Warfarin is the most commonly used long-acting anticoagulant in China and abroad, and is the only vitamin K antagonist currently in clinical use. The efficacy of the drug varies widely among patients, so the dose should be adjusted at any time according to the results of coagulation-related laboratory tests, such as the International Normalized Ratio (INR), and patients should not be given warfarin if they are not equipped to monitor coagulation-related tests, otherwise it may cause serious consequences such as bleeding or even endanger their lives. The pharmacological effects of warfarin and its use Warfarin mainly interferes with the hepatic synthesis of vitamin K-dependent coagulation factors II, VII, IX and X, thereby inhibiting blood clotting. Because it is an indirect anticoagulant, it works only in vivo and has no anticoagulant effect in vitro. The half-lives of coagulation factors II, VII, IX and X are 6, 20-30, 45-72 and >60 hours, respectively. Therefore, it takes at least 36-48 hours after oral administration of warfarin to show anticoagulant effect. After discontinuation of the drug, the synthesis of the above coagulation factors also takes some time, so the coagulation function also takes many days to gradually recover. Warfarin can be started in combination with heparin or low-molecular-weight heparin, and then discontinued after the warfarin has taken effect. The goal of warfarin dose adjustment is to increase prothrombin time by >50%, reduce activity to 20%-30%, and maintain INR at 2.0-3.0. When warfarin is started, prothrombin time should be tested daily and the dose should be adjusted according to the test results. The test interval should be gradually extended to 3 days, 1 week, 2 weeks, or even 4 weeks. In case of cumulative overdose or underdose during warfarin use, the dose should be fine-tuned at any time. Warfarin is not recommended for the prophylaxis of all postoperative thrombotic disorders because of the wide individual variation in the use of warfarin and the fact that it takes approximately 2 weeks from the start of use to achieve a good and stable coagulation state. Factors affecting the anticoagulant effect of warfarin 1. Factors synergistic with warfarin Fluoroquinolone antimicrobials According to the Canadian Adverse Drug Reaction Bulletin (No. 3, 2004), cases of increased anticoagulant activity due to the combination of fluoroquinolone antimicrobials and warfarin have been reported repeatedly. The mechanisms by which fluoroquinolone antimicrobials increase the anticoagulant effect of warfarin include: (1) replacement of warfarin by fluoroquinolones from the protein binding sites on which they act; (2) reduction in the number of intestinal flora producing vitamin K and coagulation factors by antibiotics; and (3) indirect slowing of warfarin metabolism. Most fluoroquinolone antimicrobials inhibit cytochrome P450-mediated metabolic reactions, thereby reducing the clearance of some drugs metabolized by this pathway, making other drugs applied simultaneously, especially those with a lower therapeutic index (e.g., warfarin), more likely to exhibit toxic reactions. Therefore, fluoroquinolone antimicrobials may enhance the effects of warfarin or its derivatives, and the prothrombin time and INR of patients should be closely monitored when the two drugs are used together, and warfarin dosage should be adjusted at any time, especially in elderly patients. Macrolide antibiotics The Australian Adverse Drug Reaction Bulletin states that interactions between warfarin and all four macrolide antibiotics have been reported (see table). One of the patients, a 79-year-old woman, died of extensive bleeding 8 days after the addition of erythromycin. In contrast, however, a US study showed no significant change in INR after the addition of azithromycin in warfarin users. Despite this, patients taking warfarin with azithromycin should be monitored more closely. Tramadol The Australian Adverse Drug Reaction Monitoring Committee has received reports of 11 cases of increased INR and bleeding after the addition of tramadol in patients taking warfarin. In these patients, the INR returned to its initial state 1-4 days after discontinuation of tramadol with no change in warfarin dosage. In another pharmacodynamic study, however, only 2 of the 19 patients on a constant dose of phenprocoumon showed a significant increase in INR (to 6.0 and 7.3, respectively) after the addition of tramadol, while the mean INR values of all patients did not change to a statistically significant extent. These results suggest that the effect of tramadol on the anticoagulant effect of warfarin is related to the metabolic variation in a small number of patients. Therefore, the INR of patients treated with warfarin should be monitored closely for the first few days to 1 week after the addition of tramadol to prevent serious coagulation abnormalities. Fish oil is a -3 polyunsaturated fatty acid that affects platelet aggregation and/or vitamin K-dependent clotting factor function, resulting in lower levels of thromboxane A2 in platelets. In addition, it can reduce the level of factor VII, so that the anticoagulant effect of the former can be enhanced by appropriate supplementation of fish oil in patients taking warfarin. These findings have been confirmed by case reports. Antiphospholipid antibodies can cause an increase in INR It has been reported that some patients with antiphospholipid antibodies syndrome have a significant increase in INR after long-term warfarin administration. During anticoagulation therapy, INR values are often used to assess a patient’s coagulation status, and an elevated INR represents a decrease in the activity of coagulation factors II, VII, and X. However, in rare cases, the presence of non-vitamin K-dependent inhibitors or interfering substances may affect the INR assay. In this case, the anticoagulant effect of warfarin can be evaluated by directly measuring the concentration of coagulation factors. Genetic variants A study at the University of Washington showed that the expression products of the CYP2C9*2 and CYP2C9*3 genes, which are key enzymes in the metabolism of warfarin, increase the risk of bleeding during warfarin anticoagulation when variants occur in these two genes. There are also case reports that amoxicillin can cause an increase in INR and hematuria, and interferon can increase the anticoagulant effect of warfarin. A randomized, double-blind, placebo-controlled clinical trial by Yuan et al. at the University of Chicago showed that American ginseng could weaken the anticoagulant effect of warfarin. Therefore, physicians are advised to ask their patients if they have taken American ginseng before administering warfarin. Ribavirin Schulman of Sweden reported a case of a 61-year-old male patient who had undergone heart valve replacement, was on long-term warfarin therapy, and was treated with ribavirin for hepatitis C infection from a blood transfusion. The physician found that the patient’s warfarin dosage needed to be increased by 40% to maintain the desired anticoagulant effect. The mechanism of interaction between the two drugs is not known, but it is recommended that prothrombin time be tested at least once a week while on ribavirin. The therapeutic window for warfarin is very narrow and any factor that can have a minor effect on anticoagulation may lead to serious consequences. Therefore, it is important not to change the treatment regimen easily if warfarin is used in combination with other drugs (e.g., antihypertensive drugs). If additional drugs are required for treatment, prothrombin time and/or INR should be monitored at all times. Complications of long-term warfarin bleeding Bleeding is the most common adverse effect of long-term warfarin use, especially in elderly patients, and hemorrhage is a very common serious adverse effect. This is evidence of the effectiveness of warfarin anticoagulation. A study by Johnson et al. at Monash University in Australia showed a higher incidence of major bleeding in older patients with atrial fibrillation taking warfarin. The researchers retrospectively analyzed data from 228 patients aged ≥76 years with atrial fibrillation who had been taking warfarin for a mean of 28 months, 42% of whom were male and had a mean age of 81.1 years. The results showed that there were 53 major bleeds in 41 patients, with an annual rate of 10.0%, of which 24 (45.3%) were life-threatening major bleeds and 5 (9.4%) were fatal major bleeds, while the annual stroke rate was only 2.6%. Hemorrhage is the result of warfarin overdose or the effect of other drugs taken at the same time. If a warfarin overdose or other bleeding disorder (such as intracranial hemorrhage) occurs while taking warfarin, prompt antagonistic treatment is required. Patients with intracranial hemorrhage have a mortality rate of up to 50% within 30 days of onset, which is slow to be corrected by traditional methods (e.g., fresh blood transfusions and vitamin K countermeasures) and is not effective in arresting the expansion of the hematoma. Meschia et al. at Mayo Hospital reported that recombinant coagulation factor VIIa can be administered intravenously to safely and rapidly counteract the anticoagulant activity of warfarin. The investigators administered a single intravenous infusion of recombinant coagulation factor VIIa to seven patients with a median age of 87 years with a mean time interval of 6.2 hours between onset and dosing. As a result, recombinant coagulation factor VIIa rapidly reversed the anticoagulant activity of warfarin and reduced the INR from 2.7 before treatment to 1.08. All 5 patients survived except 2 who died during hospitalization. These results need to be confirmed in a prospective study in a larger population. In China, there are reports of abdominal bleeding and intestinal obstruction associated with long-term warfarin use. Osteoporotic fractures in men A retrospective study by Gage et al. at the University of Washington showed an increased risk of osteoporotic fractures in men with atrial fibrillation who were taking warfarin for a long time. The study analyzed data from 4461 patients on long-term warfarin (≥1 year on the drug) and 7587 controls who were not treated with warfarin. The results found that the risk of osteoporotic fracture was 25% higher in long-term warfarin users than in non-warfarin users, and that the risk of fracture was increased only in men on long-term warfarin (OR=1.63), while there was no associated risk in women on the drug (OR=1.05). The risk of osteoporotic fracture was not increased in those taking the drug for a short period of time (<1 year). Further analysis revealed that independent risk factors for osteoporotic fracture included older age, susceptibility to falls, comorbid hyperthyroidism, neurological deterioration, and alcohol abuse. Soft tissue necrosis There have been reports of breast necrosis and even mastectomy after warfarin administration in the 1960s, and other areas such as skin, soft tissue, subcutaneous tissue, male external genital necrosis and extensive soft tissue necrosis have been reported, but the total number of cases is not large and similar reports have not been seen in China.