Sometimes Less is Better: The Treatment of Venous Thromboembolism - Background Information - Case Study Collection - National Center for Case Study Teaching in Science

Approximately 2 million people annually develop venous thromboembolism (VTE) in the United States; of those, 600,000 are hospitalized and 60,000 die. Many more are “clinically silent.”

Venous thromboembolism (VTE) is a potentially life-threatening medical condition that has a propensity for recurrence after an initial diagnosis of either deep vein thrombosis (DVT) or pulmonary embolism (PE).

Pharmacotherapeutic management often consists of a brief period (approximately one week) of intravenous heparin or subcutaneous low molecular weight heparin (LMWH) anticoagulant in conjunction with the initiation of oral warfarin therapy. While warfarin therapy, if maintained within a narrow therapeutic range, is successful in preventing the recurrence of DVT and PE, it has many associated problems, including frequent monitoring, many drug interactions, and potentially significant adverse effects, particularly when nearing the upper limit of the therapeutic range. There is, therefore, a desire within the medical community to find options that improve the margin of safety (lower therapeutic ranges), improve patient convenience and adherence (less frequent monitoring), and help to clarify the question of how long a patient should be maintained on warfarin therapy and at what intensity of anticoagulation.

The three primary risk factors for development of venous thrombosis (also known as Virchow’s triad) include: (1) stasis, (2) vascular damage, and (3) hypercoaguability. Predisposing factors for each are outlined below:

The majority of thrombus forms in the lower extremities, although they can form anywhere. Once a thrombus is formed, the following may result:

Oral Anticoagulation Therapy: Warfarin (Coumadin®)

I. Pharmacology

Stasis	Vascular Damage	Hypercoaguability
Immobilization Acute myocardial infarction Congestive heart failure Stroke Post-operative recovery	Surgery Orthopedic Thoracic Abdominal Genitourinary Trauma Fractures of spine Fractures of pelvis Fractures of femur or tibia Spinal cord injuries Venulitis Thromboangiitis obliterans Behcet’s disease Homocysteinuria	Hypercoaguable States Factor V Leiden Antithrombin III deficiency Protein C deficiency Protein S deficiency Antiphospholipid antibodies Systemic lupus erythematosus Myeloproliferative diseases Dysfibrinogenemia Disseminated intravascular coagulation Other Pregnancy Estrogen use Neoplasms (lung, ovary, testes, breast, pancreas, stomach, urinary tract)

Symptoms of Deep Vein Thrombosis (DVT)	Symptoms of Pulmonary Embolism (PE)
unilateral leg swelling local leg pain local leg tenderness local leg redness local leg warmth	difficulty breathing increased respiratory rate increased heart rate chest pain coughing up blood

A. Mechanism of Action

Warfarin inhibits the reductase enzymes responsible for vitamin K recycling, thereby resulting in a slowing of the rate of synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X) and anticoagulant proteins C and S. There is a dose-dependent effect of warfarin on the vitamin K-dependent coagulation factors—the higher the dose, the greater the effect.

During initiation of therapy with warfarin, the anticoagulant effects achieved are dependent on the half-lives of the coagulation factors (VII—4 to 6 hrs, IX—24 hrs, X—48 to 72 hrs, and II—60 hrs), anticoagulant proteins (C—8 hrs and S—30 hrs), and the dose.

Warfarin therapy only prevents: thrombus formation, extension of a previously formed thrombus, and secondary thromboembolic complications. It does not result in thrombolysis of a formed clot nor does it reverse ischemic damage that has already occurred.

B. Monitoring

The anticoagulant effect of warfarin is assessed utilizing the International Normalized Ratio (INR), a standardized method for monitoring warfarin therapy. The formula for calculating the INR is as follows:

formula

PT refers to the prothrombin time, a measure that reflects the effects of warfarin on three of the four vitamin K-dependent coagulation factors (II, VII, and X) as a function of the half-lives of these factors. C is a power value representing the International Sensitivity Index (ISI). This is a measure of the responsiveness of a reagent (thromboplastin), utilized in the determination of the PT, to reduction of the vitamin K-dependent coagulation factors as compared to an international reference.

Depending on the patient specific indication for warfarin, the target INR range will either be 2.0 to 3.0 or 2.5 to 3.5.

II. Pharmacokinetics

When administered orally, bioavailability is >90%. Warfarin undergoes stereoselective hepatic metabolism in the CYP450 isoenzyme system (primary) and by reductases (secondary). The S isomer, which is 3–5 times more potent than the R isomer, is principally metabolized by CYP450 2C9. R-warfarin is metabolized by CYP450 1A2 and 3A4. The half-life of S-warfarin is approximately 20 to 45 hours while that of R-warfarin is approximately 35 to 90 hours. Inactive warfarin metabolites are excreted in urine (major) and bile (minor).

III. Adverse Effects

The predominant adverse effect of warfarin is bleeding ranging from mild (ecchymosis, epistaxis, petechiae) to major or life-threatening (intracranial, retroperitoneal, ocular, gastrointestinal). The incidence of minor bleeding may likely be >15% annually while that of major bleeding is likely 5–9% annually, with a 2X higher incidence when the INR is >3.

IV. Interactions

Warfarin has numerous drug-drug, drug-herbal product, and drug-food/nutrient interactions. Interactions may occur as a result of the following:

There are many common agents and medications that have been proven or are implicated in interactions with warfarin. As many patients who are receiving warfarin therapy are also on concomitant therapies, these interactions make managing warfarin challenging (the list below is not intended to be all-inclusive):

Sometimes Less is Better:The Treatment of Venous Thromboembolism

Background Information