Strübing's disease - Marchiafava, or Marchiafava's disease - Micheli - is a rare hematological disease, life-threatening and characterized by venous and arterial thrombosis, intravascular hemolysis, systemic lesions of internal organs. The clinical symptoms of the disease are quite diverse. Among the most typical signs are paroxysmal lumbar, abdominal pain, general weakness, dark urine. The main diagnostic method for determining paroxysmal nocturnal hemoglobinuria is flow cytometry (low expression of GPI-related proteins on blood cells). Monoclonal antibodies are used as the main pathogenetic therapy. Also used are folates, iron supplements, blood transfusions.
General characteristics of the disease
Paroxysmal nighthemoglobinuria is a severe chronic pathology of the blood, which is based on hemolysis inside the vessels. The disease is characterized by a high mortality rate. With this disease, there is a change in the structures of erythrocytes, platelets and neutrophils. Marchiafava-Micheli's disease was first described in detail in 1928 by an Italian pathologist E. Marchiafava, as well as his student Micheli. The prevalence of pathology in the world (per 100,000 people) is 15.9 cases. The average age of manifestation of the pathological process in most cases is 30 years. Women are slightly more likely to suffer from this disease. Pathology is often combined with aplastic anemia and myelodysplastic syndrome.
Causes of occurrence
The underlying cause of paroxysmal nocturnal hemoglobinuria (in the ICD-10 pathology code D59.5) are somatic mutations in stem cells located in the bone marrow, which lead to hemolysis, dysregulation of the complement system, arterial and venous thrombosis, bone marrow failure. The mutation is localized, as a rule, in the X-linked gene of phosphatidylinositolglycan class A (PIG-A). This disease, despite the nature of its origin, is not inherited, but acquired in the process of life.
In the presence of an abnormal cell clone in the peripheral blood, many physiological factors can activate the complement system, provoking an exacerbation or initial clinical manifestation of Marchiafava-Micheli disease. Such factors are operationalinterventions, a variety of infectious diseases, and even intense physical activity and stressful situations. The main cause of exacerbation of paroxysmal nocturnal hemoglobinuria in women is pregnancy. Now consider the pathogenesis of pathology.
Pathogeny of paroxysmal nocturnal hemoglobinuria
The complement system is the most important structure of the human immune system. During its activation, special proteins (complement components) are produced in the body, which destroy foreign microorganisms (viruses, bacteria, fungi). To prevent such proteins from attacking their own blood cells, special protective elements are formed on their membranes - complement inhibitors. With the development of paroxysmal hemoglobinuria, due to a mutation, deficiency of the glycosylphosphatidylinositol anchor develops, which contributes to a change in the structures of blood cells: a decrease in the expression of proteins on the cell surface. Excessive activation of some elements of the complement system is observed. C5b forms a membrane attack complex, which causes hemolysis of erythrocytes inside the vessels. In this case, a large amount of hemoglobin is released into the vascular circulation, then penetrates into the urine, which gives it a dark, and in some cases even black color.
In addition, neutrophils (granulocytic leukocytes) are destroyed. C5a stimulates platelet activation and aggregation, resulting in arterial and venous thrombosis throughout the body. Atpathoanatomical examination often reveals hemosiderosis of the kidneys, dystrophy and necrosis of the tubules of the kidneys, deposits of hydrochloric hematin. Signs of aplasia appear in the bone marrow structures - a decrease in the number of hematopoietic sprouts.
Classification
The main criteria that underlie the classification of Marchiafava-Micheli disease are the detection of pathological clones in the blood, the absence or presence of hemolysis, as well as concomitant pathological processes accompanied by bone marrow failure - myelodysplastic syndrome, aplastic anemia, myelofibrosis. In medicine, there are three types of this disease:
- Classic shape. There are laboratory and clinical signs of hemolysis without bone marrow failure.
- Subclinical form. Diagnosed in patients whose blood contains cells with the PNH phenotype, but no signs of hemolysis.
- Marchiafava-Micheli syndrome with blood pathologies. Such a diagnosis is made in cases where people have symptoms of hemolysis, a clone of cells with a PNH phenotype is detected in the blood.
Symptomatics
In most cases, the pathology develops gradually. The main symptoms of Marchiafava-Micheli disease are directly related to hemolysis. First, the patient has a pronounced general weakness, dizziness, malaise. The skin, sclera and oral mucosa sometimes acquire a yellow color. Many patients experience difficulty in breathing and swallowing. Approximately a quarterpatients notice that the urine becomes excessively dark or even black (most often in the morning or at night). Men may have erectile dysfunction.
Thrombosis
The cause of pain in paroxysmal nocturnal hemoglobinuria is thrombosis. Thrombi can form anywhere, but their most common localization is the lumbar region and the abdominal cavity. With thrombosis of the mesenteric vessels, attacks of abdominal pain are observed, with blockage of the renal vessels - pain in the lower back. Thrombosis of the veins of the liver (Budd-Chiari syndrome) provokes pain in the right hypochondrium, the development of jaundice, an increase in the size of the abdomen due to hepatomegaly and accumulation of fluid in the peritoneum. With the development of bone marrow failure, hemorrhagic syndrome occurs - bleeding gums, nosebleeds, petechial rashes.
Diagnosis of Marchiafava-Micheli disease
Patients with this pathology are observed by hematologists. On examination, they evaluate the color of the skin and mucous membranes. The abdomen is also palpated, the circumstances that preceded the onset of symptoms (colds, hypothermia, stress) are established.
The diagnostic examination program includes:
- Biochemical blood test that shows signs of hemolysis - increased levels of lactate dehydrogenase and indirect bilirubin, low concentrations of haptoglobin, ferritin andserum iron. Often there is an excess of the reference values of urea, hepatic transaminases and creatinine.
- General blood and urine tests, which show a decrease in the level of red blood cells and hemoglobin, an increase in the concentration of reticulocytes. In some cases, a decrease in the number of granulocytic leukocytes and platelets is found. Urinalysis shows high levels of hemosiderin, iron and free hemoglobin.
- The verification test, which is the most accurate method to confirm the presence of a pathological process, is flow cytometry. With the help of monoclonal antibodies, a decrease or absence of expression of protective proteins on the membranes of erythrocytes, granulocytes and monocytes can be detected.
- Instrumental studies that are used for suspected arterial or venous thrombosis. These studies include echocardiography, electrocardiography, CT of the brain, abdominal cavity and chest, sometimes with contrast.
Treatment
Patients with Marchiafava-Micheli disease are hospitalized in the hematology department, and with severe anemia - in the intensive care and intensive care unit. To avoid a fatal outcome, doctors should start targeted (specific) treatment as early as possible. Patients with a subclinical form of pathology without signs of hemolysis do not need therapy - in this case, observation by a hematologist and regular monitoring of laboratory tests are indicated.indicators. Clinical guidelines for paroxysmal nocturnal hemoglobinuria should be strictly followed.
Conservative Therapy
Effective conservative methods that completely eliminate the manifestations of the disease do not yet exist. Therapeutic measures are taken to maintain the normal state of the patient, reduce the intensity of hemolysis, the likelihood of complications (renal failure, thrombosis). Conservative therapy for paroxysmal nocturnal hemoglobinuria (PNH) includes the following areas:
- Targeted treatment. The main drug, which is highly effective and affects the main link in the pathogenesis of the disease, is eculizumab. It is a monoclonal antibody that is able to bind to the C5 component of complement and block its splitting into C5a and C5b. As a result, the formation of pro-inflammatory cytokines and the membrane attack complex, which cause hemolysis, platelet aggregation and destruction of neutrophils, is suppressed.
- Symptomatic treatment. To enhance the resistance of red blood cells, folic acid and vitamin B12 are prescribed, with iron deficiency - oral forms of iron medications with vitamin C. Anticoagulants are prescribed for the treatment and prevention of thrombosis.
- Immunosuppressive treatment of Marchiafava-Micheli disease. In order to restore and stabilize the processes of hematopoiesis, cytostatics (cyclosporine, cyclophosphamide) are used. In a small number of patients, antithymocyte globulin is effective.
- Other wayselimination of hemolysis. In order to stop hemolysis, glucocorticosteroids and androgens are also used, but the effectiveness of these drugs is very low. Whole blood transfusion may be the primary treatment.
Surgical treatment
The only way to achieve a cure for Marchiafava-Micheli disease is allotransplantation of stem cells, which is carried out according to the results of HLA typing in order to select a suitable donor. Such operations are resorted to very rarely, since they are associated with the occurrence of a large number of complications that are incompatible with life (veno-occlusive liver disease, graft-versus-host disease). Surgery is recommended for those who are resistant to conventional therapies.
Complications
The disease is characterized by a large number of dangerous complications. The most common are thromboses, of which about 60% lead to death as a result of stroke, myocardial infarction, pulmonary embolism. Due to the toxic effect of hemoglobin on the tubules of the kidneys, about 65% of patients have chronic kidney disease, which causes death in 8-18% of cases. In about 50% of patients, small vessel thrombosis in the lungs provokes pulmonary hypertension. Less often, as a result of bone marrow failure, people die from infections and massive bleeding.
