Genetic Testing Could Help Identify Breast Cancer Patients at High Risk of Venous Thromboembolism

AACR: Genetic testing could help identify breast cancer patients with high risk of experiencing venous thromboembolism (VTE), a serious and potentially fatal complication that can occur during cancer treatment, according to results of a study published in Clinical Cancer Research, a journal of the ​American Association for Cancer Research.

Thrombosis - a question of clotting

British Heart Foundation: Thrombosis is the process by which clotting occurs whenever there is damage to a blood vessel. It involves small cells in the blood called platelets, and proteins which circulate throughout the bloodstream. During clot formation, these platelets and proteins are rapidly stimulated to form a clot in order to plug the site of damage and prevent blood from leaking out of the vessel. Blood clotting, although critical in healthy healing (it forms the scab when you cut yourself) can also be dangerous…

Venous thrombosis

Author : Dr Emile R. Mohler Physician University of Pennsylvania

2008-07-28

Venous Thrombosis

 

Emile R. Mohler, M.D.

Director, Vascular Medicine University of Pennsylvania health system

Penn Web Site: http://www.uphs.upenn.edu/cardio/faculty/mohler.html

 

Introduction

Deep venous thrombosis (DVT) is a clinical disorder caused by a blood clot in a large vein of the body. This is known in medical terminology as a thrombus.  The condition is also called a venous thromboembolism (VTE) as the thrombus can travel from the vein to the lungs and cause a pulmonary embolus, which may be life threatening.  It is estimated that 60,000 people in the United States die each year from pulmonary embolus.

Venous Anatomy

The body has superficial veins located near the skin and deep veins located closer to the bones (Figure 1). The superficial veins empty into the deeper veins and in the lower extremities blood flows from the legs into the pelvis.  At the level of the umbilicus, the venous blood enters the inferior vena cava and then the right side of the heart.  Similarly, venous blood from the upper extremities enters the superior vena cava and then flows down to the right side of the heart.  Approximately 70- 80% of DVTs occur in the thigh region and 20- 30% occur in the calf.  A clot in the veins of the thigh is more likely to travel to the lung than one in the calf ¹.  The superficial veins can also develop a thrombus but clots in the superficial veins rarely travel to the deeper system of the body and are not generally life-threatening.  The most common site for a DVT is the leg.  A DVT can also develop in an arm vein or even in the pelvis.

What causes DVT?

The cause for a DVT is attributed to 3 factors, either alone or in combination: 1) slow (or sluggish) blood flow through a deep vein, 2) a damaged inner lining of the vein, and 3) a tendency to develop a thrombus quickly (thrombophilia).  The factors of this triad increase the threshold of developing DVT.

The risk of DVT increases with age.  There are also situations that predispose to the development of DVT some of which include prolonged bed rest such as after a surgical procedure or medical illness where blood flow in the legs may not be as brisk as usual (Table 1).  It is well recognized that people with active cancer are predisposed to developing DVT.  Also, the presence of an abnormal clotting gene increases the risk of DVT.  Medical conditions such as varicose veins, severe obesity, congestive heart failure, and chronic respiratory failure predispose to DVT.  Medications with estrogen, such as birth control pills, also increase risk of DVT.  Long travel with restricted movement, as may occur with an overseas airline flight, is associated with a small risk of DVT.

Table 1. Risk Factors for DVT

Surgery

Prolonged immobilization

Birth control pills

Obesity

Cancer

Inflammatory bowel disease

Varicose veins

Hereditary disposition to clotting

 

What are the symptoms of DVT?

The symptoms typically associated with DVT are pain, tenderness, and swelling in the area where the clot occurs.  The skin may be warm to the touch and discolored.  If the thrombus travels to the lung (pulmonary embolus), shortness of breath and chest discomfort (especially with deep breathing) may occur.  It is important to seek immediate medical attention if these symptoms occur.  The physical examination may reveal a tender, firm vein called a “palpable cord.” The doctor may squeeze the affected area to determine if pain is present.  If only one leg is swollen, this is more suspicious for a DVT than if both legs are swollen.  However, a DVT can simultaneously develop in both legs, causing bilateral swelling.

How is the diagnosis of DVT made?

The diagnosis of DVT can be difficult to establish based only upon the medical history and physical examination as a variety of disorders such as musculoskeletal problems and congestive heart failure can present similarly (Table 2).

Table 2. Cause of leg swelling and pain that may mimic DVT.

Venous Insufficiency

Musculoskeletal strain or bruising

Lymphatic blockage

Heart Failure

Cellulitis

Bakers cyst

Furthermore, the valves in the veins may not work correctly leading to back pressure and swelling, so-called venous insufficiency.  The swelling due to venous insufficiency may mimic the swelling of DVT.  Thus, further evaluation is usually necessary, with an imaging study to confirm the suspected diagnosis of DVT.  The clinical suspicion of DVT can be substantiated with medical criteria called the Wells criteria².  This algorithm of care is based upon the presence of criteria associated with increased risk of DVT such as cancer, paralysis, being bed ridden for more than 3 days, major surgery within last 4 weeks, entire leg swollen and one leg larger in circumference compared with the other.

Although there is no specific blood test for DVT, a blood clotting test called D-dimer, if negative, indicates a very low likelihood of DVT³.  However, the D-dimer test is not specific for DVT as elevated levels of this protein are also seen in hospitalized patients with other conditions.  Thus, the D-dimer test is only useful if negative and indicates a low probability of DVT.  For example, a “normal” D-dimer test (usually less than 500 ng/ml for enzyme test) in conjunction with a low Wells probability score appears useful in excluding DVT and forgoing further testing with ultrasound^{4, 5}.

The diagnosis of DVT is made noninvasively and accurately with an ultrasound imaging scan of the leg veins ⁶.  You will be asked to lie on a medical bed and saline gel will be applied on the skin above the veins.  A small ultrasound probe will be placed on the skin and the veins observed on a monitor (Figure 2).  There is no radiation involved in this study.  The body usually dissolves the clot over several months and blood flow through the veins returns to normal.  However, sometimes the vein remains permanently damaged and may be severely narrowed or remain occluded.  New, small veins called collaterals may develop around the occluded vein. Patients with residual clot on ultrasound have a higher risk of recurrent DVT than those with normal veins⁷.

A more invasive test called venography may be performed, where the anatomy is imaged after injecting  contrast dye into a leg vein.  Also, a special computed tomography scan (CT) using contrast dye^{8, 9} or magnetic resonance venography (MRV)¹⁰ can be used to evaluate for DVT.  However, because of the relative invasive nature of these tests they are not considered first line evaluation.  The diagnosis of a pulmonary embolus is made with a special type of chest CT scan, a nuclear lung scan, or a pulmonary angiogram.

How is DVT treated?

The treatment of DVT is with a blood thinner known in medical terminology as an anticoagulant¹¹.  It is estimated that if anticoagulation is not given, that 50% of individuals will experience a pulmonary embolus¹². Heparin is the anticoagulant given initially for treatment of DVT.  The type and mode of administration of heparin has evolved from so called “standard” heparin to “low molecular weight” heparin (Table 3). 

Table 3.  Types of Heparin

Standard (unfractionated) heparin

Enoxaparin (Lovenox)

Dalteparin ((Fragmin)

Tinzaparin (Innohep)

Nadroparin

Fondaparinux (Arixtra)

In the past, heparin was given intravenously (by vein) in the hospital but now heparin can be given subcutaneously (skin injection) in the home.  Heparin does not work by dissolving the clot, but rather, by preventing more clot from forming in the veins.  Patients with a massive DVT, symptomatic pulmonary embolism, other high risk medical conditions, and increased risk of bleeding are usually admitted to the hospital for anticoagulation.

Warfarin (Coumadin) is given shortly after starting heparin and the heparin is usually continued for 4-5 days¹³.  The blood clotting ability is inhibited with warfarin and the level of inhibition is assessed with a test called the prothrombin time which is expressed as the INR (International Normalized Ratio) level.  Warfarin works by inhibiting vitamin K which is an essential factor for producing clotting factors in the liver.  Unfortunately, various foods high in vitamin K content, such as found in green leafy vegetables, interfere with the effectiveness of warfarin, which makes dietary vigilance a must when using this medication (Table 4). 

Table 4.  Vitamin K Content of Selected Foods
Food	Vitamin K content (µg/100g)
Kale	726
Turnip greens	650
Collards	440
Spinach	413
Brussels Sprouts	250
Soy bean oil	198
Broccoli	147
Cabbage	110
Lettuce	75
Olive oil	56
Butter	30
Margarine	30

The initial dose of warfarin is 5-10 mg per day for the first 2 days, and adjusted thereafter according to the INR level.  The therapeutic INR level is 2.0 to 3.0.  Various drugs can also interact with warfarin so it is important to monitor the INR closely when drugs changes are made.  In general, the length of treatment with warfarin is typically 3- 6 months but may be prolonged indefinitely, especially if the reason for the thrombus is unknown¹⁴.  A prolonged course of warfarin is advocated in those with recurrent DVT and those with a continuing risk for DVT, such as active malignancy.

In severe cases of DVT involving the pelvic veins, a drug that promotes the dissolving of a clot called a thrombolytic may be necessary.  The thrombolytic is typically given via a catheter in a vein in the leg.  Patients not medically qualified for anticoagulation may receive a filter in the inferior vena cava (a large pelvic vein) to prevent the clot from traveling to the lung.  The filter does not prevent more clot from forming but acts as a barrier to a dislodged clot so that it does not enter the lung.  Rarely, a complication may occur where the filter migrates from the point of attachment or a clot develops on the filter material; this impedes blood flow, causing severe leg swelling.

Treatment of distal DVT

The presence of DVT in the calf (distal DVT) has a lower risk of traveling to the lung.  The medical recommendation for treating isolated calf DVT with anticoagulation is not as strong as more proximal DVT in the thigh.  However, many physicians advocate treatment of an isolated and symptomatic DVT in the calf with anticoagulation for at least six to twelve weeks.  Those asymptomatic patients with an isolated calf DVT, if not treated with anticoagulation, may undergo serial ultrasound monitoring of the lower extremity to ensure that the clot is resolving and not moving higher in the leg.

Are there complications to anticoagulation?

A potential serious complication of anticoagulation is bleeding.  The bleeding may occur in the intestinal tract, the brain, or other parts of the body.  However, this risk is typically outweighed by the benefit of anticoagulation.  Heparin can rarely cause a low platelet count so monitoring of the platelet level in the blood is required if taking this drug for a prolonged time.  Some patients are not considered a candidate for anticoagulation, such as those involved in a motor vehicle accident with head trauma, or those with recent stroke.

Are there long-term problems after having a DVT?

Approximately one quarter to one third of patients who have DVT develop residual leg swelling and discomfort called post thrombotic syndrome (PTS)¹⁵.  This syndrome may result from damage to valves in the veins and/or vein narrowing which does not allow for normal flow from the legs up to the lungs.  This results in back pressure on the veins forcing fluid into the tissue and causing swelling.  The situation may improve over time with prolonged anticoagulation.  In order to reduce risk and symptoms of PTS, a special stocking called a graduated compression stocking is prescribed.  This garment is especially made to put pressure at the ankle level with gradual decrease in pressure at the knee which provides support to the veins and facilitates upward blood flow.  Patients with DVT are encouraged to be as active as possible but are advised to try and avoid prolonged standing, which may result in pooling of blood in the legs and swelling.

Pregnancy and DVT

While the risk of DVT in young women is low, it is slightly increased with pregnancy.  This risk for DVT is highest during the period immediately after delivery (postpartum).  Woman with an inherited increased risk of clotting may be given prophylactic anticoagulation to prevent DVT.  If a DVT occurs during pregnancy, heparin is given as is recommended for the nonpregnant patient.  Warfarin crosses from the blood stream into the baby’s circulation and can cause fetal damage during the first trimester of pregnancy and therefore heparin is usually continued until delivery.  After delivery, warfarin is given for 4-6 weeks.

How is DVT prevented?

DVT can be prevented in the hospital setting by receiving anticoagulation according to medical guidelines.  Leg exercises such as flexing the calf muscles while sitting and occasionally walking are recommended during prolonged and confined travel in order to promote circulation and reduce sluggish blood flow. Since cigarette smoking increases the tendency of blood to clot, it is very important to stop smoking.  Regular aerobic exercise is also thought to reduce risk of DVT.

More information

Web Sources:

Vascular Disease Foundation: http://www.vdf.org/

American Venous Forum: http://www.venous-info.com/

Venous Coalition: http://www.vdf.org/community/vdc.php

Biology of Leg Disorders: http://www.legdisorders.org/default.aspx