thought that it was due to warfarin anticoagulation, but after re-opening the chest, active bleeding spots were found that were easy to stop surgically. It is indeed not easy to maintain the ideal anticoagulation strength with individual differences in warfarin dosage, narrow therapeutic window, complex interactions with other drugs, and the influence of natural foods on its anticoagulant effect, which is used appropriately for a long time. It is important to remember that taking warfarin, it is very important that in the absence of certainty, do not take the drug blindly by chance, must go to the hospital to test INR. blind man walking at night, dangerous ah!