Thrombophilia: Causes, Symptoms, Types, Diagnosis and Treatment

Also known as hypercoagulability, it is a predisposition to the development of blood clots.

Thrombophilia means that the blood has a greater tendency to form clots .

Causes of thrombophilia

Thrombophilia can be inherited or acquired during a person’s life.

Conditions that lead to thrombophilia that can be acquired or developed during life include blood abnormalities, such as too many red blood cells ( polycythemia ) or too many platelets (thrombocytosis or thrombocythemia), placement of a mechanical heart valve, or abnormal development of proteins or antibodies.

You are more likely to develop a blood clot in one of the large veins in your leg (deep vein thrombosis) or a pulmonary embolism, where the blood clot breaks loose, travels in the circulation, and lodges in the arteries that supply the blood vessels. lungs.

How does thrombophilia affect blood clotting?

The human body is equipped with a sophisticated and balanced blood clotting system, in which platelets (the ‘clotting’ blood cells) and multiple clotting proteins are mixed to prevent both excessive bleeding and excessive clotting.

When a blood vessel is cut and injured, small cells called platelets adhere to the wall of the damaged vessel to form a plug.

Thrombus (blood clot) formation is good after blood vessel injuries, regardless of whether the injury is due to an accidental cut, severe trauma, a broken bone, or surgery.

If blood clotting did not occur, you would experience unstoppable (and even fatal) bleeding.

This normal blood clot formation should be located in the area where the blood vessel injury occurred and should be stopped as soon as blood leakage from the vessels is contained and / or the vessel injury has healed or repaired.

Proteins in the blood called clotting factors cause strands called fibrin to form around the plug. These strands become entangled with the platelet plug to form an even stronger blood clot.

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

In the presence of thrombophilias, the well-balanced coagulation system has a predisposition toward thrombosis, which is also known as “hypercoagulability” or “hypercoagulable state.”


Thrombophilias can be defined as a group of inherited or acquired disorders that increase a person’s risk of developing thrombosis (abnormal “blood clotting”) in the veins or arteries.

Hereditary thrombophilia was first described in the 1960s, when researchers discovered an antithrombin deficiency.

Antithrombin is a natural anticoagulant that blocks both the conversion of prothrombin to thrombin and the conversion of factor X to its active form, factor Xa.

Protein C and protein S deficiencies were described in the 1980s. Protein C and protein S are natural anticoagulants that, in combination with each other, degrade or destroy factor V.

Symptoms of thrombophilia

Most people with thrombophilia have no symptoms and never have health problems. Symptoms only occur if the thrombophilia causes a blood clot.

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

Warning signs of deep vein thrombosis include:

  • Pain, swelling, and tenderness in the leg (usually the calf).
  • A strong pain in the affected area.
  • Warm skin in the area of ​​the clot.
  • Red skin, especially on the back of the leg below the knee.

The deep vein thrombosis usually affects only one leg, but not always. The pain may be worse when you bend your foot toward the knee.

Part of the blood clot can sometimes break loose and travel through the bloodstream. This can be dangerous because the clot lodges in the lungs.

Known as a pulmonary embolism, this serious and life-threatening condition can prevent blood from reaching the lungs.

The symptoms of a pulmonary embolism are:

  • Chest or upper back pain.
  • Short of breath.
  • Cough (usually dry, but you can cough up blood or mucus that contains blood).
  • Dizziness or vertigo .
  • Fainting.

See your GP immediately if you have any combination of the above symptoms. You can also call your local service after hours for advice, for an ambulance if your symptoms are severe.

Diagnosis of thrombophilia

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

You may be referred to a specialist in the diagnosis and treatment of blood disorders (hematologist) if blood test results indicate that you have thrombophilia.

Current evidence for thrombophilia has limitations. They may be able to help identify the condition, but cannot always determine the cause of an increased tendency for blood clotting.

Types of thrombophilia

There are many different types of thrombophilia.

Some types of thrombophilias can be inherited (inherited), while others develop later in life: acquired (not inherited) or both. Hereditary thrombophilias are abnormalities of the genes responsible for making clotting proteins (known as genetic mutations).

People born with an inherited thrombophilia are also known as “carriers” of that particular genetic mutation.

Acquired thrombophilias are due to increased levels of certain clotting substances in the blood or special proteins called antibodies that can also lead to clotting.

The most common acquired thrombophilias are commonly found during surgery, injury, or medical conditions, including congestive heart failure and certain respiratory conditions, and are called antiphospholipid antibodies (APLAs).

These represent a family of several different individual antibodies that can, as a group or independently, lead to coagulation events and also to recurrent spontaneous abortions.

Some thrombophilias can have both a genetic predisposition and be acquired. Inherited and acquired thrombophilias appear to “tilt” the well-balanced clotting system toward clotting (thrombosis).

Such an imbalance in the clotting system results in an increased risk of clotting events, such as deep vein thrombosis (DVT) or pulmonary embolism (PE).

However, just because a person who has a thrombophilia has a higher chance of developing abnormal clotting than a person without thrombophilia does not mean that the previous person will have a clotting event.

Fortunately, not everyone with thrombophilia will have a blood clot in their lifetime, while, unfortunately, many patients who experience thrombotic events (such as deep vein thrombosis) may not have any detectable thrombophilia.

The main types of thrombophilia are described below.

Factor V Leiden

Factor V Leiden is a type of thrombophilia caused by a faulty gene. It is the most common type of inherited thrombophilia and tends to be seen in white Europeans and Americans.

The risk of developing a deep vein thrombosis at some point in life increases, but most carriers of the gene are never affected.

Research studies have estimated that nearly 10% of the world’s population has underlying thrombophilia, the most common being factor V Leiden and mutations in the prothrombin gene.

Prothrombin 20210

Prothrombin 20210, or the prothrombin gene mutation, is another type of thrombophilia caused by inheriting a faulty gene.

The 20210A allele of the prothrombin gene has been confirmed to be one of the most prevalent genetic factors associated with venous thrombosis. It is present in 5.0 to 6.2% of unselected patients with venous thrombosis and 0.7 to 2.6% of control subjects.

Prothrombin is the precursor molecule for thrombin, which activates factors V and VIII and converts fibrinogen to fibrin.

In 1996, researchers sequenced the prothrombin genes of probands from 28 families with unexplained thrombophilia and identified a transition from G to A at nucleotide position 20210, in the 3 ′ untranslated region of the gene, which is associated with increased risk of venous thrombosis.

Patients with the 20210A allele have significantly higher levels of plasma prothrombin, which is believed to mediate the procoagulant effect. The genetic variant is assumed to cause elevated prothrombin levels, but the mechanism is unknown.

Prothrombin is a protein in the blood that helps it clot. People who have the faulty gene make too much prothrombin. This results in a greater tendency for blood clots, such as deep vein thrombosis.

As with Factor V Leiden, prothrombin 20210 is more common in white people, particularly Europeans.

Heterozygotes for the 20210A allele have a 2- to 5-fold increased risk of thrombosis compared to unaffected control subjects. Hereditary inheritance of the 20210A variant appears to increase the risk of thrombosis in patients with other forms of thrombophilia.

Patients with factor V Leiden or protein C, protein S, or antithrombin deficiency who have had deep vein thrombosis are significantly more likely than control subjects to also carry the 20210A allele.

The number of thrombotic events per patient is also higher for such heterozygous compounds.

Protein C, protein S, and antithrombin deficiency

Deficiencies of the endogenous anticoagulant proteins protein C, protein S, and antithrombin (AT) were the first identified genetic causes of thrombophilia.

Until several years ago they represented the majority of the few cases in which a hereditary cause of thrombosis could be identified.

In contrast to resistance to activated protein C (PCA) and prothrombin 20210A, which are monogenic disorders, deficiency of each of these three proteins can be caused by several different mutations, resulting in a quantitative or functional deficiency.

In general, these deficiencies have an autosomal dominant pattern of inheritance, and homozygotes generally die in utero or shortly after birth.

The clinical expression of heterozygosity varies widely, and it is increasingly clear that the coexistence of other genetic abnormalities causing a predisposition to thrombosis contributes to this phenotypic diversity.

The earliest estimates of the risk of thrombosis associated with deficiencies of these proteins were derived largely from case-control studies and research of thrombophilic relatives.

These estimates are now recognized as excessive, and some of the seemingly high risks are attributed to the presence of multiple genetic defects in these families.

Protein C

Heterozygous protein C deficiency has been associated with deep vein thrombosis, pulmonary thromboembolism, superficial venous thrombophlebitis, and, rarely, arterial thrombosis.

Some protein C-deficient heterozygotes remain asymptomatic. An analysis of protein C antigen levels in more than 5,400 normal, unselected adults suggested a prevalence of heterozygotes of 1: 200 to 1: 300.

Affected individuals identified by this type of population-based screening do not appear to be at substantially increased risk of thrombosis.

In contrast, patients with protein C deficiency who have had a thromboembolic event have a comparatively higher risk of thrombosis, as are members of their family.

Pregnancy is well recognized as a high-risk clinical situation for people with protein C deficiency.

Asymptomatic thrombosis-prone heterozygotes may have similar serum protein C antigen levels or even the same protein C gene mutation.

The coexistence of additional thrombophilic conditions in a subset of patients probably explains much of this clinical variability.

Factor V Leiden is highly prevalent among people with symptomatic protein C deficiency, and individuals heterozygous for both conditions have more than double the risk of thrombosis compared to family members with protein C deficiency.

Protein S

Protein S is a cofactor for activated protein C. The prevalence of protein S deficiency in a large sample of unselected subjects has not been determined.

Relatives of heterozygotes with symptomatic protein S deficiency are at increased risk for thromboembolic disease and are more likely to have recurrent, juvenile, and idiopathic thromboembolism.

Pregnancy-related thromboembolic events occur at a higher rate that is comparable to that seen in patients with protein C deficiency.

The prevalence of factor V Leiden and the prothrombin 20210A allele is increased in thrombophilic families with protein S deficiency, and the risk of thrombosis is increased in people with both defects.


Antithrombin is an endogenous anticoagulant that binds to and blocks the biological activity of thrombin and other activated coagulation proteins involved in the coagulation cascade.

As with protein C and S deficiencies, there is striking phenotypic variability among antithrombin-deficient patients.

In a cohort of 28 asymptomatic heterozygotes identified by blood donor screening, only one developed venous thromboembolism during a 5-year follow-up period.

In contrast, thromboembolic events are common among antithrombin-deficient subjects identified on the basis of a personal or family history of thrombosis.

About half of these selected antithrombin-deficient patients develop thrombosis before age 40, and about half of the events occur unprovoked.

The incidence of pregnancy-related thrombosis in women with antithrombin deficiency is higher than that of women with protein C or protein S deficiency, 44% to 68%.

The prevalence of factor V Leiden is increased in antithrombin-deficient thrombophilic families, and limited evidence suggests that the likelihood of thromboembolism is substantially increased in patients heterozygous for both conditions.

Antiphospholipid syndrome

Antiphospholipid syndrome, also known as Hughes syndrome, is an immune system disorder that can develop in the future.

Your body produces antibodies that attack phospholipids, fat molecules that are believed to keep your blood at the correct consistency.

Antibodies bind to phospholipids, increasing the risk of a blood clot. Unlike inherited thrombophilias, blood clots in people with antiphospholipid syndrome can occur in a vein or artery.

Women with antiphospholipid syndrome are at increased risk for complications during pregnancy, such as miscarriage, stillbirth, high blood pressure in pregnancy (pre-eclampsia), and young babies.

Treatment of thrombophilia

Many people with thrombophilia will not need treatment. You will only need treatment if you develop a blood clot or are at risk of developing one.

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 a heparin injection. Newer oral anticoagulants are also available now, and are sometimes used instead of warfarin to treat deep vein thrombosis and pulmonary embolism.

Warfarin and heparin

The warfarin and heparin are anticoagulant drugs called anticoagulants. They interfere with the clotting process and can be used to treat or prevent deep vein thrombosis and pulmonary embolism.

You may be prescribed warfarin if you need a blood thinner to treat one clot and prevent another from occurring. It takes a few days for it to work properly.

If you have a clot and need immediate treatment, you will usually be given heparin injections for a few days along with warfarin; heparin injections will work right away.

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

A heparin injection can be given on its own to prevent clots from forming, and it can 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 during pregnancy. Both warfarin and heparin are safe to use while breastfeeding.

International normalized index (IIN) test

Your doctor will need to adjust your warfarin dose to just the right amount, just enough to stop your blood from clotting, but not so much that you risk bleeding problems.

You will need a regular blood test called an international normalized ratio (INR) to measure your blood clotting ability while taking warfarin.

The international normalized ratio test will be required less frequently once your ideal dose has been reached – the goal is usually an international normalized ratio of 2-3.

New oral anticoagulants

In recent years, a number of new oral anticoagulants are available to treat and prevent blood clots. They are given in a fixed dose without the necessary control with warfarin.

The newer oral anticoagulants are not suitable for everyone and should not be used during pregnancy or breastfeeding. They should only be used under the guidance of a specialist to treat people with thrombophilia.

Lifestyle tips

If you have thrombophilia, you should be aware of the symptoms of a blood clot and see your GP right away if you think you have one.

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

  • Lose weight if you are overweight.
  • Stop smoking.
  • Eat a healthy and balanced diet and exercise regularly.

Avoid being immobile for long periods of time – being inactive can cause a deep vein thrombosis

If you are pregnant or planning to become pregnant, discuss this with your GP and inform your midwife and obstetrician about your condition.

You may need to take low-dose aspirin or heparin injections during pregnancy to avoid problems during pregnancy or miscarriage.

If you are going to have a major operation, be sure to tell the healthcare professionals who are treating you about your condition. You may need a heparin injection to prevent blood clots.

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

Risk of blood clots

Anyone can get a blood clot, but you’re at the greatest risk if you’ve been unwell for long periods of time and can’t move around much.

Blood clots can be related to long air travel or the contraceptive pill, but you are much more likely to have one after entering the hospital.

About two-thirds of all blood clots occur during or just after a hospital stay.