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Interpretive Handbook

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Test 9236 :
Prothrombin Time, Plasma

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The prothrombin time (PT) represents the time elapsed between 1) addition of a standardized mixture of tissue thromboplastin and calcium to citrate anticoagulated plasma and 2) detection of clot formation, representing fibrin polymerization resulting from the generation of thrombin, which proteolytically transforms fibrinogen to fibrin.

 

Tissue thromboplastin is a mixture of phospholipid vesicles and tissue factor (TF), a protein cofactor. Tissue thromboplastins have traditionally been prepared from animal tissue extracts (brain, placenta, lung), however, the recent availability of recombinantly derived human TF combined with purified phospholipid mixtures allows preparation of well-defined tissue thromboplastin with several potential advantages.

 

Together with phospholipid, TF forms a complex with coagulation factor VII/VIIa (activated factor VII), providing an enzyme-cofactor complex which, in the presence of ionic calcium, activates proenzyme coagulation factor X to the enzyme factor Xa. Factor Xa, in turn, forms a complex with phospholipid, calcium, and activated factor V (Va, a protein cofactor) to form prothrombinase, which hydrolyzes factor II substrate (prothrombin) to the active coagulant enzyme thrombin. Thrombin hydrolyzes fibrinogen (factor I) by cleaving specific peptides (fibrinopeptides A and B), to form fibrin monomer, which assembles into fibrin polymers (a clot).

 

The PT is not sensitive to deficiencies of coagulation factors VIII, IX, XI, XII ("intrinsic pathway" factors), or factor XIII, although the TF/VIIa complex can activate factor IX (in addition to factor X). A prolonged PT indicates deficiency of 1 or more coagulation factors (I, II, V, VII, or X) or the presence of a coagulation inhibitor.

 

The PT is the most common test used for monitoring oral anticoagulant therapy (warfarin or Coumadin, and congeners).Oral anticoagulants reduce the activities of the 4 vitamin K-dependent procoagulant factors (factors II, VII, IX, and X), and the PT is sensitive to 3 of them.

 

The PT requires standardization because there are numerous thromboplastins and coagulation testing instruments, and they all vary in their responsiveness to the concentrations or activities of coagulation proteins. The international normalized ratio (INR) is a method of standardizing PT reporting for monitoring the intensity of oral anticoagulant therapy. The INR is the ratio of the patient's PT to the laboratory’s mean normal (reference) PT. The international sensitivity index (ISI) is an experimentally derived measurement, usually provided by the thromboplastin manufacturer, reflecting thromboplastin (and PT) sensitivity to coagulation deficiencies. More sensitive thromboplastins have a low ISI (1.0-1.2), whereas less sensitive thromboplastins have a higher ISI (eg, 2.0-3.0). Calculation of the INR is as follows:

 

INR = (Patient's PT/mean PT of reference range) ISI where:

-INR=international normalized ratio

-ISI=international sensitivity index

 

Recommended INR therapeutic ranges for orally administered drugs are as follows:

-Anticoagulation intensity: INR

-Standard intensity: 2.0 to 3.0

-Higher intensity: 3.0 to 4.5

 

The INR is used only for patients on stable oral anticoagulant therapy. It makes no significant contribution to the diagnosis or treatment of patients whose PT is prolonged for other reasons.

 

At Mayo Clinic and for Mayo Medical Laboratories clients, the PT test is performed with a sensitive thromboplastin (ISI 1.0 +/- 0.05), containing phospholipid and recombinantly derived TF.

Useful For Suggests clinical disorders or settings where the test may be helpful

Monitoring intensity of oral anticoagulant therapy when combined with INR reporting

 

Screening assay to detect deficiencies of 1 or more coagulation factors (factors I, II, V, VII, X) due to:

-Hereditary or acquired deficiency states

-Vitamin K deficiency

-Liver disease

-Specific coagulation factor inhibitors

 

Screening assay to detect coagulation inhibition ("circulating anticoagulants") associated with:

-Specific coagulation factor inhibitors

-Lupuslike anticoagulant inhibitors (antiphospholipid antibodies)

-Nonspecific prothrombin time inhibitors (eg, monoclonal immunoglobulins, elevated fibrin degradation products)

Interpretation Provides information to assist in interpretation of the test results

The prothrombin time (PT) test varies in its sensitivity to the activity of coagulation factors II, V, VII, and X, and is least sensitive to decreased factor II.

 

Mixing studies with normal plasma (ie, adding various proportions of normal pooled plasma to patient plasma) are useful in initial evaluation of prolonged PT when the cause of a prolonged PT is unknown (eg, not attributable to known oral anticoagulation or known coagulation factor deficiency):

-Typically an equal volume mixture (1:1) of patient and normal plasma shortens the prolonged PT into the normal (reference) range when there is a deficiency of 1 or more of the clotting factors (I, II, V, VII, X). Failure to normalize the PT in 1:1 mixing suggests presence of an inhibitor (eg, specific factor inhibitor, lupuslike anticoagulant or antiphospholipid antibody, non-specific inhibitor).

-Typically the addition of patient plasma of 1/10 or 2/10 volume of normal plasma shortens the prolonged PT, at least halfway toward the upper normal range, when there is a deficiency of 1 or more relevant coagulation factors. Inhibition is implied by failure to significantly shorten the PT.

-Additional coagulation testing may be needed to define the cause of an unexplained prolonged PT (eg, other clotting time tests, coagulation factor assays, testing for presence of a lupuslike anticoagulant). Mixing studies and such additional testing may be included in consultative testing (Coagulation Consultation).

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Not useful for detecting deficiencies of coagulation factors that have no influence on the prothrombin time (PT) test (eg, factors VIII, IX, XI, XII, XIII). International normalized ratio (INR) reporting of the PT is useful only for monitoring intensity of stable oral anticoagulant therapy. The activity of coagulation factor V (labile factor) typically may be 10% to 20% lower in frozen-thawed plasma specimens than in fresh specimens, even under optimum conditions of processing and transportation, or may be even lower if these conditions are suboptimal, and may lead to a falsely prolonged PT.

 

In an occasional individual, a more marked decrease of factor V activity may occur with freeze-thaw of plasma. Hence, the PT of frozen-thawed plasma potentially may be slightly more prolonged than would be observed in testing of fresh specimen. Frozen plasma kept on dry ice (solid carbon dioxide) in closed shipping containers may have spurious prolongation of PT, due to acidification of plasma by absorbed carbon dioxide. Exposure of thawed plasma to a normal atmosphere for a few minutes usually eliminates this spurious effect.

 

The PT is much less sensitive to heparin effect than is the activated partial thromboplastin time (APTT), and therapeutic concentrations of heparin usually cause only slight prolongation of the PT (< or =1 sec with normal plasma, thromboplastin ISI 1.0, heparin < or =1 microgram/mL).

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

PROTHROMBIN TIME

9.5-13.8 seconds

 

INTERNATIONAL NORMALIZED RATIO (INR)

0.8-1.2

The INR is used only for patients on stable oral anticoagulant therapy. It makes no significant contribution to the diagnosis or treatment of patients whose PT is prolonged for other reasons.


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