What happens when blood clots?

Coagulation is a mechanism which protects against excessive blood loss when the body is injured. This occurs by the formation of a blood clot (thrombus). 

Figure: Scanning electron microscopic image of  a thrombus (stained) consisting of red blood cells, blood platelets (blue) and fibrin fibres (yellow). Copyright © 2001 Dennis Kunkel Microscopy, Inc. All rights reserved.

The process of blood coagulation is very complex. There is an equilibrium between factors which promote coagulation and factors which inhibit coagulation. In addition to numerous proteins which are activated and thus amplified in a multistep process (blood coagulation cascade), blood platelets (thrombocytes) also play a role in coagulation. Together they form the thrombus. Disorders in this system can increase the coagulability of blood (thrombophilia) or diminish the ability of blood to clot (haemophilia).

When blood vessels are damaged the blood is exposed to substances (e.g. collagen) which it does not usually come into contact with. This leads to an aggregation of thrombocytes and to the activation of the blood coagulation cascade. 

Figure:  Simplified blood coagulation cascade. Red arrows: inhibition. Important components of the cascade are highlighted in grey. Enlarged view.

At the end of the activation chain (cascade) cross-linked fibrin is formed which stabilizes the aggregate of blood platelets. All blood coagulation factors have an inactive form and an active form marked with an "a". An activated factor can convert the next factor from an inactive into an active form until finally fibrin is formed. These interactions result in an amplification of  the original signal  for blood coagulation

The blood coagulation-promoting factors V and VII accelerate the conversion of factor X to Xa by IXa and accelerate the formation of thrombin from prothrombin by Xa. Factors which reduce blood coagulation are protein C, protein S and thrombomodulin. Thrombomodulin forms a complex with protein C and protein S which inactivates the (blood coagulation promoting) factors VIII and and V. The thrombomodulin/protein C/protein S complex is in turn activated by thrombin.

Another protein, antithrombin, inhibits the action of various coagulation factors. Other proteins stimulate or inhibit the cascade. All interactions, factors and interdependencies maintain haemostasis which is an equilibrium between bleeding and coagulation tendency. 

Disorders of haemostasis lead to an increase in the tendency  of blood to coagulate (thrombophilia) or to an increased bleeding tendency (haemophilia).
Abnormal amounts and impairments in the function of blood platelets can cause coagulation disorders (e.g. inhibition of aggregation by aspirin); however, disorders of the coagulation cascade are more common since it is very sensitive to functional impairment due to its complexity. 

Haemophilia is the most well-known blood coagulation disorder in which bleeding is very difficult to stop after an injury. Haemophilia A is caused by inadequate amounts of factor VIII and haemophilia B is caused by a deficiency in factor IX.

Figure:  Queen Victoria of England (1819-1901), the most prominent carrier of hereditary X-chromosome linked haemophilia.

Thrombophilia can affect the arteries as well as the veins. A chronic arterial thrombosis results in a deficiency in the oxygen supply to the tissues (ischaemia). Such a thrombosis can occur anywhere in the body and in the worst case leads to a cardiac infarct or stroke. In venous thrombosis thrombi are mainly formed in the deep veins of the legs. If they become detached (e.g. when a person stands up after a long-haul flight) and are transported by the bloodstream through the body, they can travel to the lung where they can trigger a dreaded pulmonary embolism which can often be fatal. A quarter of a million people in the USA alone develop a thrombosis each year in the leg veins of which 30-50 % are associated with a subsequent pulmonary embolism of various degrees of severity. 

Who is at increased risk?

The "Ärztezeitung" reported that more than 6600 people die annually in Great Britain from pulmonary embolism as a result of a long-haul flight. This phenomenum is now referred to in the literature as the "Economy Class Syndrome". Due to the lack of leg room, a passenger on long flights has a 2.5-fold increased risk of developing a thrombosis. Also long periods of bed confinement, certain autoimmune diseases and cancer promote the formation of thrombi.

Figure: In Germany alone more people die every year from a pulmonary embolism as a result of a long-haul flight than those that die in traffic accidents.

Of course not everyone is at the same risk. Numerous risk factors play a role such as smoking, overweight, too little sport, high blood pressure, high cholesterol values, age, gender, genetic predisposition. Some factors cannot be changed but others can be influenced by a more healthy lifestyle and drug treatment. 

To what extent do my genes determine the risk of developing a thrombosis?
Small changes in certain genes (mutations) can result in a multiplication of the risk of developing a thrombosis, especially in combination with certain risk factors that are influenced by one's lifestyle (e.g. smoking, overweight, contraceptive pill etc.).

In recent years scientists have discovered some important mutations which considerably increase the risk of developing venous thromboses. A mutation in the gene for factor V which was first described in 1994 and was named factor V Leiden after the town where it was discovered in Holland, results in an increased coagulation tendency which is known clinically as APC resistance. The carriers of such mutations have a factor V variant which is more resistant to inactivation by activated protein C than normal factor V. As a result  more activated factor V is present in blood which is associated with an increased clotting tendency (thrombophilia).

Factor V Leiden is particularly widespread in Northern Europe. Here the prevalence of heterzygotic carriers is 4-7 % and that of homozygotic carriers is 0.06-0.25 %. Heterozygotic means that one of the two gene copies which each gene in the cell has, carries the mutation but the other is unchanged (wildtype). Individuals that are homozygous for the mutation have the mutation in both gene copies.
It is remarkable that factor V Leiden is particularly prevalent in some regions. Thus ca. 10 % of the Southern Swedes and Greeks are heterozygous for factor V Leiden.

Figure: Young female smokers with a factor V Leiden mutation who take oral contraceptives have a particularly high thrombotic risk.

Another widespread mutation affects the gene for prothrombin (factor II). The mutation which was first described in 1996 is referred to as prothrombin mutation 20210 and results in the accumulation of prothrombin in blood. This also increases the thrombotic tendency. The prevalence of the heterozygotic mutation in the European population is ca. 1-2 % and up to 6 % in Spain. 

An increased homocysteine level is also assumed to increase the risk for arterial as well as for venous thromboses. Homocysteine is an intermediate product of metabolism; it is further metabolized by three main enzmyes. A very common variant of the gene for one of these enzymes methylene tetrahydrofolate reductase (MTHFR) which is very common in Europe results in an unstable MTHFR version ( thermolabile MTHFR) and elevated homocysteine levels in homozygotes. 15 % of  Europeans are homozygous and 30-40% are heterozygous for this variant.

In addition there are numerous other mutations which can lead to thrombophilia. However, these are relatively rare and are only important when the above-mentioned genetic risk factors and the lifestyle can be ruled out as the cause of  thrombophilia. 

The following table shows the relative risks for known mutations in combination with certain other risk factors. 

How can I prevent a thrombosis?

Before long-haul flights and also in the case of known risk factors such as smoking, overweight, oral contraceptive use etc. it is advisable to test for the genetic risk factors V Leiden, prothrombin 20210 and MTHFR. The ThromboType®-test from Hain Lifescience is a reliable method for the combined determination of the factor V Leiden and prothrombin 20210 mutations.  This can be complemented with the GenoType® MTHFR test for the thermolabile variant of  MTHFR. Ask your family doctor about the rapid, simple and reliable tests from Hain Lifescience GmbH!

Doctors can determine an individual's risk profile from the genetic status together with external risk factors and initiate preventive measures in consultation with the patient. This can range from simple gymnastic exercises over tailor-made surgical stockings to drug treatment. 

Depending on the genetic cause of the thrombophilia, the doctor will administer vitamin preparations, low-dose aspirin or even coagulation inhibitors. In such an anticoagulation therapy heparin or warfarin is administered which inhibit the blood coagulation cascade and have an anti-coagulant effect. 

Prevention is anyway very simple for long haul flights: drink enough (non-alcoholic drinks!), stand up frequently and move as much as possible. 

Although it is not possible to directly derive a treatment from this knowledge about mutations, specific preventive measurements can considerably reduce the risk of a thrombotic event!