Clinical Information

Prothrombin is a plasma protein with a molecular weight of 68,700 Da. It is an unstable protein that can split easily into smaller compounds, one of which is thrombin. Prothrombin is formed continually by the liver, and it is continually being used throughout the body for blood clotting. If the liver fails to produce prothrombin, in a day or so the prothrombin concentration in the plasma falls to levels too low to provide normal blood coagulation. Vitamin K is required by the liver for normal activation of prothrombin as well as other clotting factors. Therefore, either lack of vitamin K or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin concentration so low that a bleeding tendency results.

Prothrombin time (PT) is used as a screening test to detect a deficiency of one or more of the clotting factors of the extrinsic coagulation system (I, II, V, VII, or X) due to a hereditary or acquired deficiency, liver disease, vitamin K deficiency, or presence of inhibitors. Inhibitors include specific coagulation factor inhibitors, Lupus-like anticoagulant inhibitors (eg, antiphospholipid antibodies), and nonspecific prothrombin time inhibitors (eg, monoclonal immunoglobulins, elevated fibrin degradation products). Mixing studies with normal plasma are useful in initial evaluation of prolonged PT when the cause is unknown (eg, not attributable to known oral anticoagulation or known coagulation factor deficiency). One of the following tests may be appropriate, depending on the clinical picture:

-ALUPP / Lupus Anticoagulant Profile, Plasma

-AATHR / Thrombophilia Profile, Plasma and Whole Blood

-ALBLD / Bleeding Diathesis Profile, Limited, Plasma

-APROL / Prolonged Clot Time Profile, Plasma

PT results produced by different assays may vary significantly as there are differences in activity of the tissue factor and the instrument used to perform the test. Tissue factor is isolated from a variety of sources by assay manufacturers, and different batches may have different activity. Calculation of the international normalized ratio (INR) addresses this problem by normalizing the PT result. For this reason, INR is used to monitor oral anticoagulant therapy (warfarin or Coumadin).

Warfarin inhibits the enzyme vitamin K epoxide reductase complex 1 (VKORC1), which is responsible for converting vitamin K to its active, reduced form. By inhibiting VKORC1, warfarin decreases the available active form of vitamin K in the tissues. Thus, when warfarin is given to a patient, the amounts of active prothrombin and factors VII, IX, and X, all formed by the liver degrade and are replaced by inactive factors. Although the coagulation factors continue to be produced, they have greatly decreased coagulant activity.

Bleeding is the primary adverse reaction associated with warfarin use, and warfarin is among the top 10 drugs with the largest number of serious adverse events reported to the FDA. For these reasons, monitoring therapy closely and adjusting dose accordingly is critical.

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