Introduction

International normalized ratio (INR) is the preferred test of choice for patients taking vitamin K antagonists (VKA). It can also be used to assess the risk of bleeding or the coagulation status of the patients. Patients taking oral anticoagulants are required to monitor INR to adjust the VKA doses because these vary between patients. The INR is derived from prothrombin time (PT) which is calculated as a ratio of the patient’s PT to 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

PT, the time in seconds, is measured in plasma to form a clot in the presence of sufficient concentration of calcium and tissue thromboplastin by activating coagulation via the extrinsic pathway. The reference values for INR take into account in PT measurement in device related variations, type of reagents used, and sensitivity differences in the TF activator. INR value is dimensionless and ranges from a score of 2.0 to 3.0. [1][2][3][4]Optimizing the patient’s INR therapeutic range can be challenging as narrow therapeutic range had been seen in VKAs and can be affected by patient's characteristics, co-morbid conditions, diet, and other drug interactions. Patients are monitored every 3–4 weeks or less at the thrombosis centers (TC), point-of-care (POC) clinics, or in the home setting.

Specimen Collection

Conventional coagulation testing (CCT) can be performed in the laboratory setting to measure PT/INR. However, given the higher CCT turnaround time including collection, transportation, and processing of blood samples, Point-of-care coagulation test (POCT) also known as “bedside testing” or “near-patient testing" has been developed. It can be performed at or near the patients with the advantage of shorter turnaround time and improved clinical outcome. POC devices are used in practitioner offices, long-term care facilities, pharmacies, or for patient self-testing or self-management. Potential advantages of POC devices include improved convenience to patients, better treatment adherence, frequent measurement and fewer thromboembolic and bleeding complications. [5]However, POC devices tend to overestimate low INR values and underestimate high INR values. Patient with antiphospholipid antibodies have been found to have higher error rate in INR determination. In additon, apart from adherence and treatment satisfaction some patient found to be more anxious about the PT/INR monitoring.

Procedures

It is recommended by the Clinical and Laboratory Standard Institutes (2017) that the blood specimens for INR/PT testing in the laboratory setting should be collected from venous blood and it is directly obtained into a tube with a light blue top. The tube contains an anticoagulant. The acceptable anticoagulant is the concentration of sodium citrate 3.2%. The tubes must be filled to within 90% of the full collection volume. The tube should be then inverted a few times, gently and as soon as possible, for proper mixing with the anticoagulant. The total time between sample collection and testing should not exceed 24 hours.

Providers should be vigilant if the specimen is taken from a vascular-assisted device because there may be possible heparin contamination that may interfere with INR reliability. On the other hand, capillary whole blood can be obtained from POC-PT systems by a fingerstick which is then applied to a test strip or cartridge. The INR value from POCT is considered acceptable if it does not exceed plus or minus 0.5 INR units by the reference laboratory INR value.

Indications

The indications for obtaining an INR value are:[6]

1. Bleeding diathesis in patients with coagulation factors deficiency (fibrinogen and factors II, V, VII, or X, or a combined deficiency) in the extrinsic pathway
2. Disseminated intravascular coagulation (DIC)
3. Baseline sample collection before starting anticoagulation
4. Monitoring the efficacy and safety while the patients are on warfarin due to clinical conditions with an increased risk of thrombosis such as mechanical heart valves, persistent atrial fibrillation, venous thromboembolism, stroke, and peripheral arterial disease
5. Test for liver synthetic function and to calculate the model for end-stage liver diseases (MELD) score in end-stage liver disease

INR monitoring is most commonly required for the patients who are on warfarin, a vitamin K antagonist. The dose of warfarin is adapted based on INR scores so that it remains in the therapeutic range to prevent thrombosis from subtherapeutic INR or hemorrhagic complications from supratherapeutic INR. The anticoagulant effect of warfarin indicated by an INR in the target range also guides us when to discontinue heparin.

Potential Diagnosis

The INR is commonly used as a surrogate for the PT value. PT/INR can be prolonged in:

1. VKAs: Warfarin inhibits the gamma-carboxylation of the vitamin K-dependent factors, including factors II (prothrombin), VII, IX, and X. The full anticoagulation effect is reflected approximately one week after administration of warfarin as the factors with the shortest half-life (factor VII) is initially depleted, but the factors with a longer half-life (e.g., prothrombin) takes a longer time to be depleted.[7]
2. Other anticoagulants: Heparins (unfractionated or low molecular weight), direct factor Xa inhibitor administration (rivaroxaban, apixaban, edoxaban),direct thrombin inhibitor administration (argatroban, dabigatran), and fondaparinux can cause prolongation of PT and the aPTT by acting on the common pathway factors.
3. Liver dysfunction: Liver synthesized both vitamin K-dependent and vitamin K-independent clotting factors. Also, warfarin metabolized in the liver. Thus, the liver disease is associated with prolongation of PT/INR. However, even with elevated PT/INR, these patients are not "auto-anticoagulated," because they often reflect homeostatic abnormalities in the coagulation factors and thus increase thrombotic risk.
4. Vitamin K deficiency: Malnutrition, prolonged use of broad-spectrum antibiotics and fat malabsorption syndrome can prolong the PT/INR.
5. DIC: Prolonged PT/INR results from the consumption of the coagulation factor in the clotting process.
6. Factor deficiency: Coagulation factors deficiency in the extrinsic pathway or acquired inhibitors (autoantibodies) of fibrinogen and factors II, V, VII, or X, or a combined deficiency involving one of these factors can lead to prolongation of PT/INR
7. Antiphospholipid antibodies: Lupus anticoagulants can prolong the PT/INR if it has the specificity for factor II (prothrombin). However, isolated prolongation of the aPTT is more common.

In contrast, shortening of PT usually reflects a technical error in specimen collection and preparation technique.

Normal and Critical Findings

For normal patients who are not on anticoagulation, the INR is usually 1.0 regardless of the ISI or the particular performing laboratory. [8]For patients who are on anticoagulant therapy, the therapeutic INR ranges between 2.0 to 3.0. INR levels above 4.9 are considered critical values and increase the risk of bleeding. The therapeutic INR range differs in a patient with prosthetic valve:

• For patients with an On-X mechanical bileaflet aortic valve with no other risk factors for thromboembolism, the INR goal is 2 to 3 for the first three months after valve surgery; and after three months the goal is 1.5 to 2.
• For patients with a bileaflet (other than On-X) or current generation, single-tilting disk, mechanical, aortic, prosthetic valve with no other risk factors for thromboembolism, the target INR is 2.5.
• For patients with a mechanical aortic prosthetic valve (other than On-X) and an additional risk factor for thromboembolic events (atrial fibrillation, previous thromboembolism, left ventricular systolic dysfunction, or hypercoagulable condition) or an older generation mechanical aortic valve prosthesis (ball-in-cage), the INR goal is 3.
• For patients with a mechanical mitral prosthetic valve (including On-X valve) or mechanical tricuspid prosthetic valve, the target INR is 3.

Interfering Factors

Multiple factors that can interfere the INR value are listed below:

Adherence to the VKAs

VKAs are commonly associated with monitoring, and dose adjustments along with food and drug interactions make the adherence difficult in clinical practice.

Drug Interactions

Following are the drugs that cause prolongation of INR:

• Antibiotics: especially cotrimoxazole, macrolides, metronidazole, and fluoroquinolones
• Antifungals: azoles (fluconazole)
• Chemotherapeutics: imatinib, Fluorouracil (5-FU)
• Amiodarone
• Allopurinol
• Serotonin reuptake inhibitors (fluoxetine, sertraline) 

Several medications may decrease INR value, for example:

• Antibiotics: Dicloxacillin, nafcillin
• Azathioprine
• Antiepileptics (Carbamazepine, phenobarbital, phenytoin)
• Saint John's Wort
• Vitamin K

Comorbidities

Chronic liver disease may interfere with warfarin dosage, INR value, and coagulation homeostasis. Acute illness such as infections and gastrointestinal illnesses may impact the INR control.

Complications

INR level below the target range is associated with increased risk of thrombosis. Research showed that more than three-fold risk of recurrent venous thromboembolism is associated with the subtherapeutic INR level.

On the other hand, INR above the therapeutic range is associated with increased risk of bleeding among which the most concerning condition is an intracranial hemorrhage. Patients can also present with gastrointestinal bleeding, hematuria or bleeding from any other site.

Patient Safety and Education

Clinical practice guidelines developed by the American College of Chest Physicians recommend educating and involving patients on INR testing, follow up, and result and dosing decisions that increase clinical benefit and cost-effectiveness. Also, intensive patient education (educating the patients beyond the usual VKAs information by distributing a pamphlet or by the primary care provider) has been proposed to reduce adverse events related to anticoagulation. However, no clinical trial has been conducted to date.

Clinical Significance

Timely INR monitoring and patient-centered education on INR management is an integral part of patient care. INR management in the therapeutic range remains a challenge, and hopefully, providers will be able to achieve optimal outcomes for their patients through clinical practice guidelines.