Oral Anticoagulants

Clinical Laboratory Science, Spring 2004 by McGlasson, David L

ABBREVIATIONS: AMS = anticoagulation management service; DVT = deep vein thrombosis; GLA = gamma-carboxyl glutamic acid; GLU = glutamic acid; INR = international normalized ratio; IRP = international reference plasma; ISI = international sensitivity index; OAT = oral anticoagulant therapy; POC = point-of-care device; PT = prothrombin time; VTE = venous thromboembolism; WHO = World Health Organization.

INDEX TERMS: coagulation, ISI, OAT.

Clin Lab Sci 2004;17(2):107

HISTORY OF ORAL ANTICOAGULATION

The discovery of oral medications to control thrombotic disorders in humans probably started with a report in 1922 by U.S. veterinarian Frank W Schofield. Dr Schofield reported a bleeding diathesis in cattle that simulated hemorrhagic septicemia and "black leg syndrome". He hypothesized that this disorder was due to feeding spoiled sweet clover to the cattle.1

In 1935, while studying the sterol metabolism of chicks in Copenhagen, 1943 Nobel Prize winner Henrik Dam discovered a bleeding tendency in the chicks fed a diet deficient in lipids. These results suggested the chicks lacked a substance necessary for normal coagulation; "Koagulations-Vitamin" or vitamin K. He studied this vitamin further with respect to its occurrence and biological function in animals and plants as well as its application in human medicine.2

In 1933 a Wisconsin farmer arrived at Karl Paul Link's laboratory at the University of Wisconsin-Madison with a pail of blood that would not coagulate. He also brought a small heap of spoiled sweet clover and a dead heifer in the back of his truck. Isolation and purification of the hemorrhagic compound led to the discovery of dicumarol (3,3-methylene-bis- {4-hyroxycoumarin}).3 Clinical studies were immediately started on this compound, establishing the basis for rodenticides and the first oral anticoagulant. The compound greatly diminished prothrombin activity and delayed the clotting mechanism in blood. The first prophylactic and therapeutic effects and the drug's mechanism in influencing deep vein thrombosis were described in 1942.4-6 Link, in 1948, went to the director of the Wisconsin Alumni Research Foundation with the suggestions that the foundation patent the newly synthesized 3-(1-phenyl-3-oxobutyl) 4-hydroxycoumarin as a rodenticide, and that it had applications for human use. Link stated, "From the beginning I had an intuitive feeling that this might be a good thing. A pretty bad thing for rats, but a good thing for humans."7 The compound now known as Warfarin® is the most commonly used coumarin derivative worldwide. The term Warfarin is an acronym for the Wisconsin Alumni Research Foundation in recognition of its synthesis at the University of Wisconsin in 1948. The available compounds in different countries are either coumarin derivatives or indanedione derivatives.8

The vitamin-K dependent coagulation factors (FII, FVII, FIX, and FX) are produced in the liver as nonfunctional precursors. These precursors are activated in the presence of vitamin K by gamma-carboxylation of their glutamic acid (GLU) residues, forming gamma-carboxy glutamic acid (GLA). Carboxylation allows these coagulation factors to bind calcium, which is essential for their adhesion to platelet phospholipid membranes. The coumarins produce their anticoagulant effect on the vitamin-K dependent proteins by inhibiting the vitamin K conversion cycle and thus producing partially carboxylated proteins with reduced procoagulant activity.9 Vitamin K antagonists also inhibit carboxylation of the regulatory anticoagulant proteins C and S as well as protein Z and osteocalcin. The reduction of the inhibitors of the coagulation mechanism could therefore cause a procoagulant effect.9

MONITORING ORAL ANTICOAGULANT THERAPY

Patients on oral anticoagulant therapy (OAT) require constant monitoring using the prothrombin time (PT). The PT responds to levels of three of the four vitamin K-dependent procoagulant factors, FII, FVII, and FX.

Physicians monitor patients on OAT by ordering monthly repeat measurements of the PT assay. They are then able to maintain each subject in a designated therapeutic range. There are many variables in the performance of the PT that may affect the test results. These include specimen collection and processing, instrumentation used to perform the assay, and the sensitivity of the thromboplastin reagent used to perform the PT assay. Each thromboplastin's sensitivity is indicated by its international sensitivity index (ISI). A wide variability in thromboplastin sensitivity has created problems for physicians when trying to monitor patients in different institutions with different reagent/instrument combinations. A subject monitored with a low sensitivity reagent (high ISI) may give a short PT of 14 seconds, while the same patient measured using a high sensitivity reagent (low ISI) may give a time of 18 seconds. These results may drastically affect the interpretation of the PT assay and the warfarin dosage in individual subjects.10