In a series of hemolytic diseases, a special group consists of pathologies that cause an abnormal predisposition of blood to the formation of blood clots. Increased coagulation ability may be acquired or genetic in nature. According to statistics, the most common causes of hereditary thrombophilia are mutations in the F2 and F5 genes, one of which is called the “Leiden factor”.
Increased congenital coagulopathy is always associated with abnormalities in the amount or structure of proteins involved in blood coagulation. In the case of the Leiden mutation, it is due to a change in the amino acid composition of prothrombin, which is encoded by coagulation factor F5.
Leiden mutation - what is it?
In medicine, some diseases are named according to the cause of their occurrence. In this case, the nature of the name of the pathology indicates that the Leiden mutation is a violation associated with an abnormal change in a certain part of the human genotype. Phenotypically, it manifests itself in the synthesis of the anomalous form of one of the coagulation factors, which leads to a shift in homeostasis towards increased blood coagulation.
Thus, the Leiden mutation is a hereditary disease, expressed in a predisposition to the formation of abnormal clots, clogging blood vessels, and due to a change in the gene encoding factor FV. Symptomatic manifestation of this defect is characteristic only for a small number of carriers of pathology, but the risk of thrombosis is increased in all.
The frequency of the mutation of the F5 gene (Leiden) is the same for both men and women. This hereditary defect is the cause of thrombosis in 20-60% of cases. Among the entire European population, 5% of people are the owners of the Leiden mutation.
General characteristics of the mutation
The Leiden mutation is manifested in the polymorphism of the F5 gene, which is expressed in the replacement of one of the nucleotides with another. In this case, adenine is replaced by guanine at the G1691A position of the template sequence. As a result, at the end of transcription and translation, a protein is synthesized whose primary structure differs from the initial (correct) variant by one amino acid (arginine is replaced by glutamine). It would seem that a slight difference, but it is it that becomes the cause of the dysregulation of blood coagulation.
To understand the relationship between the amino acid conversion in the F5 protein and hypercoagulation, it is necessary to understand how a blood clot forms. The key to this process is the conversion of fibrinogen to fibrin, which is preceded by a whole chain of reactions.
How is a blood clot formed?
The formation of a thrombus is based on the polymerization of fibrinogen, leading to the formation of a branched three-dimensional network of protein filaments, in which blood cells get stuck. As a result, a clot forms, clogging the vessel. However, fibrinogen molecules begin to connect with each other only after proteolytic activation, which is carried out by the thrombin protein. It is this protein that acts as a pivot arm in the blood coagulation scheme. However, thrombin is normally present in the blood in the form of its precursor, prothrombin, which requires a whole chain of sequential reactions to activate.
Proteins that are involved in this cascade are called coagulation factors. They have Roman designations according to the order of their discovery. Most factors are proteins. Activators for each subsequent link in the reaction chain are the previous one.
The launch of the coagulation cascade begins when tissue factor enters the vessel. Then various proteins are activated along the chain, which ultimately leads to the conversion of prothrombin to thrombin. Each stage of the cascade can be suspended as a result of the action of the corresponding inhibitor.
Factor v
Factor V is a globular plasma protein that forms in the liver and is involved in the coagulation process. This protein is otherwise called proaccellerin.
Prior to thrombin activation, the FV protein has a single chain structure. After proteolytic cleavage with the removal of the D-domain, the molecule acquires the conformation of two subunits connected by weak non-covalent bonds. This form of pro-accelerin is referred to as FVa.
Activated FV protein acts as a coenzyme for coagulation factor Xa, which converts prothrombin to thrombin. Proaccelerin serves as a catalyst for this reaction, accelerating it 350 thousand times. Thus, without factor V, the final stage of the coagulation cascade would last a very long time.
The mechanism of the pathological action of a mutation
Normal FV protein is inactivated by protein C, which takes effect when coagulation must be stopped. Factor C binds to a specific FVa site and translates it into FV form, stopping the catalysis of thrombin formation. In the presence of a Leiden mutation, a protein is synthesized that is not susceptible to the action of protein C (APC), since amino acid replacement occurs precisely at the site of interaction with the inhibitor. As a result, factor Va cannot be deactivated, which significantly reduces the effectiveness of the negative regulation necessary to stop the formation of a blood clot and its subsequent dilution.
Thus, we can conclude that the Leiden mutation is a pathology that manifests itself through resistance to anticoagulant activity and thus increases the risk of thrombosis. This phenomenon is called protein C resistance.
Properties of the mutant protein
In addition to resistance to protein C, the F5 gene polymorphism gives the protein synthesized on its basis two more properties:
- ability to enhance prothrombin activation;
- an increase in cofactor activity in relation to the inactivation of the FVIIIa protein, which is involved in the inhibition of coagulation.
Thus, the mutant factor V simultaneously works in two directions. On the one hand, it starts the blood coagulation process, and on the other, it prevents regulatory proteins from stopping it. But it is precisely the suppression (suppression) mechanisms that protect the body from the pathological manifestations of many physiological reactions (for example, inflammatory).
Thus, we can say that the Leiden mutation is a hereditary phenomenon that disrupts the negative regulation of blood coagulation, increasing the risk of abnormal blood clots that are harmful to the normal functioning of the body. With this pathology, one of the coagulation factors is always active.
Nevertheless, such blood clots do not occur every second and everywhere, since many proteins are involved in blood coagulation, which are interconnected with each other and with regulatory systems. Therefore, a malfunction of one factor does not lead to a radical failure of the entire mechanism of coagulation inhibition. In any case, factor V is not a key control lever of the coagulation system.
As a result, to argue that the Leiden mutation is a genetic disorder that will certainly lead to thrombophilia is incorrect, since the protein does not act directly, but indirectly, through a violation of the negative control mechanism. In addition to turning off factor V, other ways to stop the coagulation process are present in the body. Therefore, the Leiden mutation only worsens the deactivation of the coagulation system, and does not completely destroy it.
In addition, pathology manifests itself only in the case when the formation of a blood clot is already initiated by any reason. Prior to the launch of the coagulation cascade, the presence of a mutant protein does not cause any changes in the body.
Pathogenesis and symptoms
In most cases, the Leiden mutation does not have any symptomatic manifestations. The carrier can live peacefully without even knowing about its existence. But sometimes the presence of a mutation leads to the periodic formation of blood clots. In this case, the symptoms will depend on the location of the blood clots.
The risk of thrombosis depends on the number of mutated F5 genes. The presence of one copy increases the likelihood of abnormal clots by 8 times compared with the owner of the normal genotype at this locus. In this case, the Leiden mutation is considered heterozygous. If there is homozygous in the genotype (two copies of the mutated gene), the risk of thrombophilia increases up to 80 times.
Most often, the symptomatic manifestation of a Leiden mutation is provoked by other factors of thrombosis, including:
- decrease in blood circulation;
- serious pathologies of the cardiovascular system;
- sedentary lifestyle;
- taking hormone replacement therapy (HRT);
- operations;
- pregnancy.
The formation of abnormal clots occurs in 10% of mutation carriers. The most common pathology is manifested in DVT (deep vein thrombosis).
Deep Vein Thrombosis
Most often, deep vein thrombosis is localized in the lower extremities, but can also develop in the brain, eyes, kidneys and liver. The occurrence of blood clots in the legs may be accompanied by:
- swelling
- pain
- fever;
- redness.
Sometimes DVT does not have symptomatic manifestations.
Superficial Vein Thrombosis
Thrombosis of superficial veins with a Leiden mutation is much less common than deep. It is usually accompanied by redness, fever, and soreness in the area of clot formation.
Clot formation in the lungs
The formation of a blood clot in the lungs (otherwise a pulmonary embolism) is one of the dangerous manifestations of a Leiden mutation, accompanied by symptoms such as:
- sudden shortness of breath
- chest pain when inhaling;
- secretion of blood sputum when coughing;
- tachycardia.
This pathology is a complication of DVT and occurs when a blood clot comes off the venous wall and enters the lungs through the right heart, blocking blood flow.
Danger of mutation during pregnancy
During pregnancy, a Leiden mutation is associated with a small risk of miscarriage or premature birth. The frequency of such phenomena in women with F5 gene polymorphism is 2-3 times higher. Pregnancy also increases the risk of thrombosis in carriers of the mutation.
Some studies show that the presence of Leiden factor increases the likelihood of developing the following series of complications:
- preeclampsia (high blood pressure);
- slow fetal growth;
- premature separation of the placenta from the uterine wall.
Despite these risks, most women with this mutation have a normal pregnancy. Leiden factor even gives a certain advantage, reducing the likelihood of developing extensive postpartum hemorrhage. Nevertheless, all women with a Leiden mutation during pregnancy are recommended strict medical supervision.
Disease treatment
The treatment of the Leiden mutation is carried out only in the presence of thrombophilia and is symptomatic. It is impossible to exclude the cause of the disease, because medicine does not have methods that allow changing the genome.
The pathological manifestations of the Leiden mutation are eliminated by taking anticoagulants. In the case of recurring thrombosis, these drugs are prescribed on a regular basis.