Introduction

The international normalized ratio (INR) is the preferred parameter for monitoring patients taking vitamin K antagonists.[1] This variable is also used to assess the risk of bleeding and to evaluate the coagulation status of these patients. Individuals on oral anticoagulants must monitor their INR values to adjust doses of vitamin K antagonists.[2] The INR is derived from the prothrombin time (PT) and calculated as the ratio between the patient's PT and a control PT, standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the following formula:

INR = (Patient PT ÷ Control PT)^ISI, where ISI is the international sensitivity index.[3]

PT, measured in seconds, represents the time required for plasma to form a clot in the presence of a sufficient concentration of calcium and tissue thromboplastin, which activates coagulation through the extrinsic pathway. The reference values for INR account for variations in PT measurement due to device-related differences, the type of reagents used, and sensitivity differences in the tissue factor activator.[4][5] INR is dimensionless, and values for individuals without health issues are typically 1.1 or lower.[6]

Optimizing a patient's INR and ensuring it remains within the therapeutic range can be challenging, as vitamin K antagonists have a narrow therapeutic window. Factors such as the patient's characteristics, comorbid conditions, diet, and intake of potentially interfering medications can affect the INR. Patients are typically monitored every 3 to 4 weeks or more frequently at thrombosis centers, point-of-care (POC) clinics, or in-home settings.[7]

Specimen Collection

Conventional coagulation testing (CCT) is typically performed in a laboratory to measure PT and INR. However, the longer turnaround times associated with CCT due to sample collection, transportation, and processing led to the development of POC testing, also known as bedside testing or near-patient testing. POC testing may be performed at or near the patient, offering the advantage of shorter turnaround times and potentially improved clinical outcomes. POC testing devices are commonly used in practitioner offices, long-term care facilities, pharmacies, and homes for patient self-testing or self-management.

The potential benefits of POC testing devices include enhanced patient convenience, better treatment adherence, more frequent measurements, and reduced risk of thromboembolic and bleeding complications.[8] However, POC testing devices tend to overestimate low INR values and underestimate high INR values.[9] In addition, patients with antiphospholipid antibodies have been shown to experience higher error rates in INR determination.[10] Although adherence and treatment satisfaction can improve with POC testing, some patients report increased anxiety regarding PT and INR monitoring.[11]

Procedures

In 2017, the Clinical and Laboratory Standards Institute recommended that blood specimens for PT and INR testing in the laboratory setting should be obtained through intravenous extraction and collected directly into a tube with a light blue top. This tube contains 3.2% sodium citrate as the anticoagulant.[12] The tubes must be filled to at least 90% of their total capacity. The tube should be gently inverted several times immediately after collection to ensure proper mixing of blood and anticoagulant. The total time between sample collection and testing should not exceed 24 h.[13]

Healthcare professionals should be vigilant when the specimen is obtained from a vascular-assisted device, as heparin contamination may reduce the reliability of INR measurement.[14] Capillary whole blood may be obtained from POC-INR testing systems through fingerstick, with the blood applied to a test strip or cartridge. The INR value from POC testing is acceptable if it does not deviate by more than ±0.5 INR units from the reference laboratory INR value.[15]

To determine the INR using POC instruments, a test strip or cartridge is inserted into the monitor, and the patient's blood sample is applied. The blood reconstitutes the dried thromboplastin reagent, initiating clotting reactions in the presence of calcium, leading to clot formation, detected as an endpoint.[9] POC-INR devices incorporate various types of endpoint detection systems.

Electronic quality control is available in some systems. In such tools, an electronic device is inserted into the monitor in place of the test strip, producing an electronic signal that tests the electronic system within the POC monitor.[16]

Certain manufacturers of POC-INR systems provide test strips with built-in quality control. For example, some systems perform a test strip integrity check by analyzing a strip containing resazurin, a compound sensitive to light, humidity, and temperature. Electrochemical measurements of the chemical ensure that INR values are displayed if the integrity check of the test strip is satisfactory.[17]

Besides internal quality control checks, participation in external quality assurance or proficiency testing is recommended in certain countries for healthcare professionals conducting POC-INR testing. External quality assurance programs are readily accessible in the United States and Europe. These programs typically evaluate local results against a target range, which is established based on results submitted by other users of the same device.[18] The most commonly used target range extends from 15% above to 15% below the peer group's median, though other ranges have also been used.[19][20]

Notably, POC-INR results may differ from those obtained in local clinical laboratories, particularly when values fall outside the therapeutic range.[21] To ensure quality control, a venous sample is often collected simultaneously with the POC test and analyzed in a suitable laboratory. Some patients show discrepancies between INR readings obtained using different methods, even when stabilized on oral anticoagulant therapy.[22] A potential cause of this discrepancy is the presence of lupus anticoagulant, though inconsistencies may also occur in the absence of lupus anticoagulant.[23]

Indications

Indications for obtaining an INR value include the following:

• Bleeding diathesis in patients with deficiencies in coagulation factors, including fibrinogen, factors II, V, VII, and X, individually or combined, in the extrinsic pathway
• Disseminated intravascular coagulation
• Baseline sample collection before initiating anticoagulation therapy
• Monitoring the efficacy and safety of warfarin in patients with clinical conditions that increase the risk of thrombosis, such as mechanical heart valve placement, persistent atrial fibrillation, venous thromboembolism, stroke, and peripheral arterial disease.
• Testing liver synthetic function and calculating the Model for End-Stage Liver Disease (MELD) score in cases of end-stage liver disease.[24]

INR monitoring is most commonly required for patients taking warfarin, a vitamin K antagonist. The warfarin dose is adjusted based on INR values to maintain the therapeutic range, which prevents thrombosis due to subtherapeutic INR and hemorrhagic complications from supratherapeutic INR. The anticoagulant effect of warfarin, as indicated by an INR within the target range, also helps determine when to discontinue heparin therapy.[25]

The current INR system is primarily designed to monitor patients on vitamin K antagonist therapy. As a result, the ISI does not ensure consistent standardization of INR measurements across laboratories for monitoring liver disease.[26] This interlaboratory variation in INR values contributes to discrepancies in MELD scores. Although harmonizing results with a liver-specific ISI has shown promise, most laboratories are not equipped to manage dual INR systems, and commercially available thromboplastins currently lack an ISI specifically assigned to liver disease.[27]

Potential Diagnosis

The INR is commonly used as a surrogate for PT values. PT and INR may be deranged in the following conditions:

• Intake of vitamin K antagonists: Warfarin inhibits the γ-carboxylation of vitamin K-dependent clotting factors, including factors II (prothrombin), VII, IX, and X. The full anticoagulant effect of warfarin is typically observed approximately 1 week after administration. This delay occurs because factors with shorter half-lives, such as factor VII, are depleted first, whereas those with longer half-lives, such as prothrombin, take more time to be fully depleted.[28]

• Administration of other anticoagulants: Unfractionated and low-molecular-weight heparins; direct factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban; direct thrombin inhibitors, such as argatroban and dabigatran; and fondaparinux can prolong PT and activated partial thromboplastin time (aPTT) by acting on common pathway factors.[29]

• Liver dysfunction: The liver synthesizes vitamin K–dependent and –independent clotting factors and metabolizes warfarin. Consequently, liver disease is associated with PT and INR derangements. However, patients with elevated PT or INR due to liver dysfunction are not considered auto-anticoagulated. Instead, these individuals often experience a complex imbalance in coagulation factors, which can paradoxically increase their risk of thrombosis.

• Vitamin K deficiency: Conditions such as malnutrition, prolonged use of broad-spectrum antibiotics, and fat malabsorption syndromes can lead to vitamin K deficiency, resulting in abnormal PT and INR values.[30]

• Disseminated intravascular coagulation: PT and INR elevation occurs in disseminated intravascular coagulation due to the continuous consumption of coagulation factors by uncontrolled clotting mechanisms.[31]

• Factor deficiency: Abnormal PT and INR can result from deficiencies in extrinsic pathway factors or acquired inhibitors (autoantibodies) targeting fibrinogen or factors II, V, VII, or X, individually or in combination.[32]

• Presence of antiphospholipid antibodies: Lupus anticoagulants can elevate PT and INR if they target prothrombin. However, isolated prolongation of the aPTT is more commonly observed in these cases.[33]

In contrast, lower PT values typically reflect a technical error in specimen collection and preparation.

Normal and Critical Findings

For patients not on anticoagulation therapy, the INR is typically 1.0, regardless of the ISI or the performing laboratory.[34] Meanwhile, the therapeutic INR value ranges between 2.0 and 3.0 for patients on anticoagulant therapy.[35] INR values exceeding 4.9 are considered critical and significantly increase the risk of bleeding.[36]

The target INR range may vary for patients with prosthetic heart valves.[37][38] For patients with an On-X mechanical bileaflet aortic valve and no additional risk factors for thromboembolism, the target INR is 2 to 3 during the first 3 months after valve surgery and 1.5 to 2.0 thereafter. For individuals with a bileaflet mechanical valve, excluding an On-X valve, or a current-generation single-tilting disk mechanical aortic prosthetic valve and no additional thromboembolic risk factors, the target INR is 2.5.

The target INR is 3.0 for patients with a mechanical aortic prosthetic valve, excluding On-X, who have an additional risk factor for thromboembolic events, such as atrial fibrillation, a history of thromboembolism, left ventricular systolic dysfunction, or a hypercoagulable condition. This target also applies to patients with an older-generation mechanical aortic valve prosthesis, such as ball-in-cage valves. Similarly, the target INR is 3.0 for patients with a mechanical mitral prosthetic valve, including an On-X valve, or a mechanical tricuspid prosthetic valve.[39]

Interfering Factors

Factors that can affect the accuracy of INR determination include the following:

• Adherence to vitamin K antagonists: Vitamin K antagonists require regular monitoring and dose adjustments, and their interactions with food and drugs can make adherence challenging in clinical practice.
• Drug interactions: Medications can elevate or lower the INR.
  • Medications that can increase the INR include the following:
    • Antibiotics: Cotrimoxazole, macrolides, metronidazole, and fluoroquinolones
    • Antifungals: Azoles such as fluconazole
    • Chemotherapeutics: Imatinib and 5-fluorouracil
    • Others: Amiodarone, allopurinol, and serotonin reuptake inhibitors such as fluoxetine and sertraline
  • Medications that can decrease the INR include the following:
    • Antibiotics: Dicloxacillin and nafcillin
    • Others: Azathioprine; antiepileptics such as carbamazepine, phenobarbital, and phenytoin; St. John's Wort; and vitamin K
• Comorbidities: Chronic liver disease can affect warfarin's effectiveness, INR values, and coagulation homeostasis. Acute illnesses, such as infections and gastrointestinal diseases, may also impact INR control.[40][41]

Complications

An INR level below the target range increases the risk of thrombosis. Research indicates that a subtherapeutic INR level is associated with more than a 3-fold increased risk of recurrent venous thromboembolism.[42] Conversely, an INR above the therapeutic range raises the risk of bleeding, with intracranial hemorrhage being the most concerning. Patients may also experience gastrointestinal bleeding, hematuria, or bleeding from other sites.[43]

Patient Safety and Education

The clinical practice guidelines developed by the American College of Chest Physicians recommend educating and involving patients in INR testing, follow-up, and decisions related to results and dosing to improve clinical outcomes and cost-effectiveness. In addition, intensive patient education, by providing more detailed information on vitamin K antagonists through pamphlets or primary care consultations, has been proposed as a strategy to reduce adverse events related to anticoagulation. However, no clinical trial investigating these practices has been conducted to date.[44]

Clinical Significance

The INR is a cornerstone of anticoagulation management, providing a standardized measure for monitoring patients on vitamin K antagonists such as warfarin. Maintaining an optimal INR within the therapeutic range is critical for balancing the risk of thromboembolism with the potential for hemorrhagic complications. Given the narrow therapeutic window of these medications, even minor deviations in INR can significantly impact patient outcomes.

Regular INR monitoring enables timely dose adjustments, ensuring the efficacy of anticoagulation therapy while minimizing adverse events. Although CCT remains the gold standard for INR assessment, POC testing has emerged as a convenient alternative. POC testing delivers faster results and has the potential to improve patient adherence. However, it can introduce variability in INR measurements, necessitating careful interpretation and validation against laboratory-based methods to ensure accuracy.

INR monitoring is essential for patients with mechanical heart valves, atrial fibrillation, and venous thromboembolism, where long-term anticoagulation is required. The target INR range varies depending on the clinical indication, with stricter parameters for high-risk patients. Deviations from the therapeutic range—whether subtherapeutic or supratherapeutic—can have serious consequences. Subtherapeutic INR values increase the risk of thrombotic events, whereas supratherapeutic INR values elevate the likelihood of life-threatening bleeding, including intracranial and gastrointestinal hemorrhages.    

Several factors contribute to INR variability, including dietary vitamin K intake, drug interactions, comorbid conditions, and patient adherence to therapy. Medications such as antibiotics, antifungals, and chemotherapeutic agents can significantly alter INR levels, requiring close monitoring when these drugs are initiated or discontinued. In addition, conditions such as liver disease, disseminated intravascular coagulation, and vitamin K deficiency can further complicate INR management.    

The accuracy of INR testing depends on proper specimen collection and adherence to standardized laboratory protocols. Blood samples must be correctly drawn, anticoagulated, and analyzed within the appropriate timeframe to avoid erroneous results. Although POC-INR devices incorporate quality control mechanisms, discrepancies between POC and laboratory INR values remain a concern, particularly for patients with antiphospholipid antibodies or those outside the therapeutic range. In such cases, confirmatory laboratory testing is recommended to guide clinical decisions.

Patient education is a critical component of effective INR management. Informing patients about factors that influence INR stability, the importance of adherence, and the signs of bleeding or thrombosis can improve outcomes and reduce hospitalizations related to anticoagulation complications. Emerging strategies, such as patient self-testing and self-management models, have shown promise in enhancing INR control and reducing adverse events. However, these approaches may not be suitable for all patients.

As anticoagulation therapies evolve, with the increasing use of direct oral anticoagulants that do not require routine INR monitoring, the clinical relevance of INR measurement remains paramount for patients on vitamin K antagonists. Ongoing research into INR standardization, quality control measures, and novel monitoring strategies continue to refine best practices in patient care. Ultimately, optimizing INR monitoring, ensuring test accuracy, and fostering patient engagement are essential for minimizing the risks associated with anticoagulation therapy and improving long-term outcomes.