Paroxysmal nocturnal hemoglobinuria is a rare life–threatening hematological disease characterized by intravascular hemolysis, arterial and venous thrombosis, systemic damage to internal organs. The clinical picture is diverse. The most typical symptoms include general weakness, paroxysmal abdominal, lumbar pain, darkening of urine. The main diagnostic method is flow cytometry (reduced expression of GPI–bound proteins on blood cells). Monoclonal antibodies (eculizumab) are used as the main pathogenetic treatment. Iron preparations, folates, and blood transfusions are also used.
D59.5 Paroxysmal nocturnal hemoglobinuria (Markiafava-Mikeli)
Paroxysmal nocturnal hemoglobinuria (PNH, Markiafava-Mikeli disease, Streubing-Markiafava disease) is a severe chronic blood disease with a high mortality rate, which is based on intravascular hemolysis. With this pathology, the structure of erythrocytes, neutrophils and platelets changes. PNH was first described in detail by the Italian pathologist E. Markiafava and his student Micheli in 1928. The prevalence is 15.9 cases per 100,000 people. The average age of onset of the disease is 30 years. Women suffer somewhat more often (the ratio with men is 1.2:1). Pathology is often combined with myelodysplastic syndrome, aplastic anemia.
The main cause of paroxysmal nocturnal hemoglobinuria is a somatic mutation in bone marrow stem cells, leading to a violation of the regulation of the complement system, hemolysis, venous and arterial thrombosis, bone marrow failure. The mutation is localized in the X-linked phosphatidylinositol glycan class A (PIG-A) gene, Despite the etiology, the disease is not inherited, but acquired during life.
In the presence of a pathological clone of cells in the peripheral blood, many physiological and pathological factors can activate the complement system, causing the first clinical manifestation or exacerbation of nocturnal hemoglobinuria. Such factors include surgical interventions, various infections and even intense physical activity (especially marching). Pregnancy is considered to be the main cause of exacerbation of Markiafava-Mikeli disease in women.
The complement system is an important part of the immune system of the human body. During its activation, special proteins (complement components) are synthesized that destroy foreign microorganisms (bacteria, viruses, fungi). To prevent these proteins from attacking their own blood cells, special protective markers are formed on their membrane – complement inhibitors (on erythrocytes – CD 55, CD 59, on granulocytes – CD16, CD 24, on monocytes – CD14, CD 48).
In paroxysmal hemoglobinuria, as a result of mutation, a deficiency of the glycosylphosphatidylinositol anchor (GPI-AP) develops, which leads to a change in the structure of the shaped blood elements, namely– to a decrease in the expression of protective proteins on their surface. Excessive activation of some components of the complement system is observed. C5b forms a membrane-attacking complex that causes intravascular hemolysis of erythrocytes, in which a large amount of hemoglobin is released into the bloodstream, then enters the urine, which gives it a specific dark and sometimes black color.
Granulocytic leukocytes (neutrophils) are also destroyed. C5a stimulates platelet activation and aggregation, resulting in venous and arterial thrombosis throughout the body. Pathoanatomic examination often reveals hemosiderosis of the kidneys, dystrophy and necrosis of the renal tubules, deposits of hydrochloric acid hematin. There are signs of aplasia in the bone marrow – a decrease in the volume of hematopoietic sprouts.
The main criteria underlying the classification of paroxysmal nocturnal hemoglobinuria are the detection of pathological clones in the blood, the presence or absence of hemolysis, as well as concomitant diseases accompanied by bone marrow insufficiency – aplastic anemia (AA), myelodysplastic syndrome (MDS), myelofibrosis (MLF). There are three forms of PNH:
- Classic. There are clinical and laboratory signs of hemolysis without bone marrow insufficiency.
- PNH in blood diseases. It is exposed in cases when patients with AA, MDS or MLF show signs of hemolysis, a clone of cells with the PNH phenotype is determined in the blood.
- Subclinical. It is diagnosed in patients with AA, MLF or MDS, in whom cells with the PNH phenotype are found in the blood, but there are no signs of hemolysis.
The disease often begins gradually. The main symptoms are associated with hemolysis. At first, there is a pronounced general weakness, malaise, dizziness. The skin, the mucous membrane of the oral cavity, and the sclera sometimes turn yellow. Many patients have difficulty swallowing and breathing. About a quarter of patients notice that the urine becomes dark or black (mainly at night or in the morning). Erectile dysfunction is often observed in men.
Thrombosis is the cause of pain. Blood clots can form anywhere, but their favorite localization is the abdominal cavity and lumbar region. With thrombosis of mesenteric vessels, abdominal pain attacks occur, with blockage of kidney vessels – lower back pain. Hepatic vein thrombosis (Budd-Chiari syndrome) causes pain in the right hypochondrium, increased jaundice, abdominal enlargement due to hepatomegaly and fluid accumulation in the abdominal cavity. With the development of bone marrow insufficiency, hemorrhagic syndrome is detected – nosebleeds, bleeding gums, petechial rashes on the skin.
PNH is characterized by a large number of dangerous complications. The most frequent are thrombosis (35-45%), of which 55-60% lead to death due to myocardial infarction, stroke, pulmonary embolism. Due to the toxic effect of hemoglobin on the renal tubules, about 65% of patients have chronic kidney disease, which causes death in 8-18% of cases. In 50% of patients, permanent thrombosis of small vessels of the lungs causes pulmonary hypertension. Less often, due to bone marrow insufficiency, patients die from massive bleeding and infections.
Patients with paroxysmal nocturnal hemoglobinuria are supervised by hematologists. The examination evaluates the color of the skin, mucous membranes. Palpation of the abdomen is performed for liver enlargement. The circumstances preceding the onset of symptoms (hypothermia, colds) are established. Experts clarify whether the color of urine has changed. The survey program includes:
- Blood and urine test. In the general blood test, a decrease in the content of hemoglobin and erythrocytes, a high level of reticulocytes is detected. Sometimes there is a decrease in platelets, granulocytic leukocytes (neutrophils). Urine analysis reveals a large amount of hemosiderin, free hemoglobin, iron.
- Verification test. The most accurate method to confirm paroxysmal hemoglobinuria is flow cytometry. With the help of monoclonal antibodies, a decrease or complete absence of expression of protective proteins on the membranes of CD55 and CD59 erythrocytes is detected. When using the FLAER reagent (fluorescently labeled inactivated bacterial aerolysin), a deficiency of CD24 on granulocytes, CD14 on monocytes is determined.
- Instrumental research. Instrumental diagnostic methods are used only if venous or arterial thrombosis is suspected. These include electrocardiography, echocardiography, CT of the brain, chest and abdominal organs with contrast.
Paroxysmal hemoglobinuria must first be differentiated from other diseases accompanied by hemolysis – congenital and acquired autoimmune hemolytic anemia, hemoglobinopathies. In the case of thrombosis, pathology should be distinguished from various thrombophilia – antiphospholipid syndrome, antithrombin deficiency, homocysteinemia. The combination of acute abdominal pain and anemia requires the exclusion of acute intermittent porphyria and chronic lead poisoning.
Patients are hospitalized in the hematology department, and with severe anemia (below 50 g / l) – in the intensive care unit. In order to avoid a fatal outcome, specific (targeted) treatment should be started as early as possible. Patients with a subclinical form without signs of hemolysis do not need therapy, they are shown observation by a hematologist and regular blood tests.
Effective conservative methods that completely eliminate the manifestations of the disease are not yet available. Measures are being taken to maintain a stable condition of the patient, reduce the intensity of hemolysis, the risk of life-threatening complications (thrombosis, renal failure). Conservative treatment includes the following areas:
- Targeted therapy. The main drug that has high efficiency and affects the main link in the pathogenesis of nocturnal hemoglobinuria is eculizumab. This is a monoclonal antibody that binds to the C5 component of the complement, blocks its cleavage into C5a and C5b. As a result, the formation of a membrane-attacking complex and pro-inflammatory cytokines that cause hemolysis, destruction of neutrophils, platelet aggregation is inhibited.
- Other methods of hemolysis elimination. If eculizumab is unavailable, glucocorticosteroids (prednisone), androgens (danazol) can be used to relieve hemolysis, but their effectiveness is very low. Therefore, due to the extremely high cost of eculizumab, transfusions of whole blood and its components (erythrocyte mass or suspension) remain the main treatment for most patients. Sometimes the introduction of a thrombotic concentrate is required.
- Symptomatic therapy. To increase the stability of red blood cells, folic acid and vitamin b12 are prescribed, with severe iron deficiency, oral forms of iron preparations with ascorbic acid are used with caution, since iron can provoke increased hemolysis. Anticoagulants (low molecular weight heparins, warfarin) are prescribed for the treatment and prevention of thrombosis.
- Immunosuppressive therapy. In some cases, especially when PNH is combined with aplastic anemia and myelodysplastic syndrome, cytostatics (cyclophosphamide, cyclosporine) are used to restore normal hematopoiesis. In a small number of patients, the administration of antithymocytic globulin is effective.
The only way to achieve a complete cure for the disease is allotransplantation of stem cells based on the results of HLA typing to select a suitable donor. This operation is rarely resorted to, since it is associated with the occurrence of a large number of complications incompatible with life (graft versus host reaction, veno-occlusive liver disease). Intervention is recommended for resistance to conservative therapies.
Most recently, a clinical trial of a new drug, ravulizumab, was completed. It has a similar mechanism of action to eculizumab. The main difference is a longer half–life and, consequently, a longer therapeutic effect, which allows it to be administered with a lower frequency than eculizumab. Currently, the search is underway for other medicinal methods of pathogenetic effects on PNH.
The development of artificial anchor structures (Prodaptin) capable of restoring the expression of inhibitory proteins, in particular CD59 on the surface of blood cell membranes, is at the earliest stage, which will protect them from complement. This method is more physiological, since it does not inhibit the complement system attacking foreign microorganisms. The new drug may be more effective and safer than complement-binding antibodies (eculizumab, ravulizumab).
Prognosis and prevention
Paroxysmal hemoglobinuria is a severe life–threatening disease with a large number of complications. Within 5 years from the moment of diagnosis, 35% of patients die, after 10 years – 50%. Only a quarter of patients live longer than 25 years. The most dangerous adverse consequences leading to death are thrombosis (about 60%), pulmonary hypertension (40-45%) and chronic renal failure (8-18%). It is highly discouraged for women to use oral contraceptives, as these medications increase the likelihood of thrombosis.
Eculizumab increases the risk of infection with encapsulated bacteria, especially meningococcus. Therefore, a conjugated tetravalent vaccine must be administered 2 weeks before the start of taking the drug. If urgent use of the drug is necessary in an unvaccinated patient, a 2-week course of prophylaxis with antibiotics active against Neisseria meningitidis (benzylpenicillin) is prescribed.
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