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 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.

Contents 1 Laboratory measurement 1.1 Methodology 1.2 International normalized ratio 1.3 Interpretation 1.4 Factors determining accuracy 2 Statistics 3 Near-patient testing 3.1 Guidelines 4 History 5 References

[edit] Laboratory measurement

[edit] Methodology

The prothrombin time is most commonly measured using blood plasma. Blood is drawn into a test tube containing liquid citrate, which acts as an anticoagulant by binding the calcium in a sample. The blood is mixed, then centrifuged to separate blood cells from plasma. In newborns, whole blood is used.^{[citation needed]}

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. If the tube is underfilled or overfilled with blood, the standardized dilution of 1.1 is no longer valid. 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.

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.

[edit] International normalized ratio

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

[edit] 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.

A high INR level such as INR=5 indicates that there is a high chance of bleeding, whereas if the INR=0.5 then there is a high chance of having a clot. Normal range for a healthy person is 0.9–1.3, and for people on warfarin therapy, 2.0–3.0, although the target INR may be higher in particular situations, such as mechanical heart valves.

Condition	Prothrombin time	Partial thromboplastin time	Bleeding time
Vitamin K deficiency	prolonged	prolonged	unaffected
Von Willebrand disease	prolonged	unaffected	prolonged
Disseminated intravascular coagulation	prolonged	prolonged	prolonged
Haemophilia	unaffected	prolonged	unaffected

[edit] Factors determining accuracy

Lupus anticoagulant, a circulating inhibitor predisposing for thrombosis, may skew PT results, depending on the assay used.^[1] 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,^[2] casting doubt on the long-term tenability of PT/INR as a measure for anticoagulant therapy.^[3]

[edit] Statistics

An estimated 800 million PT/INR assays are performed annually worldwide.^[3]

[edit] Near-patient testing

In addition to the laboratory method outlined above, near-patient testing (NPT) or home INR monitoring 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 be gaining acceptance for its ability to deliver results close in accuracy to those of the lab.^[4]

In a typical NPT setup a small table-top device is used; for example the Roche Coaguchek S, 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. 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,^{[citation needed]} while in the UK and the USA this remains in the hands of a health care professional.

A significant advantage of home testing is the evidence that patient self-testing with medical support and patient self-management (where patients adjust their own anticoagulant dose) improves anticoagulant control. A meta analysis which reviewed 14 trials showed that home testing led to a reduced incidence of complications (bleeding and thrombosis) and improved the time in the therapeutic range, which is an indirect measure of anticoagulant control.^[5]

Other advantages of the NPT approach are that 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.^{[citation needed]}

[edit] Guidelines

International guidelines were published in 2005 to govern home monitoring of oral anticoagulation by the International Self-Monitoring Association for Oral Anticoagulation.^[6] The international guidelines study stated, “The consensus agrees that patient self-testing and patient self-management are effective methods of monitoring oral anticoagulation therapy, providing outcomes at least as good as, and possibly better than, those achieved with an anticoagulation clinic. All patients must be appropriately selected and trained. Currently available self-testing/self-management devices give INR results which are comparable with those obtained in laboratory testing.”

Medicare coverage for home testing of INR has been expanded in order to allow more people access to home testing of INR in the USA. The release on the 19th March 2008 said, “[t]he Centers for Medicare & Medicaid Services (CMS) expanded Medicare coverage for home blood testing of prothrombin time (PT) International Normalized Ratio (INR) to include beneficiaries who are using the drug warfarin, an anticoagulant (blood thinner) medication, for chronic atrial fibrillation or venous thromboembolism.” In addition, “[t]hose Medicare beneficiaries and their physicians managing conditions related to chronic atrial fibrillation or venous thromboembolism will benefit greatly through the use of the home test.”^[7]

[edit] History

The prothrombin time was discovered by Dr Armand Quick and colleagues in 1935,^[8] and a second method was published by Dr Paul Owren^[9] (also called the "p and p" or "prothrombin and proconvertin" method). It aided in the identification of the anticoagulants dicumarol and warfarin,^[10] 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.^[11] The INR became widely accepted worldwide, especially after endorsement by the World Health Organisation.^[12]

[edit] References

v • d • e Serology: blood tests Clinical biochemistry Metabolic panel/ plasma osmolality BMP: electrolytes (Na+/K+, Cl-/HCO3-) • renal function, BUN-to-creatinine ratio (BUN/Creatinine) • Glucose • Ca CMP: BMP + protein tests (Human serum albumin, Serum total protein) • liver function tests (ALP, ALT, AST, Bilirubin) Acid-base homeostasis Arterial blood gas/Arterial blood gas sampling • Base excess • Anion gap • CO2 content Iron Transferrin saturation = Serum iron / Total iron-binding capacity Blood sugar Glucose test • Glucose tolerance test • Glycemia • Noninvasive glucose • C-peptide • Fructosamine • Random glucose test • Glycosylated hemoglobin Endocrine ACTH stimulation test • Thyroid function tests Cardiac marker Troponin test • Creatine kinase • Glycogen phosphorylase isoenzyme BB Other Beutler test • MELISA • RAST test • Blood lipids • Tumor marker Hematology Clotting vWF: Ristocetin induced platelet agglutination clotting factors: Prothrombin time • Partial thromboplastin time other/general coagulation: Bleeding time • Thrombin clotting time  • animal enzyme (Reptilase time, Ecarin clotting time, Dilute Russell's viper venom time) • Thromboelastography fibrinolysis: Euglobulin lysis time • D-dimer CBC/Red blood cell indices Hematocrit • Hemoglobin • RBC count ratios: Mean corpuscular hemoglobin • Mean corpuscular hemoglobin concentration • Mean corpuscular volume Fetal hemoglobin: Apt-Downey test • Kleihauer-Betke test Other Blood film Immunology Infections viral infection: HIV (HIV test, BDNA test) • Monospot test bacterial infection: syphilis (VDRL, Rapid plasma reagin, Wassermann test, FTA-ABS) • rickettsia (Weil-Felix test) • helicobacter (HelicoCARE direct) • streptococcus (Antistreptolysin O titre) protozoan infection: toxoplasmosis (Sabin-Feldman dye test) Inflammation C-reactive protein • Erythrocyte sedimentation rate see also reference ranges for blood tests