Prothrombin time
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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 12 - 15 seconds; the range for the INR is 0.8-1.2. It is used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway.
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Background
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. Deficiencies in vitamin K, which can be caused by warfarin, liver or biliary damage (leading to poor absorption of ingested vitamin K), or lack of intestinal colonization by bacteria in newborns, result in an increased prothrombin time.
Measurement
Laboratory method
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 Vacutainer® 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 put through a coagulation machine, 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. Tissue factor (aka Factor III or thromboplastin) is added, and the time the sample takes to clot is measured optically.
The prothrombin ratio is the prothrombin time for a patient, divided by the result for control plasma.
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 so that patients can check their own INRs 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. (It should not be forgotten that none of these methods is absolutely constant: two consecutive lab INRs from the same sample might easily vary as much as a lab INR can from an NPT measurement for the same patient.)
In a typical NPT setup a small table-top device is used; for example the Roche Coagucheck S (CoaguChek XS launched on 1st February 2006), or the more recently (2005) introduced HemoSense INRatio. 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.
Practice varies on whether the patient also decides the dose: in most cases in the UK it appears that it is still the clinic or GP who does this, though in principle it is possible for the patient to do it for themselves, and indeed this is widespread in some other countries, such as Germany. In the USA patients change their dose only on the advice of their physician.
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 for patients with mechanical heart valves, while private insurers may cover for other indications.
There is some evidence to suggest that NPT may be less accurate for certain patients, for example those who have the lupus anticoagulant. However a patient considering moving to this method of testing would in any case always need to discuss it with a haematologist, and the issue of NPT's appropriateness for the particular patient's condition would undoubtedly need to be looked at.
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 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.
<math> {INR}= \left(\frac{PT_{test}}{PT_{normal}}\right) ^ {ISI} </math>fr:Taux de prothrombine