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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and Keywords: International normalized ratio, INR, prothrombin ratio, PR, PT

Overview

The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage and vitamin K status. The reference range for prothrombin time is usually around 12-15 seconds; the normal range for the INR is 0.8-1.2. PT measures factors II, V, VII, X and fibrinogen. It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway.

Historical Perspective

The prothrombin time was discovered by Dr Armand Quick and colleagues in 1935,[1] and a second method was published by Dr Paul Owren[2] (also called the "p and p" or "prothrombin and proconvertin" method). It aided in the identification of the anticoagulants dicumarol and warfarin[3], and was used subsequently as a measure of activity for warfarin when used therapeutically.

The INR was introduced in the early 1980s when it turned out that there was a large degree of variation between the various prothrombin time assays, a discrepancy mainly due to problems with the purity of the thromboplastin (tissue factor) concentrate.[4] The INR became widely accepted worldwide, especially after endorsement by the World Health Organisation[5]

Causes of Elevated PT

Laboratory Measurement

Methodology

The prothrombin time can be measured roughly on whole blood (which is done in neonates), but is more commonly measured from blood plasma. Blood is drawn into a test tube containing liquid citrate. Citrate acts as an anticoagulant by binding the calcium in a sample. The blood is mixed, then centrifuged to separate blood cells from plasma.

The plasma is analyzed by a medical technologist on an automated instrument at 37°C, which takes a sample of the plasma. An excess of calcium is added (thereby reversing the effects of citrate), which enables the blood to clot again. For an accurate measurement the proportion of blood to citrate needs to be fixed; many laboratories will not perform the assay if the tube is underfilled and contains a relatively high concentration of citrate. This is because Vacutainer test tubes generally contain a powdered anticoagulant to prevent blood from clotting. For the prothrombin time test the appropriate sample is the blue top tube, or citrate tube, which is a liquid anticoagulant. Just as adding solvent to any solution will dilute it, adding liquid anticoagulant to blood will dilute it. This dilution will cause a falsely long prothrombin time. So, all analysis takes this dilution into account by multiplying the result by 1.1 to account for the dilution. If a tube is underfilled or overfilled with blood, the standardized dilution of 1.1 is no longer valid.

Tissue factor (also known as factor III or thromboplastin) is added, and the time the sample takes to clot is measured optically. Some laboratories use a mechanical measurement, which eliminates interferences from lipemic and icteric samples.

The prothrombin ratio is the prothrombin time for a patient, divided by the result for control plasma.

International Normalized Ratio (INR)

Because of differences between different batches and manufacturers of tissue factor (it is a biologically obtained product), the INR was devised to standardise the results.

Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4.

The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used.

Click here for more details about the use of INR for warfarin monitoring.

Interpretation

The prothrombin time is the time it takes plasma to clot after addition of tissue factor (obtained from animals). This measures the quality of the extrinsic pathway (as well as the common pathway) of coagulation.

The speed of the extrinsic pathway is greatly affected by levels of factor VII in the body. Factor VII has a short half-life and its synthesis requires vitamin K. The prothrombin time can be prolonged as a result of deficiencies in vitamin K, which can be caused by warfarin, malabsorption or lack of intestinal colonization by bacteria (such as in newborns). In addition, poor factor VII synthesis (due to liver disease) or increased consumption (in disseminated intravascular coagulation) may prolong the PT.

Factors Determining Accuracy

Lupus anticoagulant, a circulating inhibitor predisposing for thrombosis, may skew PT results, depending on the assay used.[6] Variations between various thromboplastin preparations have in the past led to decreased accuracy of INR readings, and a 2005 study suggested that despite international calibration efforts (by INR) there were still statistically significant differences between various kits[7], casting doubt on the long-term tenability of PT/INR as a measure for anticoagulant therapy.[8]

Statistics

An estimated 800 million PT/INR assays are performed annually worldwide.[8]

Near-Patient Testing

In addition to the laboratory method outlined above, near-patient testing (NPT) is becoming increasingly common in some countries. In the United Kingdom, for example, near-patient testing is used both by patients at home, and by some anticoagulation clinics (often hospital-based) as a fast and convenient alternative to the lab method. After a period of doubt about the accuracy of NPT results, a new generation of machines and reagents seems to gaining acceptance for its ability to deliver results close in accuracy to those of the lab.[9]

In a typical NPT setup a small table-top device is used; for example the Roche Coagucheck® XS (2011), or the HemoSense INRatio®2. A drop of capillary blood is obtained with an automated finger-prick, which is almost painless. This drop is placed on a disposable test strip with which the machine has been prepared. The resulting INR comes up on the display a few seconds later. Similar testing methods are used by diabetics on insulin, and are easily taught and practiced.

Local policy determines whether the patient or a coagulation specialist (nurse, general practitioner or hospital doctor) interprets the result and determines the dose of medication. In Germany, patients may adjust the medication dose themselves, while in the UK and the USA this remains in the hands of a health care professional.

The advantages of the NPT approach are obvious: it is fast and convenient, usually less painful, and offers, in home use, the ability for patients to measure their own INRs when required. Among its problems are that quite a steady hand is needed to deliver the blood to the exact spot, that some patients find the finger-pricking difficult, and that the cost of the test strips must also be taken into account. In the UK these are available on prescription so that elderly and unwaged people will not pay for them and others will pay only a standard prescription charge, which at the moment represents only about 20% of the retail price of the strips. In the USA, NPT in the home is currently reimbursed by Medicare and many private insurers for patients with mechanical heart valves, atrial fibrillation, deep vein thrombosis, and pulmonary embolism for patients on long term Coumadin therapy.

Weekly Patient Self PT/INR Testing is covered by many insurances and can be obtained by going through an Independent Diagnostic Testing Facility (IDTF)[2]. To enroll in the program patients must have a qualifying diagnosis, be on long term Coumadin therapy, have been anticoagulated for at least 90 days, and are willing and able to test on a weekly basis. Patients then undergo a face to face training and education on how to use the meter and report their test results. Test results are then called in or reported online to the IDTF and transmitted instantaneously to the physician or clinic for interpretation. A company called Advanced Cardio Services provides patients with Medicare and private insurances with this all inclusive service. [3]

There is some evidence to suggest that NPT may be less accurate for certain patients, for example those who have the lupus anticoagulant. It is advised that patients with Lupus and Anti-phospholipid antibody syndrome should have a lab test performed using the Tilt-Tube method. This is because the reagents in the test strips contain phospholipids that may interact with the anti-phospholipid antibodies, thus causing falsely high INR readings.

An alternative approach to performing PT/INR determinations in NPT settings was presented in 2006 by the Swedish company ZAFENA. The company's product, Simple Simon PT (SSPT), has transformed the hospital laboratory's wet-chemistry method, performed at 37°C on plasma samples, to ambient room temperature performance on either whole-blood or plasma. SSPT yields accuracy and precision comparable to those of hospital laboratory methods. The day-to-day quality of the testing is assured by conventional control plasmas. Results are obtained within 90 seconds on 10 microliters of sample. The small, battery powered measuring device is suited for a doctor's office or the small laboratory of a primary care unit. Since, the SSPT does a concomitant determination of the hematocrit of the sample, blood and plasma may be interchangeably analyzed, and the effects of hematocrit variations are accounted for. Portions of PT reagent are stored in capped reaction tubes aboard the measuring device and can immediately be put to use; no temperature equilibration time is required. The possibility of using SSPT for internet supported, distance independent PT/INR determinations, e.g. in home settings, has been explored in a demonstrator project supported jointly by the government agency Vinnova and KK-stiftelsen foundation, both of Sweden. Simple Simon PT has found users in Sweden, Norway and Denmark. http://www.zafena.se/English/SimpleSimon

Treatment of Elevated PT

An elevated PT can be reversed in some cases by the administration of IV Vitamin K. Adequate synthetic function of the liver must be present for this to be effective. There can be allergic reactions to Vitamin K reactions. Fresh frozen plasma (FFP) can be administered to rapidly replenish depleted factors responsible for an elevated PT.

References

  1. Quick AJ, Stanley-Brown M, Bancroft FW. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sc 1935;190:501.
  2. Owren PA, Aas K. The control of dicumarol therapy and the quantitative determination of prothrombin and proconvertin. Scand J Clin Lab Invest 1951;3:201-8. PMID 14900966.
  3. Campbell HA, Smith WK, Roberts WL, Link KP. Studies on the hemorrhagic sweet clover disease. II. The bioassay of hemorrhagic concentrates by following the prothrombin level in the plasma of rabbit blood. J Biol Chem 1941;138:1-20.
  4. Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med 2001;134:409-17. PMID 11242501.
  5. Expert Committee on Biological Standardization. Requirements for thromboplastins and plasma used to control oral anticoagulant therapy. World Health Organ Tech Rep Ser 1983;33:81-105.
  6. Della Valle P, Crippa L, Garlando AM, Pattarini E, Safa O, Vigano D'Angelo S, D'Angelo A. Interference of lupus anticoagulants in prothrombin time assays: implications for selection of adequate methods to optimize the management of thrombosis in the antiphospholipid-antibody syndrome. Haematologica 1999;84:1065-74. PMID 10586206.
  7. Horsti J, Uppa H, Vilpo JA. Poor agreement among prothrombin time international normalized ratio methods: comparison of seven commercial reagents. Clin Chem 2005;51:553-60. PMID 15665046.
  8. 8.0 8.1 Jackson CM, Esnouf MP. Has the time arrived to replace the quick prothrombin time test for monitoring oral anticoagulant therapy? Clin Chem 2005;51:483-5. PMID 15738512.
  9. Poller L, Keown M, Chauhan N, Van Den Besselaar AM, Tripodi A, Shiach C, Jespersen J; ECCA Steering Group Members. European Concerted Action on Anticoagulation. Correction of displayed international normalized ratio on two point-of-care test whole-blood prothrombin time monitors (CoaguChek Mini and TAS PT-NC) by independent international sensitivity index calibration. Br J Haematol 2003;122:944-9. PMID 12956765.



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