005199

Prothrombin Time (PT)



Reference Interval:

Nonmedicated patients: INR 0.8-1.2

Recommended therapeutic ranges for oral anticoagulant therapy:6

INR 2.0-3.0:

• Prophylaxis of venous thrombosis

• Treatment of venous thrombosis

• Treatment of pulmonary embolism

• Prevention of systemic embolism

− tissue heart valves

− AMI to prevent systemic embolism (if oral anticoagulant therapy is elected to prevent recurrent MI, and INR of 2.5-3.5 is recommended, consistent with US Food and Drug Administration recommendations)

• Bileaflet mechanical valve in aortic position

Mechanical prosthetic valves (high risk): INR 2.5-3.5
Use:

Evaluation of the extrinsic coagulation system; aid in screening for congenital and acquired deficiencies of factors II, V, VII, X, and fibrinogen.7-9 This test is used clinically for the therapeutic monitoring of warfarin (Coumadin®) anticoagulant therapy.
Limitations:

The PT test may not be sensitive to slight deficiencies of single factors.10 Heparin can extend the PT.10 Lupus anticoagulants may affect prothrombin time producing results that do not accurately reflect the true level of anticoagulation. The PT (and aPTT) results can be extended in patients receiving antithrombin anticoagulants such as hirudin and argatroban.10 These patients can be monitored for warfarin effectiveness with a chromogenic factor X assay, which is not affected by lupus anticoagulant or thrombin inhibitors.10
Methodology:

Prothrombin time reagent containing thromboplastin and calcium chloride is mixed with the patient plasma and the time to clot formation is measured photo-optically. The calcium chloride overcomes the citrate anticoagulant and allows the tissue factor in the thromboplastin to initiate coagulation. The prolongation of the clotting time correlates with the degree of deficiency or inhibition of the extrinsic pathway factors.
Additional Information:

The thromboplastin reagent used by LabCorp consists of recombinant tissue factor mixed with synthetic phospholipid. Recombinant tissue factor is free from contamination with coagulation factors that can be found in tissue factor extracted from other sources. This serves to increase the PT assay’s sensitivity for factor efficiencies. Prothrombin time results are reported in seconds and are also converted to international normalized ratio (INR) values. The INR serves to normalize results obtained from different laboratories for the variable responsiveness of different thromboplastin reagents. Each thromboplastin is assigned an activity Index (ISI) based on comparison to an international reference thromboplastin from the World Health Organization. The formula for calculating the INR is

INR = [patient’s results / normal patient average](ISI)

The ISI of the thromboplastin used in the LabCorp assay is near 1.0. The use of low ISI thromboplastin serves to improve the precision of therapeutic monitoring by enhancing sensitivity of the prothrombin assay.

The PT is sensitive to deficiencies of extrinsic and common pathway factors X, VII, V, II, and fibrinogen.7-9 The PT is more responsive to deficiencies of factors X and V than is the aPTT. Congenital deficiencies of these factors are relatively rare and cause bleeding disorders of varying severity. Refer to individual test descriptions for more information. Acquired deficiencies of the vitamin K-dependent factors II and VII may occur during warfarin therapy and in patients with vitamin K deficiency. Diminished levels of all the factors of the extrinsic pathway can also occur in consumptive coagulopathies, such as disseminated intravascular coagulation (DIC), and as the result of decreased factor production as can be seen with severe liver disease or malnutrition. Specific inhibitors of extrinsic pathway factors are extremely rare, but may produce a prolonged PT.7-9 Lupus anticoagulants (LA) may cause a prolonged PT due to nonspecific factor inhibition. Some individuals with LA can develop antibodies that bind to and increase the rate of clearance of prothrombin (factor II). These patients typically have an extended PT due to reduced factor II level and an increased risk of bleeding.

Coumarins, a family of compounds that inhibit the vitamin K-dependent carboxylation of several coagulation factors, are commonly used to limit fibrin clot formation in individuals with increased risk of venous or arterial thrombosis.6,11,12 Warfarin, also referred to as Coumadin®, is the most commonly used coumarin in North America.11 Overdosing with warfarin can increase the risk of hemorrhage and inadequate dosing decreases the efficacy of anticoagulation. Unfortunately, a large number of factors can affect the pharmacological potency of these oral anticoagulants. These factors are reviewed in considerable detail in the American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy.12 Therapeutic monitoring is essential to maintain the dosage within the appropriate range range. Because the PT is sensitive to deficiencies of vitamin K-dependent factors II and VII, it is used to monitor warfarin therapy.

Coumarins inhibit the carboxylation of procoagulant factors II, VII, IX, X, and anticoagulants proteins C and S to a similar extent. Steady-state levels of these proteins are all reduced to a similar degree, based on the dose and effectiveness of the oral anticoagulant given; however, during the initial days of treatment, the rate of decline of factor levels is dependent on their half-life. Since factor VII has a short half-life relative to other vitamin K-dependent factors, the levels of this factor drop much more precipitously than the others.11

Superwarfarins, such as brodifacoum, are often found in rat poison and may cause prolongation of the PT. Patients suffering brodifacoum poisoning respond to vitamin K often bringing their PT into the normal range briefly, but since the drug is stored for long periods of time in fat, the PT rises again over time.
Footnotes:

1. Adcock DM, Kressin DC, Marlar RA, “Effect of 3.2% vs 3.8% Sodium Citrate Concentration on Routine Coagulation Testing,” Am J Clin Pathol, 1997, 107(1):105-10. PubMed 8980376

2. Reneke J, Etzell J, Leslie S, et al, “Prolonged Prothrombin Time and Activated Partial Thromboplastin Time Due to Underfilled Specimen Tubes With 109 mmol/L (3.2%) Citrate Anticoagulant,” Am J Clin Pathol, 1998, 109(6):754-7. PubMed 9620035

3. “National Committee for Clinical Laboratory Standardization: Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline,” Fifth Edition, Villanova: NCCLS Document H21-A5:28(5), 2008.

4. Gottfried EL, Adachi MM. “Prothrombin Time and Activated Partial Thromboplastin Time Can Be Performed on the First Tube,” Am J Clin Pathol, 1997, 107(6):681-3. PubMed 9169665

5. McGlasson DL, More L, Best HA, et al, “Drawing Specimens for Coagulation Testing: Is a Second Tube Necessary?” Clin Lab Sci, 1999, 12(3):137-9. PubMed 10539100

6. Hirsh J, Dalen J, Anderson DR, et al, “Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range,” Chest, 2001, 119(1 Suppl):8S-21S. PubMed 11157640

7. Adcock DM, Bethel MA, Macy PA, et al, Coagulation Handbook, Esoterix Coagulation, 2006.

8. Roberts HR, Escobar MA, “Less Common Congenital Disorders of Hemostasis,” Consultative Hemostasis and Thrombosis, Kitchens CS, Alving BM, Kessler CM, eds, Philadelphia, PA: WB Saunders Co, 2002, 57-71.

9. Triplett DA, “Coagulation Abnormalities,” Clinical Laboratory Medicine, McClatchey KD, ed, 2nd ed, Philadelphia, PA: Lippincott Williams and Wilkins, 2002, 1033-49.

10. Van Cott EM, Laposata M, “Coagulation,” Laboratory Test Handbook With Key Word Index, Jacobs DS, DeMott WR, Oxley DK eds, Hudson, OH: Lexi-Comp, 2001, 327-58.

11. Francis CW, Berkowitz SD, “Antithrombotic and Thrombolytic Agents,” Consultative Hemostasis and Thrombosis, Kitchens CS, Alving BM, Kessler CM, eds, Philadelphia, PA: WB Saunders Co, 2002, 375-91.

12. Hirsh J, Fuster V, Ansell J, et al, “American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy,” Circulation, 2003, 107(12):1962-711.PubMed 12668507