PNG disease. Causes, symptoms and types of hemoglobinuria
Materials are presented from teaching aid RUDN University
Anemia. Clinic, diagnosis and treatment / Stuklov N.I., Alpidovsky V.K., Ogurtsov P.P. – M.: Medical Information Agency LLC, 2013. – 264 p.
Copying and reproducing materials without indicating the authors is prohibited and is punishable by law.
Paroxysmal nocturnal hemoglobinuria(PNH) is an acquired clonal hemolytic anemia associated with a defect in the blood cell membrane, therefore the disease is considered in the group of membranopathies and is the only acquired membranopathy among the diseases of this group. The mutation leading to the membrane defect in PNH occurs at the level of the pluripotent stem cell, and the cause of the mutation remains unclear.
PNH occurs with a frequency of 1:500,000 of the population. People of all age groups get sick, but more often – at the age of 30 – 40 years. Men and women get sick equally often.
Etiology and pathogenesis
Point gene mutation PIGA on chromosome 22 or the X chromosome of a pluripotent stem cell (PSC) leads to disruption of the formation of phosphatidylinolinic acid and proteins on the surface of blood cells CD 55 and CD 59, forming a system in normal cells that blocks the damaging effect on the membrane of activated complement due to the formation of a cascade CD 5b –9 – a complex that proteolytically affects the cell membrane.
Thus, the absence of factors on the surface of blood cells that interfere with complement function leads to the lysis of defective erythrocytes, neutrophils and platelets.
With PNH, there are two clones in the blood of patients: normal and pathological, and the clinical picture and severity of the disease largely depend on the ratio of these clones.
Clinic
The proteolytic action of activated complement leads to intravascular destruction of defective red blood cells, which manifests itself hemoglobinuria. Activation of complement occurs at night during sleep, due to a shift in pH to the acidic side.
Clinically, hemolysis during sleep is manifested by the release of black urine during morning diuresis, complaints of malaise, dizziness, and the appearance of yellowness of the sclera. In addition, hemolysis can be provoked by infectious diseases and certain medications.
In addition to the anemic symptoms associated with hemolysis, important role playing at the PNG clinic thrombotic complications, caused by the release of thromboplastin and a number of active enzymes from destroyed cells.
Often, one of the first complaints of the patient is abdominal pain, simulating a variety of acute abdominal pathologies. Abdominal pain is associated with thrombosis of small mesenteric arteries.
Thrombophlebitisoccurs in 12% of patients with PNH and can occur in different ways. In one of the options, the condition of patients outside of crises is quite satisfactory, the content Hb – about 80 – 90 g/l. In other patients, severe hemolytic crises follow one after another, leading to severe anemia. They are often accompanied by thrombotic complications.
Laboratory data
During a hemolytic crisis, there may be sharp decline hemoglobin level to 20 g/l and below, and a parallel decrease in the number of red blood cells. During the period of remission, content Hb and red blood cells increases, however, in in rare cases reaches lower limit norms. Unlike most membranopathies, a defect in the erythrocyte membrane in PNH is not accompanied characteristic changes forms pathological red blood cells. Anemia in most cases is normocytic and normochromic in nature. However, with significant loss of iron in the urine (as a result of hemoglobinuria and hemosiderinuria), hypochromia of erythrocytes develops. The content of reticulocytes is increased, but to a much lesser extent than in congenital membranopathies with a similar intensity of hemolysis. Abnormal hemoglobins and decreased enzyme activity (except for acetylcholinesterase) were not detected in erythrocytes in PNH. The osmotic resistance of erythrocytes is not changed. When erythrocytes from patients with PNH are incubated under sterile conditions, greater than normal autohemolysis is observed, which, however, does not decrease with the addition of glucose.
The number of leukocytes in most cases is reduced due to neutropenia. Sometimes there is a left shift in the leukogram.
The platelet count is also usually low. Platelet functions are not impaired.
When researching bone marrow erythroid hyperplasia and signs of bone marrow hematopoiesis deficiency are detected in the form of impaired ripening of red cells and granulocytic elements, as well as a decrease in the number of megakaryocytes, often with impaired lacing blood platelets. In some patients with PNH, along with signs of dyshematopoiesis, bone marrow hypoplasia, characteristic of aplastic anemia, is detected.
In cases where complement-sensitive PNH erythrocytes and symptoms of intravascular hemolysis are detected in patients with previously established hematopoietic aplasia, PNH syndrome, which has developed against the background of aplastic anemia, is diagnosed.
However, one should remember about rare cases of PNH, which end in aplastic anemia due to depletion of bone marrow hematopoiesis by severe hemolytic crises and other adverse effects (infections, certain medicinal agents, etc.).
An important laboratory sign of PNH is hemoglobinuria. The content of free hemoglobin in plasma due to intravascular destruction of erythrocytes in PNH, depending on the severity of hemolysis, ranges from 11 to 280 mg% (with a norm of up to 4 mg%).
The bilirubin content is usually slightly increased, mainly due to the unconjugated fraction. The level of serum iron in PNH depends on the phase of the disease: during hemolytic crises, due to the release of hemoglobin iron into the plasma, ferritinemia is observed, and during a quiet period, due to the loss of iron in the urine, hypoferritinemia is observed. Iron deficiency in PNH, in contrast to iron deficiency anemia, is accompanied by a simultaneous decrease in total and latent iron-binding capacity, apparently due to a violation of transferrin synthesis in the liver.
Urine examination reveals hemoglobinuria in most patients with PNH. With PNH, hemoglobin appears in the urine at its relatively low concentration in plasma, which is associated with a decrease in the content of plasma haptoglobin. During excretion of hemoglobin by the kidneys, part of it is reabsorbed and deposited in the tubular epithelium in the form of hemosiderin, which is then excreted in the urine. Interestingly, hemosiderinuria in PNH can be detected more often than hemoglobinuria, since it also develops outside of a hemolytic crisis.
Diagnosticsdisease is associated with the identification of characteristic clinical picture, laboratory signs of intravascular hemolysis (hemoglobinemia (red color of blood serum after centrifugation), decreased haptoglobin in the blood, slight indirect billirubinemia, increased LDH, hemoglobinuria, hemosiderinuria). The diagnosis of PNH is based on the detection of complement-sensitive erythrocytes characteristic of this disease. For this purpose they are used Hema acid test and more sensitive sucrose test.
When performing the Hem test, the red blood cells being tested are incubated in normal serum acidified to pH 6.4. Under these conditions, only complement-sensitive erythrocytes are lysed. It should be remembered that with a low content of PNH red blood cells in the patient’s blood and with low complement activity in the serum, the Hem test can give negative results.
More sensitive is the sucrose test, in which the red blood cells being tested and a small amount of normal serum are placed in an isotonic sucrose solution. In conditions undervoltage in a sucrose medium, more active fixation of complement on the surface of erythrocytes and lysis of complement-sensitive PNH erythrocytes occurs.
Evidence of the presence of a PNH clone is the detection on the cell membrane of signs characteristic of damage to the PIG A gene. Modern methods Flow cytofluorometry makes it possible to determine the presence of erythrocytes with complete or partial deficiency of CD59 molecules on the membrane, however, pathological erythrocytes cannot always be detected, given the presence of their pronounced hemolysis. The most reliable is the study of monocyte granulocytes, since nucleated cells are less susceptible to the action of complement.
Treatment
Due to the lack of clear ideas about the pathogenesis of PNH, treatment of this disease is currently symptomatic.
To combat anemia, replacement blood transfusions are used, the frequency of which depends on the severity of hemolysis and compensatory activity of the bone marrow. It should be remembered that transfusion of fresh whole blood to patients with PNH is often accompanied by increased hemolysis. The reason for this reaction is unclear. Patients with PNH better tolerate transfusions of whole blood or red blood cells with long storage periods (more than 7–8 days) and transfusions of 3–5 times washed red blood cells freed from leukocytes and platelets. The use of washed red blood cells is the best transfusion method in the treatment of PNH. When a reaction occurs to washed red blood cells due to the development of isosensitization, individual selection of a donor is necessary according to the indirect Coombs reaction (Fig. 12).
An important place in the treatment of PNH is occupied by iron supplements and androgenic hormones. Therapy with iron supplements is recommended for patients with PNH when hypochromia of erythrocytes and a decrease in serum iron levels are detected during the quiet course of the disease. Iron supplements should be used carefully (in small doses and only peros ), since their ability to provoke severe hemolytic crises in some patients with PNH is known.
The use of androgens in PNH is based on the stimulating effect of these hormones on erythropoiesis. Prescribing Nerabol or its analogues at a dose of 30 – 40 mg/day promotes more rapid recovery hemoglobin level after a hemolytic episode and thereby significantly reduces the need for blood transfusions. The use of androgens is especially effective in PNH with hematopoietic hypoplasia.
The treatment strategy for thrombotic complications depends on the location of thrombosis, its duration and the state of the coagulation system. In cases where this complication threatens the patient’s life, it is necessary to use complex thrombolytic and anticoagulant therapy (fibrinolysin or urokinase, nicotinic acid, heparin and anticoagulants indirect action) according to general therapeutic rules and in sufficient dosages.
Since there are reports of increased hemolysis after heparin administration, this anticoagulant should be used with great caution.
Splenectomy for PNH is not indicated because postoperative period often complicated by thrombosis of mesenteric vessels. The risk of surgery is acceptable only in the presence of severe symptoms of hypersplenism: deep leukopenia, complicated by frequent infections and/or thrombocytopenia, accompanied by severe hemorrhagic syndrome.
A modern genetic technology drug Eculizumab (Soliris, SOLIRIS®) has been developed, which is registered by the FDA (Food and Drug Administration) for the treatment of children and adults suffering from PNH. Eculizumab is a glycosylated humanized monoclonal antibody - immunoglobulin kappa (IgG2/4k) that binds to human complement protein C5 and inhibits the activation of complement-mediated cell lysis. The antibody consists of constant regions of human immunoglobulin and complementary-determined regions of mouse immunoglobulin, embedded in the variable regions of the light and heavy chains human antibody. Eculizumab contains two heavy chains, each containing 448 amino acids, and two light chains, each containing 214 amino acids. The molecular weight is 147870 Da. Eculizumab is produced in cultured murine myeloma cell line NS0 and purified using affinity and ion exchange chromatography. The production process of the substance also includes processes of specific inactivation and removal of viruses.
Eculizumab suppresses the terminal activity of human complement, having high affinity for its C5 component. As a consequence, the cleavage of the C5 component into C5a and C5b and the formation of the terminal complement complex C5b–9 are completely blocked. Thus, eculizumab restores the regulation of complement activity in the blood and prevents intravascular hemolysis in patients with PNH. On the other hand, terminal complement deficiency is accompanied by an increased incidence of infections with encapsulated microorganisms, mainly meningococcal infection. At the same time, eculizumab maintains the content of early complement activation products necessary for opsonization of microorganisms and excretion immune complexes. Prescribing Soliris to patients is accompanied by a rapid and stable decrease in terminal complement activity. In most patients with PNH, a plasma eculizumab concentration of about 35 μg/ml is sufficient to completely inhibit intravascular hemolysis induced by terminal complement activation.
With unique new clinical results and emerging therapeutic options for physicians to preserve full life and the health of patients, Eculizumab was registered in an accelerated manner, without conducting a third phase clinical trials– this will save many lives, both children and adults.
In this regard, following registration in the USA, the European Committee for medicines issued a positive opinion on the accelerated registration of Eculizumab in Europe, which is also expected in the near future.
Considering high cost eculizumab, the impossibility of using it to influence the cause of the disease and the fact that it must be used throughout life, a reserve strategy is most applicable to it, intended specifically for patients with a high number of PNH cells or for patients with a tendency to thrombosis, independent of the size PNG clone.
Currently the only way radical treatment PNH is an allogeneic bone marrow transplant.
Course and prognosis
The prognosis depends on the severity of the underlying disease, worse in patients dependent on blood transfusions, with severe thrombosis. In 10% of patients, spontaneous remissions of the disease are observed, in others it transforms into aplastic anemia, MDS, in 5% - into acute leukemia. On average, life expectancy is 10 – 15 years.
PNH is chronic and is currently still completely incurable disease. The severity of PNH and prognosis largely depend on the size of the complement-sensitive erythrocyte population, the compensatory ability of the bone marrow and the occurrence of complications, especially venous thrombosis. Idea of a severe prognosis for PNH beyond lately in connection with the introduction of active symptomatic therapy has changed significantly.
The number of patients who have been in a state of clinical and hematological compensation for a long time and who are undergoing treatment at this time has increased. normal image life. The frequency of severe life-threatening thrombosis. In some patients, over time, there is a mitigation of the disease with a decrease in the proportion of complement-sensitive erythrocytes. In rare cases, the complete disappearance of pathological red blood cells is described, which indicates the fundamental possibility of curing the disease.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disease manifested by persistent hemolytic anemia, paroxysmal or persistent hemoglobinuria, and intravascular hemolysis. The rarity of this type of hemolytic anemia is characterized by the fact that PNH affects 1 person in half a million, mostly young people.
Causes of the disease present moment time is not known with certainty. It is assumed that it occurs due to the occurrence of an abnormal clone of red blood cells prone to intravascular hemolysis. In turn, the inferiority of red blood cells is a consequence of structural and biochemical defects in their membrane. It is known that lipid peroxidation is activated in a defective membrane, which contributes to the rapid lysis of red blood cells; in addition, in pathological process abnormal clones of granulocytes and platelets are involved. The main role in the occurrence of thrombotic complications of PNH belongs to the intravascular destruction of erythrocytes and the initiation of blood coagulation by factors released during this process. PNH, as a rule, begins gradually and proceeds chronically with periodic crises. Crises provoke viral infections, surgical interventions, psycho-emotional stress, menstruation, use of a number of medications and foods.
Symptoms of paroxysmal nocturnal hemoglobinuria
Symptoms of PNH during a crisis:
- paroxysmal pain in the abdominal cavity;
- pain in lumbar region;
- icterus skin and sclera; hyperthermia; facial pastiness;
- black color of urine, mainly at night;
- a sharp decrease in blood pressure;
- transient enlargement of the spleen;
- cessation of urine output.
In some cases hemolytic crisis ends fatally.
Symptoms of PNH outside of crisis:
- general weakness;
- pale skin color with a jaundiced tint;
- anemia;
- tendency to thrombosis; hematuria; increased blood pressure; liver enlargement; dyspnea; heartbeat; frequent infectious diseases.
Diagnostics
- Blood test: anemia (normochromic, later hypochromic), moderate leukocytopenia and thrombocytopenia, serum iron level is significantly reduced.
- Examination of urine: black staining, hemoglobinuria, hemosiderinuria, proteinuria. The Gregersen urine benzidine test is positive.
- Ham's specific test is positive.
- The specific Hartmann test is positive.
- Bone marrow puncture: hyperplasia of the red hematopoietic lineage, but with severe course Bone marrow hypoplasia and an increase in the amount of adipose tissue in the bone marrow may also be observed.
Treatment of paroxysmal nocturnal hemoglobinuria
Treatment of PNH is symptomatic and consists mainly of replacement blood transfusions, the volume and frequency of which depend on the “response” to these measures. In the treatment of PNH, methandrostenolone is used at a dose of 30-50 mg/day for at least 2-3 months. The fight against bone marrow hypoplasia is carried out by intravenous use of antithymocyte immunoglobulin at a dose of 150 mg/day for 4 to 10 days. It is recommended to take iron supplements per os in small dosages. Sometimes good effect give corticosteroids high dosages. Bone marrow hypoplasia with the development of thrombotic complications are indications for its transplantation. Described isolated cases recovery from PNH, in some cases the duration favorable course The disease lasts several decades.
Essential drugs
There are contraindications. Specialist consultation is required.
What is Paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease) -
Paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease, Strübing-Marchiafava disease)- acquired hemolytic anemia associated with intravascular destruction of defective red blood cells.
Paroxysmal nocturnal hemoglobinuria is a rare acquired disease caused by a violation of the erythrocyte membrane and characterized by chronic hemolytic anemia, intermittent or constant hemoglobinuria and hemosiderinuria, phenomena of thrombosis and bone marrow hypoplasia. Paroxysmal nocturnal hemoglobinuria is one of the rare forms of hemolytic anemia. There is 1 case of this disease per 500,000 healthy individuals. This disease is usually first diagnosed in people in the 20-40 age group, but can also occur in older people.
What provokes / Causes of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease):
Paroxysmal nocturnal hemoglobinuria is an acquired disease, apparently caused by an inactivating somatic mutation in one of the stem cells. The mutant gene (PIGA) is located on the X chromosome; the mutation disrupts the synthesis of glycosylphosphatidylinositol. This glycolipid is necessary for fixation to the cell membrane of a number of proteins, including CD55 (a factor that accelerates complement inactivation) and protectin.
To date, patients with paroxysmal nocturnal hemoglobinuria have been found to lack about 20 proteins on their blood cells. Along with the pathological clone, patients also have normal stem cells and blood cells. The proportion of pathological cells differs in different patients and even in the same patient at different times.
It is also assumed that paroxysmal nocturnal hemoglobinuria occurs due to the proliferation of a defective clone of bone marrow stem cells; such a clone gives rise to at least three populations of erythrocytes that differ in sensitivity to activated complement components. Increased sensitivity to complement in to the greatest extent inherent in young circulating red blood cells.
In paroxysmal nocturnal hemoglobinuria, leukocytes and platelets, like erythrocytes, are also characterized by structural defects in their membranes. The absence of immunoglobulins on the surface of these cells suggests that paroxysmal nocturnal hemoglobinuria does not belong to autoaggressive diseases. Accumulated data indicate the presence of two independent populations of erythrocytes - pathological (not surviving to maturity) and healthy. The uniformity of damage to the membranes of erythrocytes, leukocytes and platelets is an argument in favor of the fact that most likely pathological information is received by the common precursor cell of myelopoiesis. The leading role in the genesis of thrombotic complications belongs to the intravascular destruction of red blood cells and stimulation of the coagulation process by factors released during their breakdown.
Pathogenesis (what happens?) during Paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease):
Due to the absence of two proteins - decay accelerating factor (CD55) and protectin (CD59, inhibitor of the membrane attack complex) - the sensitivity of erythrocytes to the lytic action of complement is increased. The decay accelerating factor destroys C3-convertases and C5-convertases of the classical and alternative pathways, and protectin prevents the polymerization of the C9 component, catalyzed by the C5b-8 complex, and, therefore, disrupts the formation of the membrane attack complex.
Platelets also lack these proteins, but their lifespan is not shortened. On the other hand, complement activation indirectly stimulates platelet aggregation and increases blood clotting. This probably explains the tendency to thrombosis.
Symptoms of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease):
There is an idiopathic form of paroxysmal nocturnal hemoglobinuria and paroxysmal nocturnal hemoglobinuria in the form of a syndrome that accompanies a number of diseases. A unique variant of idiomatic paroxysmal nocturnal hemoglobinuria, the development of which is preceded by a phase of hematopoietic hypoplasia, is also rare.
Symptoms of paroxysmal nocturnal hemoglobinuria very variable - from mild benign to severe aggressive. In the classic form, hemolysis occurs while the patient is sleeping (nocturnal hemoglobinuria), which may be due to slight decrease at night blood pH. However, hemoglobinuria is observed only in approximately 25% of patients, and in many not at night. In most cases, the disease manifests itself with symptoms of anemia. Hemolytic outbreaks may occur after severe infection physical activity, surgical intervention, menstruation, blood transfusions and the administration of iron supplements for therapeutic purposes. Hemolysis is often accompanied by bone and muscle pain, malaise and fever. Characteristic signs include pallor, jaundice, bronze coloration of the skin and moderate splenomegaly. Many patients complain of difficulty or pain in swallowing, and spontaneous intravascular hemolysis and infections often occur.
Paroxysmal nocturnal hemoglobinuria often accompanies aplastic anemia, preleukemia, myeloproliferative diseases and acute myeloid leukemia. The detection of splenomegaly in a patient with aplastic anemia should serve as a basis for examination to identify paroxysmal nocturnal hemoglobinuria.
Anemia is often severe, with hemoglobin levels of 60 g/L or lower. Leukopenia and thrombocytopenia are common. In a smear peripheral blood As a rule, a picture of normocytosis is observed, however, with prolonged hemosiderinuria, iron deficiency occurs, manifested by signs of anisocytosis and the presence of microcytic hypochromic erythrocytes. The reticulocyte count is elevated unless there is bone marrow failure. The bone marrow at the onset of the disease is usually hyperplastic, but later hypoplasia and even aplasia may develop.
Level alkaline phosphatase in neutrophils it is reduced, sometimes to the point of its complete absence. All signs of intravascular hemolysis may be present, but severe hemosiderinuria is usually observed, leading to iron deficiency. In addition, chronic hemosiderinuria causes iron deposition in renal tubules and dysfunction of their proximal parts. Antiglobulin test, as a rule, is negative.
Venous thrombosis occurs in approximately 40% of patients and is the main cause of death. The veins of the abdominal cavity (hepatic, portal, mesenteric and others) are usually affected, which is manifested by Budd-Chiari syndrome, congestive splenomegaly and abdominal pain. Thrombosis of the dural sinuses is less common.
Diagnosis of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease):
Diagnosis of paroxysmal nocturnal hemoglobinuria should be suspected in patients with hemolytic anemia, accompanied by black urine, leuko- and thrombocytopenia, and thrombotic complications. Important has microscopy of urine sediment stained for iron to detect hemosiderinuria, a positive benzidine Gregersen urine test.
Normochromic anemia is detected in the blood, which can later become hypochromic. The number of reticulocytes is slightly increased. The number of leukocytes and platelets is reduced. The plasma content of free hemoglobin is increased. In some cases, there is a decrease in serum iron and an increase in bilirubin levels. Protein and hemoglobin levels may be detected in the urine.
The myelogram usually shows signs of increased erythropoiesis. In a bone marrow biopsy, there is hyperplasia of hematopoietic tissue due to an increase in the number of erythro- and normoblasts, accumulation of hemolyzed erythrocytes in the lumens of dilated sinuses, and areas of hemorrhage. It is possible to increase the number of plasmatic and mast cells. The number of granulocytes and megakaryocytes is usually reduced. In some patients, fields of devastation may be detected, represented by edematous stroma and fat cells. A noticeable increase in adipose tissue in the bone marrow is detected when the disease is accompanied by the development of hematopoietic hypoplasia.
Specific for paroxysmal nocturnal hemoglobinuria are the Hem test (acid test) and the Hartman test (sucrose test), since they are based on the most characteristic sign for this disease - hypersensitivity PNH-defective erythrocytes to complement.
Paroxysmal nocturnal hemoglobinuria can begin with previous hypoplasia of hematopoiesis, sometimes it occurs at later stages. At the same time, there are cases with the appearance of signs of intravascular hemolysis at various stages of the disease, with positive acid and sugar tests. In such cases, they talk about PNH syndrome or hypoplastic anemia. We describe patients who developed acute myeloblastic leukemia and erythromyelosis against the background of paroxysmal nocturnal hemoglobinuria, transient syndrome of paroxysmal nocturnal hemoglobinuria with acute myeloblastic leukemia, osteomyelosclerosis and cancer metastases to the bone marrow. In hereditary dyserythropoietic anemia with multinucleated normoblasts, positive test Hema.
In some cases it is necessary to carry out differential diagnosis between paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia with warm hemolysins, when a sucrose test can give false positive result. A cross-sucrose test using the patient’s blood serum and donor red blood cells, which reveals the presence of hemolysins, helps in correct diagnosis. In the sucrose test, complement activation is ensured by the low ionic strength of the incubation solution. This test is more sensitive but less specific than the Ham test.
The most sensitive and specific method is flow cytofluorimetry, which allows one to determine the absence of protectin and factor accelerating complement inactivation on erythrocytes and neutrophils.
Differential diagnosis carried out with some forms of autoimmune hemolytic anemia, occurring with intravascular hemolysis, kidney disease (with severe proteinuria), aplastic anemia, lead intoxication. In case of severe anemia, transfusions of red blood cells washed with isotonic sodium chloride solution are indicated; for the prevention and treatment of thrombosis - anticoagulant therapy. For iron deficiency, iron supplements are prescribed. Tocopherol preparations are useful, as well as anabolic hormones (nerobol, retabolil).
Treatment of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease):
Treatment of paroxysmal nocturnal hemoglobinuria symptomatic because specific therapy does not exist. The main method of treatment for patients with paroxysmal nocturnal hemoglobinuria is transfusion of washed (at least 5 times) or thawed red blood cells, which, as a rule, are well tolerated by patients for a long time and do not cause isosensitization. Transfusions of freshly prepared whole blood or red blood cells with a shelf life of less than 7 days are contraindicated due to the possibility of increased hemolysis and the development of hemoglobinuria crises due to the presence of leukocytes in these transfusion media, which leads to the formation of anti-leukocyte antibodies and complement activation.
The volume and frequency of transfusions depend on the patient's condition, the severity of anemia and the response to blood transfusion therapy. In patients with paroxysmal nocturnal hemoglobinuria, frequent transfusions can produce anti-erythrocyte and anti-leukocyte antibodies.
In these cases, red blood cell mass is selected according to indirect sample Coombs, it is washed repeatedly with saline solution.
In the treatment of paroxysmal nocturnal hemoglobinuria, Nerobol is used in daily dose 30-50 mg for at least 2-3 months. However, in a number of patients, after discontinuation of the drug or during treatment, a rapid increase in hemolysis is observed. Sometimes taking drugs from this group is accompanied by changes in functional tests liver, usually of a reversible nature.
To combat bone marrow hypoplasia, antithymocyte immunoglobulin is usually used, as in aplastic anemia. A total dose of 150 mg/kg is prescribed intravenously for 4-10 days.
In patients with paroxysmal nocturnal hemoglobinuria, due to constant loss of iron, iron deficiency often develops in the body. Since increased hemolysis is often observed when taking iron supplements, they should be used orally and in small doses. Anticoagulants are indicated after surgical intervention, however, they should not be administered for a long time. There are a number of reports of sudden development of hemolysis after heparin administration.
It has been reported that some patients benefited from corticosteroids in high doses; The use of androgens may be helpful.
Bone marrow hypoplasia and thrombosis, especially in young patients, are indications for transplantation of HLA-matched bone marrow from sibling or sisters (if any) are already at early stage diseases. To destroy the pathological clone of cells, conventional preparatory chemotherapy is sufficient.
The effectiveness of splenectomy has not been established, and the operation itself is poorly tolerated by patients.
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Other diseases from the group Diseases of the blood, hematopoietic organs and certain disorders involving the immune mechanism:
| B12 deficiency anemia |
| Anemia caused by impaired synthesis and utilization of porphyrins |
| Anemia caused by a violation of the structure of globin chains |
| Anemia characterized by the carriage of pathologically unstable hemoglobins |
| Fanconi anemia |
| Anemia associated with lead poisoning |
| Aplastic anemia |
| Autoimmune hemolytic anemia |
| Autoimmune hemolytic anemia |
| Autoimmune hemolytic anemia with incomplete heat agglutinins |
| Autoimmune hemolytic anemia with complete cold agglutinins |
| Autoimmune hemolytic anemia with warm hemolysins |
| Heavy chain diseases |
| Werlhof's disease |
| von Willebrand disease |
| Di Guglielmo's disease |
| Christmas disease |
| Marchiafava-Miceli disease |
| Randu-Osler disease |
| Alpha heavy chain disease |
| Gamma heavy chain disease |
| Henoch-Schönlein disease |
| Extramedullary lesions |
| Hairy cell leukemia |
| Hemoblastoses |
| Hemolytic-uremic syndrome |
| Hemolytic-uremic syndrome |
| Hemolytic anemia associated with vitamin E deficiency |
| Hemolytic anemia associated with glucose-6-phosphate dehydrogenase (G-6-PDH) deficiency |
| Hemolytic disease of the fetus and newborn |
| Hemolytic anemia associated with mechanical damage to red blood cells |
| Hemorrhagic disease of the newborn |
| Malignant histiocytosis |
| Histological classification of lymphogranulomatosis |
| DIC syndrome |
| Deficiency of K-vitamin-dependent factors |
| Factor I deficiency |
| Factor II deficiency |
| Factor V deficiency |
| Factor VII deficiency |
| Factor XI deficiency |
| Factor XII deficiency |
| Factor XIII deficiency |
| Iron deficiency anemia |
| Patterns of tumor progression |
| Immune hemolytic anemias |
| Bedbug origin of hemoblastoses |
| Leukopenia and agranulocytosis |
| Lymphosarcoma |
| Lymphocytoma of the skin (Caesary disease) |
| Lymphocytoma of the lymph node |
| Lymphocytoma of the spleen |
| Radiation sickness |
| March hemoglobinuria |
| Mastocytosis (mast cell leukemia) |
| Megakaryoblastic leukemia |
| The mechanism of inhibition of normal hematopoiesis in hemoblastoses |
| Obstructive jaundice |
| Myeloid sarcoma (chloroma, granulocytic sarcoma) |
| Myeloma |
| Myelofibrosis |
| Disorders of coagulation hemostasis |
| Hereditary a-fi-lipoproteinemia |
| Hereditary coproporphyria |
| Hereditary megaloblastic anemia in Lesch-Nyan syndrome |
| Hereditary hemolytic anemia caused by impaired activity of erythrocyte enzymes |
| Hereditary deficiency of lecithin-cholesterol acyltransferase activity |
| Hereditary factor X deficiency |
| Hereditary microspherocytosis |
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RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols Ministry of Health of the Republic of Kazakhstan - 2015
Paroxysmal nocturnal hemoglobinuria [marchiafava-micheli] (D59.5)
Oncohematology
General information
Brief description
Recommended
Expert advice
RSE at the RVC "Republican Center"
healthcare development"
Ministry of Health
And social development
Republic of Kazakhstan
dated July 9, 2015
Protocol No. 6
Definition:
Paroxysmal nocturnal hemoglobinuria (PNH)- it is rare, acquired, life-threatening, progressive systemic disease blood, characterized by chronic intravascular hemolysis, bone marrow failure, increased risk development of thrombotic complications, renal failure And pulmonary hypertension. .
Protocol name: Paroxysmal nocturnal hemoglobinuria in adults
Protocol code:
ICD-10 code:
D59.5 - Paroxysmal nocturnal hemoglobinuria.
Date of development of the protocol: 2015
Abbreviations used in the protocol:
* - drugs purchased as part of a one-time import;
AA - aplastic anemia;
AH - arterial hypertension;
BP - blood pressure;
ALaT - alanine aminotransferase;
ACaT - aspartate aminotransferase;
HIV - human immunodeficiency virus;
GGTP - gammaglutamyl transpeptidase;
ELISA - enzyme immunoassay;
CT - computed tomography;
LDH-lactate dehydrogenase;
MDS - myelodysplastic syndrome;
MPO - myeloperoxidase;
NE - naphthyl esterase;
UAC - general analysis blood;
PNH - paroxysmal nocturnal hemoglobinuria;
sPNH - subclinical paroxysmal hemoglobinuria;
BMT - bone marrow transplantation;
Ultrasound Doppler ultrasound;
USDG - Doppler ultrasound;
Ultrasound - ultrasound examination;
EF - ejection fraction;
FGDS - fibrogastroduodenoscopy;
RR - respiratory rate;
HR - heart rate;
ECG - electrocardiography;
EchoCG - echocardiography;
NMRT - nuclear magnetic resonance tomography;
CD - cluster of differentiation;
HLA - human leukocyte antigen system;
Hb - hemoglobin;
Ht - hematocrit;
Tr - platelets.
Protocol users: therapists, doctors general practice, oncologists, hematologists.
Level of evidence scale.
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Classification
Clinical classification:
There are 3 main forms of PNH.
1. Classic shape characterized by clinical and laboratory signs of intravascular hemolysis without signs of other diseases associated with bone marrow failure (aplastic anemia (AA), myelodysplastic syndrome (MDS), idiopathic myelofibrosis).
2. PNH diagnosed in patients with AA (AA/PNG), MDS (MDS/PNG) and extremely rarely with myelofibrosis (idiopathic myelofibrosis/PNH), when in these diseases there are clinical and/or laboratory signs of intravascular hemolysis, and a clone of cells with the PNH phenotype is determined in the peripheral blood.
3. Subclinical form diseases ( AA/sPNH, MDS/sPNH, idiopathic myelofibrosis/sPNH), diagnosed in patients without clinical and laboratory signs hemolysis, but in the presence of a minor clone of cells with the PNH phenotype (usually<1 %). Следует отметить, что субклиническое течение ПНГ может отмечаться и при большем размере клона.
Isolation of the subclinical form of PNH does not have independent clinical significance, but is necessary to ensure monitoring of such patients due to the likelihood of an increase in the size of the clone and progression of hemolysis, which may dominate clinical manifestations and require appropriate therapy.
Taking into account the fact that the subclinical form of PNH in AA and/or MDS has no independent clinical significance.
Classic PNG shape.
Patients with classic PNH typically have severe intravascular hemolysis with increased serum lactate dehydrogenase (LDH) levels, reticulocytosis, and decreased haptoglobin levels. With this variant of PNH, there are no definitive morphological signs of other bone marrow pathologies (AA, MDS, myelofibrosis) and no karyotype abnormalities are characteristic
PNH against the background of bone marrow failure syndromes (AA/PNH, MDS/PNH).
In patients with AA/PNH and MDS/PNH, clinical and laboratory signs of intravascular hemolysis are diagnosed. At different stages of the development of the disease, symptoms of bone marrow failure or intravascular hemolysis may prevail, and in some cases there is a combination of both. Despite the fact that in patients with a small PNH clone, the disease usually occurs with minimal symptoms and only laboratory signs of intravascular hemolysis are noted, monitoring is necessary (twice a year). This is due to the fact that over time, expansion of the clone is possible with the development of severe hemolysis and a high risk of thrombotic complications.
Subclinical form of PNH (AA/sPNH, MDS/sPNH).
Patients with subclinical PNH do not have any clinical or laboratory signs of hemolysis. Small populations of GPIAP-deficient cells can only be detected using highly sensitive flow cytometry. The subclinical form of PNH can be diagnosed against the background of diseases characterized by impaired bone marrow function, mainly AA and MDS. It is very important to carefully monitor these patients to identify signs of hemolysis and clone expansion, since 15-17% of patients with AA / subclinical PNH have Over time, the hemolytic form of AA/PNH develops.
Diagnostics
List of basic and additional diagnostic measures:
Basic (mandatory) diagnostic examinations carried out at the outpatient level:
· general blood test (counting reticulocytes in a smear);
· immunophenotyping of peripheral blood to determine the percentage of PNH erythrocytes of types I, II and III using flow cytometry;
· biochemical blood test (total bilirubin, direct bilirubin, LDH);
· Coombs test;
· myelogram.
Additional diagnostic examinations carried out on an outpatient basis:
· determination of the concentration of folic acid and vitamin B12;
· coagulogram;
standard cytogenetic examination of bone marrow;
general urinalysis
· ELISA for markers of viral hepatitis;
· ELISA for HIV markers;
· ELISA for markers of herpes group viruses;
· HLA - typing;
· ECG;
· Ultrasound of the abdominal organs (liver, spleen, pancreas, gall bladder, lymph nodes, kidneys, in women - pelvis;
The minimum list of examinations that must be carried out when referring for planned hospitalization:
· general blood test (counting leukemia, platelets and reticulocytes in a smear);
· myelogram;
· blood type and Rh factor
· biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALaT, ACaT, GGTP, glucose, LDH, C-reactive protein, alkaline phosphatase);
· Coombs test;
· Ultrasound of the abdominal organs and spleen;
· Ultrasound of the pelvic organs - for women.
Basic (mandatory) diagnostic examinations carried out at the hospital level:
General blood test (counting leukemia, platelets and reticulocytes in a smear);
- immunophenotyping of peripheral blood to determine the percentage of PNH erythrocytes of types I, II and III using flow cytometry;
- biochemical blood test (total bilirubin, direct bilirubin, LDH);
- Coombs test
- myelogram.
- standard cytogenetic examination of the bone marrow;
- ELISA for markers of viral hepatitis;
- ELISA for HIV markers;
- ELISA for markers of herpes group viruses;
· X-ray of the chest organs.
Additional diagnostic examinations carried out at the hospital level:
· determination of haptoglobin level.
· blood type and Rh factor;
· biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALaT, ACaT, glucose, LDH, GGTP, C-reactive protein, alkaline phosphatase);
· iron metabolism (determining the level of serum iron, total iron-binding capacity of serum and ferritin level);
· Determination of the concentration of folic acid and vitamin B12;
· coagulogram;
· HLA - typing;
general urine analysis;
· determination of hemosiderin level in urine;
· Reberg-Tareev test (determination of glomerular filtration rate);
· ECG;
· Ultrasound of the abdominal organs (liver, spleen, pancreas, gall bladder, lymph nodes, kidneys, in women - pelvis;
X-ray of the chest organs;
· Doppler ultrasound of arteries and veins;
· echocardiography;
· FGDS (dilatation of the veins of the esophagus);
daily blood pressure monitoring;
· 24-hour ECG monitoring.
Diagnostic measures carried out at the stage of emergency medical care:
· collection of complaints and medical history;
· physical examination.
Diagnostic criteria for diagnosis:
Complaints and anamnesis:
- weakness;
- rapid fatigue;
- increased bleeding.
Anamnesis:
you should pay attention to:
- long-term weakness;
- rapid fatigue;
- frequent infectious diseases;
- acute attacks of pain in the lumbar region;
- darkening of urine, mainly at night and in the morning;
- Budd-Chiari syndrome (hepatic vein thrombosis);
- thrombosis of various localizations;
- increased bleeding;
- the appearance of hemorrhagic rashes on the skin and mucous membranes;
- dispensary registration for AA or MDS.
Physical examination[
8
]:
- a combination of pallor and yellowness of the skin;
- hemorrhagic rashes - petechiae, ecchymoses of various localizations;
- shortness of breath;
- tachycardia;
- enlarged liver;
- enlarged spleen.
Laboratory research:
If PNH is suspected, flow cytometry allows an accurate diagnosis to be made. Flow cytometry is the most sensitive and informative method.
· General blood test: The reticulocyte count is usually elevated, and peripheral blood smears show red blood cells morphologically no different from normal. Due to hemolysis, normoblasts are often present in the blood, and polychromatophilia is noted. As a result of significant losses of iron in the urine, patients with PNH are highly likely to develop iron deficiency, and then the red blood cells take on the appearance characteristic of IDA - hypochromic with a tendency to microcytosis. The number of leukocytes and platelets is often reduced. Pancytopenia of varying severity may also be observed. However, unlike aplastic anemia, reticulocytosis usually occurs along with cytopenia.
· Biochemical blood test: The amount of bilirubin, free hemoglobin and methemoglobin in the blood serum is increased. There are signs of intravascular hemolysis, that is, a decrease or absence of haptoglobin, an increase in LDH, an increased level of free hemoglobin and iron in the urine. Low haptoglobin levels are consistently observed in intravascular hemolysis but also occur in cases of extravascular hemolysis, especially chronic hemolysis. Since haptoglobin is also an acute-phase reagent, its sharp decrease or absence is most informative.
· In urine: Hematuria and proteinuria may be detected. Constant signs of diagnostic significance are hemosiderinuria and the detection of bloody detritus in the urine.
· Morphological study: Erythroid hyperplasia is detected in the bone marrow. Bone marrow hypoplasia and a reduced content of siderocytes and sideroblasts are often detected.
· Immunophenotyping: An early and reliable sign of the PNH phenotype is the expression of GPI-related proteins: the expression of CD14 and CD48 is determined on monocytes, CD16 and CD66b - on granulocytes, CD48 and CD52 - on lymphocytes, CD55 and CD59 - on erythrocytes, CD55, CD58.
Instrumental studies:
· Ultrasound of the abdominal organs: increase in the size of the liver and spleen.
· Doppler ultrasound of arteries and veins: the presence of thrombosis of arteries and veins
· ECG: Impaired conduction of impulses in the heart muscle.
· EchoCG: signs of heart failure (HF)<60%), снижение сократимости, диастолическая дисфункция, легочная гипертензия, пороки и регургитации клапанов.
· Whole body CT/NMRI: detection of thrombosis (cerebral, portal, etc.)
· CT scan of the thoracic segment: infiltrative changes in lung tissue, signs of pulmonary hypertension.
· FGDS: varicose veins of the esophagus.
· Spirography: Pulmonary function testing.
Indications for consultation with specialists:
· doctor for x-ray endovascular diagnostics and treatment - installation of a central venous catheter from a peripheral access (PICC);
· hepatologist - for the diagnosis and treatment of viral hepatitis;
· gynecologist - pregnancy, metrorrhagia, menorrhagia, consultation when prescribing combined oral contraceptives;
· dermatovenerologist - skin syndrome No.
· infectious disease specialist - suspicion of viral infections;
· cardiologist - uncontrolled hypertension, chronic heart failure, heart rhythm and conduction disorders;
· neurologist acute cerebrovascular accident, meningitis, encephalitis, neuroleukemia;
· neurosurgeon - acute cerebrovascular accident, dislocation syndrome;
· nephrologist (efferentologist) - renal failure;
· oncologist - suspicion of solid tumors;
otorhinolaryngologist - for the diagnosis and treatment of inflammatory diseases of the paranasal sinuses and middle ear;
· ophthalmologist - visual impairment, inflammatory diseases of the eye and appendages;
· proctologist - anal fissure, paraproctitis;
· psychiatrist - psychosis;
· psychologist - depression, anorexia, etc.;
· resuscitator - treatment of severe sepsis, septic shock, acute pulmonary injury syndrome with differentiation syndrome and terminal conditions, installation of central venous catheters.
· rheumatologist - Sweet's syndrome;
· thoracic surgeon - exudative pleurisy, pneumothorax, pulmonary zygomycosis;
· transfusiologist - for the selection of transfusion media in case of a positive indirect antiglobulin test, ineffective transfusions, acute massive blood loss;
· urologist - infectious and inflammatory diseases of the urinary system;
· phthisiatrician - suspicion of tuberculosis;
· surgeon - surgical complications (infectious, hemorrhagic);
· maxillofacial surgeon - infectious and inflammatory diseases of the dentofacial system.
Differential diagnosis
Differential diagnosis.
Differential diagnosis is made with other types of hemolytic anemia, and with the cytopenic variant of PNH - with aplastic anemia.
B-12 deficiency anemia. Often there is a need for differential diagnosis of PNH, which occurs with pancytopenia and hemolysis, and B12-deficiency anemia with hemolytic syndrome. In both of these diseases, hemolysis is quite pronounced. The differences between these diseases are presented in the table:
Table. Differential diagnostic differences between B12-deficiency anemia and PNH.
| Signs | B12 deficiency anemia with hemolytic syndrome | PNH with pancytopenia |
| Nosological essence | Anemia caused by impaired formation of red blood cells and hemoglobin due to vitamin B-12 deficiency | A variant of acquired hemolytic anemia - intravascular hemolysis, PNH |
| Black urine | - | + |
| The appearance of hemosiderin and hemoglobin in the urine | - | + |
| Increased content of free hemobin in the blood | - | + |
| Blood color index | Increased (hyperchromic anemia) | Decreased (hypochromic anemia) |
| Iron content in blood | Normal or slightly increased | Reduced |
| Megaloblastic type of hematopoiesis (according to myelogram) | Characteristic | Not typical |
| Hypersegmented neutrophils in peripheral blood | Characteristic | Not typical |
Aplastic anemia. It is necessary to differentiate AA from PNH when aplastic anemia is accompanied by the development of hemolytic syndrome. It is known that paroxysmal nocturnal hemoglobinuria is manifested by anemia, a tendency to leukopenia, and thrombocytopenia. Thus, the diagnostic situation can be quite complicated when the symptoms of both diseases are very similar. It should be emphasized here that the leading symptoms of paroxysmal nocturnal hemoglobinuria are hemosiderinuria and hemoglobinuria, as well as a high level of free hemoglobin in the plasma. These symptoms are not present in aplastic anemia. The differential diagnosis of these two diseases is presented in the table.
Table. Differential diagnostic differences between AA with hemolysis and PNH.
| Signs | AA with hemolysis | PNG |
| Passage of intensely dark (black) urine, mainly at night | - | + |
| Pain in the abdomen and lumbar region | - | + |
| Thrombosis of peripheral vessels of the extremities, kidneys and other localizations | - | + |
| Enlarged spleen | - | + |
| Reticulocytosis | - | + |
| High level of free hemoglobin in the blood | - | + |
| Bone marrow aplasia | Characteristic | It is rare, more often there is hyperplasia of the red hematopoietic lineage |
| Hyperplasia of hematopoietic tissue in trephine biopsy specimen | - | + |
| Hemosiderinuria and hemoglobinuria | - | + |
Autoimmune hemolytic anemia. Due to the presence of hemoglobinuria and hemosiderinuria in patients, it is necessary to differentiate between PNH with autoimmune hemolytic anemia. Main differential diagnostic differences:
· in case of autoimmune hemolytic anemia, sucrose and Hema tests are negative, in case of Marchiafava-Micheli disease - positive;
· in autoimmune hemolytic anemia with warm hemolysins, the patient’s serum causes hemolysis of the donor’s red blood cells.
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Treatment
Treatment goals:
Achieving and maintaining remission (see paragraph 15 - Indicators of treatment effectiveness).
Treatment tactics:
Non-drug treatment:
Mode II: general security.
Diet: Neutropenic patients are not recommended to follow a specific diet ( level of evidence B).
Drug treatment.
The general algorithm for the treatment of patients with PNH, depending on the form of the disease and the severity of hemolysis, is presented in the figure.
Treatment algorithm for patients with PNH.
Eclizumab therapy.
Eculizumab is a humanized monoclonal antibody that binds to the C5 component of complement. This prevents the cleavage of C5 into C5a and C5b, thereby inhibiting the formation of pro-inflammatory cytokines (via C5a) and MAC (via C5b).
Currently, one multicenter, randomized, double-blind, placebo-controlled trial, TRIUMPH, assessed the effectiveness of eculizumab in stabilizing hemoglobin levels and reducing transfusion dependence in 87 transfusion-dependent patients with PNH over 6 months of therapy.
The study included patients over 18 years of age who had undergone at least 4 transfusions of erythrocyte-containing media over the past year, with an erythrocyte PNH clone type III of at least 10%, a platelet level of at least 100 thousand/μl, and an increase in LDH of ³1.5 normal. All patients received an anti-meningococcal vaccine before starting therapy.
The main result of the study was stabilization of hemoglobin levels in 49% of patients receiving eculizumab (p<0,001) и снижение необходимости в трансфузиях в этой группе до нуля (в группе плацебо за 6 месяцев потребовалось от 6 до 16 трансфузий), а также улучшение качества жизни.
The results of this study provided the basis for FDA approval of eculizumab for transfusion-dependent PNH with hemolysis.
A study by R. Hillman et al. and subsequent prospective studies have certain limitations that make it difficult to extrapolate their results to all patients with PNH, which are detailed in the FDA report and the Cochrane review by Arturo J Martí-Carvajal:
· Efficacy was studied only in patients over 18 years of age;
· Data on elderly patients is also limited (only 15 patients in the study were over 65 years old);
· The study included only transfusion-dependent patients with hemolysis;
· The small number of patients with thrombotic episodes and the high frequency of prescription of anticoagulant prophylaxis do not allow us to assess the effect of eculizumab on the risk of thrombotic complications and recommend against the use of anticoagulants in patients receiving eculizumab. The relative reduction in the frequency of thrombotic episodes during anticoagulant prophylaxis and eculizumab therapy is 81%;
· The quality of life questionnaire used has not been validated for patients with PNH and the improvement in quality of life could only be associated with an increase in hemoglobin levels;
· Short observation period;
· The study was sponsored by the manufacturer of the drug;
· There are no data on the effect of eculizumab compared with placebo on overall survival, the risk of transformation to AML and MDS. An increase in overall survival was shown in only one study with historical control (period from 1997 to 2004). In 2013, data from three prospective studies of 195 patients with PNH and hemolysis were published and showed a 97.6% survival rate at 36 months, but no comparison with a placebo group was made.
· Data on the use of eculizumab in pregnant women are limited. Pregnancy increases the incidence of severe life-threatening complications of PNH. There is a high probability that eculizumab crosses the blood-placental barrier and breast milk. Due to the rarity of the disease, there are currently no controlled studies of the effectiveness of eculizumab in pregnant women. Two cases of prescribing eculizumab to pregnant women from 4 and 5 weeks of gestation with subsequent uncomplicated pregnancies and the birth of healthy children are described.
· Even with long-term treatment, lasting about 30 months, about 18% of patients remain transfusion dependent. A possible explanation for this phenomenon is the participation in the processes of intravascular hemolysis of the C3 fragment of complement, which is not inhibited by eculizumab.
Eculizumab may be recommended for inclusion in the treatment program for the following categories of patients with classic PNH over 18 years of age:
Transfusion dependence due to chronic hemolysis ( level of evidence A);
presence of thrombotic complications ( level of evidenceD);
pregnancy in patients with PNH ( level of evidenceD).
When determining indications for eculizumab therapy, LDH levels alone should not be taken into account.
Method of administration and dosage of eculizumab
The drug is administered intravenously, by drip, over 25-45 minutes - for adults.
The course of treatment includes a 4-week initial cycle followed by a maintenance cycle. The initial cycle is 600 mg of the drug once a week for 4 weeks. Maintenance therapy - 900 mg in the 5th week, followed by 900 mg of the drug every (14±2) days.
"Breakthrough" hemolysis.
The standard eculizumab therapy regimen is sufficient for complete and stable blockade of complement-mediated hemolysis. In some patients, due to
peculiarities of drug metabolism or during infections, “breakthrough” hemolysis may develop. In this situation, signs of hemolysis appear within 2-3 days
before the next administration of eculizumab. Patients may develop hemoglobinuria, return of the original symptoms (shortness of breath, weakness, spasm of smooth muscles, etc.), the need for transfusions, increase in the level of LDH, reticulocytes and decrease in the level of haptoglobin. Treatment of breakthrough hemolysis involves reducing the interval between administrations of eculizumab to 12 days or increasing the dose to 1200 mg for 1-2 administrations.
Prevention and treatment of menincococcal infection.
During treatment with eculizumab, it is necessary to monitor the appearance of symptoms of infection and promptly prescribe antibiotics for bacterial infections. When meningococcal infection is diagnosed, the next administration of the drug is canceled.
The mechanism of action of the drug eculizumab suggests an increased risk of developing meningococcal infection ( Neisseria meningitidis) against the background of its use (level of evidence B).
All patients must be vaccinated against meningococcus 2 weeks before starting the drug, as well as revaccination between 2.5-3 years of therapy. The most preferred tetravalent conjugate vaccine is against serotypes A, C, Y and W135. If urgent treatment with eculizumab is necessary in an unvaccinated patient, therapy may be initiated against the background of appropriate antibiotic prophylaxis, which should continue for 2 weeks after vaccination against meningococcal infection.
Symptomatic therapy.
When treating with eculizumab, symptomatic therapy includes the administration of folic acid (5 mg/day), vitamin B12 (for deficiency), iron supplements (for deficiency), anticoagulants (warfarin, low molecular weight heparin) for thrombotic complications, transfusions of blood products depending on clinical symptoms, hydration during the development of a hemolytic crisis. Iron supplements should be prescribed with caution due to the possibility of increased hemolysis.
Anticoagulant therapy.
After a thrombotic event, long-term (lifelong) therapy with anticoagulants (coumarin derivatives or heparins) may be recommended. Therapy for Budd-Chiari syndrome requires the patient to be in a specialized surgical department for local and systemic thrombolysis. Anticoagulant therapy for primary prevention of thrombosis may be indicated in selected cases when a PNH clone is detected in ≥ 50% of granulocytes and in the presence of additional risks of thrombotic complications, with the exception of patients with bone marrow aplasia.
Transfusion support.
Indications for transfusion of blood components:
Erythrocyte suspension/mass.
· in relation to erythrocyte suspension/mass, selection by blood type and Rh factor is necessary;
· for patients with a history of multiple transfusions, it is advisable to select for the following antigens: Kell, Duffy, Kidd, MNSs;
· immediately before transfusion of erythrocyte suspension/mass, it is necessary to conduct a compatibility test with standard sera;
· threshold values at which the need for transfusion of red blood cell suspension/mass is considered: Hb<80 г/мл, Ht <25%;
· calculation of the maximum volume of erythrocyte suspension/mass is determined by the following formula: Hb (g/dL) x4 x recipient weight (kg).
Platelet concentrate.
· Platelet concentrate must be selected according to blood type and Rh factor;
· transfusion of platelet concentrate to prevent bleeding, carried out at Tr level<10 тыс кл/мкл;
· patients with febrile fever, bleeding of mucous membranes are recommended to undergo transfusion of platelet concentrate at Tr level<20 тыс кл/мкл;
· when planning an invasive intervention for a patient, it is recommended to carry out a transfusion of platelet concentrate at the level of Tr<50 тыс кл/мкл;
· therapeutic dose of platelets recommended for adults: 3 x 10 11 cells/l in a volume of 200-300 ml.
Assessing the effectiveness of transfusion:
stopping bleeding;
Determination of platelet level the next day - persistent Tr level<20 тыс кл/мкл свидетельствует о рефрактерности к трансфузиям;
· If all causes of thrombocytopenia are excluded, it is necessary to test for the presence of anti-leukocyte antibodies;
· If antibodies are detected, platelet transfusion must be carried out from an HLA-compatible donor.
Fresh frozen plasma.
Since FFP contains complement, its transfusions can provoke the development of hemolysis in patients with PNH. It is advisable to avoid transfusions of FFP in PNH.
Drug treatment provided on an outpatient basis:
− list of essential medicines indicating the release form (having a 100% probability of use):
Antineoplastic and immunosuppressive drugs
. eculizumab*300 mg, concentrate for solution for infusion, 10 mg/ml.
· filgrastim, solution for injection 0.3 mg/ml, 1 ml;
· ondansetron, solution for injection 8 mg/4ml.
Antibacterial agents
Azithromycin, tablet/capsule, 500 mg;
· amoxicillin/clavulanic acid, film-coated tablet, 1000 mg;
· moxifloxacin, tablet, 400 mg;
Ofloxacin, tablet, 400 mg;
· ciprofloxacin tablet, 500 mg;
· metronidazole, tablet, 250 mg, dental gel 20g;
· erythromycin, tablet 250 mg.
· anidulafungin, lyophilized powder for solution for injection, 100 mg/vial;
· clotrimazole, solution for external use 1% 15ml;
Fluconazole, capsule/tablet 150 mg.
· acyclovir, tablet, 400 mg, gel in tube 100,000 units 50 g;
Famciclovir, tablets, 500 mg.
Solutions used to correct disturbances in water, electrolyte and acid-base balance
· dextrose, solution for infusion 5% 250ml;
· sodium chloride, solution for infusion 0.9% 500ml.
· heparin, solution for injection 5000 IU/ml, 5 ml; (for flushing the catheter)
· rivaroxaban, tablet;
tranexamic acid, capsule/tablet 250 mg;
· ambroxol, solution for oral administration and inhalation, 15 mg/2 ml, 100 ml;
· atenolol, tablet 25 mg;
· drotaverine, tablet 40 mg;
Levofloxacin, tablet, 500 mg;
Lisinopril, 5 mg tablet;
· methylprednisolone, tablet, 16 mg;
· omeprazole, capsule 20 mg;
Prednisolone, tablet, 5 mg;
· dioctahedral smectite, powder for preparation of suspension for oral administration 3.0 g;
· torasemide, tablet 10 mg;
· fentanyl, therapeutic transdermal system 75 mcg/h; (for the treatment of chronic pain in cancer patients)
Drug treatment provided at the inpatient level:
− list of essential medicines indicating the release form (having a 100% probability of use):
· eculizumab*300 mg, concentrate for solution for infusion, 10 mg/ml.
− list of additional medicines indicating the release form (less than 100% probability of use):
Medicines that weaken the toxic effect of anticancer drugs
. filgrastim, solution for injection 0.3 mg/ml, 1 ml;
. ondansetron, solution for injection 8 mg/4ml.
Antibacterial agents
· azithromycin, tablet/capsule, 500 mg, lyophilized powder for the preparation of solution for intravenous infusion, 500 mg;
· amikacin, powder for injection, 500 mg/2 ml or powder for solution for injection, 0.5 g;
· amoxicillin/clavulanic acid, film-coated tablet, 1000 mg, powder for solution for intravenous and intramuscular administration 1000 mg+500 mg;
· vancomycin, powder/lyophilisate for solution for infusion 1000 mg;
· gentamicin, solution for injection 80 mg/2 ml 2 ml;
· imipinem, cilastatin powder for solution for infusion, 500 mg/500 mg;
· sodium colistimethate*, lyophilisate for the preparation of solution for infusion, 1 million units/bottle;
· metronidazole tablet, 250 mg, solution for infusion 0.5% 100 ml, dental gel 20 g;
Levofloxacin, solution for infusion 500 mg/100 ml, tablet 500 mg;
linezolid, solution for infusion 2 mg/ml;
· meropenem, lyophilisate/powder for solution for injection 1.0 g;
· moxifloxacin, tablet 400 mg, solution for infusion 400 mg/250 ml
· ofloxacin, tablet 400 mg, solution for infusion 200 mg/100 ml;
· piperacillin, tazobactam powder for solution for injection 4.5 g;
tigecycline*, lyophilized powder for solution for injection 50 mg/bottle;
Ticarcillin/clavulanic acid, lyophilized powder for the preparation of solution for infusion 3000 mg/200 mg;
cefepime, powder for solution for injection 500 mg, 1000 mg;
· cefoperazone, sulbactam powder for solution for injection 2 g;
· ciprofloxacin, solution for infusion 200 mg/100 ml, 100 ml, 500 mg tablet;
· erythromycin, tablet 250 mg;
· ertapenem lyophilisate, for the preparation of solution for intravenous and intramuscular injections 1 g.
Antifungal drugs
· amphotericin B*, lyophilized powder for solution for injection, 50 mg/vial;
· anidulofungin, lyophilized powder for solution for injection, 100 mg/vial;
voriconazole, powder for solution for infusion 200 mg/bottle;
voriconazole, tablet, 50 mg;
· itraconazole, oral solution 10 mg/ml 150.0;
· caspofungin, lyophilisate for the preparation of solution for infusion 50 mg;
· clotrimazole, cream for external use 1% 30g, solution for external use 1% 15ml;
· micafungin, lyophilized powder for the preparation of solution for injection 50 mg, 100 mg;
· fluconazole, capsule/tablet 150 mg, solution for infusion 200 mg/100 ml, 100 ml.
Antiviral drugs
· acyclovir, cream for external use, 5% - 5.0, tablet - 400 mg, powder for solution for infusion, 250 mg;
· valacyclovir, tablet, 500 mg;
· valganciclovir, tablet, 450 mg;
· ganciclovir*, lyophilisate for solution for infusion 500 mg;
Famciclovir, tablets, 500 mg No. 14.
Medicines used for pneumocystosis
· sulfamethoxazole/trimethoprim, concentrate for solution for infusion (80mg+16mg)/ml, 5 ml;
· sulfamethoxazole/trimethoprim, tablet 480 mg.
Additional immunosuppressive drugs:
· dexamethasone, solution for injection 4 mg/ml 1 ml;
· methylprednisolone, tablet 16 mg, solution for injection 250 mg;
· prednisolone, solution for injection 30 mg/ml 1 ml, tablet 5 mg.
Solutions used to correct disturbances of water, electrolyte and acid-base balance, parenteral nutrition
· albumin, solution for infusion 10%, 100 ml;
· albumin, solution for infusion 20% 100 ml;
· water for injection, solution for injection 5 ml;
· dextrose, solution for infusion 5% - 250 m, 5% - 500 ml; 40% - 10 ml, 40% - 20 ml;
· potassium chloride, solution for intravenous administration 40 mg/ml, 10 ml;
· calcium gluconate, solution for injection 10%, 5 ml;
· calcium chloride, solution for injection 10% 5ml;
· magnesium sulfate, solution for injection 25% 5 ml;
· mannitol, solution for injection 15% -200.0;
· sodium chloride, solution for infusion 0.9% 500ml;
· sodium chloride, solution for infusion 0.9% 250ml;
· sodium chloride, potassium chloride, sodium acetate solution for infusion in a bottle of 200 ml, 400 ml;
· sodium chloride, potassium chloride, sodium acetate solution for infusion 200ml, 400ml;
· sodium chloride, potassium chloride, sodium bicarbonate solution for infusion 400ml;
L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L- tryptophan, L-tyrosine, L-valine, sodium acetate trihydrate, sodium glycerophosphate pentihydrate, potassium chloride, magnesium chloride hexahydrate, glucose, calcium chloride dihydrate, olive and soybean oils emulsion mixture for inf.: three-chamber containers 2 l
· hydroxyethyl starch (pentastarch), solution for infusion 6% 500 ml;
· amino acid complex, emulsion for infusion containing a mixture of olive and soybean oils in a ratio of 80:20, a solution of amino acids with electrolytes, a dextrose solution, with a total calorie content of 1800 kcal 1,500 ml three-section container.
Medicines used for intensive therapy (cardiotonic drugs for the treatment of septic shock, muscle relaxants, vasopressors and anesthetics):
· aminophylline, solution for injection 2.4%, 5 ml;
· amiodarone, solution for injection, 150 mg/3 ml;
· atenolol, tablet 25 mg;
· atracurium besylate, solution for injection, 25 mg/2.5 ml;
· atropine, solution for injection, 1 mg/ml;
· diazepam, solution for intramuscular and intravenous use 5 mg/ml 2 ml;
· dobutamine*, solution for injection 250 mg/50.0 ml;
· dopamine, solution/concentrate for the preparation of solution for injection 4%, 5 ml;
· simple insulin;
· ketamine, solution for injection 500 mg/10 ml;
· morphine, solution for injection 1% 1 ml;
· norepinephrine*, solution for injection 20 mg/ml 4.0;
· pipecuronium bromide, lyophilized powder for injection 4 mg;
· propofol, emulsion for intravenous administration 10 mg/ml 20 ml, 10 mg/ml 50 ml;
· rocuronium bromide, solution for intravenous administration 10 mg/ml, 5 ml;
· sodium thiopental, powder for the preparation of solution for intravenous administration 500 mg;
· phenylephrine, solution for injection 1% 1ml;
· phenobarbital, tablet 100 mg;
human normal immunoglobulin, solution for infusion;
· epinephrine, solution for injection 0.18% 1 ml.
Medicines affecting the blood coagulation system
· aminocaproic acid, solution 5%-100 ml;
· anti-inhibitor coagulant complex, lyophilized powder for the preparation of injection solution, 500 IU;
· heparin, solution for injection 5000 IU/ml, 5 ml, gel in tube 100000 IU 50g;
· hemostatic sponge, size 7*5*1, 8*3;
· nadroparin, solution for injection in pre-filled syringes, 2850 IU anti-Xa/0.3 ml, 5700 IU anti-Xa/0.6 ml;
· enoxaparin, solution for injection in syringes 4000 anti-Xa IU/0.4 ml, 8000 anti-Xa IU/0.8 ml.
Other medicines
· bupivacaine, solution for injection 5 mg/ml, 4 ml;
· lidocaine, solution for injection, 2%, 2 ml;
· procaine, solution for injection 0.5%, 10 ml;
· human immunoglobulin normal solution for intravenous administration 50 mg/ml - 50 ml;
· omeprazole, capsule 20 mg, lyophilized powder for the preparation of solution for injection 40 mg;
· famotidine, lyophilized powder for the preparation of solution for injection 20 mg;
· ambroxol, solution for injection, 15 mg/2 ml, solution for oral administration and inhalation, 15 mg/2 ml, 100 ml;
· amlodipine, tablet/capsule 5 mg;
· acetylcysteine, powder for solution for oral administration, 3 g;
· dexamethasone, eye drops 0.1% 8 ml;
Diphenhydramine, solution for injection 1% 1 ml;
· drotaverine, solution for injection 2%, 2 ml;
· captopril, tablet 50 mg;
· ketoprofen, solution for injection 100 mg/2ml;
lactulose, syrup 667 g/l, 500 ml;
· chloramphenicol, sulfadimethoxin, methyluracil, trimecaine ointment for external use 40g;
Lisinopril, 5 mg tablet;
· methyluracil, ointment for topical use in a tube 10% 25g;
· naphazoline, nasal drops 0.1% 10ml;
· nicergoline, lyophilisate for the preparation of injection solution 4 mg;
· povidone-iodine, solution for external use 1 l;
· salbutamol, solution for nebulizer 5 mg/ml-20 ml;
· smectitedioctahedral, powder for the preparation of suspension for oral administration 3.0 g;
· spironolactone, capsule 100 mg;
· tobramycin, eye drops 0.3% 5ml;
· torasemide, tablet 10 mg;
· tramadol, solution for injection 100 mg/2ml;
tramadol, oral solution (drops) 100 mg/1 ml 10 ml;
· fentanyl, therapeutic transdermal system 75 mcg/h (for the treatment of chronic pain in cancer patients);
· folic acid, tablet, 5 mg;
· furosemide, solution for injection 1% 2 ml;
· chloramphenicol, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
· chlorhexidine, solution 0.05% 100ml;
· chloropyramine, solution for injection 20 mg/ml 1 ml.
Drug treatment provided at the emergency stage: is not carried out.
Other types of treatment:
Other types of treatment provided on an outpatient basis: do not apply.
Other types of services provided at the stationary level:
Bone marrow transplantation (level of evidence B)
Indications for BMT in PNH are similar to severe aplastic anemia.
While eculizumab helps control intravascular hemolysis and associated complications of PNH, primarily transfusion dependence, allogeneic bone marrow transplantation (BMT) remains the only radical method to achieve a cure for this disease. However, BMT is associated with high mortality. Thus, in a retrospective study on 26 patients with PNH from Italy who received BMT, the 10-year survival rate was 42%, and the probability of 2-year survival in 48 patients who received BMT from an HLA-identical sibling, according to the International Bone Marrow Transplantation Registry, amounted to 56%. Regardless of the indications for which BMT is performed, the incidence of complications remains very high. The incidence of graft-versus-host disease in patients with PNH is 42-54%, half of the patients develop veno-occlusive liver disease, non-engraftment or rejection, and, in addition, the risk of expansion of the PNH clone remains. BMT and associated complications negatively affect the quality of life of patients.
Other types of treatment provided during emergency medical care: do not apply.
Features of management of pregnant patients.
Pregnancy in PNH is associated with high levels of maternal and child mortality (11.6% and 7.2%, respectively).
Currently, only isolated cases of eculizumab therapy during pregnancy with a favorable outcome for the mother and fetus have been described. There are no teratogenic effects of the drug. During pregnancy, eculizumab therapy should not be discontinued. If the patient has not previously received eculizumab, the drug can be prescribed during pregnancy. In this case, eculizumab therapy should be continued for 3 months after delivery. In cases of breakthrough hemolysis during pregnancy, a dose adjustment of the drug may be required (for example, maintenance therapy 900 mg per week).
Surgical intervention:
Surgical intervention provided on an outpatient basis: is not carried out.
Surgical intervention provided in an inpatient setting:
With the development of infectious complications and life-threatening bleeding, patients undergo surgical interventions for emergency indications.
Further management:
During therapy with eculizumab, the following laboratory tests are recommended: complete blood count with determination of reticulocytes, LDH, blood creatinine, brain natriuretic peptide B (if possible), D-dimer, serum iron, ferritin, direct antiglobulin test. The size of the PNH clone is monitored based on the results of highly sensitive flow cytometry.
In patients receiving eculizumab, a statistically significant increase in the size of the PNH clone is observed. In the TRIUMPH study, the type III PNH clone of erythrocytes increased from 28.1% to 56.9% over 26 weeks, while it did not change in the placebo group. If eculizumab is discontinued, monitoring of the size of the PNH clone, the level of reticulocytes, haptoglobin, LDH, bilirubin, and D-dimers is necessary for timely detection of hemolysis and prevention of potential complications.
Indicators of treatment effectiveness:
A specific system for assessing the response to therapy in PNH has not yet been developed. When assessing the effect of treatment, the following are taken into account:
· clinical manifestations - weakness;
· hemoglobin level;
· the need for transfusions of blood components;
thrombotic episodes;
· hemolysis activity (level of reticulocytes, LDH, haptoglobin).
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Paroxysmal nocturnal hemoglobinuria is a rare acquired life-threatening blood disease. The pathology causes the destruction of red blood cells - erythrocytes. Doctors call this process hemolysis, and the term “hemolytic anemia” fully characterizes the disease. Another name for such anemia is Marchiafava-Micheli disease, after the names of the scientists who described the pathology in detail.
Causes and essence of the disease
Paroxysmal nocturnal hemoglobinuria is uncommon - usually 1-2 cases are recorded per 1 million people in the population. This is a disease of relatively young adults, the average age of diagnosis is 35-40 years. Manifestation of Marchiafava-Miceli disease in childhood and adolescence is very rare.
The main cause of the disease is a mutation in a single stem cell gene called PIG-A. This gene is located on the X chromosome of bone marrow cells. The exact causes and mutagenic factors of this pathology are still unknown. The occurrence of paroxysmal nocturnal hemoglobinuria is closely related to aplastic anemia. It has been statistically proven that 30% of cases of identified Marchiafava-Miceli disease are a consequence of aplastic anemia.
The process of forming blood cells is called hematopoiesis. Red blood cells, white blood cells and platelets are formed in the bone marrow, a special spongy substance located in the center of some bone structures in the body. The precursors of all cellular elements of the blood are stem cells, during the gradual division of which new blood elements are formed. Having gone through all the processes of maturation and formation, the formed elements enter the bloodstream and begin to perform their functions.
For the development of Marchiafava-Micheli disease, the presence of a mutation of the above-mentioned PIG-A gene in one stem cell is sufficient. The abnormal progenitor cell continually divides and “clones” itself. So the entire population becomes pathologically altered. Inferior red blood cells mature, form and release into the bloodstream.
The essence of the changes lies in the absence on the red blood cell membrane of special proteins responsible for protecting the cell from its own immune system - the complement system. The complement system is a set of blood plasma proteins that protect the body from various infectious agents. Normally, all cells of the body are protected from their immune proteins. With paroxysmal nocturnal hemoglobinuria, such protection is absent. This leads to the destruction or hemolysis of red blood cells and the release of free hemoglobin into the blood.
Clinical manifestations and symptoms
Due to the variety of clinical manifestations, the diagnosis of paroxysmal nocturnal hemoglobinuria can sometimes be reliably made only after several months of diagnostic search. The fact is that the classic symptom - dark brown urine (hemoglobinuria) occurs only in 50% of patients. The classic presence of hemoglobin in the morning portions of urine, during the day it usually becomes lighter.
The release of hemoglobin in the urine is associated with massive resolution of red blood cells. Doctors call this condition a hemolytic crisis. It can be triggered by an infectious disease, excessive alcohol intake, physical activity or stressful situations.
The term paroxysmal nocturnal hemoglobinuria arose from the belief that hemolysis and activation of the complement system are triggered by respiratory acidosis during sleep. This theory was later disproved. Hemolytic crises occur at any time of the day, but the accumulation and concentration of urine in the bladder during the night leads to specific color changes.
The main clinical aspects of paroxysmal nocturnal hemoglobinuria:
- Hemolytic anemia is a decrease in the number of red blood cells and hemoglobin due to hemolysis. Hemolytic crises are accompanied by weakness, dizziness, and flashing “spots” before the eyes. The general condition in the initial stages does not correlate with hemoglobin levels.
- Thrombosis is the main cause of death in patients with Marchiafava-Micheli disease. Arterial thrombosis is much less common. The hepatic, mesenteric and cerebral veins are affected. Specific clinical symptoms depend on the vein involved in the process. Budd-Chiari syndrome occurs with thrombosis of the hepatic veins; blockade of cerebral vessels has neurological symptoms. A scientific review on paroxysmal nocturnal hemoglobinuria published in 2015 suggests that hepatic vascular blockage is more common in women. Dermal vein thrombosis is manifested by red, painful nodes that rise above the surface of the skin. Such lesions cover large areas, for example, the entire skin of the back.
- Insufficient hematopoiesis - a decrease in the number of red blood cells, leukocytes and platelets in the peripheral blood. This pancytopenia makes a person susceptible to infections due to the low number of white blood cells. Thrombocytopenia leads to increased bleeding.
The hemoglobin released after the destruction of red blood cells undergoes splitting. As a result, the degradation product, haptoglobin, enters the bloodstream, and hemoglobin molecules become free. Such free molecules bind irreversibly to nitric oxide (NO) molecules, thereby reducing their quantity. NO is responsible for smooth muscle tone. Its deficiency causes the following symptoms:
- stomach ache;
- headaches;
- spasms of the esophagus and swallowing disorders;
- erectile dysfunction.
Excretion of hemoglobin in the urine leads to impaired kidney function. Kidney failure gradually develops, requiring replacement therapy.
Diagnostic and therapeutic measures
At the initial stages, making a diagnosis of Marchiafava-Miceli disease is quite difficult due to the diverse clinical symptoms and scattered complaints of patients. The appearance of characteristic changes in the color of urine, as a rule, directs the diagnostic search in the right direction.
Treatment of paroxysmal nocturnal hemoglobinuria The main diagnostic tests used for paroxysmal nocturnal hemoglobinuria:
- Complete blood count - to determine the number of red blood cells, white blood cells and platelets.
- The Coombs test is an analysis that allows you to determine the presence of antibodies on the surface of red blood cells, as well as antibodies circulating in the blood.
- Flow cytometry allows for immunophenotyping, that is, to determine the presence of a particular protein on the surface of red blood cell membranes.
- Measurement of serum hemoglobin and haptoglobin levels.
- General urine analysis.
An integrated diagnostic approach makes it possible to identify Strübing-Marchiafava disease in a timely manner and begin its treatment before the manifestation of thrombotic complications. Treatment of paroxysmal nocturnal hemoglobinuria is possible with the following groups of drugs:
- Steroid hormones (Prednisolone, Dexamethasone) inhibit the functioning of the immune system, thereby stopping the destruction of red blood cells by proteins of the complement system.
- Cytostatics (Eculizumab) have a similar effect. They suppress the immune response and eliminate the signs of paroxysmal nocturnal hemoglobinuria.
- Sometimes patients need transfusions of washed red blood cells, specially selected by hematologists, to correct hemoglobin levels.
- Maintenance therapy in the form of iron and folic acid supplements.
The described treatment of paroxysmal nocturnal hemoglobinuria cannot relieve the patient of the disease, but only muffles the symptoms. A real therapeutic option is bone marrow transplantation. This procedure completely replaces the pool of abnormal stem cells, curing the disease.
The disease described in the article is potentially life-threatening without appropriate treatment. Complications in the form of thrombosis and renal failure can have serious consequences for life and health. Timely treatment can stop the progression of the disease and prolong the patient’s full life.
