What is thrombophilia

Thrombophilia also known as excessive clotting disorder or hypercoagulable disorder, means that your blood has an increased tendency to form clots ¹. You’re more likely to develop a blood clot in one of the large veins in your leg (deep vein thrombosis or DVT) or a pulmonary embolism (PE), where the blood clot breaks off, travels in the circulation and lodges in the arteries supplying the lungs. The tendency to develop a blood clot may arise because of some underlying condition that develops during a person’s lifetime (acquired thrombophilia) or may be due to certain genes passed from parent to child (inherited thrombophilia).

In the U.S., as many as 900,000 people are affected by venous thromboembolism (deep vein thrombosis or DVT) annually and about 100,000 people die each year from blood clots. Many people who develop a clot experience long-term health issues, according to the Centers for Disease Control and Prevention (CDC).

How thrombophilia affects blood clotting

Clotting is a normal response to blood vessel or tissue injury. When there is an injury and bleeding occurs, your body stops this blood loss through a complex clotting process called hemostasis. During hemostasis, the injured blood vessel constricts to reduce blood flow, platelets adhere to the injury site and clump together to form a loose platelet plug, and the coagulation cascade is initiated. During the cascade process, the body sequentially activates proteins in the blood called clotting factors, proteins that produce a net of fibrin strands that weave through the platelet plug and stabilize the resulting blood clot. These strands get tangled up with the platelet plug to form an even stronger blood clot. This clot functions as a barrier to further blood loss, one that stays in place until the injury has healed, and eventually the clot is broken down by the body.

Usually, the body activates the clotting process, regulates its speed and volume with feedback mechanisms, and after the site has healed, breaks down the clot and removes it in a process called fibrinolysis. When something goes wrong with blood clot formation or breakdown, excessive blood clot formation may occur.

If you have thrombophilia, you have an imbalance in clotting chemicals. You either have too much or too little of the substance that stops clotting (clotting factor).

• Activation problems: Some conditions cause activation of the clotting process when there is no injury and no need for a clot to form. For example, anything that interrupts the smooth blood vessel walls, essential for unimpeded blood flow, may increase risk of clot formation.

• Regulation problems: Clot formation is carefully regulated by the body. Even as a clot forms to stop bleeding at the site of an injury, the body begins to activate proteins that will slow clot production, much like the brakes in a car. If clot production is not regulated well, excessive clotting may result.

• Clot breakdown problems: After an injury is healed, proteins are activated that break down and remove the clot (fibrinolysis). Dysfunction or deficiency in the breakdown proteins can cause excessive clotting.

The tendency to develop a clot may arise because of some underlying condition that develops during a person’s lifetime (acquired) or may be due to certain genes passed from parent to child (inherited). Acquired conditions are far more commonly the cause of clots than inherited disorders. When someone has experienced a blood clot in a vein or artery (thrombotic episode), a physical examination and thorough patient history may reveal one or more contributing factors that led to inappropriate blood clot formation.

Blood clot risk

Anyone can get a blood clot, but you’re most at risk if you’ve been unwell for long periods and unable to move around much.

Blood clots may be linked to long plane journeys or the contraceptive pill, but you’re much more likely to have one after going into hospital. About two-thirds of all blood clots occur during or just after a hospital stay.

Thrombophilia causes

There are many different types of thrombophilia. Some types are inherited, while other types develop later in life (acquired thrombophilia). The main types of thrombophilia are outlined below.

Inherited thrombophilia

Certain inherited gene mutations may predispose someone to forming blood clots.

Some of the most common inherited factors contributing to blood clots include:

• Factor V Leiden mutation (Activated protein C resistance)—a mutation in the gene that makes the factor V protein; Factor V is activated normally, but it is resistant to degradation by activated protein C, which regulates the clotting process.
• Prothrombin 20210 mutation (factor 2 mutation)—a mutation that results in an increased amount of prothrombin (factor II) in the circulation, which is associated with an increased risk for venous blood clots
• MTHFR mutation—a mutation in this gene may predispose someone to high levels of homocysteine, which can increase the risk of excessive clotting.

Some inherited conditions are relatively rare and are usually due to genetic mutations that lead to a deficiency or dysfunction in the coagulation protein that the gene produces. Examples include:

• Antithrombin (formerly known as antithrombin 3)—this is a factor that helps decrease the activity of the clotting process by inhibiting factors Xa, IXa, XIa, and thrombin. Inherited deficiency of antithrombin can lead to a clot formation.
• Protein C—helps regulate the speed of the coagulation cascade by degrading activated factors V and VIII
• Protein S—a cofactor with protein C
• Elevated factor VIII levels—persistently elevated factor VIII levels that are not associated with inflammation or other acquired conditions but are associated with an increased thrombotic risk
• Dysfibrinogenemia—abnormal fibrinogen leads to fibrin that does not break down normally. Patients with dysfibrinogenemia may have bleeding or clotting complications. Dysfibrinogenemia can be inherited or acquired.

In all of these inherited disorders (except for antithrombin deficiency), people may inherit one mutated gene copy and one normal gene copy (heterozygous) or two mutated gene copies (homozygous). If someone has two mutated gene copies, the person tends to have a more severe form of the condition, and if the person is heterozygous in more than one condition, the risk of clotting tends to be additive (and sometimes the risk is multiplied). With inherited hypercoagulable disorders, the first thrombotic episode may be seen at a relatively young age (less than 50 years of age). The patient may have recurrent thrombosis, a family history of thrombosis, and blood clots in unusual sites, such as veins of the brain, liver or kidneys.

Factor V Leiden thrombophilia

Factor V Leiden thrombophilia is an inherited disorder of blood clotting caused by a faulty F5 gene ². Factor V Leiden thrombophilia is the most common type of inherited thrombophilia, and tends to be seen in white Europeans and Americans. Between 3 and 8 percent of people with European ancestry carry one copy of the factor V Leiden mutation in each cell, and about 1 in 5,000 people have two copies of the mutation. The mutation is less common in other populations.

People with factor V Leiden thrombophilia have a higher than average risk of developing a type of blood clot called a deep venous thrombosis (DVT) at some point in life, but the majority of carriers of the gene are never affected. DVTs occur most often in the legs, although they can also occur in other parts of the body, including the brain, eyes, liver, and kidneys. Factor V Leiden thrombophilia also increases the risk that clots will break away from their original site and travel through the bloodstream. These clots can lodge in the lungs, where they are known as pulmonary emboli. Although factor V Leiden thrombophilia increases the risk of blood clots, only about 10 percent of individuals with the factor V Leiden mutation ever develop abnormal clots.

The factor V Leiden mutation is associated with a slightly increased risk of pregnancy loss (miscarriage). Women with this mutation are two to three times more likely to have multiple (recurrent) miscarriages or a pregnancy loss during the second or third trimester. Some research suggests that the factor V Leiden mutation may also increase the risk of other complications during pregnancy, including pregnancy-induced high blood pressure (preeclampsia), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). However, the association between the factor V Leiden mutation and these complications has not been confirmed. Most women with factor V Leiden thrombophilia have normal pregnancies.

Factor V Leiden thrombophilia causes

A particular mutation in the F5 gene causes factor V Leiden thrombophilia. The F5 gene provides instructions for making a protein called coagulation factor V. This protein plays a critical role in the coagulation system, which is a series of chemical reactions that forms blood clots in response to injury.

The coagulation system is controlled by several proteins, including a protein called activated protein C (APC). APC normally inactivates coagulation factor V, which slows down the clotting process and prevents clots from growing too large. However, in people with factor V Leiden thrombophilia, coagulation factor V cannot be inactivated normally by APC. As a result, the clotting process remains active longer than usual, increasing the chance of developing abnormal blood clots.

Other factors also increase the risk of developing blood clots in people with factor V Leiden thrombophilia. These factors include increasing age, obesity, injury, surgery, smoking, pregnancy, and the use of oral contraceptives (birth control pills) or hormone replacement therapy. The risk of abnormal clots is also much higher in people who have a combination of the factor V Leiden mutation and another mutation in the F5 gene. Additionally, the risk is increased in people who have the factor V Leiden mutation together with a mutation in another gene involved in the coagulation system.

Factor V Leiden thrombophilia inheritance pattern

The chance of developing an abnormal blood clot depends on whether a person has one or two copies of the factor V Leiden mutation in each cell. People who inherit two copies of the mutation, one from each parent, have a higher risk of developing a clot than people who inherit one copy of the mutation. Considering that about 1 in 1,000 people per year in the general population will develop an abnormal blood clot, the presence of one copy of the factor V Leiden mutation increases that risk to 3 to 8 in 1,000, and having two copies of the mutation may raise the risk to as high as 80 in 1,000.

Prothrombin 20210 thrombophilia

Prothrombin 20210 or the prothrombin gene mutation, is another type of thrombophilia caused by inheriting a faulty gene. Prothrombin thrombophilia is the second most common inherited form of thrombophilia after factor V Leiden thrombophilia ³. As with Factor V Leiden, prothrombin 20210 is more common in white people, particularly Europeans. Approximately 1 in 50 people in the white population in the United States and Europe has prothrombin 20210 thrombophilia. Prothrombin 20210  thrombophilia is less common in other ethnic groups, occurring in less than one percent of African American, Native American, or Asian populations.

Prothrombin is a protein in the blood that helps it clot. People who have the faulty gene produce too much prothrombin. People who have prothrombin thrombophilia are at somewhat higher than average risk for a type of clot called a deep venous thrombosis (DVT), which typically occurs in the deep veins of the legs. Affected people also have an increased risk of developing a pulmonary embolism (PE), which is a clot that travels through the bloodstream and lodges in the lungs. Most people with prothrombin thrombophilia never develop abnormal blood clots, however.

Some research suggests that prothrombin thrombophilia is associated with a somewhat increased risk of pregnancy loss (miscarriage) and may also increase the risk of other complications during pregnancy. These complications may include pregnancy-induced high blood pressure (preeclampsia), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). It is important to note, however, that most women with prothrombin thrombophilia have normal pregnancies.

Prothrombin 20210 thrombophilia causes

Prothrombin thrombophilia is caused by a particular mutation in the F2 gene. The F2 gene plays a critical role in the formation of blood clots in response to injury. The protein produced from the F2 gene, prothrombin (also called coagulation factor 2), is the precursor to a protein called thrombin that initiates a series of chemical reactions in order to form a blood clot. The particular mutation that causes prothrombin thrombophilia results in an overactive F2 gene that causes too much prothrombin to be produced. An abundance of prothrombin leads to more thrombin, which promotes the formation of blood clots.

Other factors also increase the risk of blood clots in people with prothrombin thrombophilia. These factors include increasing age, obesity, trauma, surgery, smoking, the use of oral contraceptives (birth control pills) or hormone replacement therapy, and pregnancy. The combination of prothrombin thrombophilia and mutations in other genes involved in blood clotting can also influence risk.

Prothrombin 20210 thrombophilia inheritance pattern

The risk of developing an abnormal clot in a blood vessel depends on whether a person inherits one or two copies of the F2 gene mutation that causes prothrombin thrombophilia. In the general population, the risk of developing an abnormal blood clot is about 1 in 1,000 people per year. Inheriting one copy of the F2 gene mutation increases that risk to 2 to 3 in 1,000. People who inherit two copies of the mutation, one from each parent, may have a risk as high as 20 in 1,000.

Protein C deficiency thrombophilia

Protein C deficiency is an inherited disorder that increases the risk of developing abnormal blood clots; the condition can be mild or severe. Mild protein C deficiency affects approximately 1 in 500 individuals. Severe protein C deficiency is rare and occurs in an estimated 1 in 4 million newborns ⁴.

Individuals with mild protein C deficiency are at risk of a type of blood clot known as a deep vein thrombosis (DVT). These clots occur in the deep veins of the arms or legs, away from the surface of the skin. A DVT can travel through the bloodstream and lodge in the lungs, causing a life-threatening blockage of blood flow known as a pulmonary embolism (PE). While most people with mild protein C deficiency never develop abnormal blood clots, certain factors can add to the risk of their development. These factors include increased age, surgery, inactivity, or pregnancy. Having another inherited disorder of blood clotting in addition to protein C deficiency can also influence the risk of abnormal blood clotting.

In severe cases of protein C deficiency, infants develop a life-threatening blood clotting disorder called purpura fulminans soon after birth. Purpura fulminans is characterized by the formation of blood clots in the small blood vessels throughout the body. These blood clots block normal blood flow and can lead to localized death of body tissue (necrosis). Widespread blood clotting uses up all available blood clotting proteins. As a result, abnormal bleeding occurs in various parts of the body, which can cause large, purple patches on the skin. Individuals who survive the newborn period may experience recurrent episodes of purpura fulminans.

Protein C deficiency thrombophilia causes

Protein C deficiency is caused by mutations in the PROC gene ⁴. This gene provides instructions for making protein C, which is found in the bloodstream and is important for controlling blood clotting. Protein C blocks the activity of (inactivates) certain proteins that promote blood clotting.

Most of the mutations that cause protein C deficiency change single protein building blocks (amino acids) in protein C, which disrupts its ability to control blood clotting. Individuals with this condition do not have enough functional protein C to inactivate clotting proteins, which results in the increased risk of developing abnormal blood clots. Protein C deficiency can be divided into type 1 and type 2 based on how mutations in the PROC gene affect protein C ⁴. Type 1 is caused by PROC gene mutations that result in reduced levels of protein C, while type 2 is caused by PROC gene mutations that result in the production of an altered protein C with reduced activity. Both types of mutations can be associated with mild or severe protein C deficiency; the severity is determined by the number of PROC gene mutations an individual has.

Protein C deficiency thrombophilia causes inheritance pattern

Protein C deficiency is inherited in an autosomal dominant pattern, which means one altered copy of the PROC gene in each cell is sufficient to cause mild protein C deficiency ⁴. Individuals who inherit two altered copies of this gene in each cell have severe protein C deficiency ⁴.

Protein S deficiency thrombophilia

Protein S deficiency is an inherited disorder of blood clotting. People with this condition have an increased risk of developing abnormal blood clots. Mild protein S deficiency is estimated to occur in approximately 1 in 500 individuals ⁵. Severe protein S deficiency is rare; however, its exact prevalence is unknown.

Individuals with mild protein S deficiency are at risk of a type of clot called a deep vein thrombosis (DVT) that occurs in the deep veins of the arms or legs. If a DVT travels through the bloodstream and lodges in the lungs, it can cause a life-threatening clot known as a pulmonary embolism (PE). Other factors can raise the risk of abnormal blood clots in people with mild protein S deficiency. These factors include increasing age, surgery, immobility, or pregnancy. The combination of protein S deficiency and other inherited disorders of blood clotting can also influence risk. Many people with mild protein S deficiency never develop an abnormal blood clot, however.

In severe cases of protein S deficiency, infants develop a life-threatening blood clotting disorder called purpura fulminans soon after birth. Purpura fulminans is characterized by the formation of blood clots within small blood vessels throughout the body. These blood clots disrupt normal blood flow and can lead to death of body tissue (necrosis). Widespread blood clotting uses up all available blood clotting proteins. As a result, abnormal bleeding occurs in various parts of the body and is often noticeable as large, purple skin lesions. Individuals who survive the newborn period may experience recurrent episodes of purpura fulminans.

Protein S deficiency thrombophilia causes

Protein S deficiency is caused by mutations in the PROS1 gene ⁵. This gene provides instructions for making protein S, which is found in the bloodstream and is important for controlling blood clotting. Protein S helps block the activity of (inactivate) certain proteins that promote the formation of blood clots.

Most mutations that cause protein S deficiency change single protein building blocks (amino acids) in protein S, which disrupts its ability to control blood clotting. Individuals with this condition do not have enough functional protein S to inactivate clotting proteins, which results in the increased risk of developing abnormal blood clots. Protein S deficiency can be divided into types 1, 2 and 3 based on how mutations in the PROS1 gene affect protein S ⁵.

Protein S deficiency thrombophilia inheritance pattern

Protein S deficiency is inherited in an autosomal dominant pattern, which means one altered copy of the PROS1 gene in each cell is sufficient to cause mild protein S deficiency ⁵. Individuals who inherit two altered copies of this gene in each cell have severe protein S deficiency ⁵.

Hereditary antithrombin deficiency thrombophilia

Hereditary antithrombin deficiency is a disorder of blood clotting. People with hereditary antithrombin deficiency thrombophilia are at higher than average risk for developing abnormal blood clots, particularly a type of clot that occurs in the deep veins of the legs ⁶. This type of clot is called a deep vein thrombosis (DVT). Affected individuals also have an increased risk of developing a pulmonary embolism (PE), which is a clot that travels through the bloodstream and lodges in the lungs. In hereditary antithrombin deficiency, abnormal blood clots usually form only in veins, although they may rarely occur in arteries.

About half of people with hereditary antithrombin deficiency will develop at least one abnormal blood clot during their lifetime. These clots usually develop after adolescence.

Other factors can increase the risk of abnormal blood clots in people with hereditary antithrombin deficiency. These factors include increasing age, surgery, or immobility. The combination of hereditary antithrombin deficiency and other inherited disorders of blood clotting can also influence risk. Women with hereditary antithrombin deficiency are at increased risk of developing an abnormal blood clot during pregnancy or soon after delivery. They also may have an increased risk for pregnancy loss (miscarriage) or stillbirth.

Hereditary antithrombin deficiency is estimated to occur in about 1 in 2,000 to 3,000 individuals ⁶. Of people who have experienced an abnormal blood clot, about 1 in 20 to 200 have hereditary antithrombin deficiency.

Hereditary antithrombin deficiency thrombophilia causes

Hereditary antithrombin deficiency is caused by mutations in the SERPINC1 gene ⁶. This gene provides instructions for producing a protein called antithrombin (previously known as antithrombin 3). This protein is found in the bloodstream and is important for controlling blood clotting. Antithrombin blocks the activity of proteins that promote blood clotting, especially a protein called thrombin.

Most of the mutations that cause hereditary antithrombin deficiency change single protein building blocks (amino acids) in antithrombin, which disrupts its ability to control blood clotting. Individuals with this condition do not have enough functional antithrombin to inactivate clotting proteins, which results in the increased risk of developing abnormal blood clots.

Hereditary antithrombin deficiency thrombophilia inheritance pattern

Hereditary antithrombin deficiency is typically inherited in an autosomal dominant pattern, which means one altered copy of the SERPINC1 gene in each cell is sufficient to cause the disorder ⁶. Inheriting two altered copies of this gene in each cell is usually incompatible with life ⁶; however, a few severely affected individuals have been reported with mutations in both copies of the SERPINC1 gene in each cell.

Antiphospholipid syndrome

Antiphospholipid syndrome, also known as Hughes syndrome, is an immune system disorder when your immune system mistakenly creates antibodies that attack phospholipids, fat molecules thought to keep blood at the right consistency, making your blood much more likely to clot. Unlike the inherited thrombophilias, blood clots in people with antiphospholipid syndrome can occur in a vein or artery. This can cause dangerous blood clots in the legs, kidneys, lungs and brain.

Women with antiphospholipid syndrome have an increased risk of complications during pregnancy, such as miscarriage, stillbirth, high blood pressure in pregnancy (pre-eclampsia), and small babies.

Antiphospholipid syndrome can affect people of all ages, including children and babies. But most people are diagnosed with antiphospholipid syndrome between 20 and 50 years of age, and it affects 3 to 5 times as many women as men.

It’s not clear how many people in the US have antiphospholipid syndrome.

Signs and symptoms of antiphospholipid syndrome can include:

• Deep vein thrombosis (DVT), a blood clot that usually develops in the leg. Signs of a DVT include pain, swelling and redness. These clots can travel to your lungs (pulmonary embolism).
• Arterial thrombosis (a clot in an artery), which can cause a stroke or heart attack.
  • Stroke. A stroke can occur in a young person who has antiphospholipid syndrome but no known risk factors for cardiovascular diseases.
  • Transient ischemic attack (TIA). Similar to a stroke, a TIA usually lasts only a few minutes and causes no permanent damage.
• Blood clots in the brain, leading to problems with balance, mobility, vision, speech and memory
• Repeated miscarriages or stillbirths. Other pregnancy complications include dangerously high blood pressure during pregnancy (preeclampsia), premature delivery and slow fetal growth.
• Rash. Some people develop a red rash with a lacy, net-like pattern.

Less common signs and symptoms include:

• Neurological symptoms. Chronic headaches, including migraines; dementia and seizures are possible when a blood clot blocks blood flow to parts of your brain.
• Cardiovascular disease. Antiphospholipid syndrome can cause a blood clot in your leg can damage the valves in the veins, which keep blood flowing to your heart. This can result in chronic swelling and discoloration in your lower legs. Another possible complication is heart damage.
• Bleeding. Some people have a decrease in blood cells needed for clotting. This can cause episodes of bleeding, particularly from your nose and gums. You can also bleed into your skin, which will appear as patches of small red spots.

There’s no cure for antiphospholipid syndrome, but medications can reduce your risk of blood clots.

Antiphospholipid syndrome causes

Antiphospholipid syndrome is an autoimmune condition. This means the immune system, which usually protects your body from infection and illness, attacks healthy tissue by mistake.

In antiphospholipid syndrome, the immune system produces abnormal antibodies called antiphospholipid antibodies. These target proteins attached to fat molecules (phospholipids), which makes the blood more likely to clot.

It’s not known what causes the immune system to produce abnormal antibodies. As with other autoimmune conditions, genetic, hormonal and environmental factors are thought to play a part.

Antiphospholipid syndrome can be caused by an underlying condition, such as an autoimmune disorder, infection or certain medications. You also can develop the syndrome without an underlying cause.

Genetic factors

Research into the genetics around antiphospholipid syndrome is still at an early stage, but it seems the genes you inherit from your parents may play a role in the development of abnormal antiphospholipid antibodies.

Antiphospholipid syndrome isn’t passed down directly from parents to children in the same way as other conditions, such as hemophilia and sickle cell anemia.

But having a family member with antiphospholipid antibodies increases the chance of your immune system also producing them. Studies have shown that some people with antiphospholipid syndrome have a faulty gene that plays a role in other autoimmune conditions, such as lupus. This may explain why some people develop antiphospholipid syndrome alongside another immune system condition.

Environmental factors

It’s thought that one or more environmental triggers may be needed to trigger antiphospholipid syndrome in some people.

Environmental factors that may be responsible include:

• viral infections, such as the cytomegalovirus (CMV) or parvovirus B19
• bacterial infections, such as E. coli (a bacteria often associated with food poisoning) or leptospirosis (an infection usually spread by certain animals)
• certain medications, such as anti-epileptic medicine or the oral contraceptive pill

Another theory is that many people with abnormal antiphospholipid antibodies only go on to develop antiphospholipid syndrome if they have a higher risk of developing blood clots.

For example, if they:

• eat an unhealthy diet, leading to high cholesterol levels in the blood
• don’t do enough exercise
• take the contraceptive pill or hormone replacement therapy (HRT)
• smoke
• are obese

But this doesn’t explain why some children and adults who don’t have any of these risk factors still develop antiphospholipid syndrome.

Antiphospholipid syndrome risk factors

Risk factors for antiphospholipid syndrome include:

• Your sex. This condition is much more common in women than in men.
• Immune system disorders. Having another autoimmune condition, such as lupus or Sjogren’s syndrome, increases your risk of antiphospholipid syndrome.
• Infections. This condition is more common in people who have certain infections, such as syphilis, HIV/AIDS, hepatitis C or Lyme disease.
• Medications. Certain medications have been linked to antiphospholipid syndrome. They include hydralazine for high blood pressure, the heart rhythm-regulating medication quinidine, the anti-seizure medication phenytoin (Dilantin) and the antibiotic amoxicillin.
• Family history. This condition sometimes runs in families.

It’s possible to have the antibodies associated with antiphospholipid syndrome without developing signs or symptoms. However, having these antibodies increases your risk of developing blood clots, particularly if you:

• Become pregnant
• Are immobile for a time, such as being on bed rest or sitting during a long flight
• Have surgery
• Smoke cigarettes
• Take oral contraceptives or estrogen therapy for menopause
• Have high cholesterol and triglycerides levels

Risk factors for thrombophilia

Some examples of underlying conditions or acquired risk factors for blood clots include:

• Venous stasis—also known as “coach-class” syndrome, describes any situation that immobilizes someone for long periods of time, such as cramped seating during long distance travel or prolonged bed rest with an illness or hospitalization. Immobility may lead to slow or restricted blood flow (venous stasis) and an increased risk of developing a blood clot, especially in the deep veins of the legs (DVT).
• Antiphospholipid syndrome—an autoimmune disorder in which a person develops antiphospholipid antibodies such as the lupus anticoagulant or cardiolipin antibody
• Cancer or malignancies—cancer may cause excessive clotting for a variety of reasons: 1) tumor growth may cause external compression on a blood vessel or, in some cases, actually extend into blood vessels (for example, renal cell cancers extending into the renal veins); 2) tumor may produce substances that can initiate and/or promote clotting (e.g., a type of leukemia known as acute promyelocytic leukemia can cause DIC); 3) treatments for cancer (radiation, chemotherapy) may leave patients more susceptible to excessive clotting.
• Trauma such as fractures or surgery—damage to blood vessels and prolonged immobilization can lead to blood clots.
• Presence of a catheter in a central vein—disruption in the flow of blood can cause blood clots to form.
• Pregnancy or recently giving birth (postpartum)—pregnant women have high levels of platelets and clotting factors and so are at increased risk for clots.
• Use of certain drugs such as:
  • Hormone replacement therapy (HRT)
  • Oral contraceptives
  • Tamoxifen
  • Heparin (which can cause heparin-induced thrombocytopenia, HIT)
• Atherosclerosis—the buildup of cholesterol,lipids, and calcium deposits in the walls of arteries; the deposits make the blood vessel walls less smooth, weaken them, and eventually form plaques that may rupture and lead to clots and to strokes and heart attacks.
• Vasculitis—inflammation of blood vessel walls may increase risk of a clot forming. Vasculitis that has healed may provide sites within blood vessels that promote formation of plaque (atherosclerosis).
• An acquired deficiency of one or more of the proteins that regulate clot formation, such as protein C, protein S, or antithrombin. When the level of these proteins drops, clot formation is less well-regulated and the risk of a clot increases.
• Disseminated intravascular coagulation (DIC)—a life-threatening, acute, acquired condition that causes tiny clots throughout the body; it uses up coagulation factors at an accelerated rate, leading to both bleeding and clotting.
• Bone marrow disorders such as myeloproliferative neoplasms.
• Paroxysmal nocturnal hemoglobinuria (PNH)—an acquired condition that can cause hemolytic anemia, bone marrow failure, kidney failure, as well as clotting, particularly in veins in the abdomen (e.g., hepatic, portal, mesenteric, splenic, renal) and in the brain (cerebral veins)
• Lupus, an autoimmune disorder
• Elevated levels of homocysteine—can be caused by a deficiency of vitamin B12
• Heart Failure— may cause slowing of blood flow (stasis)
• Obesity—this condition can contribute to atherosclerosis, which in turn can lead to excessive clotting.
• Rapid, uneven heartbeat (atrial fibrillation)—this condition can cause blood to pool in a chamber of the heart, which can increase the risk of the blood clotting.
• Blood vessel wall abnormalities (usually combined with a clotting abnormality)

Thrombophilia and pregnancy

Thrombophilia is a term which describes the increased tendency of excessive blood clotting. It is a normal phenomenon during pregnancy, where there is an increase in most clotting factors, such as factor VIII, Von Willebrand factor, platelets, fibrinogen and factor VII. During pregnancy, there is also an increase in prothrombin fragment 1 + 2 and D-dimer ⁷. Thrombophilia is a common cause of recurrent pregnancy loss and may be seen in 40–50% of cases ⁸. Pregnancy is a hypercoaguable state and if the pregnancy is affected by thrombophilia, the hypercoaguable state becomes worse and may impair blood flow through the maternal veins, leading to deep vein thrombosis, and clots in the placental blood vessels, leading to fetal growth restriction and/or fetal demise ⁹. Due to this fact, anticoagulants have become very popular for treating recurrent pregnancy loss ¹.

Thrombophilia symptoms

Most people with thrombophilia don’t have symptoms and never have health problems. Symptoms only occur if thrombophilia causes a blood clot.

If you have thrombophilia, you’re at increased risk of developing a deep vein thrombosis (DVT) or pulmonary embolism.

Warning signs of DVT include:

• pain, swelling and tenderness in your leg (usually in your calf)
• a heavy ache in the affected area
• warm skin in the area of the clot
• red skin, particularly at the back of your leg below the knee

Deep vein thrombosis (DVT) usually only affects one leg, though not always. The pain may be worse when you bend your foot up towards your knee.

Part of the blood clot can sometimes break away and travel through the bloodstream. This can be dangerous because the clot becomes lodged in the lungs. Known as a pulmonary embolism, this serious and potentially life-threatening condition can prevent blood reaching your lungs.

The symptoms of a pulmonary embolism are:

• chest or upper back pain
• shortness of breath
• coughing – usually dry, but you may cough up blood or mucus containing blood
• lightheadedness or dizziness
• fainting

If a blood clot occurs elsewhere in the body, it may cause symptoms associated with, for example, a heart attack or stroke.

Thrombophilia complications

Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Heart Attack and Stroke

Excessive clotting or thrombophilia can lead to the presence of a blood clot in a vein or artery that can potentially block the flow of blood and cause serious, life-threatening complications. Blood clots are referred to as thrombi (singular, thrombus) when they form in a blood vessel. When thrombi break off, travel through the blood and block another blood vessel in another part of the body, they are called emboli (singular, embolus) or thromboemboli.

• Blood clots most commonly form in the deep veins of the lower legs (deep venous thrombosis, or DVT). They may grow very large and block blood flow in the legs, causing pain, swelling, and tissue damage.
• While clots most commonly form in the veins of the legs, they may also form in other areas as well; for example, clots in coronary arteries are the cause of most heart attacks.
• Clots may also form on the lining of the heart or its valves, particularly when the heart is beating irregularly (atrial fibrillation) or when the valves are damaged by a disease or an abnormal condition.
• Clots also may form in large arteries as a result of narrowing and damage from atherosclerosis.
• Pieces of clots may also break off and cause an embolus that blocks an artery in another organ, such as:
  • The brain, where they can cause ischemic strokes.
  • The lungs, called pulmonary embolism or PE, where they can cause chest pain and shortness of breath.
  • The kidneys, where they can cause kidney damage.

There are a number of conditions, diseases and factors that can contribute to a person’s risk of developing a clot. A person can have more than one factor or condition that increases their risk, and the resulting risk can be cumulative. For example, a person who has an inherited risk due to the presence of Factor V Leiden mutation will likely be at greater risk if they smoke or use oral contraceptives.

Thrombophilia workup

A healthcare practitioner will investigate the underlying cause of the thrombotic episode and will try to determine the person’s risk of recurrent blood clots. The healthcare practitioner may do an extensive workup to find a cause if someone has repeated thrombotic episodes and/or if the affected person is young (less than 50 years old) and/or if the clot occurs in an unusual site in the body.

If you develop a blood clot, you may be tested for thrombophilia a few weeks or months later. A blood sample is taken to look for chemical imbalances.

You may be referred to a specialist in diagnosing and treating blood disorders (a hematologist) if the blood test results indicate you have thrombophilia.

Current tests for thrombophilia have limitations. They may be able to help identify the condition, but they can’t always determine the cause of an increased blood clotting tendency.

Thrombophilia testing

Initial testing is usually performed to determine if a person has or has had a blood clot (thrombotic episode) and, if so, to help determine the person’s risk of a repeat thrombotic episode. Although it may be fairly simple to identify that a person has a clot, identification of the underlying cause may take more time and effort. This is because several of the diagnostic tests that need to be done are affected by an existing or recent blood clot and by any blood-thinning (anticoagulant) therapy that is given.

Often, the healthcare practitioner may have to order a few tests and treat the person’s existing blood clot first. Several weeks or months later, when the person is able to come off of anticoagulant therapy, the the healthcare practitioner can order other tests to finish the evaluation of the cause of the clotting. Follow-up testing is important in helping to determine a person’s risk of developing recurrent blood clots.

The table below lists some of the tests in alphabetical order. For detailed information about each test, click on the name of the test to go to the specific article.

Not all of the tests listed in the table are needed for each person with excessive clotting disorders. If somebody has been diagnosed as having a blood clot in a vein (venous thrombosis), the first step is to rule out obvious acquired causes, such as major surgery (e.g., orthopedic), trauma, immobilization, congestive heart failure, cancer, myeloproliferative neoplasms, or nephrotic syndrome.

Routine laboratory tests include:

• Routine coagulation tests: partial thromboplastin time (PTT), prothrombin time (PT), fibrinogen
• D-dimer

As to other tests, the following general guide is used to determine what tests should be performed based on patient age and personal and family history.

• If a person has a first episode of venous thrombosis at an age younger than 50, or has a history of recurrent clotting episodes, or has a parent, sibling or child (first-degree relative) with documented thromboembolism at age younger than 50, then a test panel is often performed, including factor V Leiden mutation and prothrombin gene G20210A mutation, antiphospholipid antibodies (including lupus anticoagulant work-up), homocysteine, protein C, protein S and antithrombin. If results of these tests are not revealing, additional tests may be needed to rule out rare causes of clotting disorders.

• If a person has a first episode of venous thrombosis at an age older than 50 without known acquired risk factors and there is no personal or family history of recurrent episodes, then a limited test panel is often performed, including factor V Leiden mutation and prothrombin gene G20210A mutation, antiphospholipid antibodies (including lupus anticoagulant) and homocysteine.

The medical and family histories plus laboratory testing may reveal that a person has more than one factor or condition that increases their risk of excessive clotting, and the resulting risk can be cumulative. For example, a person whose laboratory tests indicates the presence of Factor V Leiden mutation will likely be at greater risk if they also are bed-ridden or hospitalized for some time (prolonged immobilization).

Table 1. Tests for thrombophilia

Test	Description	Ordered When/To	Abnormal Results May Indicate
Anticardiolipin antibodies (Includes cardiolipin antibody, beta-2 glycoprotein antibody, and lupus anticoagulant)	Detects the presence of one or more of these antibodies	To evaluate recurrent blood clots and/or miscarriages	Antiphospholipid syndrome
Antithrombin Activity	Measures the activity of antithrombin	To evaluate someone for recurrent blood clots; to detect acquired or inherited deficiency	Low activity may increase risk of clots.
Antithrombin Antigen	Measures quantity of antithrombin	When results from the test for activity are consistently low	Decreased production or increased use of factor; may increase thrombotic risk.
D-dimer	Detects or measures the level of a specific type of fibrin degradation product	Used to detect and evaluate for the presence of a blood clot	If elevated, indicates recent clotting activity; may be due to condition such as a thromboembolism or DIC (disseminated intravascular coagulation).
Factor V Leiden mutation (may include activated protein C resistance testing)	Identifies a genetic mutation that results in formation of an activated Factor V that resists degradation by activated protein C	When an inherited risk factor is suspected as a cause of a blood clot	The presence of the mutation increases the risk of thrombosis.
Fibrinogen	Tests measure the function and the amount of fibrinogen	As part of an evaluation for a clotting disorder	If low, may indicate decreased production or increased use; may be elevated with inflammation; it is an acute phase reactant.
Flow cytometry	Presence of certain surface proteins on blood red cells and white cells	When paroxysmal nocturnal hemoglobinuria (PNH) is suspected	Increased risk of venous thrombosis (abdominal and cerebral veins)
Homocysteine	Measures the level in blood	To determine a cause of recurrent blood clots	If elevated, increased cardiac risk and risk of thrombosis.
Lupus Anticoagulant (LA) (Panel of tests may include LA-sensitive PTT, Dilute Russell Viper Venom Test (DRVVT), and/or Platelet Neutralization Procedure (PNP))	Panel of tests used to check for Lupus anticoagulant	To evaluate someone with recurrent blood clots and/or miscarriages; when results of the PTT are prolonged	When PTT or LA sensitive PTT and DRVVT are prolonged, it suggests LA, usually confirmed with additional testing; if present, increased risk of thrombosis.
Methylenetetrahydrofolate Reductase (MTHFR)	Identifies genetic mutation	Used when the homocysteine level is elevated with no clear acquired etiology	Presence of the mutation confers an increased risk for developing elevated homocysteine levels.
Protein C Activity	Function of protein C	To evaluate someone for recurrent blood clots; may be acquired or inherited deficiency or dysfunction	Protein C helps regulate blood clot formation by degrading activated Factors V and VIII. If activity is low, there is an increased risk of thrombosis.
Protein C Antigen	Quantity of protein C	Tested when protein C activity is low.	If decreased, may be due to inherited or acquired condition; increased risk of thrombosis.
Protein S Activity	Function of protein S	As part of an evaluation of recurrent blood clots; may be acquired or inherited deficiency or dysfunction	Protein S is a cofactor that helps protein C regulate clot formation. Low activity may increase risk of excess clotting.
Protein S Antigen (free and total)	Quantity of total and free protein S	Tested when protein S activity is low.	Only free protein S is available to assist protein C; total protein S includes free protein S and inactive bound protein S. If low, increases risk of clotting.
Prothrombin 20210 mutation	Detects inherited genetic mutation	When a person has recurrent blood clots and an inherited risk factor is suspected	If present, increases risk of thrombosis.
PTT (Partial Thromboplastin Time)	Measures the time it takes for a clot to form in a blood sample after reagents are added	As part of an initial workup; screens for lupus anticoagulant; also used to monitor anticoagulant therapy	A prolonged PTT suggests need for further tests; may indicate nonspecific inhibitor (such as lupus anticoagulant).

Imaging Tests

One or more of the following imaging studies may be used to detect the presence of a blood clot and/or examine blood vessels:

• Venous ultrasound: This test is usually the first step for confirming a venous blood clot. Sound waves are used to create a view of your veins. A Doppler ultrasound may be used to help visualize blood flow through your veins. If the results of the ultrasound are inconclusive, venography or MR angiography may be used.
• CT Angiography of the chest: If your doctor suspects you have a pulmonary embolism, you may undergo a CT angiography scan. The most common cause of a pulmonary embolism is a fragment from a leg or pelvic clot that has broken off and traveled through the veins to the lung. You may be sent for a chest x-ray if your doctor believes you may have a condition other than a blood clot.
• CT angiography of the abdomen and pelvis: This type of CT scan may be used if your doctor suspects a blood clot somewhere in your abdomen or pelvis. It may also be used to rule out other conditions that cause the same symptoms as blood clots.
• CT angiography of the head and neck: If you are exhibiting the symptoms of a stroke, your doctor will order an emergency CT scan of the head in order to confirm the presence of a clot. In some cases, your doctor may order a cerebral angiography exam. A carotid ultrasound could also be performed to see if a fragment from a blood clot in your neck has traveled to your brain.

Thrombophilia treatment

Many people with thrombophilia won’t need treatment. You’ll only need treatment if you develop a blood clot or you’re at risk of developing a clot.

This will depend on the type of thrombophilia you have and factors such as your age, weight, lifestyle and family history.

You may need to take warfarin tablets or have an injection of heparin. Newer oral anticoagulants are also now available, and are sometimes used instead of warfarin to treat DVT and pulmonary embolism.

Warfarin and heparin

Warfarin and heparin are anti-clotting medicines called anticoagulants. They interfere with the clotting process and can be used to treat or prevent DVT and pulmonary embolism.

You may be be prescribed warfarin if you need an anticoagulant to treat a clot and prevent another one occurring. It takes a few days to work properly.

If you have a clot and need immediate treatment, you’ll usually be given heparin injections for a few days alongside warfarin – the heparin injections will work straight away.

The injections will either be given in hospital or at home. You no longer need to have an injection when the warfarin tablets start working properly.

A heparin injection may be given on its own to prevent clots forming, and may also be used to treat people with thrombophilia or antiphospholipid syndrome before and after surgery or during pregnancy.

Unlike warfarin, heparin is safe to take in pregnancy. Both warfarin and heparin are safe to use while breastfeeding.

Women who are pregnant and have a blood clot will usually receive subcutaneous anticoagulation with low-molecular weight heparin (LMWH). People who have antithrombin deficiencies may benefit from antithrombin factor replacement when they cannot take anticoagulant therapy (for example, around the time of surgery). Protein C concentrates can be used to temporarily replenish protein C deficiencies, and aspirin therapy (which affects platelet function) may be useful in some instances.

International normalised ratio (INR) test

Your doctor will need to adjust your warfarin dose to just the right amount – enough to stop your blood easily clotting, but not too much that you’re at risk of bleeding problems.

You’ll need a regular blood test called the international normalised ratio (INR) to measure your blood clotting ability while taking warfarin.

The INR test will be needed less frequently once your ideal dose has been reached – an INR of 2-3 is usually the aim.

New oral anticoagulants

In recent years, a number of new oral anticoagulants have become available for treating and preventing blood clots. They’re given in a fixed dose without the monitoring that’s necessary with warfarin.

New oral anticoagulants aren’t suitable for everyone and shouldn’t be used during pregnancy or breastfeeding. They should only be used under the guidance of a specialist to treat people with thrombophilia.

Lifestyle and home remedies

If you have thrombophilia, you need to be aware of the symptoms of a blood clot and see your doctor immediately if you think you have one.

You should also take the following precautions to lower your risk of developing blood clots:

• lose weight if you’re overweight
• stop smoking
• eat a healthy, balanced diet and exercise regularly
• avoid being immobile for long periods – being inactive can cause a DVT

See your doctor before long-distance travel if you’re at risk of getting a DVT, or if you’ve had a DVT in the past.

If you’re planning a long-distance plane, train or car journey (journeys of 6 hours or more), make sure you:

• drink plenty of water
• avoid drinking excessive amounts of alcohol because it can cause dehydration
• avoid taking sleeping pills because they can cause immobility
• perform simple leg exercises, such as regularly flexing your ankles
• take occasional short walks when possible – for example, during refuelling stopovers
• wear elastic compression stockings. The below-knee stockings apply gentle pressure to the ankle to help blood flow. They come in a variety of sizes and there are also different levels of compression. Class 1 stockings (exerting a pressure of 14-17 mmHg at the ankle) are generally sufficient. It’s vital that compression stockings are measured and worn correctly. Ill-fitting stockings could further increase the risk of DVT. Flight socks are available from pharmacies, airports and many retail outlets. Take advice on size and proper fitting from a pharmacist or another health professional.

If you’re pregnant or planning to get pregnant, discuss this with your doctor and tell your midwife and obstetrician about your condition.

You may need to take low-dose aspirin or heparin injections while you’re pregnant to prevent problems occurring during pregnancy or miscarriage.

If you’re having a major operation, make sure you tell the healthcare professionals treating you about your condition. You may need a heparin injection to prevent a blood clot forming.

Women with thrombophilia shouldn’t take the combined oral contraceptive pill or hormone replacement therapy (HRT) because it further increases the risk of developing a blood clot.

References

1. Thrombophilia and Recurrent Pregnancy Loss: Is heparin still the drug of choice?. Sultan Qaboos Univ Med J. 2014;14(1):e26-36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916273/
2. Factor V Leiden thrombophilia. https://ghr.nlm.nih.gov/condition/factor-v-leiden-thrombophilia
3. Prothrombin thrombophilia. https://ghr.nlm.nih.gov/condition/prothrombin-thrombophilia
4. Protein C deficiency. https://ghr.nlm.nih.gov/condition/protein-c-deficiency
5. Protein S deficiency. https://ghr.nlm.nih.gov/condition/protein-s-deficiency
6. Hereditary antithrombin deficiency. https://ghr.nlm.nih.gov/condition/hereditary-antithrombin-deficiency
7. Hathaway WE, Goodnight SH., Jr . Thrombosis in pregnancy. In: Hathaway WE, Goodnight SH Jr, editors. Disorders of Hemostasis and Thrombosis: A clinical guide. New York: McGraw-Hill Professional; 1993. pp. 430–6
8. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Visser J, Ulander VM, Helmerhorst FM, Lampinen K, Morin-Papunen L, Bloemenkamp KW, Kaaja RJ. Thromb Haemost. 2011 Feb; 105(2):295-301.
9. Deep vein thrombosis in pregnancy. Colman-Brochu S. MCN Am J Matern Child Nurs. 2004 May-Jun; 29(3):186-92.