Antithrombin III Deficiency

Antithrombin III deficiency is a rare blood disorder that disrupts the body’s natural ability to control blood clotting, putting people at risk for dangerous blood clots that can affect the legs, lungs, and other vital organs.

Table of contents

• What is Antithrombin III Deficiency?
• How Common is This Condition?
• Symptoms and When They Appear
• Causes and Inheritance
• How is it Diagnosed?
• Treatment Options
• What to Expect
• Prevention and Family Screening

What is Antithrombin III Deficiency?

Antithrombin III deficiency is a blood clotting disorder that makes people more likely to develop abnormal blood clots. Antithrombin is a protein in the blood that helps keep blood from clotting too much. It works by blocking certain substances that cause clotting, particularly thrombin (the main clotting factor) and other clotting proteins known as factors Xa, IXa, and VIIa.^[1][3]

When antithrombin isn’t working properly or there isn’t enough of it, clotting can continue without the normal brakes to stop it. This is similar to starting to fill a bathtub with water and walking away—someone needs to be there to turn the water off to keep the bathtub from overflowing, just like antithrombin needs to stop the clotting before it goes on too long.^[1]

People with this condition are at high risk for deep vein thrombosis (a blood clot in a deep vein of the body, usually in the legs) and pulmonary embolism (a clot that travels to the lungs).^[1] In fact, antithrombin deficiency has one of the highest risks of blood clots among all inherited clotting disorders, with patients being about 20 times more likely to have a blood clot compared to the general population.^[7]

There are two types of antithrombin III deficiency. The inherited form is a genetic disorder passed down through families. The acquired form develops due to other medical conditions or treatments that lower antithrombin levels, such as liver disease, kidney disease, severe infections, or use of certain medications.^[3][4]

How Common is This Condition?

Antithrombin III deficiency is rare. About one person in every 2,000 to 3,000 people has this condition, though some sources suggest it could affect anywhere from 1 in 500 to 1 in 5,000 individuals.^[1][7] The inherited form is the most commonly diagnosed during childhood, usually after a family member with the condition has been identified or after a child experiences a blood clot.^[3]

Among people who develop blood clots in their veins, about 1% to 5% have antithrombin deficiency.^[5] Of patients hospitalized each year for blood clots in the United States, up to 3% may have hereditary antithrombin deficiency.^[7]

Symptoms and When They Appear

The symptoms of antithrombin III deficiency vary from person to person, but the first blood clot usually happens before age 40. About 70% of all patients with hereditary antithrombin deficiency will have a blood clot before the age of 35.^[7] However, having the genetic mutation doesn’t necessarily mean a person will develop a blood clot.^[1]

The most common symptoms include:^[1]

• Deep vein thrombosis (DVT), which causes swelling, redness, and pain in the arms or legs^[4]
• Pulmonary embolism, which can cause cough, shortness of breath, pain when taking deep breaths, chest pain, and in severe cases, death^[4]

Although less common, blood clots can also develop in veins in the brain and abdomen.^[1] Blood clots in the brain can cause a stroke, while those in other locations produce symptoms depending on where they travel.^[4]

Approximately 50% of individuals with hereditary antithrombin deficiency will develop at least one blood clot in their lifetime, usually after adolescence. By age 50, about 85% of patients will have experienced at least one clotting episode.^[7] About 6 in 10 patients with hereditary antithrombin deficiency have recurring blood clots.^[7]

The risk of blood clots increases with certain situations, including surgery, pregnancy and childbirth, not moving the body enough, increasing age, traumatic injuries, and use of estrogen-containing medications such as oral contraceptives.^[1][11] Between 3% and 50% of pregnant women with antithrombin deficiency develop blood clots, and up to 70% may experience blood clot complications during pregnancy or after giving birth.^[1][7]

Causes and Inheritance

Hereditary antithrombin III deficiency is caused by a mutation in the SERPINC1 gene (also called the AT3 gene) located on chromosome 1. This gene provides instructions for making the antithrombin protein.^[1][3]

The condition is inherited in an autosomal dominant pattern, meaning a person needs to inherit only one copy of the altered gene from one parent to have the condition.^[3][5] There is a 50% chance of passing the mutation on to each child, regardless of their sex.^[1]

In rare cases, babies can inherit antithrombin deficiency from both parents, resulting in a severe form called homozygous antithrombin III deficiency. This condition is rarely compatible with life, and most affected babies do not survive. These infants experience arterial and venous blood clots, particularly if they undergo invasive procedures.^[1][3]

Acquired antithrombin III deficiency occurs when antithrombin levels drop due to other medical conditions or treatments. Common causes include:^[3][5]

• Disseminated intravascular coagulation (DIC)
• Liver disease
• Kidney disease or nephrotic syndrome
• Severe infections or sepsis
• Certain blood disorders affecting small blood vessels
• Complications from bone marrow transplantation
• Use of oral contraceptives or estrogen therapy
• Treatment with heparin

How is it Diagnosed?

To diagnose antithrombin III deficiency, a healthcare provider will perform:^[1]

• A physical examination
• Review of medical history
• A blood test that specifically measures antithrombin levels

A clinical suspicion for antithrombin deficiency may arise in patients with recurring blood clots in veins, blood clots that occur during childhood, or blood clots during pregnancy.^[5] Testing for antithrombin activity can confirm deficiency if the levels are less than 70% of normal. Normal antithrombin levels range from 80% to 120%.^[5][6]

During a physical exam, doctors may look for signs such as:^[4]

• A swollen leg or arm
• Decreased breath sounds in the lungs
• A rapid heart rate

Additional laboratory studies may include tests for other clotting disorders, such as protein C and protein S deficiency, factor V Leiden, and other inherited blood clotting conditions.^[3] Genetic testing for abnormalities in the SERPINC1 gene can be done to confirm the diagnosis.^[5]

Imaging studies may also be used to identify blood clots:^[3]

• Ultrasound with compression of the affected area to diagnose deep vein thrombosis
• Lung imaging to detect pulmonary embolism
• Echocardiography, especially in patients with evidence of clots in arteries

Treatment Options

Treatment for antithrombin III deficiency depends on whether a person has experienced a blood clot and their current risk level. People who have antithrombin deficiency but haven’t had a blood clot don’t need to take blood thinners.^[1]

After a blood clot has occurred, treatment typically includes blood-thinning medicines, also called anticoagulants. The most commonly prescribed anticoagulant is warfarin (Coumadin), which may be taken for a few months or possibly long-term.^[1][8] The duration of warfarin therapy for the first blood clot is usually at least 3 to 6 months, though treatment may continue indefinitely if the underlying risk cannot be removed.^[8]

Patients who experience a second blood clot, particularly in the abdominal area, are at significant risk for more life-threatening or organ-threatening clots and are often candidates for lifelong anticoagulation therapy.^[8] Direct oral anticoagulants (DOACs) can also provide long-term treatment.^[8]

During pregnancy, healthcare providers may prescribe heparin injections to prevent blood clots, as warfarin can harm the developing baby.^[1] Low molecular weight heparin is frequently used to prevent blood clots and stop existing clots from getting larger, though its effectiveness may be reduced in people with antithrombin deficiency, requiring careful monitoring.^[8]

For patients with severe deficiency or those undergoing high-risk procedures such as surgery, antithrombin III concentrates may be given. These are products made from human blood plasma that replace the missing antithrombin.^[3][11] Antithrombin concentrates are also used for pregnant women with antithrombin deficiency to prevent complications.^[11]

Patients taking blood thinners need regular monitoring. Because warfarin or heparin can cause bleeding, healthcare providers check to ensure patients are getting the right amount of medicine. A prothrombin time (PT) test can tell if the warfarin dose is correct, allowing the provider to adjust it so patients don’t get dangerous clots but don’t bleed too much either.^[1]

What to Expect

Most people with antithrombin III deficiency have a good outlook if they stay on anticoagulant medicines as prescribed.^[4] About one of every two to three people with this condition may develop blood clots in adulthood.^[1]

The risk of blood clots increases with certain factors:^[1]

• Having surgery
• Not moving the body enough
• Increasing age
• Pregnancy and childbirth

Hereditary antithrombin deficiency is something a person is born with, so it lasts for life.^[1] Blood clots can cause serious complications and even death, particularly when they occur in the lungs.^[4] However, with proper treatment and monitoring, many people with this condition can manage their risk effectively.

Prevention and Family Screening

Once a person is diagnosed with antithrombin III deficiency, all close family members should be screened for this disorder.^[4] Blood-thinning medicines can prevent blood clots from forming and prevent complications related to clotting.^[4]

Women with antithrombin III deficiency should avoid using oral contraceptives, as these medications can increase the risk of blood clots.^[11] Lifestyle modifications can also help reduce the risk of blood clots, including:^[16]

• Regular exercise
• Maintaining a healthy weight
• Avoiding smoking
• Staying hydrated
• Moving around during long periods of sitting, such as on long flights

People with antithrombin deficiency should contact their healthcare provider if they experience symptoms of a blood clot, such as swelling, redness, or pain in the legs or arms, or breathing problems.^[4] Regular check-ups with healthcare providers are essential for monitoring antithrombin levels and adjusting medications as needed to prevent complications.^[1]