INR Levels and Prothrombin Time

The hemostasis and coagulation system is a homeostatic balance between factors encouraging clotting and the factors encouraging clot dissolution. The first reaction of the body to active bleeding is blood vessel constriction. In small vessel injury, this may be enough to stop bleeding. In large vessel injury, hemostasis is required to form a clot that will durably plug the hole until healing can occur. The primary phase of the hemostatic mechanism involves platelet aggregation to blood vessel. Next, secondary hemostasis occurs. The first phase of reactions is called the intrinsic system. Factor XII and other proteins form a complex on the subendothelial collagen in the injured blood vessel. Through a series of reactions, activated factor XI (XIa) is formed and activates factor IX (IXa). In a complex formed by factors VIII, IX, and X, activated X (Xa) is formed.

 

At the same time, the extrinsic system is activated and a complex is formed between tissue thromboplastin (factor III) and factor VII (which is exposed after cellular injury). Activated factor VII (VIIa) results. Factor VIIa can directly activate factor X. Alternatively, VIIa can activate IX and X together.

 

In the third reaction, factor X is activated by the proteases formed by the two prior reactions and by activated factor IX. This reaction is a common pathway that provides the link between the intrinsic and the extrinsic systems. In the fourth and final reaction, prothrombin is converted into thrombin by activated factor X in the presence of factor V, phospholipid, and calcium.

 

Thrombin not only converts fibrinogen to fibrin in “clot stabilization” but also stimulates platelet aggregation and activates factors V, VIII, and XIII. Once fibrin is formed, it is then polymerized into a stable gel. Factor XIII cross-links the fibrin polymers to form a stable clot.

 

Almost immediately three major activators of the fibrinolytic system act on plasminogen, which was previously absorbed into the clot, to form plasmin. Plasmin degenerates the fibrin polymer into fragments, which are cleared by macrophages.

 

The PT measures the clotting ability of factors I (fibrinogen), II (prothrombin), V, VII, and X (i.e., the extrinsic system and common pathway). When these clotting factors exist in deficient quantities, the PT is prolonged. Many diseases and drugs are associated with decreased levels of these factors. These include the following:

  1. Hepatocellular liver disease (e.g., cirrhosis, hepatitis, and neoplastic invasive processes). Factors I, II, V, VII, IX, and X are produced in the liver. With severe hepatocellular dysfunction, synthesis of these factors will not occur, and serum concentration of these factors will be decreased.
  2. Obstructive biliary disease (e.g., bile duct obstruction secondary to tumor or gallstones or intrahepatic cholestasis secondary to sepsis or drugs). As a result of the biliary obstruction, the bile necessary for fat absorption fails to enter the gut, and fat malabsorption results. Vitamins A, D, E, and K are fat soluble and also are not absorbed. Because the synthesis of factors II, VII, IX, and X depends on vitamin K, these factors will not be adequately produced, and serum concentrations will fall. Hepatocellular liver disease can be differentiated from obstructive biliary disease by determination of the patient’s response to parenteral vitamin K administration. If the PT returns to normal after 1 to 3 days of vitamin K administration (10 mg intramuscularly twice a day), one can safely assume that the patient has obstructive biliary disease that is causing vitamin K malabsorption. If, on the other hand, the PT does not return to normal with the vitamin K injections, one can assume that severe hepatocellular disease exists and that the liver cells are incapable of synthesizing the clotting factors no matter how much vitamin K is available.
  3. Coumarin ingestion. The coumarin derivatives dicumarol and warfarin (Coumadin, Panwarfin) are used to prevent coagulation in patients with thromboembolic disease (e.g., pulmonary embolism, thrombophlebitis, arterial embolism). These drugs interfere with the production of vitamin K–dependent clotting factors, which results in a prolongation of PT, as already described. The adequacy of coumarin therapy can be monitored by following the patient’s PT. For anticoagulation, the INR typically should be between 2.0 and 3.0 for patients with atrial fibrillation, and between 3.0 and 4.0 for patients with mechanical heart valves. However, the ideal INR must be individualized for each patient

 

PT test results used to be given in seconds, along with a control value. The control value usually varied somewhat from day to day because the reagents used varied. The patient’s PT value was supposed to be approximately equal to the control value. Some laboratories used to report PT values as percentages of normal activity, because the patient’s results were compared with a curve representing normal clotting time. A normal PT result was 85% to 100%.

 

To have uniform PT results for physicians in different parts of the country and the world, the World Health Organization has recommended that PT results now include the use of the international normalized ratio (INR) value. The reported INR results are independent of the reagents or methods used. Many hospitals are now reporting PT times in both absolute and INR numbers. Factors such as weight, body mass index, age, diet, and concurrent medications are known to affect warfarin dose requirements during anticoagulation therapy. Warfarin interferes with the regeneration of reduced vitamin K from oxidized vitamin K in the VKOR (vitamin K oxidoreductase) complex. A recently identified gene for the major subunit of VKOR, called VKORC1, has been identified and may explain up to 44% of the variance in warfarin dose requirements. Furthermore, warfarin is metabolized in part by the cytochrome P-450 enzyme CYP2C9. The CYP2C9*2 and CYP2C9*3 genetic mutations have been shown to decrease the enzyme activity of these metabolizing enzymes, which has led to warfarin sensitivity and, in serious cases, bleeding complications. A warfarin metabolism genetic test panel is available that can identify any mutations in the VKORC1-1639, CYP2C9*2, or CYP2C9*3 genes. With this information, an algorithm has been identified that may be more accurate than PT for warfarin dosing.

 

Coumarin derivatives are slow acting, but their action may persist for 7 to 14 days after discontinuation of the drug. The action of a coumarin drug can be reversed in 12 to 24 hours by slow parenteral administration of vitamin K (phytonadione). The administration of plasma will even more rapidly reverse the coumarin effect. The action of coumarin drugs can be enhanced by drugs such as aspirin, quinidine, sulfa, and indomethacin. Barbiturates, chloral hydrate, and oral contraceptives cause increased coumarin drug binding and therefore may decrease the effects of coumarin drugs.

 

 

 

Causes of INR and Prothrombin Time False Indications

  • Alcohol intake can prolong PT times. Alcohol diminishes liver function. Many factors are made in the liver. Lesser quantities of coagulation factors result in prolonged PT times.
  • A diet high in fat or leafy vegetables may shorten PT times. Absorption of vitamin K is enhanced. Vitamin K–dependent factors are made at increased levels, thereby shortening PT times.
  • Diarrhea or malabsorption syndromes can prolong PT times. Vitamin K is malabsorbed, and as a result, factors II, VII, IX, and X are not made.
  • Drugs that may cause increased levels include Allopurinol, Aminosalicylic Acid, Barbiturates, Beta-Lactam Antibiotics, Chloral Hydrate, Cephalothins, Chloramphenicol, Cholestyramine, Cimetidine, Clofibrate, Colestipol, Ethyl Alcohol, Glucagon, Heparin, Methyldopa, Neomycin, Oral Anticoagulants, Propylthiouracil, Quinidine, Quinine, Salicylates, and Sulfonamides.
  • Drugs that may cause decreased levels include Anabolic Steroids, Barbiturates, Chloral Hydrate, Digitalis, Diphenhydramine, Estrogens, Griseofulvin, Oral Contraceptives, and Vitamin K.

 

 

 

Normal INR Levels and Prothrombin Time

Normal INR Levels range between 0.8 to 1.1. A critically high INR level would exceed 5.5.

Normal Prothrombin Time ranges between 11 to 12.5 seconds (85% to 100%). With a full anticoagulant therapy, Normal Prothrombin Time would exceed 1.5 to 2 times the control value (20%-30%).

 

 

 

Causes of High INR Levels (Prolonged Prothrombin)

  • Liver Disease (Including  Cirrhosis and Hepatitis): Coagulation factors are made in the liver. With liver disease, synthesis is inadequate and the PT is increased.
  • Hereditary Dactor Deficiency: A genetic defect causes a decrease in a coagulation factor. The PT is increased. Factors II, V, VII, or X could be similarly affected.
  • Vitamin K Deficiency: Vitamin K–dependent factors (II, VII, IX, X) are not made. The PT is increased.
  • Bile duct Obstruction: Fat-soluble vitamins, including vitamin K, are not absorbed. Vitamin K–dependent factors (II, VII, IX, X) are not made. The PT is increased.
  • Coumarin Ingestion: Synthesis of the vitamin K–dependent coagulation factors is inhibited. The PT is increased.
  • Disseminated Intravascular Coagulation (DIC): Coagulation factors are consumed in the intravascular coagulation process. The PT is increased.
  • Massive Blood Transfusion: Coagulation is inhibited by the anticoagulant in the banked blood. Furthermore, with massive bleeding the factors are diluted out by the “factor-poor” banked blood.
  • Salicylate Intoxication.