The International Normalized Ratio (INR) is the preferred test for patients taking vitamin K antagonists. It is used to determine the risk of bleeding or blood clotting status. Currently, special devices are used around the world to determine the international normalized attitude.
Prothrombin time
The oral anticoagulant Warfarin (also called coumadin) is a vitamin K antagonist that is widely used to prevent venous thrombosis. It inhibits the post-translational carboxylation of coagulation factors II, IX, VII, and X, which reduces their ability to interact with phospholipid membranes. The degree of anticoagulation achieved by Warfarin is controlled by a general coagulation test known as prothrombin time (PTV). It is carried out on citrate plasma. PTV is initiated by the addition of tissue factor along with phospholipids and calcium chloride. This combination is called thromboplastin.
Concept and meaning
An international normalized attitude was introduced in an attempt to standardize PTV. In its initial manifestation, prothrombin time was very variable, because different thromboplasts were non-standardized and obtained from many different sources. INR does not have units (this ratio) and is determined with an accuracy of one decimal place. The first step in its calculation is the “normalization” of PTV by comparing it with the geometric mean of the prothrombin time of a healthy adult population. At the second stage, this ratio rises to the degree denoted by MIC, or the international sensitivity index. It is a function of the thromboplastin reagent. Two groups of data are used to obtain the MIC of normal healthy people and patients stabilized with Warfarin.
The definition of the international sensitivity index does not include patients whose prothrombin time is prolonged, for example, due to severe liver disease. The relationship between normal and warfarin patients makes no predictions about the relationship between the working thromboplastin reagent and the INR standard for liver disease. Its increased value in the latter case does not protect patients from deep venous thrombosis.
Formula
Patients taking oral anticoagulants should monitor INR. The World Health Organization uses the following formula for international normalization:
INR = PTV (thrombosed time) of the patient ÷ control of the PTV.
PTV is measured in plasma. It determines the number of seconds required to form a clot in the presence of a sufficient concentration of calcium and thromboplastin tissue, activating coagulation through an external path. The norm of the international normalized relationship ranges from 2 to 3. It may depend on the characteristics of the patient, concomitant diseases, nutrition and other drugs. Observations are carried out every 3-4 weeks in thrombosis centers, medical care centers or at home.
Possible Samples
A routine coagulation test can be performed in a medical laboratory. This requires long lead times, including the collection, transportation and processing of blood samples. Therefore, a test was developed to determine the international normalized attitude, also known as “bedside” or “periopathological” testing. It can be performed on patients with the advantage of a shorter time turnaround and improved clinical outcome. Devices for express determination of the international normalized attitude are used in doctors' offices, long-term medical care, pharmacies and for patient self-monitoring. Potential benefits of these instruments include convenience, better handling, frequent measurement and the lowest risk of bleeding. However, they tend to overestimate low values and underestimate the high values of INR.
Testing Procedure
Clinical and laboratory institutes of the standard (2017) recommend that samples for analysis of international normalized ratios be collected from venous blood. It should be received in a tube with a light blue top, containing an anticoagulant. Basically, it is a 3.2% sodium citrate concentrate. The tube should be 90% full. Then it is turned over several times to properly mix the blood with an anticoagulant. The total time between sampling and testing should not exceed 24 hours.
Express method. Features
In addition to laboratory research, it is allowed to use the express definition of an international normalized relationship. For this, capillary blood from a finger is applied to a test strip or cartridge. The value is considered acceptable if it does not exceed plus or minus 0.5 units in comparison with the laboratory result.
What is the test for?
A patient may need this test if they are taking medications that change the way they clot. Anti-clotting drugs are useful if the patient is at risk of stroke. The attending physician uses INR to find out if the medicine is anti-clotting or if the dosage needs to be changed. This test also helps diagnose and manage liver diseases and bleeding.
Related tests
If the attending physician is concerned about liver function or the risk of bleeding in the patient, he may prescribe additional tests:
Platelet count.
Prothrombin time.
Study of partially activated thromboplastin time.
Fibrin D-dimer.
Fibrinogen level.
Thrombin time.
When applied
Indications for obtaining the INR value are:
- Bleeding diathesis in patients with deficiency of blood coagulation factors on the external path.
- Intravascular disseminated blood coagulation.
- Basic sampling before anticoagulation.
- Monitoring the effectiveness and safety when the patient is under the action of "Warfarin". To eliminate the risk of blood clots in the heart, atrial fibrillation and venous thromboembolism.
- A test for the synthetic function of the liver and the calculation of a model for assessing the terminal stage of its disease.
Potential diagnosis
The international normalized ratio is usually used as a surrogate for the value of the prone time. It increases in the following cases:
- The use of anticoagulants. Warfarin inhibits gamma-carboxylation of vitamin K-dependent factors. The full anticoagulation effect is expressed within one week after taking Warfarin. The use of other anticoagulants (heparin, rivaroxaban, apixaban, edoxaban, dabigatran, argatroban) can lead to prolongation of the PTV.
- Liver dysfunction. The liver synthesizes coagulation factors dependent and independent of vitamin K. Warfarin is metabolized in it. Liver diseases are associated with prolongation of PTV. With its increased value, patients are not “auto-anticoagulants” because they reflect homeostatic anomalies in coagulation factors and increase thrombotic risk.
- Vitamin K deficiency. Malnutrition, prolonged use of antibiotics of a different spectrum of activity and fat malabsorption syndrome can prolong PTV.
- Intravascular disseminated coagulation increases the thrombosed time.
- Deficiency of coagulation factors in the external tract, acquired fibrinogen inhibitors, or combined deficiency can lead to prolongation of PTV.
- Antiphospholipid antibodies. Lupus anticoagulants may prolong prothrombotic time.
Normal and critical results
For normal patients who are not on anticoagulation, the international normalized ratio is usually 1.0. For patients who are on anticoagulant therapy, INR ranges from 2 to 3. Levels above 4.9 are considered critical and increase the risk of bleeding. The therapeutic range of INR differs in patients with prosthetic valve:
- With a mechanical bicuspid aortic valve without other risk factors for thromboembolism, the international normalized ratio is 2-3 during the first trimester after valve surgery. Three months later, from 1.5 to 2.
- With a new generation double-leaf valve, the INR is 2.5.
- With a mechanical aortic prosthetic valve and an additional risk factor for thromboembolic events (atrial fibrillation, previous thromboembolism, left ventricular systolic dysfunction, hypercoagulable state) or an older generation mechanical aortic valve prosthesis, the international normalized ratio is 3.
- With a mechanical mitral or tricuspid prosthetic valve, the target INR is 3.
Disturbing factors
Several factors that may influence the value of an international normalized relationship are listed below:
- Rules for the use of anticoagulants. Control and dose adjustment along with food and drug interactions make treatment difficult in clinical practice.
- Drug Interactions. Drugs that cause an increase in INR: antibiotics, antifungal agents, chemotherapeutic drugs, third-generation antidepressants, amiodarone, alopurinol. Several drugs may decrease the value of INR. For example, dicloxacillin, nafcillin, azathioprine, antiepileptic drugs, vitamin K, St. Johns wort extract.
- Chronic liver disease can interfere with the dosage of Warfarin, the value of the international normalized ratio and coagulation homeostasis.
- Acute infections and gastrointestinal illnesses can tighten the management of INR.
Possible risks
An INR level below the target range is associated with an increased risk of thrombosis. Studies have shown that a more than three-fold risk of recurrence of venous thromboembolism is associated with a sub-therapeutic level of international normalized attitudes.
An INR higher than the therapeutic range is associated with an increased risk of bleeding, among which the most alarming condition is intracranial hemorrhage. It can also be hematuria or gastrointestinal bleeding.
Safety and patient education
To reduce the adverse effects associated with anticoagulants, intensive patient education through the distribution of brochures has been proposed. Clinical guidelines recommend testing patients for knowledge of the fundamentals of an international normalized relationship. Portable devices for measuring it become available for most patients.
Clinical significance
Timely monitoring of INR and patient-oriented education to manage it is considered a prerequisite for caring for patients. The international normalized attitude in the therapeutic nomenclature offers a promising opportunity for optimal outcomes for patients through clinical practice guidelines.