A Chinese patient with cardiogenic stroke and warfarin resistance: a case report

Abstract

Background

Warfarin is the most commonly used oral anticoagulant drug in clinical practice due to its effective anticoagulant effect and low cost. Warfarin plays a crucial role in the anticoagulant treatment of patients with thrombotic diseases such as atrial fibrillation, heart valve replacement, and deep vein thrombosis. In general, low-dose warfarin can effectively achieve the optimal international normalized ratio (INR) for patients requiring anticoagulation therapy. In some cases, patients may require significantly higher doses of warfarin to achieve an INR in the desired range; failure to achieve this is commonly referred to as warfarin resistance. We report a rare case of cerebral infarction caused by atrial fibrillation and warfarin resistance in China.

Case presentation

A Chinese patient with atrial fibrillation complicated by cerebral infarction had been taking warfarin for 2 years, and the dose was gradually increased to 12.5 mg per day; however, the INR remained below the standard. The patient was considered to be resistant to warfarin. The cause of warfarin resistance in this patient is unknown, but we speculate that pharmacodynamic and genetic factors may be involved. Finally, we chose to replace warfarin with rivaroxaban to avoid the risk of bleeding at high doses. To date, there has been no bleeding or infarcts since the patient was discharged. In cases where the cause of warfarin resistance cannot be determined, alternative drugs may be more appropriate.

Conclusions

When considering warfarin resistance, it is important to actively search for the cause of resistance early on. If the cause is determined, appropriate measures should be taken. If the cause is not determined or cannot be resolved, the dose can be gradually increased under close monitoring, alternatives can be actively adopted, and patients can be informed and educated.

Background

Acute ischemic stroke (AIS) is a condition characterized by an interruption or reduction in cerebral blood supply, resulting in ischemia and hypoxia of brain tissue, ultimately leading to neurological deficits. The management of AIS should be initiated as early as possible, with prompt assessment and imaging to exclude hemorrhagic stroke. If the patient meets the eligibility criteria, thrombolytic therapy should be administered. In cases of large vessel occlusion, mechanical thrombectomy may be considered as a therapeutic option.Subsequent evaluation should focus on identifying the underlying etiology to guide the selection of long-term antithrombotic therapy. Most patients with AIS require continued antiplatelet therapy, such as aspirin or clopidogrel, to reduce the risk of recurrent stroke. For patients with cardioembolic stroke, particularly those related to atrial fibrillation, anticoagulant therapy—such as warfarin or non-vitamin K antagonist oral anticoagulants (NOACs)—should be considered to prevent further thromboembolic events.

Warfarin, a vitamin K antagonist, is a commonly used anticoagulant drug for the prevention and treatment of venous and arterial embolic diseases, such as atrial fibrillation, rheumatic heart disease, valvular heart disease, and deep vein thrombosis. The use of a warfarin dose is determined by patient race, age, sex, weight, and genetics, narrowing the treatment window and increasing individual differences [1, 2]. To evaluate the efficacy and safety of warfarin, it is important to maintain the international normalized ratio (INR) within the therapeutic range (2–3) [3, 4]. Our patient was considered to have warfarin resistance, as high doses of warfarin were unable to bring her INR within the target treatment range, despite this being achievable for most people with ordinary doses. There have been few reported cases of warfarin resistance in China, and the use of high doses of the drug is rare. The purpose of this case report is to provide clinicians with an idea of possible causes and solutions when a patient is found to have warfarin resistance.

Case presentation

A 50-year-old female (height: 165 cm, weight: 69 kg, and BMI: 25.3 kg/m²) with cerebral infarction and atrial fibrillation was admitted to our hospital. Emergency head computed tomography and computed tomography angiography (CTA) scans revealed no significant abnormalities except for subtotal occlusion of the P1 segment of the right posterior cerebral artery. Emergency MRI of the head revealed bilateral thalamic infarction. An electrocardiogram indicated rapid atrial fibrillation. Emergency tests revealed that the patient’s neutrophil percentage was 80.6%. Coagulation, renal function, electrolyte, and blood gas tests revealed no abnormalities. Her medical history included a 2-year history of atrial fibrillation with no medication use and previously elevated blood pressure, with a maximum systolic blood pressure of 180 mmHg. Physical examination revealed a temperature of 36.6 °C, a pulse rate of 90 beats/minute, a respiration rate of 20 breaths/minute, and a blood pressure of 176/98 mmHg. The heart rate was 103 beats/minute, with arrhythmia and variation in the first heart sound. Physical examination revealed lethargy and uncooperativeness. The patient’s pupils measured approximately 2.5 mm, and direct and indirect light reflection was absent. The patient could not move her limbs cooperatively, but her limbs could unconsciously move autonomously. Her tendon reflexes were normal, and her bilateral pathological signs were positive. The patient’s National Institutes of Health Stroke Scale (NIHSS) score was 11. The admission diagnoses were as follows: (1) cerebral infarction (cardioembolic type according to the Trialoforg 10172 for acute stroke treatment classification); (2) atrial fibrillation. and (3) hypertension.

During treatment, the patient experienced cerebral infarction, and the blood vessel was located in the posterior cerebral artery. The onset time was short, and the symptoms were severe. Emergency endovascular treatment was performed due to indications for emergency vascular surgery. The patient was conscious when she returned to the ward after the operation. She was able to speak and move her limbs autonomously without any discomfort. The NIHSS score was determined again, and a score of 2 was given. Her NIHSS score was 0 on the day following the surgery. According to the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke (2018 edition), further examination of the head showed no bleeding, and anticoagulation therapy was started on the second day after surgery.

For anticoagulant selection, NOACs, including apixaban, rivaroxaban, dabigatran, and edoxaban, are preferred for most patients due to their comparable efficacy to warfarin and a lower risk of bleeding. Additionally, NOACs do not require routine INR monitoring, offering greater convenience, though they come at a higher cost. Warfarin remains the treatment of choice for patients with severe renal insufficiency, mechanical heart valves, or antiphospholipid syndrome, but it necessitates regular INR monitoring (target range: 2.0–3.0) while being more cost-effective. Taking economic factors into account, the patient and their family opted for warfarin due to its lower cost. The initial anticoagulant therapy included a subcutaneous injection of low-molecular-weight heparin calcium (0.6 ml every 12 h) alongside a daily dose of 3 mg of warfarin.

Regarding the expected treatment result, the INR was expected to reach the target value of 2–3 within one week. However, despite a continuous increase in the warfarin dose to 5 mg during hospitalization, the INR remained below the standard. At this point, the patient was discharged from the hospital. Her medication continued to be adjusted in the outpatient clinic. During the out-of-hospital follow-up, the warfarin dose was increased to 12.5 mg, but the INR did not reach the target value for stabilization (Figure 1). We believe that the patient was warfarin resistant.

The causes of warfarin resistance are primarily linked to genetic factors, drug interactions, and vitamin K intake. Genetic factors, such as mutations in the VKORC1 gene, can lead to reduced metabolic efficiency of warfarin, necessitating higher doses to achieve the desired anticoagulant effect. Additionally, certain medications (such as antibiotics and antiepileptic drugs) may interfere with the metabolism of warfarin, altering its effectiveness. Furthermore, a high intake of vitamin K (e.g., from green vegetables) enhances the synthesis of clotting factors, which can diminish warfarin’s anticoagulant action, contributing to drug resistance.

The patient did not have any drugs, foods or related diseases that could affect warfarin absorption or metabolism. We considered a high probability that stable blood concentrations could be achieved, but this needed to be confirmed by blood tests. However, there is no condition for detecting the warfarin blood concentration in our hospital, and we suggested that the patient go to another hospital for further examination; this proposal was rejected by the patient and her family.

We further considered the possibility of genetic factors. We contacted a testing company and offered the patient a free genetic test for warfarin resistance, and the patient’s genotypes were found to be CYP2C9 *1/*1, VKORC1 rs9923231 (CT) and CYP4F2 rs2108622 (CC). The results suggested that high doses of warfarin should be avoided to reduce the risk of bleeding (Table 1). In summary, based on these genetic test results, the patient needed a lower dose of warfarin to reduce the risk of bleeding, but low doses did not achieve a stable INR.

Since the hospital did not test the warfarin blood concentration and failed to identify any factors affecting its pharmacodynamics, the cause of warfarin resistance in this patient remains unknown. However, for this patient, although no further embolization events occurred after discharge, due to concerns about the risk of bleeding due to a high warfarin dose, warfarin was replaced with rivaroxaban after communication with the family at a time when the domestic price of rivaroxaban was reduced.

Table 1 The results of the patient’s gene polymorphisms

Discussion

The ageing population has led to an increase in the number of patients with chronic atrial fibrillation. This has resulted in a significant increase in the incidence of cardiovascular and cerebrovascular diseases related to thromboembolism. Consequently, the number of patients using warfarin for long-term anticoagulant therapy has also increased. Warfarin is the most commonly used oral anticoagulant drug in clinical practice due to its effective anticoagulant effect and low cost [5, 6]. Warfarin plays a crucial role in the anticoagulant treatment of patients with thrombotic diseases such as atrial fibrillation, heart valve replacement, and deep vein thrombosis [3]. Warfarin inhibits the synthesis of vitamin K-dependent clotting factors in the liver, thereby inhibiting the production of blood clots [7]. To achieve a stable anticoagulation effect, it is necessary to closely monitor the prothrombin time (PT) and INR of patients and adjust the dose accordingly. The anticoagulation intensity index (INR) was maintained at 2.0 ~ 3.0 [8, 9]. In some cases, patients may require significantly higher doses of warfarin to achieve an INR in the desired range; failure to achieve this is commonly referred to as warfarin resistance. Patients who are resistant to warfarin often require longer periods to reach a stable dose and may even experience anticoagulation failure due to constant medication adjustments. Therefore, these patients are at a greater risk of thromboembolism than the general population. Based on this patient’s symptoms, signs, and auxiliary examinations, the diagnosis of cardiogenic cerebral embolism and atrial fibrillation was clear. Treatment with warfarin was deemed reasonable, but despite the use of high doses of warfarin, the ideal INR could not be achieved, indicating warfarin resistance.

At present, there is no evidence-based medical evidence in China or abroad about what warfarin dose can be used to diagnose resistance, and only a few reports on this topic exist. Due to inconsistent definitions of warfarin resistance, no data are available on the incidence of warfarin resistance. Existing studies and case reports have shown that warfarin resistance is more common in black people, followed by white people, and warfarin resistance is less common in Asian people [10,11,12]. Some foreign scholars defined the diagnostic criterion for Caucasian and black people as 10.0 mg/d [13], and Yuan et al. defined warfarin resistance as a dose greater than 6.0 mg/d for Taiwanese patients [10]. Li Zhao et al. [14] reported a case of a Chinese female who took a warfarin dose of 27 mg/day, and her INR was still below the standard.

According to the pharmacological mechanism of warfarin, warfarin resistance can be divided into two categories: pharmacokinetic resistance and pharmacodynamic resistance [15]. According to the causes of resistance acquisition, warfarin resistance can be divided into hereditary resistance and acquired resistance [16, 17].

Warfarin resistance due to altered pharmacokinetic processes (reduced warfarin absorption or increased clearance) is called pharmacokinetic resistance. Common causes of decreased absorption include diarrhoea, vomiting, and concomitant medication use (e.g., cholestyramine inhibits warfarin absorption and weakens its anticoagulant effect). Common causes of increased clearance include hypoproteinaemia, hyperlipidaemia, smoking, and drug combinations (e.g., rifampicin and carbamazepine). Warfarin resistance due to changes in the pharmacodynamic process (the anticoagulant effect of warfarin is weakened) is called pharmacodynamic resistance. The reason for this pharmacodynamic resistance may be an increase in VKOR activity or synthesis, a decrease in the affinity between warfarin and VKOR, or an increase in coagulation factor synthesis or activity. The detection of warfarin plasma concentrations in resistant patients can help distinguish between pharmacokinetic resistance and pharmacodynamic resistance. For this patient, the type of resistance was difficult to distinguish because of the patient’s refusal to undergo blood concentration detection. However, the patient had no problems with drug absorption or clearance, and we hypothesized that the type of resistance might be pharmacodynamic.

Warfarin resistance that results in increased warfarin metabolism or decreased anticoagulation due to genetic variation is called hereditary resistance. There are more than 30 known genes related to warfarin pharmacodynamics and pharmacokinetics. The gene polymorphisms of the vitamin K epoxide reductase complex subunit 1 gene (VKORCl) and cytochrome P450 2C9 gene (CYP2C9) are the two main genetic factors that affect individual differences in warfarin doses [15, 18, 19]. In this case, after obtaining the patient’s consent, we performed further free genetic testing and found that her genotypes were CYP2C9 *1/*1, VKORC1 rs9923231 (CT), and CYP4F2 rs2108622 (CC).

Cytochrome P450 2C9 (CYP2C9) is a member of the cytochrome P450 mixed-function oxidase system, is encoded by the CYP2C9 gene, and is located in the endoplasmic reticulum [20]. CYP2C9 expression is induced by rifampicin, and it is involved in the hydroxylation metabolism of S-warfarin. The polymorphism of this gene leads to individual differences in CYP2C9 enzyme activity [17, 21]. Patients with the CYP2C9*2 and *3 alleles require a lower dose of warfarin, while those with the CYP2C9*1 and *1 genotypes do not require a dose adjustment. In other words, for this patient, there was no need to adjust the warfarin dose based on the results regarding this gene.

VKORC1 encodes the catalytic subunit of the vitamin K epoxide reductase complex [21,22,23]. This complex is responsible for reducing inactive vitamin K 2,3-epoxides to active vitamin K in the endoplasmic reticulum. Vitamin K is necessary for the carboxylation of glutamate residues and acts synergistically with gamma carboxylase in thrombin production. Polymorphisms in the VKORC1 gene may affect sensitivity or tolerance to the warfarin vitamin K epoxide reductase inhibitor by altering its expression. The patient in question had the TT/CT genotype, which may increase the risk of hypercoagulation and bleeding, shorten the time to reach the target INR, and require a reduced dose of warfarin.

The CYP4F2 gene encodes cytochrome P450 4F2, which is a member of the cytochrome P450 mixed-function oxidase system [24]. CYP4F2 is located in the endoplasmic reticulum and oxidizes substrates to produce hydroxyl derivatives. Additionally, it is responsible for the inactivation and degradation of leukotriene B4, a potent inflammatory mediator. CYP4F2 polymorphisms are closely related to the toxicity and dose differences of vitamin K antagonists in patients with atrial fibrillation. The relationship between genotype and the risk of excessive warfarin anticoagulation was as follows: CC > CT/TT. Individuals who carry the homozygous (TT) and heterozygous (CT) forms of the CYP4F2*3 allele require higher doses of warfarin to achieve the same targeted anticoagulation effect as individuals with the wild-type genotype (CC) [25]. This patient had the CC genotype and therefore required a reduced dose of warfarin.

Warfarin resistance due to acquired nongenetic factors is called acquired resistance. The causes of acquired resistance may include poor patient compliance, increased vitamin K intake, decreased warfarin absorption, and increased warfarin clearance. Certain medications that might interact with warfarin were not used while the patient was on this medication. To determine the patient’s compatibility with warfarin, we conducted a thorough investigation of her diet and ensured that she avoided foods that may affect warfarin metabolism. In addition, the patient did not have any conditions that significantly affected drug absorption.

Therefore, the cause of warfarin resistance in this patient could not be determined. In summary, for this patient, we could not determine the warfarin blood concentration or perform additional genetic tests, so we speculate that pharmacodynamics and genetic causes are highly likely.

What should we do for patients with warfarin resistance? First, we should actively identify the causes of warfarin resistance. If acquired resistance is due to transient causes (e.g., vitamin K infusion, vitamin K-rich diet), warfarin resistance can be quickly corrected by eliminating these factors; if this factor cannot be eliminated (for example, if an interfering drug must be taken), the warfarin dose may be gradually increased under close monitoring of the patient’s INR value and clinical manifestations, or the treatment may be changed. Patients should be educated about this medication. Patients, including those without warfarin resistance, should be advised to take their medication regularly, maintain a constant diet, and regularly review the INR as directed by their doctor.

It is important to note that Acenocoumarol and Phenprocoumon, coumarin anticoagulants similar to warfarin, exert their anticoagulant effects by inhibiting VKORC1 and reducing the synthesis of clotting factors. While these drugs share a similar mechanism of action with warfarin, there may be differences in their metabolic pathways, which could affect their efficacy in some patients with variants in the VKORC1 and CYP2C9 genes. For instance, the metabolism of acenocoumarol and phenprocoumon is also dependent on the CYP enzyme system, so patients with CYP2C9 genetic variants may experience slower drug clearance, leading to a diminished or ineffective drug response, ultimately resulting in drug resistance. Therefore, for warfarin-resistant patients, coumarin anticoagulants may not be suitable.

For patients with warfarin resistance, if the resistance is found to be severe, alternative anticoagulants could be considered, such as direct DOACs. Since DOACs have a distinct anticoagulant mechanism compared to warfarin, they may remain effective even in the presence of resistance to coumarin-based drugs.

For this patient, although there were no bleeding side effects, there was a risk of bleeding with high doses of warfarin. Therefore, in consultation with the patient and her family, we chose an alternative medication: rivaroxaban. The price of the drug had decreased, making it affordable for the patient. According to another report, a Chinese woman, for whom the exact cause of warfarin resistance could not be determined, took 27 mg of warfarin daily, but her INR still did not meet the standard, and her doctors also changed the medication used [14].

Although newer anticoagulants (NOACs) such as apixaban, rivaroxaban, and dabigatran are excellent alternatives due to their convenience and lower bleeding risk, they should be avoided in patients with mechanical heart valves, severe renal insufficiency, severe liver impairment, and antiphospholipid syndrome. The main reasons for this include: the safety and efficacy of NOACs in patients with mechanical valves have not been fully established; NOACs are metabolized by the liver and kidneys, and impaired liver and kidney function may lead to incomplete drug clearance, resulting in drug accumulation and an increased bleeding risk. Additionally, some patients with antiphospholipid antibodies are at high risk for thrombosis, and the efficacy and safety of NOACs in these patients are limited.

For patients who cannot use NOACs and cannot achieve the desired anticoagulant effect with warfarin, antiplatelet therapy (such as aspirin or clopidogrel) may be considered. Although antiplatelet therapy is less effective than warfarin in preventing thrombosis, it can serve as an alternative treatment in low-risk atrial fibrillation patients, especially when the stroke risk is low or when drug resistance is present. Mechanical atrial fibrillation management (e.g., left atrial appendage occlusion) may also be considered. This procedure reduces the risk of stroke associated with atrial fibrillation by preventing blood clot formation in the left atrial appendage, making it suitable for patients who are drug-resistant or contraindicated for anticoagulants. In conclusion, for warfarin-resistant situations where NOACs cannot be used, a combination of drug therapy, mechanical interventions, or antiplatelet therapy may be necessary to ensure both efficacy and safety for the patient.

Conclusion

This case presents a rare instance of warfarin resistance in a Chinese patient with atrial fibrillation complicated by cerebral infarction. Despite increasing the warfarin dosage over two years, the patient’s INR remained persistently below the therapeutic range. Warfarin resistance can stem from genetic factors or alterations in pharmacokinetics and pharmacodynamics, posing significant challenges in achieving effective anticoagulation. When resistance occurs, it is crucial to actively investigate its underlying cause and consider alternative treatments, such as direct oral anticoagulants. In this case, due to the heightened bleeding risk associated with high-dose warfarin, rivaroxaban was chosen after thorough discussion with the patient and family. This case underscores the importance of early identification and management of warfarin resistance, as well as the potential advantages of alternative anticoagulant therapies in resistant cases.

Fig. 1

The dependence of the INR on the warfarin dose in a 50-year-old female patient with atrial fibrillation and cerebral infarction. Abbreviations: INR, international normalized ratio