RU2336096C1 - Method of hepatitis type c treatment - Google Patents

Abstract

FIELD: medicine; gastroenterology.

SUBSTANCE: before pharmacotherapy course including Ribavirin and Interferon alpha-2a, 5 cryoplasmasorbtion procedures (CPS) are performed every 2 days. Thereafter these procedures are repeated once a month until pharmacotherapy termination.

EFFECT: method provides intensified effect of specified medicines in combination within viraemid pre-reduction by initial stage of therapy and improves efficiency of treatment within the whole course.

2 cl, 7 dwg, 4 tbl, 2 ex

Description

The invention relates to medicine, namely therapy, and can be used in the treatment of viral hepatitis C, especially in cases of disease with extrahepatic manifestations.

Hepatitis C virus infects about 10% of the world's population. In two-thirds of cases, hepatitis C develops chronic hepatitis, which usually is asymptomatic until cirrhosis, liver cancer, or liver failure develops. The effectiveness of the combined drug therapy of hepatitis C used today does not exceed 45-56%.

A known method for the treatment of hepatitis C using the antiviral drug ribaverin (see, for example, [1] US Patent No. 4211771, IPC A61K 31/41, 1980; [2]; RF Patent No. 2255735, A61K 31/41, 2005) .

The disadvantage of this method is the low therapeutic efficacy (about 25%), the inability to prevent and treat extrahepatic manifestations of the disease.

There is also a method of treating viral hepatitis C using recombinant interferon-alpha (IFN-alfa). According to this method, the administration of IFN-alfa subcutaneously, intramuscularly, leads to a persistent clinical effect in 10-25% of cases [1]. The method is used to treat hepatitis in adults by administering IFN-alfa in a dose of 3 to 10 million ME 3 times a week for 0.5-1 years, depending on the genotype of the virus [2].

The disadvantages of the method, as in the previous analogue, is its low therapeutic efficacy, the inability to prevent and treat extrahepatic manifestations of the disease. So, the virological response to treatment is only 19%, and when using the pegylated form of the drug (pegasis) - 39% [3].

There is also a method of treating viral hepatitis C, where in order to reduce the dose of IFN-alfa, the method of extracorporeal pharmacotherapy is used, when the patient's whole heparinized blood in the volume of 10% circulating blood in the presence of 0.5-1 million ME recombinant interferon-alpha is incubated at a temperature of +37 ° C for 90-180 minutes, after which the blood is reinfused into the vascular bed of the same patient, and the procedure is performed 1-2 times a week for 1-2 months (see, for example, patent No. 2158604, 2000). .

The main disadvantage of this method is that despite the 50% positive response received by the authors immediately after the end of treatment, 1 year after the end of treatment (this is the time for evaluating the results of hepatitis C treatment in accordance with international criteria), the percentage of recovery was much lower and amounted to only 21%

The 10% BCC intake (for an adult approximately 500 ml) is the maximum dose even for healthy people who are adapted to blood loss (donors) and can cause cardiovascular complications. According to our observations, the use of this method in 4% of cases led to a decrease in blood pressure, despite the ongoing replacement therapy with crystalloid solutions.

IFN-alfa is not approved by the Russian Pharmacological Committee for intravenous administration. Since it is a substance of protein nature, this route of administration can cause various pathological reactions, up to the development of shock.

The introduction of interferon-alpha in this way for 1 month of treatment in 43% of cases led to different severity of leukopenia and thrombocytopenia. When you try to increase the dose of the drug to accepted in international protocols for a single injection (3 million ME, n = 1), these changes increase significantly.

The technology is focused only on those pharmacological effects that are inherent in the action of IFN-alfa. At the same time, there are a number of other factors in the developmental mechanisms and prognosis of the treatment of hepatitis C and its extrahepatic manifestations. One of these factors is viral load. An increase in HCV RNA titer is known to increase as the disease progresses. A higher level of viremia correlates with more severe organ damage, i.e. one of the factors of severity of hepatitis C is viral load [4, 5, 6, 7, 8]. A higher level of HCV RNA allows predicting the worst treatment outcome [9, 10, 11] or is a predictor of its lack of therapeutic effectiveness [12].

Closest to the claimed technical solution is a method of treating hepatitis C using a combination of recombinant IFN-alfa-2b and ribavirin, which gives a synergistic effect. This method is recognized as the most effective treatment option for chronic hepatitis C [13].

The disadvantages of the method are:

a) Lack of therapeutic efficacy. So, the virological response to treatment is only 44%, and when using the pegylated form of the drug (pegasis) - 56% [14]. Given the cost of drug treatment (about $ 2,500 per month), the price-quality ratio of such treatment is extremely low.

b) The impossibility of targeted treatment of extrahepatic manifestations of hepatitis C, such as antiphospholipid syndrome, cryoglobulinemia, etc. The frequency (45%) and severity of these complications have a significant impact on the course and prognosis of the disease [13].

The objective of the proposed method is to increase the effectiveness of the treatment of viral hepatitis C, the prevention and treatment of its extrahepatic manifestations.

The task is achieved by the fact that before starting drug therapy with ribavirin and interferon alfa-2a, 5 cryoplasmosorption procedures are performed with an interval of 2 days, and then these procedures are repeated once a month until the end of the course of drug therapy.

During the first cryoplasmosorption procedure, plasmapheresis is carried out with the removal of 25-30% of the volume of circulating plasma, which is replaced by an equal volume of physiological solution. Cryoprecipitate is released and removed from the resulting plasma. It is used for replacement therapy in the second plasma exchange procedure, in which 40-45% of the circulating plasma volume is taken. After cryoprecipitate is removed, it is used for substitution therapy in the third plasma exchange procedure, in which 55-60% of the circulating plasma volume is taken. After removal of cryoprecipitate, it is used for replacement therapy in the fourth plasma exchange procedure, which also takes 55-60% of the circulating plasma volume. After removal of cryoprecipitate, it is used for replacement therapy in the fifth plasma exchange procedure, which also takes 55-60% of the plasma. After cryoprecipitate is removed from the plasma, it is used for replacement therapy in the sixth plasma exchange procedure, in which 70-75% of the circulating plasma is sampled. After cryoprecipitate is removed, this plasma is used for replacement therapy in the seventh plasma exchange procedure, which takes 85-90% of the circulating plasma volume. After removing cryoprecipitate, this plasma is used for replacement therapy in the eighth plasma exchange procedure, in which 95-100% of the circulating plasma volume is taken. In the future, the last procedure is repeated 1 time per month until the end of the course of drug therapy (table 1).

Cryoplasmosorption is a semi-selective plasma modification technology obtained by plasmapheresis, combining the method of cryoapheresis and plasmosorption. The method of cryoapheresis is based on the ability of a number of biologically active plasma substances to cold polymerize and precipitate in the presence of heparin (low density lipoproteins, immunoglobulins, immune complexes, fibrinogen, etc.). Unlike plasmapheresis, after removal of pathogenic products, the plasma returns to the patient again. The proposed method allows you to:

1. To increase the effectiveness of drug antiviral therapy by removing a significant amount of viral particles from the blood together with cryoprecipitate (see table 3). It is clear that under these conditions, the effect of antiviral drugs and drugs that activate antiviral immunity will be more effective the less viral particles you have to cope with.

2. Remove from the blood plasma cryoglobulins that accumulate in it during viral hepatitis, causing the development of mixed cryoglobulinemia. This effect allows the prevention and treatment of extrahepatic manifestations of hepatitis C characteristic of cryoglobulinemia [13]:

- Lymphocytic sialadenitis

- Cutaneous necrotizing vasculitis

- Multiform and erythema nodosum

- Non-Hodgkin B-lymphoma

- Urticaria

- Arthritis, arthralgia

- Glomerulonephritis

- Pulmonary vasculitis

- Myopathic syndrome

- Peripheral polyneuropathy

3. Remove large molecular proteins, paraproteins, antibodies, circulating immune complexes and coagulation factors that cause the development of secondary diseases characteristic of hepatitis C (for example, Waldenstrom macroglobulinemia, Guillain-Barré syndrome, antiphospholipid syndrome, etc.) from blood plasma [13].

Thus, the application of the proposed method avoids the disadvantages of the prototype and achieve the task.

The technical solution is illustrated by 4 tables and 2 drawings, where:

- table 1 presents some indicators of the plasma of patients with viral hepatitis C before and after cryoapheresis;

- in table 2 - some technological characteristics of the procedures of cryoapheresis;

- in table 3 - the change in the level of viremia in the plasma during the in vitro experiment;

- in table 4 - indicators of the blood test of the patient K. before and after treatment;

- figure 1 - diagram of the procedure;

- figure 2 - the frequency and time of the procedures of cryoapheresis.

- On a photo 1-5 - a type of plasma at different stages of cryoplasmosorption.

The proposed technical solution meets the criterion of "novelty", since the combination of ribavirin and interferon alpha-2a therapy with cryoplasmosorption has not been previously described.

In practice, the method is as follows.

1. The patient undergoes plasmapheresis to obtain heparinized plasma at the rate of 25-30% of the patient’s circulating plasma volume (CP), followed by the replacement of the circulating plasma volume deficiency with a crystalloid solution in the same volume. To the resulting plasma add heparin at a rate of 12.5 IU / ml and freeze at -25 ° C.

2. After 1 day, the frozen plasma is placed in an environment with a temperature of + 4-6 ° C, where after thawing within 24 hours, a precipitate (cryoprecipitate) is formed. After that, the plasma is centrifuged for 15 min at 700 g, the precipitate is removed, and the supernatant is additionally passed through a carbon hemosorbent column (for example, SKN, Simplex-F, VNIITU-1, etc.). By this time (after about 48 hours), the plasma exchange is repeated with the removal of heparinized plasma at the rate of 40-45% of the RCP, and the circulating plasma volume deficiency is filled up with the modified autoplasma obtained during 1 plasmapheresis session and subjected to cryoplasmosorption, the rest of the circulating plasma volume deficiency is filled up with crystalloid solution. Re-taken plasma is again subjected to freezing at -25 ° C.

3. After another 48 hours, cryoplasmosorption of the removed plasma is carried out and a third plasma exchange session is carried out with the plasma removed in the volume of 55-60% of the RCP, the circulating plasma volume deficit is filled up with the autoplasma obtained during 2 plasma exchange sessions and subjected to cryoplasmosorption, the rest of the circulating plasma volume deficiency is filled up with crystalloid solution. The taken plasma is again subjected to freezing at a temperature of -25 ° C.

4. After another 48 hours, cryoplasmosorption of the removed plasma is carried out and a fourth plasma exchange session is carried out with the plasma removed in the volume of 55-60% of the RCP; the circulating plasma volume deficit is completely compensated by the autoplasma obtained during 3 plasma exchange sessions and subjected to cryoplasmosorption. The resulting plasma is frozen at -25 ° C.

5. After another 48 hours, cryoplasmosorption of the removed plasma is carried out and the fifth plasma exchange session is carried out with plasma removal in the volume of 55-60% of the RCP, the circulating plasma volume deficit is compensated by the autoplasma obtained during 4 plasma exchange sessions and subjected to cryoplasosorption. The resulting plasma is frozen at -25 ° C.

6. After the fifth procedure, drug therapy is started with interferon-alpha-2a preparations (for example, Pegasis 180 mcg sc once a week) and ribavirin at a dose of 800-1200 mg / day, depending on the weight of the patient. The duration of drug therapy is 6-12 months, depending on the genotype of the virus.

7. One month after the fifth procedure, cryoplasmosorption of the removed plasma is carried out and a 6th plasma exchange session is carried out with the plasma removed in the amount of 70-75% of the RCP, the circulating plasma volume deficit is filled with autoplasma obtained during the 5th plasma exchange session and subjected to cryoplasmosorption, the remaining circulating volume deficit plasma make up for crystalloid solution. The resulting plasma is frozen at -25 ° C.

8. 1 month after the 6th procedure, cryoplasmosorption of the removed plasma is carried out and a 7th plasma exchange session is performed with the plasma removed in the amount of 85-90% of the RCP, the circulating plasma volume deficit is filled with autoplasma obtained during the 6th plasma exchange session and subjected to cryoplasmosorption, the remaining circulating volume deficit plasma make up for crystalloid solution. The resulting plasma is frozen at -25 ° C.

9. One month after the 7th procedure, cryoplasmosorption of the removed plasma is carried out and an 8th plasma exchange session is carried out with the plasma removed in the volume of 95-100% of the RCP, the circulating plasma volume deficit is compensated by the autoplasma obtained during the 7th plasma exchange session and subjected to cryoplasmosorption, the remaining circulating volume deficit plasma make up for crystalloid solution. The resulting plasma is frozen at -25 ° C.

10. In the future, the procedure is repeated similarly to paragraph 9 once a month until the end of the course of drug therapy.

11. The amount of plasma removed during the first plasmapheresis session is due to the prevention of the development of hemodynamic and metabolic disorders as a result of a deficit in the volume of circulating plasma. Removal of plasma in a volume of 30% of the CPC with the substitution of an equal volume of the crystalloid solution is not accompanied by such violations. The removal of large volumes of plasma during 2 and subsequent plasma exchange sessions also does not cause hemodynamic and metabolic disturbances, since a significant volume of the removed plasma is simultaneously replaced by autoplasma removed during the previous plasma exchange and subjected to cryoplasmosorption, as well as crystalloid solution.

12. The number of sessions before drug therapy allows you to process about two volumes of circulating plasma. Processing a sufficiently large plasma volume is caused by the need to remove pathogenic factors not only from the circulating plasma, but also from the tissues and cerebrospinal fluid, which can enter the systemic circulation according to the principle of concentration gradient.

13. The interval between 1-5 sessions of plasma exchange (48 h) is due to the time required for secondary processing of the plasma and adaptation of the patient’s body after a session of extracorporeal hemocorrection (A.P. Gavrilov, 1988).

The time interval between the procedures carried out during drug therapy (1 time per month) is due to the need to maintain a low level of viremia until the end of drug therapy and to remove from the bloodstream pathological products that accumulate during extrahepatic manifestations of hepatitis C and which are formed during continuous and prolonged use of drugs (antibodies , CECI, etc.).

EXAMPLES OF SPECIFIC IMPLEMENTATION.

Example 1. Carrying out extracorporeal modification of plasma:

In the experiment, 400 ml (1 plastic bag) of platelet-poor plasma removed during hardware plasmapheresis in a patient with viral hepatitis C was used. 1 ml of heparin was added to the obtained plasma and the plasma was frozen at -25 ° C. After 2 days, the frozen plasma was thawed at a temperature of + 4 ° C, during which a loose cryoprecipitate was formed. After that, the plasma bag was centrifuged for 15 min at 700 g, as a result of which a dense precipitate formed at the bottom of the bag. Under sterile conditions, the supernatant was transferred to another plastic bag, the sediment bag was removed, and the supernatant was additionally passed through a column of 50 g of carbon hemosorbent to remove fine precipitates (simplex F). The results of the study of plasma for the presence of viral particles in it before and after the procedure are presented in table 3.

Example 2. Patient K., 39 years old, was admitted to the clinic of gravitational blood surgery of the medical center "Capital" 08/30/05. Complaints of nausea, loss of appetite, headaches, fatigue, skin rash on the outer surface of the shoulders and mammary glands , joint and muscle pain (Meltzer syndrome). 08/17/04 completed a 6-month course of treatment with pegasis and ribovirin (according to the standard scheme). A blood test performed during treatment revealed the following hepatitis C virus markers and its complications (see table). After the examination, the diagnosis was established: chronic active viral hepatitis C, genotype 2a, secondary antiphospholipid syndrome, mixed cryoglobulinemia, erythema nodosum.

Was treated according to the proposed scheme for 6 months. When calculating plasma exfusion volumes, the following indicators were taken into account: female gender, weight 71 kg, height 165 cm, Ht 38, circulating plasma volume 2600 ml. The procedures were performed on a Haemonetics PCS ² hematological blood separator. Fractional systemic heparinization at the rate of 2.5 ME per 1 ml of the resulting plasma.

1. During the first procedure, 780 ml of plasma (30% of the CPP) was obtained (Photo 1). To compensate for the volume of circulating plasma, 800 ml of physiological saline was added. 9750 IU of heparin was introduced into packets with the obtained plasma, and the plasma was frozen at a temperature of -25 ° C (Photo 2). After 24 hours, packages with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets (see photo 3). After this, the plasma was separated from the precipitate formed (Photo 4) and passed through a Simplex-F hemosorbent column (Photo 5).

2. The plasma processed in this way was used for plasma replacement in the 2nd cryoplasmosorption procedure, which was performed 2 days after the first. During the second procedure, 1170 ml of plasma (45% CPP) was removed. In addition to their own plasma, 400 ml of physiological saline was additionally used for plasma substitution. 14625 IU of heparin was added to the plasma bags and the plasma was frozen at -25 ° C. After 24 hours, packages with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column.

3. The plasma processed in this way was used for plasma replacement in the 3rd cryoplasmosorption procedure, which was performed 2 days after the second. During the third procedure, 1560 ml of plasma (60% CPP) was removed. In addition to their own plasma, 400 ml of physiological saline was additionally used for plasma substitution. 19500 IU of heparin was added to the plasma bags and the plasma was frozen at a temperature of -25 ° C. After 24 hours, packages with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column.

4. The plasma processed in this way was used for plasma replacement in the 4th cryoplasmosorption procedure, which was performed 2 days after the third. During the fourth procedure, 1560 ml of plasma (60% CPP) was removed. 19500 IU of heparin was added to the plasma bags and the plasma was frozen at a temperature of -25 ° C. After 24 hours, packages with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column.

5. The plasma processed in this way was used for plasma replacement in the 5th cryoplasmosorption procedure, which was performed 2 days after the fourth. During the fifth procedure, 1560 ml of plasma (60% CPP) was removed. 19500 IU of heparin was added to the plasma bags and the plasma was frozen at a temperature of -25 ° C.

Immediately after the fifth procedure, drug therapy was started, the duration of which was 6 months. Medicines were prescribed according to the scheme: Pegasis 180 mcg sc once a week (No. 24) + ribavirin 400 mg 2 times a day (course - 24 weeks).

6. 1 month after the fifth procedure, packets with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column. The plasma processed in this way was used for plasma replacement in the 6th cryoplasmosorption procedure, which was performed 1 month after the fifth. During the sixth procedure, 1950 ml of plasma (75% CPP) was removed. For plasma substitution, we used our own plasma obtained in the fifth procedure. In addition to their own plasma, 400 ml of physiological saline was additionally used for plasma substitution. 24375 ME of heparin was added to plasma bags and plasma was frozen at -25 ° C.

7. One month after the sixth procedure, packets with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column. The plasma treated in this way was used for plasma replacement in the 7th cryoplasmosorption procedure, which was performed 1 month after the sixth. During the seventh procedure, 2340 ml of plasma (90% CPP) was removed. For plasma substitution, we used our own plasma obtained in the sixth procedure. In addition to their own plasma, 400 ml of physiological saline was additionally used for plasma substitution. In plasma packets, 29,250 IU of heparin was added and the plasma was frozen at a temperature of -25 ° C.

8. One month after the seventh procedure, packets with frozen plasma were transferred to an environment with a temperature of + 4 ° C. One day after thawing the plasma, cryoprecipitate formed in packets. After this, the plasma was separated from the precipitate formed and passed through a Simplex-F hemosorbent column. The plasma treated in this way was used for plasma replacement in the 8th cryoplasmosorption procedure, which was performed 1 month after the fifth. During the sixth procedure, 2600 ml of plasma (100% CPP) was removed. For plasma substitution, we used our own plasma obtained in the fifth procedure. In addition to their own plasma, 400 ml of physiological saline was additionally used for plasma substitution. 32500 IU of heparin was added to plasma bags and plasma was frozen at -25 ° C.

In the future, 2 more procedures of cryoapheresis were performed 1 time per month (until the end of the term of drug therapy) in accordance with the protocol described in paragraph 8. At the same time, each time the volume of received, processed and returned plasma was 2600 ml. The plasma obtained during the last procedure was disposed of.

The described clinical manifestations of the disease stopped after 3-4 cryoplasmosorption procedures. After the 5th procedure, the skin rash completely disappeared. Control blood tests were performed 12 weeks after the start of treatment and 1 year after its completion. The research results are presented in table 4.

At the time of filing the application of the proposed method, 15 patients were treated. No complications or adverse reactions were detected. The clinical manifestations of hepatitis C and its complications were stopped in all patients, however, 2 of them (13%) revealed viremia one year after the end of treatment.

Technical appraisal and economic benefits:

- increasing the effectiveness of the treatment of chronic viral hepatitis C;

- relief of extrahepatic manifestations of chronic viral hepatitis C.

Literature

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16. Fried M.W., Shiftman M.L., Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engi J. Med. 2002; 347 (13): 975-82.

17. Manns M.P., McHutchison J.G., Gordon S.G., et al. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24 week treatment analysis of a multi-center, multinational phase III randomized controlled trial. Hepatology. 2000; 32: 297A

Table 1 Changes in the studied parameters in patients with viral hepatitis C before and after cryoplasmosorption (CPS) (M ± m, n = 8-15) Research indicators Before KPS course After the course of the KPS The number of HCV RNA (copies / ml) 2 * 10 ⁶ ± 3 * 10 ² 7 * 10 ³ ± 280 Cryoglobulins (g \ l) 1.8 ± 0.4 0.2 ± 0.03 Anticard iol and pin (IU / ml) 28.5 ± 6.2 7.1 ± 0.29 Paraproteins (g / l) 54 ± 7.6 28 ± 5.4 IgG (g \ l) 19.81 ± 1.37 9.5 ± 0.68 IgM (rVi) 3.2 ± 0.47 1.1 ± 0.39 Factor VIII,% 205.44 ± 54.71 112.57 ± 20.48 Fibronectin ng / l 1238 ± 109 320 ± 101

table 2 Volumetric characteristics of fluids removed and introduced into the body during the course of cryoplasmosorption in a patient 70 kg No. Volume of exfused plasma Returned plasma volume Blood substitute volume Procedures performed 1 day before the start of drug therapy one 780 0 800 2 1170 780 400 3 1560 1170 400 four 1560 1560 400 5 1560 1560 400 Procedures performed once a month in parallel with drug therapy 6 1950 1560 400 7 2340 1950 400 8 2600 2340 400 9 2600 * 2600 * 400 * * - Volume indicators do not change until the end of the course of treatment

Table 3 The level of HCV RNA in plasma before and after its processing by the proposed method (in vitro) Before cryoprecipitation After cryoprecipitation 8 * 10 ⁶ 9 * 10 ³

Table 4 The plasma indicators of the patient K. before and after treatment of the proposed method Research indicators Before treatment (03/27/04) 12 weeks after the start of treatment 1 year after the end of treatment (2.10.06) HCV RNA (copies / ml) 2 * 10 ⁶ 9.5 * 10 ³ Not determined ALT (mmol / L) 78 31 26

Claims (2)

1. A method of treating chronic hepatitis C by conducting a course of drug therapy with ribavirin and interferon alfa-2a, characterized in that before starting drug therapy, 5 cryoplasmosorption procedures are carried out with an interval of 2 days, and then these procedures are repeated once a month until the end of the course drug therapy. 2. The method according to claim 1, characterized in that during the first cryoplasmosorption procedure, plasmapheresis is carried out with the removal of 25-30% of the volume of circulating plasma, which is replaced with an equal volume of physiological saline, cryoprecipitate is isolated from the resulting plasma and the plasma is used for replacement therapy the second plasma exchange procedure, on which 40-45% of the circulating plasma volume is sampled and, after cryoprecipitate removal, is used for replacement therapy in the third plasma exchange procedure, on which the sampling is performed 55-60% of the circulating plasma volume, and after removal of cryoprecipitate is used for replacement therapy in the fourth plasma exchange procedure, which also take a fence 55-60% of the circulating plasma volume and after removal of cryoprecipitate are used for replacement therapy in the fifth plasma exchange procedure, which also produce sampling of 55-60% of the plasma, which after removal of cryoprecipitate is used for replacement therapy in the sixth plasma exchange procedure, which produce sampling of 70-75% of the volume of circulating plasma, which after cryoprecipitate is removed, it is used for substitution therapy in the seventh plasma exchange procedure, at which 85-90% of the circulating plasma volume is taken, which, after cryoprecipitate is removed, is used for substitution therapy in the eighth plasma exchange procedure, where 95-100% of circulating plasma volume is taken, in the future, the last procedure is repeated 1 time per month until the end of the course of drug therapy.

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