Thrombophilia: causes, symptoms, diagnosis, treatment

Thrombophilia is a chronic condition of the body, during which for a long period (months, years, throughout life) there is a tendency either to spontaneous thrombus formation or to uncontrolled spread of thrombus beyond the damage. Usually, the term "thrombophilia" is understood to mean a genetically determined state, but there are acquired states of increased propensity to thrombosis. Therefore, we believe that it is rational to divide thrombophilia into congenital and acquired.

The main role of hemostasis is to preserve the liquid state of blood in the vessels and create a hemostatic "plug" that closes the defect of the vessel during a trauma or pathological process, preventing blood loss. Hemostatic plug should not interfere with blood supply to organs.

The formation of a thrombus is a dynamic process, in which three main factors take part: the haemostatic components of the blood, the state of the vascular wall and the dynamics of the blood flow (the triad of Virchow). Normally, the components are in dynamic equilibrium, which helps maintain the haemostatic balance. Violation of any of the components of the Virchow triad can lead to a change in the hemostatic balance toward insufficient or excessive thrombus formation. In the case of thrombophilia, as a rule, several components of the hemostasis system are disrupted, and it is often not possible to isolate the leading disorder.

It is impossible to put equality between thrombophilia, thrombosis and thromboembolism, since thrombophilia only defines a potential possibility that is not necessarily realized as a thrombosis.

Thrombosis - a pathological condition associated with a violation of blood flow and ischemia of the organ due to the closure of the thrombus of the lumen of the vessel. Thromboembolism refers to the obstruction of an arterial vessel by a thrombus formed in the upper parts of the circulatory system and trapped in a vessel with a blood flow.

The development of thrombosis is a consequence of the interaction of factors of the pathogenesis of thrombosis. Thrombosis can be arterial and venous.

Arterial and intracardiac thrombi consist mainly of platelets connected by fibrin bridges, white thrombi. Arterial thrombi mainly pristenochnye. The most important factors in the formation of an arterial thrombus are congenital or acquired anomaly of the vascular wall and pathological activation of thrombocytes. The most common anomaly is atherosclerosis. In addition to it, congenital disorders of vascular development, angiomatous formations, infectious endothelial damage, iatrogenic disorders are possible.

Venous thrombi include a significant amount of erythrocytes and fibrin; they often completely obturate the lumen of the vessel. The main mechanism of the formation of a venous thrombus is associated with an increase in blood clotting and stasis. In childhood, the leading importance is the catheterization of veins for infusion.

Thrombosis in children is much less common than in adults. In the first half of life, the frequency of thrombotic episodes is 5.1 per 100 000 children per year, and after 6 months varies from 0.7 to 1.9 per 100 000 children per year. Venous thrombosis in children is about twice as common as in arterial thrombosis.

Factors of the pathogenesis of pathological thrombosis are congenital and acquired. Among the inherent factors, hereditary, usually associated with genetically determined changes in the activity of various hemostasis proteins or with a rise in the concentration of substances possessing prothrombotic activity, are distinguished among the congenital factors.

Factors of thrombophilia associated with changes in the activity of hemostasis proteins, in turn, can also be divided into several groups:

• a pathological decrease in the activity of anticoagulants;
• pathological increase in the activity of procoagulants;
• polymorphism of procoagulants, which protects them against inhibitors.

The significance of each group of factors is not the same: if the role of the factors of the first and second categories is proved, then the factors of the second category are obviously less significant.

In this group of factors can also be attributed various anomalies of vascular development, significantly increasing the risk of pathological thrombosis, which can not be attributed to hereditary.

Acquired factors are diverse. In children, they rarely become the sole cause of pathological thrombosis, but often serve as the "last straw" leading to thrombosis or embolism. Among the acquired factors in children, the leading place is occupied by intravenous catheters.

Hereditary risk factors for thrombosis in children:

• deficiency of antithrombin III;
• Protein C deficiency;
• deficiency of protenin S;
• polymorphism of the factor V gene (V Leiden factor);
• polymorphism of the prothrombin gene (single nucleotide replacement of G20210A);
• polymorphism of the platelet receptor of glycoprotein IIIa;
• dysfibrinogenemia;
• hyperlipoproteinemia;
• hyperhomocysteinemia (in children, as a rule, is hereditary);
• thalassemia (post-spleenectomy thrombosis of the hepatic veins);
• sickle-cell anemia.

Acquired risk factors for thrombosis in children:

• catheterization of veins, especially prolonged catheter placement in the vein;
• increase in blood viscosity (polycythemia, fluid loss with a decrease in bcc);
• surgery or trauma;
• infection (HIV, chicken pox, purulent thrombophlebitis);
• autoimmune diseases (lupus anticoagulant, antiphospholipid syndrome, diabetes mellitus, Behcet's disease, etc.);
• nephrotic syndrome;
• congenital malformations of the heart and blood vessels;
• oncological diseases;
• chemotherapy: asparaginase (L-asparaginase), prednisolone;
• liver disease;
• the appointment of protein concentrates C.

Factors, whose role in the development of thrombosis is unclear:

• high level of activity of coagulation factors VIII, XI, XII, von Willebrand factor, inhibitor of plasminogen activator;
• deficiency of factors XII, cofactor heparin II, plasminogen, activators of plasminogen, thrombomodulin.

The important factor, considered at a risk of pathological thrombosis, is the age of the patient. In children, the risk of thrombosis is greatest in the neonatal period. It is believed that newborns are at increased risk of thrombosis due to low fibrinolytic activity of natural anticoagulants (antithrombin III, proteins S and C (III, IIC), and relatively high factor VIII activity and von Willebrand factor.It may be more correct to speak of a less stable hemostatic balance, relatively low concentration of many hemostasis proteins, leading to the relief of thrombotic or hemorrhagic disorders.

The risk of thrombotic complications in children of preterm or with intrauterine growth retardation is increasing.

For the emergence of thrombosis in childhood requires the interaction of a number of factors. With an isolated risk factor, as a rule, thromboses manifest in adulthood. However, in patients with severe deficiency of ATIII, IIC, and ns, the development of spontaneous or provoked minimal effects of thrombosis is possible at an early age.

Among the acquired risk factors for thrombosis in the first place in children of all ages is the catheterization of the central veins. This factor is present in 90% of children with thrombosis at the age of up to one year and in 66% of children with thrombosis over the year. Moreover, children with extensive thrombosis due to catheterization of the central veins have a serious risk of long-term complications, including postthrombotic syndrome. In most cases, thromboses associated with the installation of catheters occur in the system of the inferior vena cava and in the heart. The system of the inferior vena cava can suffer when the catheter is inserted into the umbilical vein.

Laboratory diagnosis of thrombophilia

Laboratory analysis for the detection of pathogenetic factors of thrombosis should be carried out immediately after diagnosis, before the start of treatment. The recommended test suite includes: APTT, prothrombin time, fibrinogen, clotting factors V, VII, VIII, IX, XI, XII, PV, resistance to activated IIC, activity of ATIII, IIC, ns, plasminogen, D-dimers, lysis time euglobulin clot tests, lupus anticoagulant tests - Russell viper poison test, phospholipid or platelet neutralization tests, study of factor activity in consecutive dilutions of plasma, mixed tests to determine the nature of the inhibitor. The activity and presence of the plasminogen activator antigen and the plasminogen activator-1 inhibitor are determined. It is necessary to determine the level of homocysteine in the blood, as well as the genetic polymorphism of factor V Leiden, methyl tetrahydrofolate reductase, prothrombin (single nucleotide replacement G20210A).

Treatment of thrombophilia and thrombosis in children

Currently, the problem of treating children is not well understood. It is possible that for older children, approaches to the treatment of thrombosis, accepted in adults, are acceptable. Nevertheless, there are data suggesting a difference in the responses of adults and children (especially up to 6 months of age) to anticoagulant and thrombolytic treatment. Age features of the state of the hemostatic system must be taken into account when prescribing treatment.

The main tactic of managing children with thrombosis is to prescribe at the first stage of heparin therapy with the subsequent transition to long-term use of indirect anticoagulants. Recommend a minimum of 3 months after the termination of the factors of the pathogenesis of thrombosis to maintain maintenance treatment with anticoagulants. In the presence of moderate hereditary factors of thrombophilia, the effect of anticoagulants should be prolonged to 6 months, and if the serious risk of recurrence of thrombosis persists, indirect anticoagulants can be used for years.

Substituting the use of C3II or protein C (IIC) concentrates, AT III can be used to treat thrombotic episodes associated with severe IIC deficiency, ns, AT III, for thrombosis prophylaxis when necessary for invasive treatment, or when additional risk factors for thrombosis (eg, infection) , especially in young children. In newborns and children of the first months of life, anticoagulant and thrombolytic treatment may be ineffective due to the low age level of AT III and plasminogen. In this case, infusion of SZII is indicated.

In the thrombolytic treatment of arterial and venous thromboses, a recombinant tissue plasminogen activator (alteplase) is successfully used. It is effective and relatively safe to use in children a combination of prourokinase and heparin sodium (heparin).

Other anticoagulants are synthetic analogues of hirudin blocking active sites of thrombin, including those associated with fibrinogen. Do not affect APTT and do not bind to platelets, rarely cause hemorrhagic complications. There are data on their effective use in children.

Ancrod - prevents the formation of cross-links of fibrin and facilitates its cleavage with plasmin. It has proven itself in heparin-induced thrombocytopenia with thrombosis. The effectiveness of the drug in children in the treatment of thrombophilia has not yet been investigated.