For blood to flow normally in the blood vessels (arteries, veins and capillaries) a balance needs to be maintained between too much bleeding and too much clotting (coagulation). This is called haemostasis (haemo=blood, stasis=state of not flowing/moving).
A number of conditions result from the body’s inability to regulate blood flow (haemostasis):
- If the clotting system cannot adequately form a clot (thrombus), then the result is a bleeding condition called haemophilia (see Genetics Fact Sheet 40)
- If the clotting system forms clots too easily, then the result is formation of excess clots. Thrombophilia describes an increased tendency for clots to form. This Fact Sheet discusses inherited predisposition to forming blood clots (thrombophilia)
What is the blood clotting process?
Clotting of blood (thrombosis) occurs when there is conversion of fluid blood into a coagulated, solid form to prevent further blood loss from damaged tissues, blood vessels or organs. This is a complicated process made up of two systems that work together to form a clot; problems in either system can result in conditions that cause either too much, or too little clotting.
- One system involves cells called platelets that circulate in the blood combining to form a platelet ‘plug’ over damaged vessels
- Another system is based upon the actions of multiple proteins (including ‘clotting factors’) that act in conjunction to produce a clot. This system is called the coagulation cascade
The platelet system
The system can be summarised as follows:
- When a break in a blood vessel occurs, substances are exposed that normally are not in direct contact with the blood flow
- These substances (including proteins called collagen and the von Willebrand factor) allow the platelets to stick to the broken surface
- Platelets release chemicals that attract more platelets to the damaged area
The clotting factor based system (the coagulation cascade) then acts to stabilise the platelet ‘plug’ that has formed, and further seals the wound.
The coagulation cascade system
The goal of the coagulation cascade system is to form fibrin, which will form a mesh within the platelet ‘plug’ to stabilise the clot. In this system, a sequence of interactions occur between the protein clotting factors that are numbered from 1-13 and other proteins including protein C and protein S.
The factors, however, do not act in a direct sequence from 1 to 2 to 3, up to 13; so it is very complex to summarise. In addition to this, all of the factors have an inactive and an active form. Once activated, the factor will serve to activate the next factor in the sequence. There is a balance between promoting clot formation and slowing down or inhibiting clot formation (anti-coagulant action).
The coagulation cascade takes place at the site of a break in a blood vessel that has the platelet ‘plug’. The cascade involves clotting factors, which include:
- Forming prothrombin and thrombin
- Forming a fibrin mesh that, with the platelets, act to plug the break in the wall of the blood vessel
- Stabilising the fibrin mesh and completing the clot formation
What are the possible symptoms of a clotting condition?
In most cases, blood clots are preventable and most individuals with blood clots are treated successfully. A clot within a vein is referred to as a venous thromboembolism (VTE) and may:
- Develop in a deep vein (deep vein thrombosis; DVT) in the legs, which may result in leg swelling
- Form in superficial leg veins, causing pain and redness (superficial thrombophlebitis)
- Less commonly, form in veins in the arms, abdomen and inside the skull
Clots also form in the arteries. When clots obstruct blood flow in arteries, tissues lose their blood supply and may be damaged or destroyed.
Clots may grow very fast and can break apart sending small pieces of the clot (known as emboli) through the blood stream.
- An embolus lodging within vessels of the lung is known as a pulmonary embolus
- An embolus lodging in the blood vessels of the brain can cause a stroke
- Both a stroke and pulmonary embolus may be life-threatening
What are the risk factors for developing a clotting condition?
Clotting can occur in anyone, and is triggered by exposure to certain risk factors.
Risk factors include:
- Increasing age, particularly over the age of 40
- Obesity
- Prolonged immobility eg. air travel, and in people with chronic medical conditions like heart failure
- Major surgery
- A diagnosis of cancer or diabetes
- Smoking
- Taking hormone replacement therapy (HRT) or birth control pills (women)
- Pregnancy, particularly immediately after delivery
Some individuals when exposed to these risk factors have a higher chance than those do in the general population of developing clots because they have inherited a predisposition to developing clots. They may, however never develop the clots if they are not exposed to these and other unknown risk factors.
The clotting conditions which involve an inherited predisposition are called hereditary thrombophilias.
What are the major hereditary thrombophilias?
Even though clots may form at any age, generally inherited clotting conditions will not give an increased risk of clotting until young adulthood.
Hereditary thrombophilias are grouped according to their action (Table 39.1):
- Group 1 conditions: ‘Loss of function’ due to a defect or deficiency of an anticoagulant protein (protein which normally promotes blood thinning)
- Group 2 conditions: ‘Gain of function’ which result in an increased tendency towards clot formation
Group 2 conditions occur approximately 5 times more frequently than Group 1 conditions. The risk of clots forming, however, is higher for people with Group 1 conditions than Group 2 conditions.
Table 39.1: The major hereditary thrombophilia conditions
Group 1 conditions |
Antithrombin deficiency |
About 1 in every 500 individuals in the Australian population
4% to 5% of individuals who have a VTE |
Protein C deficiency |
About 1 in 500 individuals in the Australian population
2% to 4% of individuals who have a VTE |
Protein S deficiency |
3-13 in every 1000 individuals in the Australian population
2% to 4% of individuals who have a VTE |
Group 2 conditions |
Factor 5 Leiden |
About 5 in 100 people of Northern European ancestry
Rare in people of Asian or African ancestry
10% of individuals who have a VTE
30% to 50% of individuals investigated for thrombophilia. |
Prothrombin gene change |
2-3 in 100 people of Northern European ancestry
Rare in people of Asian or African ancestry
5% to10% of individuals who have a VTE
15% of patients investigated for thrombophilia. |
Genes and predisposition to clotting conditions
The cells of the body contain the genes or set of instructions for the cell to make all the necessary proteins (chemicals) for our bodies to grow and work normally (see Genetics Fact Sheet 1).
If a gene is changed so that it does not work properly, the gene is described as being faulty (ie. there is a gene mutation present). The information contained in the product of the faulty gene copy is impaired, or is not produced in the right amounts (see Genetics Fact Sheets 4 & 5).
There are different genes for the different clotting factors and other clotting proteins. If a person inherits a faulty copy of a clotting factor or clotting protein gene, they may be predisposed to developing clots.
People who have a genetic susceptibility to developing clots have a change in a thrombophilia gene that makes that gene faulty. Many people who have a faulty copy of a thrombophilia gene however, will not develop a clot over their lifetime.
Other risk factors, for example environmental factors such as lifestyle and diet and changes in other genes must also be present for the condition to develop (see Genetics Fact Sheet 11 and risk factors above).
What is the inheritance pattern in families of the faulty thrombophilia genes?
If an individual has one faulty thrombophilia gene copy, and the other partner thrombophilia gene copy is working, they are a carrier of the faulty thrombophilia gene and therefore have a higher risk for thrombosis.
They are a genetic carrier for a particular thrombophilia.
Two factors influence the pattern of inheritance of a faulty thrombophilia gene copy in families where there is a clotting condition:
- The known thrombophilia genes are located on an autosome (one of the numbered chromosomes).
- The effect of the change in a thrombophilia gene is ‘dominant’ over the information in the working copy of the gene on the partner chromosome (see Genetics Fact Sheets 1, 4 & 5).
The pattern of inheritance of the faulty gene causing a thrombophilia in families is therefore described as autosomal dominant inheritance (see Genetics Fact Sheet 9).
In Figures 39.1 and 39.2, the autosomal dominant faulty gene causing a thrombophilia is represented by ‘D’; the working copy by ‘d’.
As shown in Figure 39.1, where one of the parents has a clotting condition due to a faulty thrombophilia gene, there are four possible combinations of the genetic information that is passed on by the parents.
Figure 39.1: Autosomal dominant inheritance when one parent either has a thrombophilia condition
or is predisposed to clotting because they have inherited a faulty thrombophilia gene copy.
The autosomal dominant faulty gene copy is represented by ‘D’; the working copy by ‘d‘.
This means that, in every pregnancy, there is
- 1 chance in 2 (2 chances in 4) or 50% chance that their child will inherit the copy of the faulty thrombophilia gene and will therefore have inherited a genetic susceptibility to clots or thromboses. They are carriers of the faulty thrombophilia gene and may be affected or unaffected by the condition
- 1 chance in 2 (2 chances in 4) or 50% that their child will inherit the working copy of the gene from his/her affected parent as well as a working copy from his/her unaffected parent. In this case, the child has not inherited the faulty thrombophilia gene copy, and therefore cannot pass it on to any of his/her children
While Figure 39.1 shows the father as the parent carrying the faulty thrombophilia gene copy, the same situation would arise if it was the mother. Clotting conditions usually affect men and women equally.
As shown in Figure 39.2, where both parents have the faulty thrombophilia gene copy, there are again four possible combinations of the genetic information that is passed on by the parents.
Figure 39.2: Autosomal dominant inheritance when both parents can pass the faulty thrombophilia
gene copy to a child. Both parents either have a thrombophilia condition or are predisposed to clotting
because they have inherited a faulty thrombophilia gene copy. The faulty copy of the thrombophilia
gene that causes predisposition to clotting is represented by ‘D; the working copy of the gene by ‘d’.
This means that, in every pregnancy, there is
- 1 chance in 4 or 25% chance that their child will inherit the working copy of the thrombophilia gene from each parent. In this case, the child will not be any more susceptible to clotting than the average individual
- 1 chance in 2 (2 chances in 4) or 50% chance that that their child will inherit the copy of the faulty thrombophilia gene, and will therefore have inherited a genetic susceptibility for clots or thromboses. They are a carrier of the faulty thrombophilia gene and may be affected or unaffected by the condition
- 1 chance in 4 or 25% chance that their child will inherit the faulty thrombophilia gene copy from each parent. Having two copies of the faulty thrombophilia gene has much greater impact on the body and usually there is a much higher risk of clotting
What is the impact of the different faulty thrombophilia genes?
Genetic carriers for a particular thrombophilia have a higher risk for thrombosis. If a person has both of their thrombophilia gene copies faulty, in most cases this produces a severe form of the condition.
The risks for developing a clot are different according to the faulty gene involved (see Table 39.2).
Table 39.2: The impact of inheriting the faulty thrombophilia genes
Group 1 conditions |
Antithrombin deficiency |
About 60% of genetic carriers will develop a VTE by age 60 years.
If both antithrombin gene copies are faulty, in most cases this produces a severe form of the condition, and is generally incompatible with life. |
Protein C deficiency |
Up to 50% of genetic carriers will develop a VTE by age 60 years.
If both protein C gene copies are faulty, in most cases this produces a severe form of the condition, characterised by a skin condition and illness in newborn babies. |
Protein S deficiency |
Up to 30% of genetic carriers will develop a VTE by age 60 years.
If both protein S gene copies are faulty, in most cases this produces a severe form of the condition, characterised by a skin condition and illness in newborn babies |
Group 2 conditions |
Factor 5 Leiden gene change |
Factor 5 Leiden describes a specific gene change in the factor 5 protein
About 6% of genetic carriers will develop a clot by age 65
If both factor 5 gene copies are faulty due to the factor 5 Leiden gene change, in most cases this produces a moderate clotting condition. |
Prothrombin gene change |
Less than 5% of genetic carriers will develop a clot by age 60
If both prothrombin gene copies are faulty, less than 5% will develop a clot by age 60
If they are carriers of both a faulty prothrombin gene and the factor 5 Leiden change in their factor 5 gene, there is a moderate increase in risk for clot formation. |
How are clotting conditions diagnosed and treated?
Hereditary thrombophilias are more common in individuals with a VTE who:
- Are less than 50 years old
- Have a spontaneous thrombosis
- Have recurrent thrombosis (ie. it happens more than once in the same person)
- Have a family history of thrombosis
- Have thrombosis in unusual sites eg. nervous system and brain, abdominal veins, upper limb
If a family member is found to have a clotting condition, then this may have implications for other family members. If the family member carries a faulty gene copy causing one of the inherited thrombophilias, other family members should seek advice so that appropriate testing and treatment options are given.
Such advice is best given by a haematologist or a clinical geneticist with knowledge of thrombophilias. Treatment usually involves the thinning of blood using certain medications. It is, however, also important to know when treatment is not necessary.
For women who are found to be carriers of a faulty thrombophilia gene copy following a complication in late pregnancy, it is advisable that they see either a haematologist or a specialist obstetrician before their next pregnancy. It is important to know which blood thinning medication is appropriate for use in pregnancy and which treatments carry a potential risk to the baby’s development.
Certain medications such as oestrogen-containing oral contraceptives or hormone replacement therapy (HRT) increase the risk of clotting by 2-4 fold and are usually not recommended in women with hereditary thrombophilia. It is important for women with a thrombophilia to discuss alternative options with their doctor.
How can genetic testing help?
Genetic counselling is recommended for individuals and families with a history of bleeding, clotting or where a faulty copy of a thrombophilia gene has been detected in the family (see Genetics Fact Sheet 3).
Genetic testing may be carried out on an individual, an unborn baby (prenatal testing) or an embryo (preimplantation genetic diagnosis - PGD) (see Genetics Fact Sheets 17, 17C and 18). For the most appropriate and accurate information, contact a genetic counselling service or haematology clinic to find out whether genetic testing is available for this condition and discuss your specific options and questions.
Other Genetics Fact Sheets referred to in this Fact Sheet: 1, 3, 4, 5, 9, 11, 17, 17C, 18, 40
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