PT and INR: It's Prothrombin Time

Feeling blue? You might need to have your PT tested.

Prothrombin Time (PT) and INR

A common test ordered for the medical laboratory is the PT (also known as the Prothrombin Time, or PT/INR). This is often ordered for both routine outpatient testing to monitor anticoagulant therapy and STAT testing in the Emergency Department to evaluate actively bleeding patients or in preparation for a procedure. It is considered a coagulation test (often referred to as “coag”) along with the PTT (also known as APTT), D-Dimer, and Fibrinogen. The coagulation department is often part of the hematology, and sometimes the chemistry department.

What does the PT actually measure?

The PT measures the time it takes for blood plasma to clot after the addition of tissue factor (thromboplastin) and calcium. It assesses the extrinsic pathway of coagulation, which includes factors I (fibrinogen), II (prothrombin), V, VII, and X. A normal PT is roughly between 10 and 14 seconds, take that number with a grain of salt. What you should really pay attention to is the INR.

International Normalized Ratio (INR)

The INR is a standardized way of expressing PT results, making them comparable across different laboratories and testing systems. The reason this is necessary is that there is variation among reagents and across different populations of patients. Different regions may have slightly different “normal” values (although they shouldn’t vary wildly). The INR is calculated using the PT and the ISI of the thromboplastin reagent used in the test, as we’ll see below.

How it is collected

The PT/INR is collected in a Sodium Citrate tube (a blue top). It is very important that the correct amount of blood is collected into the tube because the additives must be at a certain concentration when the tube is filled with blood.

A platelet and a red blood cell meeting in the wild.

Clinical Significance

PT/INR is used to...

-> Monitor patients on warfarin (commonly known as Coumadin) therapy.

-> Diagnose bleeding disorders.

-> Assess liver function, as the liver produces most of the clotting factors.

-> Evaluate the effectiveness of the vitamin K-dependent clotting factors.

What does a high or low PT or INR mean?

High PT/INR

A high PT or INR indicates that the blood is taking longer than normal to clot. This can be due to several factors:

Causes of High PT/INR

Anticoagulant Therapy:

Patients taking warfarin or other anticoagulants often have elevated INR values. The goal is to keep the INR within a therapeutic range (usually 2.0 to 3.0 for most indications) to prevent clot formation.

Liver Disease:

The liver produces most of the clotting factors, so liver dysfunction can lead to a decrease in these factors and a prolonged PT/INR.

Vitamin K Deficiency:

Vitamin K is essential for the synthesis of clotting factors II, VII, IX, and X. A deficiency can result from poor dietary intake, malabsorption, or use of antibiotics that affect gut flora responsible for vitamin K production.

Disseminated Intravascular Coagulation (DIC):

In DIC, there is widespread activation of clotting, leading to consumption of clotting factors and platelets, which can result in prolonged PT/INR.

Inherited Clotting Factor Deficiencies:

Conditions such as hemophilia (though more commonly associated with the intrinsic pathway and APTT) or other rare factor deficiencies can cause prolonged PT/INR.

Medications and Substances:

Certain medications (e.g., antibiotics, amiodarone) and substances (e.g., alcohol) can interfere with clotting factor synthesis or function.

Low PT/INR

A low PT or INR means that the blood is clotting more quickly than normal. This is less common and can also have several underlying causes:

Causes of Low PT/INR

Hypercoagulable States:

Conditions such as Factor V Leiden mutation, protein C or S deficiency, and antithrombin III deficiency can lead to an increased tendency to form clots, resulting in a shorter PT/INR.

Excess Vitamin K:

High levels of vitamin K can lead to increased production of clotting factors, reducing PT/INR. This could be due to dietary excess or supplementation.

Compensatory Mechanisms:

In some chronic conditions, the body may produce more clotting factors as a compensatory mechanism, leading to a shortened PT/INR.

Laboratory Error:

Sample handling issues or technical errors during testing can result in falsely low PT/INR values.

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How is the INR calculated?

INR = (PT test / PT normal)^ISI

Where the PT normal is a geometrical mean calculated by a study the laboratory does when a new lot of PT reagent is brought into use (usually 10 healthy males and 10 healthy females not on anticoagulant therapy). You can determine this by using Excel to calculate the geomean of your set of data.

And the ISI is a value specific to the lot of PT reagent and is provided by the manufacturer of the PT reagent (usually printed on the insert that comes with the reagent). ISI stands for International Sensitivity Index.

And PT test is, well the PT result of a patient that you’re testing, of course.

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Limitations and Challenges in PT testing

Variability in Thromboplastin Reagents

Despite standardization efforts, variability in thromboplastin reagents can still affect PT and INR results. Different manufacturers' reagents can produce slightly different results, emphasizing the importance of using the ISI for standardization.

Patient Factors

Various patient-related factors can influence PT and INR results, including diet, medication interactions, liver function, and genetic variations affecting warfarin metabolism.

Laboratory Practices

Differences in laboratory techniques, equipment, and sample handling can also impact the accuracy and consistency of PT and INR measurements. PT/INR samples are usually collected in a light blue-top tube containing Sodium Citrate. Note: if there is any contamination from another tube containing anticoagulant, it will greatly affect the PT/INR values, which measure coagulation. For instance, the additive to a purple top tube is EDTA, which binds calcium, part of the prothrombin time mechanism. Don't mix tubes. Duh.

Hemolyzed Samples

Hemolysis refers to the rupture of red blood cells and the release of their contents into the plasma. Hemolyzed samples can affect PT tests in several ways:

Release of Intracellular Components: The release of intracellular components, such as enzymes and clotting factors from the red blood cells, can interfere with the clotting process measured by the PT test.

Altered Optical Density: Hemolysis can change the optical density of the plasma, leading to interference in the detection methods used in some PT test systems, especially those that rely on optical clot detection.

Artificial Prolongation or Shortening: The presence of free hemoglobin and other cellular components can cause either a falsely prolonged or shortened PT, depending on the extent of hemolysis and the specific testing method used.

Lipemic Samples

Lipemia refers to the presence of a high concentration of lipids in the blood, which can make the plasma appear cloudy or milky. Lipemic samples can affect PT tests in the following ways:

Optical Interference: Similar to hemolyzed samples, the increased turbidity due to lipids can interfere with optical clot detection methods. The light scattering caused by lipemic samples can lead to inaccurate readings of the clotting time.

Physical Interference: Lipids can also physically interfere with the clot formation process, potentially leading to erroneous PT results.

Dilution Effect: Excess lipids in the sample may dilute the plasma, which can alter the concentration of clotting factors and other components, potentially leading to inaccurate PT results.

Point-of-Care Testing options for PT/INR

Point-of-care (POC) testing devices for PT and INR are becoming increasingly popular, allowing for more convenient and rapid monitoring, particularly for patients on long-term anticoagulant therapy. These devices are particularly easy to implement, as they are often CLIA-waived (so they can be used by nurses and phlebotomists) and they are factory calibrated, meaning that they don’t need to have periodic verification studies performed, just QC. The limitation of point-of-care testing is that they are usually validated for a smaller range than a benchtop analyzer and any out-of-reportable-range high values will need to be sent to a laboratory that does a full range of testing as described above.

We got a bleeder!!!

So... Prothrombin Time (PT) and the International Normalized Ratio (INR) are indispensable tools in modern medicine, essential for monitoring anticoagulant therapy and diagnosing coagulation disorders. The calculation of the ISI and geometric mean ensures the standardization and reliability of these tests across different laboratories. Despite challenges, ongoing advancements in reagent technology and testing methods continue to enhance the accuracy and clinical utility of PT and INR, contributing to better patient outcomes and safer management of anticoagulant therapy.

Hopefully you now know why PT is used for trauma patients who are bleeding out and people going to routine checkups at their local clinic. BECAUSE IT'S USEFUL!