In a number of hemolytic diseases, pathologies that cause an abnormal predisposition of blood to form blood clots form a special group. The increased ability to coagulate 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 clotting. In the case of the Leiden mutation, it is due to a change in the amino acid composition of prothrombin, which is encoded by the clotting 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 inpart of the human genotype. Phenotypically, it manifests itself in the synthesis of an abnormal form of one of the coagulation factors, which leads to a shift in homeostasis towards increased blood clotting.
Thus, the Leiden mutation is a hereditary disease, expressed in a predisposition to the formation of abnormal clots that clog blood vessels, and is due to a change in the gene encoding the FV factor. The symptomatic manifestation of this defect is characteristic only for a small number of carriers of the pathology, but the risk of thrombosis is increased in all.
The frequency of occurrence of the F5 (Leiden) gene mutation 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 have the Leiden mutation.
General characteristics of the mutation
The Leiden mutation manifests itself 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 position G1691A of the template sequence. As a result, at the end of transcription and translation, a protein is synthesized, the primary structure of which differs from the original (correct) version by one amino acid (arginine is replaced by glutamine). It would seem a slight difference, but it is precisely this that causes dysregulation of blood coagulation.
To understand the relationship between amino acid conversion in the F5 protein and hypercoagulability, it is necessary to understand how a clot forms. The key point in this process is the conversion of fibrinogen into fibrin, which is preceded by a whole chain of reactions.
How does a clot form?
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 is formed that clogs 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 turning lever in the blood coagulation circuit. However, thrombin is normally present in the blood as its precursor, prothrombin, which requires a chain of successive reactions to activate.
The proteins involved in this cascade are called clotting factors. They have Roman designations according to the order of their discovery. Most factors are proteins. The activators for each next link in the chain of reactions are the previous one.
The launch of the coagulation cascade begins with the entry of tissue factor into the vessel. Various proteins are then 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 formed in the liver and involved in the process of coagulation. This protein is differentcalled proaccelerin.
Before thrombin activation, the FV protein has a single-stranded 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 proaccelerin is referred to as FVa.
Activated FV protein acts as a coenzyme for clotting factor Xa, which converts prothrombin to thrombin. Proaccelerin serves as a catalyst for this reaction, accelerating it 350,000 times. Thus, without factor V, the final stage of the coagulation cascade would take a very long time.
Mechanism of the pathological action of mutations
The normal FV protein is inactivated by protein C, which comes into play when it is necessary to stop coagulation. Factor C binds to a specific FVa site and converts it to the FV form, stopping the catalysis of thrombin formation. In the presence of the Leiden mutation, a protein is synthesized that is not susceptible to the action of protein C (APC), since the amino acid substitution occurs precisely at the site of interaction with the inhibitor. As a result, factor Va cannot be deactivated, greatly reducing the effectiveness of the negative regulation needed to stop the formation of a blood clot and subsequently liquefy it.
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 polymorphism of the F5 gene gives the protein synthesized on its basis two more properties:
- ability to enhance prothrombin activation;
- 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 process of blood coagulation, and on the other hand, it prevents regulatory proteins from stopping it. But it is precisely the mechanisms of suppression (suppression) that protect the body from pathological manifestations of many physiological reactions (for example, inflammatory ones).
Thus, we can say that the Leiden mutation is a hereditary phenomenon that disrupts the down regulation of blood clotting, increasing the risk of abnormal blood clots that are harmful to the normal functioning of the body. With such a pathology, one of the coagulation factors is always active.
Nevertheless, every second and widespread formation of blood clots in such people still does not occur, since many proteins are involved in blood clotting, interconnected with each other and with regulation systems. Therefore, disruption of the work of one factor does not lead to a radical failure of the entire mechanism of coagulation inhibition. In any case, the V factor is not a key control lever of the clotting system.
As a consequence, to argue that the Leiden mutation is a genetic disorder that inevitably leads to thrombophilia,incorrectly, since the protein does not act directly, but indirectly, through a violation of the negative control mechanism. In addition to turning off factor V in the body, there are other ways to stop the coagulation process. Therefore, the Leiden mutation only worsens the deactivation of the coagulation system, and does not completely destroy it.
In addition, pathology manifests itself only when the formation of a blood clot has already been initiated by any causes. Until the start of the coagulation cascade, the presence of the 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 in peace, not even suspecting 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 developing thrombosis depends on the number of mutated F5 genes. The presence of one copy increases the likelihood of abnormal clots formation 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 a homozygote in the genotype (two copies of the mutated gene), the risk of thrombophilia increases up to 80 times.
Most often symptomatic manifestation of the Leiden mutation is provoked by other factors of thrombosis, including:
- decrease in circulation;
- serious pathologies of the cardiovascular system;
- sedentary lifestyle;
- taking hormone replacement therapy(HRT);
- operations;
- pregnancy.
Abnormal clotting occurs in 10% of mutation carriers. The most common pathology manifests itself in DVT (deep vein thrombosis).
Deep vein thrombosis
Deep vein thrombosis is most often 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;
- temperature increase;
- redness.
Sometimes DVT is not symptomatic.
Superficial vein thrombosis
Thrombosis of superficial veins with Leiden mutation is much less common than deep veins. It is usually accompanied by redness, fever, and tenderness at the site of the clot.
Clot formation in the lungs
The formation of a blood clot in the lungs (otherwise pulmonary embolism) is one of the dangerous manifestations of the Leiden mutation, accompanied by symptoms such as:
- sudden shortness of breath;
- chest pain when inhaling;
- bloody sputum when coughing;
- tachycardia.
This pathology is a complication of DVT and occurs when a blood clot breaks away from the venous wall and travels through the right side of the heart to the lungs, blocking blood flow.
Danger of mutation during pregnancy
During pregnancy, the Leiden mutationaccompanied by 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 mutation carriers.
Some studies show that the presence of factor Leiden increases the likelihood of developing the following range 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 normal pregnancies. The Leiden factor even has a definite advantage in reducing the likelihood of developing major postpartum hemorrhage. However, all women with the Leiden mutation are recommended to have strict medical supervision during pregnancy.
Treatment of disease
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, since medicine does not have methods that allow you to change the genome.
Pathological manifestations of the Leiden mutation are eliminated by taking anticoagulants. In the case of recurrent thrombosis, these drugs are prescribed on a regular basis.
