Hereditary angioedema. Determination of activity of complement factor C1 inhibitor (C1INH)

- a genetic disease in which there is a deficiency of the inhibitor of the C1 component of complement. Symptoms are recurrent swelling of the skin, mucous membranes and abdominal organs, which may be accompanied by suffocation (with swelling of the larynx), vomiting and pain in the abdomen (with damage to the abdominal cavity). Diagnosis is made on the basis of examination, study of hereditary history, determination of C1-inhibitor, C4 and C2 components in blood plasma, molecular genetic studies. Treatment is carried out by compensating for the absolute or functional deficiency of the C1 inhibitor, the use of bradykinin and kallikrein blockers, and the use of fresh frozen donor plasma.

General information

Hereditary angioedema (HAE) is a variant of primary immunodeficiency, caused by a violation of the inhibition of the complement system, more precisely, its main C1 fraction. This condition was first described in 1888 by W. Osier, who identified recurrent edema in a young woman, and also found that at least five generations of her family had a similar disease. It is noteworthy that angioedema itself was discovered by I. Quincke just 6 years before the discovery of the hereditary form of this pathology - in 1882. Hereditary angioedema has an autosomal dominant transmission pattern and affects both men and women with equal frequency. According to some reports, in women the disease is more severe and occurs earlier, but reliable studies on this subject have not been made. The incidence of hereditary angioedema appears to vary considerably among different ethnic groups, resulting in very heterogeneous figures for this indicator - from 1:10,000 to 1:200,000.

Causes of hereditary angioedema

The immediate cause of the development of hereditary angioedema is a primary immunodeficiency, which consists in a deficiency or functional inferiority of an esterase inhibitor of one of the complement components - C1. As a result, the inhibition of activation of other components of this system - C4 and C2 - is also disrupted, which leads to an even greater disruption of the work of this immune mechanism. Geneticists managed to establish the gene responsible for 98% of the forms of hereditary angioedema - it is C1NH, located on the 11th chromosome and encoding the above C1 esterase inhibitor. Different mutations can lead to different forms of the disease, which have fairly similar clinical manifestations, but differ in a number of diagnostic tests.

With some types of mutation of the C1NH gene, the synthesis of the C1 inhibitor protein is completely stopped, as a result of which it is absent in the blood plasma, and the complement system is stopped by ineffective side pathways. In other cases, hereditary angioedema occurs against the background of a normal content of the inhibitor in the blood, while the genetic defect in C1NH leads to a disruption in the structure of the active center of this enzyme. As a result, the C1 inhibitor becomes functionally defective, which causes the development of pathology. There are also rare forms of hereditary angioedema in which there are no changes in the amount or activity of the C1 esterase inhibitor, or mutations in the C1NH gene - the etiology and pathogenesis of such diseases are currently unknown.

Stopping the inhibition of the activity of complement components (C1, C2, C4) leads to the launch of an immune reaction, similar in its course to an allergic one, especially urticaria. Complement components are able to expand the blood vessels of the deep layers of the dermis, increase the permeability of their walls, which provokes the diffusion of blood plasma components into the intercellular space of skin tissues and mucous membranes and leads to their edema. In addition, an important role in the pathogenesis of hereditary angioedema is played by vasoactive polypeptides - bradykinin and kallikrein, which further increase the degree of edema, and can also cause spasm of the smooth muscle of the gastrointestinal tract. These processes cause all the variety of symptoms of hereditary angioedema: swelling of the skin (in the extremities, face, neck) and mucous membranes (oral cavity, larynx, pharynx), abdominal pain and dyspeptic disorders provoked by a combination of edema and spasms.

Classification of hereditary angioedema

In total, three main types of hereditary angioedema have been identified to date. Their differences in terms of the clinical course of the pathology are very insignificant; special diagnostic techniques are used to determine the form of the disease. It is extremely important for an immunologist to find out the type of hereditary angioedema, since the tactics of treating this pathology largely depend on this:

1. Hereditary angioedema type 1 (HAE-1)- is the most common form of the disease, is recorded in 80-85% of patients with this pathology. The cause of this type of HAE is the absence of the C1NH gene or a nonsense mutation in it, as a result of which the C1 inhibitor is not formed in the body.
2. Hereditary angioedema type 2 (HAE-2)- a rarer form of pathology, detected only in 15% of patients. It is also caused by a genetic defect in C1NH, however, the expression of the C1 inhibitor protein does not stop, and the enzyme itself has an altered structure of its active center. This leads to his inferiority, and he becomes unable to properly perform his functions.
3. Hereditary angioedema type 3- a relatively recently discovered form of the disease with practically unexplored etiology and pathogenesis. It was reliably found out that in this type of edema there are no mutations in the C1NH gene, the normal amount of the C1 complement esterase inhibitor and its functional activity are preserved. There are no more data on this form (or their combination) of hereditary angioedema.

Symptoms of hereditary angioedema

As a rule, at birth and in childhood (with the exception of rare cases), hereditary angioedema does not manifest itself in any way. Quite often, the first signs of the disease occur in adolescence, as they are provoked by stress and hormonal changes that occur in the body at this time. However, often hereditary angioedema appears later - at the age of 20-30 years or even in the elderly. Most often, the development of the first attack is preceded by some provocative phenomenon: powerful emotional stress, a serious illness, surgery, taking certain medications. In the future, the “sensitivity threshold” in relation to provoking factors decreases, attacks occur more and more often - hereditary angioedema becomes recurrent.

The main manifestation of the disease in most patients is swelling of the skin and subcutaneous tissue on the hands, feet, sometimes the face and neck. In more severe cases, edematous phenomena occur on the mucous membranes of the mouth, larynx and pharynx - this may develop asphyxiation (asphyxia), which is the most common cause of death from hereditary angioedema. In other cases, symptoms from the gastrointestinal tract come to the fore: nausea, vomiting, pain and cramps in the abdomen, sometimes such a clinical picture acquires the features of an "acute abdomen". In some cases, hereditary angioedema is characterized by a combination of swelling of the skin, mucous membranes and lesions of the gastrointestinal tract.

Diagnosis of hereditary angioedema

To detect hereditary angioedema, data from a physical examination of the patient, a study of his hereditary history, determination of the amount of C1 inhibitor in the blood, as well as complement components C1, C2, C4, and molecular genetic studies are used. Examination in the acute phase of the disease reveals swelling of the skin or mucous membranes, patients may complain of abdominal pain, vomiting, diarrhea. In the blood in the presence of hereditary angioedema type 1, the C1 esterase inhibitor is completely absent, the concentrations of complement indicator components are significantly reduced. In type 2 disease, a small amount of C1 inhibitor can be detected in the blood plasma, in rare cases its level is normal, but the compound has a reduced functional activity. In all three variants of hereditary angioedema, the level of C1, C2 and C4 does not exceed 30-40% of the norm, so this indicator is a key indicator in the diagnosis of this condition.

The study of the patient's hereditary history often reveals the presence of such a disease in at least several generations of his ancestors and other relatives. However, the absence of signs of a family nature of the pathology is not an unambiguous criterion for excluding hereditary angioedema - in about a quarter of patients this condition is due to spontaneous mutations and is detected for the first time in the family. Molecular genetic diagnosis is carried out by automatic sequencing of the C1NH gene in order to identify mutations. Differential diagnosis should be made with angioedema of allergic origin and acquired forms of C1 inhibitor deficiency.

Treatment of hereditary angioedema

Therapy for hereditary angioedema is divided into two types - treatment to stop an acute attack of the disease and prophylactic medication to prevent their development. In the case of acute angioedema due to HAE, traditional anti-anaphylactic measures (adrenaline, steroids) are ineffective, it is necessary to use a native or recombinant C1 inhibitor, bradykinin and kallikrein antagonists, in their absence transfusion of fresh frozen plasma is indicated. Such treatment should be started as early as possible, ideally at the very first attacks of hereditary angioedema.

Long-term prevention of the disease is carried out in cases where attacks occur too often (more than once a month), if there was a history of laryngeal edema or suffocation, or hospitalization in the intensive care unit. Prevention includes the use of androgens, exogenous (recombinant or native) forms of C1 esterase inhibitor, antifibrinolytic drugs. With a benign course of hereditary angioedema - rare attacks and their relatively rapid disappearance - such treatment may not be prescribed. However, on the eve of surgical or dental interventions, physical and mental stress, it is recommended to take the above remedies for a short time to reduce the risk of an attack.

Forecast and prevention of hereditary angioedema

In most cases, the prognosis of hereditary angioedema is relatively favorable in terms of survival - with reasonable treatment and prevention, seizures occur extremely rarely and do not threaten the patient's life. In this case, there is always a risk of laryngeal edema, which can lead to asphyxia and death. Such patients should not only avoid significant physical and emotional stress, but it is also advisable to have a card or medallion with them indicating the diagnosis. A huge number of deaths from hereditary angioedema was due to incorrect actions of physicians who did not know the diagnosis and therefore used traditional drugs for allergic Quincke's edema, which are ineffective in HAE.

The C1 inhibitor is an inhibitor whose main function is to inhibit the complement system to prevent spontaneous activation. It is an acute phase protein that circulates in the blood. It also inhibits fibrinolytic, kinin pathways and a cascade of reactions in the blood coagulation system. Increased or decreased activity of the complement factor C1 inhibitor can indicate a number of diseases of the immune system.

Russian synonyms

C1 inhibitor, C1-INH test.

English synonyms

C1-inh, C1 esterase inhibitor.

Research method

Enzyme immunoassay (ELISA).

Units

c.u./ml (conventional units in milliliter).

What biomaterial can be used for research?

Venous blood.

How to properly prepare for research?

• Eliminate fatty foods from the diet for 24 hours before the study.
• Eliminate physical and emotional overstrain for 30 minutes before the study.
• Do not smoke for 30 minutes prior to the study.

General information about the study

The complement system is part of the innate immune system. It consists of nine proteins - from C1 to C9. They help the body recognize foreign cells that can cause disease. Certain health problems can cause deficiencies in these proteins. Blood tests are needed to check complement protein levels. One such test is the C1INH inhibitor activity test. This will help determine if there is enough C1-INH protein in the body.

Hereditary angioedema is a rare autosomal dominant disease caused by mutations in the C1 inhibitor gene (C1INH), resulting in a decrease in plasma C1 inhibitor levels or impaired protein function. The cause of the disease as a biochemical defect is a deficiency of the C1-esterase inhibitor. This is a vascular reaction of the deep layers of the skin and mucous membranes, accompanied by local expansion and increased permeability of blood vessels, resulting in tissue edema. The edema is asymmetric, with pressure on it there are no traces; disappears without a trace. It is caused by a temporary increase in blood vessel permeability mediated by the release of one or more mediators. The C1 inhibitor breaks the C1q bond to C1r2s2, thereby limiting the time during which C1s catalyzes the activation cleavage of C4 and C2. In addition, C1inh limits the spontaneous activation of C1 in plasma. With a genetic defect dinh, hereditary angioedema develops. Its pathogenesis consists in chronically increased spontaneous activation of the complement system and excessive accumulation of anaphylactins (C3a and C5a), which cause edema.

The C1INH activity test can be used to test for hereditary angioedema. Symptoms:

• swelling in the legs, face, arms, airways and gastrointestinal wall;
• abdominal pain;
• nausea and vomiting.

The study can be used to find out how a person responds to treatment for autoimmune diseases such as systemic lupus erythematosus (SLE).

When is the study scheduled?

• In the presence of angioedema;
• if a systemic autoimmune disease is suspected, in particular systemic lupus erythematosus (although the study itself, the determination of the activity of the C1 inhibitor of the complement factor does not unambiguously verify a particular diagnosis, additional laboratory and instrumental studies are required).

What do the results mean?

Reference values: 0.7 - 1.3 c.u./ml.

Reasons for increased activity of complement factor C1 inhibitor:

• infectious diseases.

The reasons for the decrease in the activity of the complement factor C1 inhibitor:

• systemic lupus erythematosus;
• recurrent bacterial infections;
• angioedema;
• sepsis.



Important Notes

• Increased activity of the complement factor C1 inhibitor can be observed in the presence of an infectious disease. However, this test to detect infections is not usually done.
• A change in the activity of the complement factor C1 inhibitor is not a diagnosis. It requires a number of laboratory and instrumental studies, consultation of a specialist.

• Antinuclear factor on Hep2 cells
• Immunological test for the determination of monospecific agglutinins in hemolytic anemia

Who orders the study?

General practitioner, internist, infectious disease specialist, hematologist, rheumatologist, immunologist, allergist, neurologist, dermatologist.

Literature

• Davis A.E. (September 2004). "Biological effects of C1 inhibitor". Drug News Perspective. 17(7): 439–46.
• Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B (November 2005). "C1 inhibitor: molecular and clinical aspects". Springer Semin. Immunopathol. 27(3): 286–98.
• Davis A.E. (January 2008). "Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema". Ann. Allergy Asthma Immunol. 100 (1 Suppl 2): ​​S7–12.
• Zuraw BL, Christiansen SC. Hereditary angioedema and bradykinin-mediated angioedema. Middleton's Allergy: Principles and Practice, 37, 588-601.

Description

Method of determination Immunochemical method (functional test).

Material under study Plasma (citrate)

The study is used in the diagnosis of hereditary angioedema.

C1-esterase inhibitor (C1-INH) - a regulatory protein that acts as an inhibitor of many serine proteases, including complement proteases C1r and C1s, as well as proteases involved in the activation of kallikrein in the kallikrein-kinin system, factor XIa, XIIa and plasmin in the blood coagulation system. Deficiency in C1 inhibitor function associated with quantitative deficiency or decreased activity is one of the most common birth defects of the complement system. It causes hereditary angioedema, which is manifested by repeated episodes of vascular edema, capturing the submucosal layer of the respiratory tract, digestive tract and subcutaneous tissue. The most dangerous is swelling of the larynx. In most cases, the disease manifests itself in childhood, less often in adulthood.

One of the underlying causes of these disorders in congenital C1-INH deficiency is inappropriate overactivation of the complement system in the classical pathway that leads to the production of anaphylactic, chemotactic, and vasoactive peptides. Another reason is an increase in vascular permeability under the influence of an excess of bradykinin, which is formed as a result of an increase in the level of kallikrein (under conditions of a deficiency of an inhibitor of the conversion reaction of prekallikrein to kallikrein).

It is advisable to determine the activity of the C1 inhibitor simultaneously with the study of C3 and C4 complement factors (). Hereditary angioedema is characterized by a deficiency of C1-INH and a low level of C4 (less than 30%).

Literature

1. Allergology and Immunology. National Guide (Short Edition). - M.: Ed. "GEOTAR-Media". 2013:640.
2. Gomples M.M. et al. C1 inhibitor deficiency: consensus document. Clinical and Experimental Immunology. 2005; 139:379-394.
3. Reagent Kit Instructions.

Preparation

The study is carried out without any therapy (after consultation with the attending physician regarding the possible withdrawal of drugs). Blood sampling is carried out no earlier than 4 hours after the last meal.

Indications for appointment

screening for deficiency of complement system proteins in the diagnosis of immunodeficiencies, which are manifested by recurrent purulent and septic infections; monitoring of immunocomplex diseases.

Interpretation of results

The interpretation of test results contains information for the attending physician and is not a diagnosis. The information in this section should not be used for self-diagnosis or self-treatment. An accurate diagnosis is made by the doctor, using both the results of this examination¤ and the necessary information from other sources: history, results of other examinations, etc.

Units

Deficiency of Cl-inhibitor (CI) leads to the appearance of a characteristic clinical syndrome - hereditary angioedema (HAE). The main clinical manifestation of hereditary angioedema is recurrent edema, which can threaten the life of the patient when developing in vital locations.

Pathogenesis of Cl-inhibitor deficiency

The cause of the deficiency is a mutation of the Cl-inhibitor gene - a serine protease that inactivates the C1r and Cls components of the complement, as well as the kallikrein-kinin system and activated factors XI and XII of the coagulation cascade. Although the C1 inhibitor is not a significant inhibitor of plasmin, it is consumed by plasmin and, in its absence, plasmin activation is one of the most important triggers for edema episodes. The main reason for the increase in vascular permeability in HAE is an excess of bradykinin, which is a consequence of excessive proteolysis of high-molecular kininogen by kallikrein.

Congenital C1I deficiency is an autosomal dominant disorder with racial and sexual distribution and is the most common of all complement system defects. In patients with hereditary angioedema, three main types of defects are distinguished: in 85% of cases, there is a decrease or absence of Cl-inhibitor due to impaired transcription; in the presence of a missense mutation in the active site, the concentration of Cl-inhibitor may be normal or even elevated, but the protein is non-functional. Type 3 HAE is caused by the presence of autoantibodies to the C1 inhibitor.

Symptoms of Cl inhibitor deficiency

Symptoms of the disease in patients with hereditary angioedema are observed mainly in the first years of life. In most of the cases described in the literature, the manifestation of the disease occurred before the age of 18 years of the patient's life, although there are cases of primary detection of the disease at the age of 52 years. Clinically, hereditary angioedema is characterized by swelling of various parts of the body. Edema occurs rapidly, reaches a maximum within 1-2 days and resolves spontaneously after 3-4 days. Edema is usually not accompanied by rash, itching, discoloration of the skin, pain symptoms. However, swelling of the intestinal wall can be manifested by severe pain in the abdomen. In this regard, patients with such manifestations of hereditary angioedema are frequent objects of surgical interventions. In some patients, anorexia, vomiting and abdominal cramps are the only clinical manifestations of hereditary angioedema, in the complete absence of subcutaneous tissue edema. Laryngeal edema is often fatal, especially among young children. The factors provoking edema have not been identified, although often patients associate attacks with stress, minor trauma, usually with swelling of the extremities. Swelling of the face and airways may occur after tooth extraction or tonsillectomy.

Diagnosis of Cl-inhibitor deficiency

The normal level of Cl-I is 0.15-0.33 g/l for adults and 0.11-0.22 g/l for children. The functional activity of Cl-I in children of the first year of life is 47-85% of that of adults. A decrease in the concentration of C1I or a significant decrease in the functional activity of C1I is diagnostic. During an acute attack of hereditary angioedema, there is a significant decrease in hemolytic titers of C4 and C2, and, unlike patients with systemic lupus erythematosus and other immunocomplex diseases, the level of C3 remains normal. Due to autosomal dominant inheritance, patients with hereditary angioedema often have a positive family history.

Treatment of Cl-inhibitor deficiency

Various drugs have been proposed for the treatment of hereditary angioedema. They can be divided into the following groups:

Androgens. In 1960, he first showed that methyltestosterone has a striking preventive effect on the severity and frequency of HAE attacks. In 1963, a synthetic analogue of methyltestosterone, Danazol, was obtained. The primary pharmacological actions of the drug are inhibition of gonadotropin, suppression of the synthesis of sex hormones, competitive binding to progesterone and androgen receptors. Danazol is used in the treatment of endometriosis, gynecomastia, increased bleeding associated with menstruation, hemophilia A and B to reduce bleeding, and in idiopathic thrombocytopenia, where the drug may increase the number of platelets. Danazol has been shown to increase Cl-I levels in most patients with hereditary angioedema. Although Danazol is one of the most commonly used agents in the prophylactic treatment of hereditary angioedema, its mechanism of action remains unknown. Unfortunately, with prolonged prophylactic use, side effects typical of androgen-type drugs are noted. There is a tendency to obesity, amenorrhea, decreased libido, increased aminotransferases and cholesterol, muscle spasms, myalgia, fatigue, headaches. The use of the drug in children and pregnant women is especially limited.

Antifibrinolytic drugs. The first successful use of antifibrinolytic drugs in hereditary angioedema was described by Swedish physicians. Alpha-aminocaproic acid, which is a plasmin inhibitor, as well as tranexamic acid, can be used with partial success for the prevention of attacks of hereditary angioedema, especially when danazol cannot be used. In acute attacks of hereditary angioedema, therapy with these drugs is ineffective. Alpha-aminocaproic acid has the following side effects: nausea, headaches, diarrhea, myositis, a tendency to develop thrombosis.

Transfusions of fresh plasma and purified Cl-I. As a rule, when attacking hereditary angioedema, transfusion of fresh frozen plasma reduces the intensity of edema within minutes. However, fresh frozen plasma containing C1-I contains all other complement components, the presence of which in the transfused preparation can worsen the patient's condition. Moreover, fresh frozen plasma is a possible source of viral infections such as HIV, hepatitis B and C. In recent years, Cl-I cryoprecipitate has been successfully used in many countries. From all points of view, C1-I is an ideal drug for patients with a high risk of developing edema of the upper respiratory tract and for patients in whom the use of Danazol does not lead to an increase in the concentration of C1-I, or is contraindicated.

Summarizing the above, it is necessary to take into account a three-phase approach to the treatment of hereditary angioedema: long-term prophylactic therapy, short-term prophylactic therapy before elective intervention, and therapy for acute attacks of hereditary angioedema. Currently, long-term prophylactic Therapy is carried out with androgens and antifibrinolytic drugs. Short course prophylactic therapy, mainly in patients with hereditary angioedema undergoing dental and surgical procedures, as well as therapy for life-threatening edema, is carried out with fresh frozen plasma and, if available, C1-I cryoconcentrate.

Treatment should be started as early as possible!

1. C1 Inhibitor Concentrate (C1-INHIBITOR).
   A) native C1 inhibitor (isolated from plasma): Berinert, Cinryze(in adolescents and adults) Cetor;
   b) recombinant C1 inhibitor (obtained from the milk of genetically modified rabbits): Rhucin.
2. Bradykinin receptor antagonists: Firazyr (Icatibant) .
   Only for adults. Research in pediatrics is ongoing.
3. Kallikrein inhibitor: Kalbitor (Ecallantide)
4. Fresh frozen plasma if it is not possible to use C1 inhibitor drugs and other modern drugs.

* according to NAO Consensus 2010

Long-term prevention of hereditary angioedema

According to Craig et al. (2009), patients require long-term prophylaxis if:

• the frequency of exacerbations of HAE more than one exacerbation per month;
• ever had swelling of the larynx;
• have ever required tracheal intubation or hospitalization in the intensive care unit / intensive care unit;
• attacks of HAE are accompanied by temporary disability or absenteeism for more than 10 days a year;
• due to attacks of HAE, there is a significant decrease in the quality of life;
• the patient has any drug addiction;
• the patient's contact with health centers is limited;
• the patient has a sharp development of exacerbations of HAE;
• if the so-called. on-demand therapy(therapy on demand).

For long-term prevention, the experts of the International Consensus on the Treatment of HAE (2010) recommend the following groups of drugs:

1. so-called. "lightweight" androgens: Stanozolol, Danazol, Oxandrolone.
   This group of drugs is quite effective, but has a large number of serious side effects. And, if a dose of more than 200 mg / day (according to Danazol) is necessary to obtain a clinical effect (state of control), then the expected benefit and the possible risk of side effects should be weighed.
2. Fibrinolysis inhibitors (antifibrinolytics): ε-aminocaproic And Tranexamic acids.
   These drugs can be effective for long-term prophylaxis, but have numerous side effects, and therefore experts prefer the use of androgens, as more effective agents, than the appointment of this group.
3. C-1 inhibitor
   a) native (plasma): Cinryze(in adolescents and adults) Berinert, Cetor,
   b) recombinant: Rhucin, Ruconest– while undergoing clinical trials for approval of use as a prophylactic agent). Its effectiveness has been shown in multicenter studies.

Short-term prevention of hereditary angioedema

The drugs used to treat exacerbations of HAE are used. In case of symptoms of the prodromal period (harbingers), it can be effective Tranexamic acid or Danazol within 2-3 days to prevent the development of an exacerbation.

Drugs used to treat and prevent hereditary angioedema

1. "Aminokapronka", most likely, will not help. It generally helps few of the HAE patients, but still, it happens that it helps. It is a pity that our doctors (due to a lack of other effective drugs, as well as a lack of knowledge about HAE) are still prescribing it.
2. Better pay attention to TRANEXAMIC ACID. In Russia and Ukraine there is such a drug TRANEKSAM. However, unfortunately, this medicine is also considered ineffective. But you can try.
3. Further, from the available there is "Danazol" with the trade names Danoval, Danol, Danazol. Typically, HAE patients take this drug at 50 mg to 200 mg per day and increase the dose if an attack is likely (and attacks do occur, but usually much less frequently). Attention! Danazol has a whole range of bad side effects, especially for women, especially if taken in high doses. But, with all the "buts", the drug works for many HAE patients.
4. There is also a drug called Stanozolol. It is effective, like Danazol, but there are much fewer side effects. Pay attention to it. In children, according to the literature, treatment with low doses of oxandrolone is more preferable.
5. During acute attacks of edema (larynx, abdomen, face) abroad (there, they have), drugs are used:
   + C1 inhibitor concentrate (Berinert, Cinryze, Cetor);
   + Recombinant C1 inhibitor concentrate (Ruconest/Rhucin);
   + B2 receptor antagonists (Firazyr).

   All these medicines are very expensive. Patients rarely pay for them themselves. The state, insurance organizations, charitable foundations help people by paying either the full cost of drugs or part of them. Very often, such expensive drugs are stored in refrigerators and "wait" for acute attacks of their owners. In order for these medicines to become available in the CIS countries, patients must take an active part in the process of treatment and diagnosis. To optimize partnerships between patients with HAE and doctors, there are associations or groups of patients with HAE in many Western countries around the world.

   Please note that Firazyr is officially registered in Russia, which means it should be available to patients. At least in the clinics of large cities for the relief of acute edema.

If none of the above in paragraph 5 is available, and there is a dangerous edema, then urgent hospitalization is necessary in the intensive care unit (it is desirable that the patient is known there, so you should agree in advance) and the introduction of fresh frozen plasma rich in C1-inhibitor (it is better to choose in advance own one and store it, for example, in the refrigerator). Caution: Recent studies on the treatment of exacerbations of HAE have shown that fresh frozen plasma may contain kininogens (precursors of bradykinin), and therefore the patient's condition may worsen.

I would like to express special gratitude to Daria Aleksandrovna Yartseva (assistant of the Department of Faculty Pediatrics, Ph.D. of Zaporozhye State Medical University, Department of Faculty Pediatrics) for her help in writing this section.

Note. Berinert P, Cinryze, Ruconest and Icatibant (Firazyr) instructions reprinted from website