Prothrombin time
Encyclopedia
The prothrombin time and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation
. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin
dosage, liver damage, and vitamin K
status. PT measures factors I
, II
, V
, VII
, and X
. It is used in conjunction with the activated partial thromboplastin time
(aPTT) which measures the intrinsic pathway.
.
. 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, a capillary whole blood specimen is used.
The plasma is analyzed by a biomedical scientist
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is underfilled or overfilled with blood, the standardized dilution of 1 part anticoagulant to 9 parts whole blood is no longer valid. For the prothrombin time test the appropriate sample is the blue top tube, or sodium citrate tube, which is a liquid anticoagulant.
Tissue factor
(also known as factor III) 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.
to clot after addition of tissue factor
(obtained from animals such as rabbits, or recombinant tissue factor, or from brains of autopsy patients). 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 functional factor VII
in the body. Factor VII has a short half-life
and the carboxylation of its glutamine residues requires vitamin K
. The prothrombin time can be prolonged as a result of deficiencies in vitamin K, warfarin
therapy, 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 for those with a mechanical heart valve
, or bridging
warfarin with a low-molecular weight heparin (such as enoxaparin
) perioperatively.
, a circulating inhibitor predisposing for thrombosis, may skew PT results, depending on the assay used. 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, casting doubt on the long-term tenability of PT/INR as a measure for anticoagulant therapy.
, 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.
In a typical NPT setup a small table-top device is used; for example the Roche
Coaguchek S, the International Technidyne Corporation Hemochron Signature, 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 (pharmacist, 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. For example, patients using services such as Philips INR@Home http://www.inrselftest.com will phone in their INR results on a weekly basis and this information is transmitted to their doctor, who is also alerted if out-of-range levels should require an immediate intervention or adjustment to medications.
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.
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.Medicare is now covering home testing for patients with chronic atrial fibrillation. Home testing requires a doctor's prescription.
There is some evidence to suggest that NPT may be less accurate for certain patients, for example those who have the lupus anticoagulant
.
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.”
s dicumarol
and warfarin
, 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. The INR became widely accepted worldwide, especially after endorsement by the World Health Organization
.
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
dosage, liver damage, and vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
status. PT measures factors I
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
, II
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
, V
Factor V
Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor...
, VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
, and X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
. It is used in conjunction with the activated partial thromboplastin time
Partial thromboplastin time
The partial thromboplastin time or activated partial thromboplastin time is a performance indicator measuring the efficacy of both the "intrinsic" and the common coagulation pathways...
(aPTT) which measures the intrinsic pathway.
Normal range
The reference range for prothrombin time is usually around 10-13 seconds; the normal range for the INR is 0.8–1.2. Clinicians desiring therapeutic anticoagulation may aim for a higher INR - in many cases ranging from 2-3 - using anticoagulants such as warfarinWarfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
.
Methodology
The prothrombin time is most commonly measured using blood plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Blood is drawn into a test tube
Test tube
A test tube, also known as a culture tube or sample tube, is a common piece of laboratory glassware consisting of a finger-like length of glass or clear plastic tubing, open at the top, usually with a rounded U-shaped bottom....
containing liquid citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
, 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, a capillary whole blood specimen is used.
The plasma is analyzed by a biomedical scientist
Biomedical scientist
A biomedical scientist is a scientist trained in biology, particularly in the context of medicine...
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 part anticoagulant to 9 parts whole blood is no longer valid. For the prothrombin time test the appropriate sample is the blue top tube, or sodium citrate tube, which is a liquid anticoagulant.
Tissue factor
Tissue factor
Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin...
(also known as factor III) 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 normalised ratio
The result (in seconds) for a prothrombin time performed on a normal individual will vary according to the type of analytical system employed. This is due to the variations between different batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results. Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an internationally reference tissue factor. The ISI is usually between 1.0 and 2.0. 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 analytical system used.Interpretation
The prothrombin time is the time it takes plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
to clot after addition of tissue factor
Tissue factor
Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin...
(obtained from animals such as rabbits, or recombinant tissue factor, or from brains of autopsy patients). This measures the quality of the extrinsic pathway (as well as the common pathway) of coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. The speed of the extrinsic pathway is greatly affected by levels of functional factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...
in the body. Factor VII has a short half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
and the carboxylation of its glutamine residues requires vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
. The prothrombin time can be prolonged as a result of deficiencies in vitamin K, warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
therapy, malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
, or lack of intestinal colonization by bacteria (such as in newborns). In addition, poor factor VII synthesis (due to liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
) or increased consumption (in disseminated intravascular coagulation
Disseminated intravascular coagulation
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
) 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 for those with a mechanical heart valve
Artificial heart valve
An artificial heart valve is a device implanted in the heart of a patient with heart valvular disease. When one of the four heart valves malfunctions, the medical choice may be to replace the natural valve with an artificial valve. This requires open-heart surgery.Valves are integral to the normal...
, or bridging
Bridging
-Construction:* Building of bridges across a gap*Cross braces used between joists to stabilize them.-Electronics:* In electronics, using a low source impedance to drive a large load impedance for maximum voltage transfer, called impedance bridging...
warfarin with a low-molecular weight heparin (such as enoxaparin
Enoxaparin
Enoxaparin is a low molecular weight heparin marketed under the trade names Lovenox and Clexane, among others. It is an anticoagulant used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection...
) perioperatively.
Factors determining accuracy
Lupus anticoagulantLupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
, a circulating inhibitor predisposing for thrombosis, may skew PT results, depending on the assay used. 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, casting doubt on the long-term tenability of PT/INR as a measure for anticoagulant therapy.
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 KingdomUnited Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, 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.
In a typical NPT setup a small table-top device is used; for example the Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
Coaguchek S, the International Technidyne Corporation Hemochron Signature, 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
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
on insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, and are easily taught and practiced.
Local policy determines whether the patient or a coagulation specialist (pharmacist, 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. For example, patients using services such as Philips INR@Home http://www.inrselftest.com will phone in their INR results on a weekly basis and this information is transmitted to their doctor, who is also alerted if out-of-range levels should require an immediate intervention or adjustment to medications.
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.
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
Medicare (United States)
Medicare is a social insurance program administered by the United States government, providing health insurance coverage to people who are aged 65 and over; to those who are under 65 and are permanently physically disabled or who have a congenital physical disability; or to those who meet other...
for patients with mechanical heart valves, while private insurers may cover for other indications.Medicare is now covering home testing for patients with chronic atrial fibrillation. Home testing requires a doctor's prescription.
There is some evidence to suggest that NPT may be less accurate for certain patients, for example those who have the lupus anticoagulant
Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. It is important to note that this disease name is actually a misnomer...
.
Guidelines
International guidelines were published in 2005 to govern home monitoring of oral anticoagulation by the International Self-Monitoring Association for Oral Anticoagulation. 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.”
History
The prothrombin time was discovered by Dr Armand Quick and colleagues in 1935, and a second method was published by Dr Paul Owren, also called the "p and p" or "prothrombin and proconvertin" method. It aided in the identification of the anticoagulantAnticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
s dicumarol
Dicumarol
Dicoumarol or dicumarol is an anticoagulant that functions as a vitamin K antagonist . It is also used in biochemical experiments as an inhibitor of reductases....
and warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
, 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. The INR became widely accepted worldwide, especially after endorsement by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
.