Markiafava-Mikeli disease (paroxysmal nocturnal hemoglobinuria): causes, symptoms, diagnosis and treatment

Stryubing disease - Markiafava, or Markiafava disease - Mikeli is a rare hematological disease that is life threatening and is 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 symptoms 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 in blood cells). Monoclonal antibodies are used as the main pathogenetic therapy. Folates, iron preparations, blood transfusion are also used.

General characteristics of the disease

Paroxysmal nocturnal hemoglobinuria is a severe chronic blood pathology, which is based on hemolysis inside the vessels. The disease is characterized by a high mortality rate. With this disease, a change in the structures of red blood cells, platelets and neutrophils occurs. Markiafava's disease - Mikeli was first described in detail in 1928 by a pathologist from Italy E. Markiafava, as well as his student Mikeli. The prevalence of pathology in the world (per 100,000 people) is 15.9 cases. The average age of the manifestation of the pathological process in most cases is 30 years. Somewhat more often, this disease affects women. Pathology is often combined with aplastic anemia and myelodysplastic syndrome.

Causes of occurrence

The underlying cause of paroxysmal nocturnal hemoglobinuria (code D59.5 is assigned in ICD-10 pathology) are somatic mutations in stem cells located in the bone marrow, which lead to hemolysis, dysregulation of the complement system, arterial and venous thromboses, and bone marrow failure. The mutation is localized, as a rule, in the X-linked class A phosphatidylinositol glycan gene (PIG-A). This disease, despite the nature of its origin, is not inherited, but acquired in the process of life.

In the presence of a pathological cell clone in the peripheral blood, many physiological factors can activate the complement system, triggering an exacerbation or initial clinical manifestation of Markiaphava-Mikeli disease. Such factors are surgical interventions, a variety of infectious diseases, and even intense physical exertion and stressful situations. The main cause of exacerbation of paroxysmal nocturnal hemoglobinuria in women is pregnancy. Now consider the pathogenesis of pathology.

Pathogenesis 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 that destroy foreign microorganisms (viruses, bacteria, fungi). To prevent such proteins from attacking their own blood cells, special protective elements — complement inhibitors — are formed on their membranes. With the development of paroxysmal hemoglobinuria due to a mutation, glycosylphosphatidylinositol anchor insufficiency 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-attacking complex, which causes hemolysis of red blood cells inside the vessels. In this case, a large amount of hemoglobin is released into the vascular bloodstream, then penetrates the urine, which gives it a dark, and in some cases even black color.

In addition, neutrophils (granulocytic leukocytes) are destroyed. C5a stimulates the activation and aggregation of platelets, resulting in arterial and venous thrombosis throughout the body. An autopsy study often reveals renal hemosiderosis, dystrophy and necrosis of the renal tubules, and deposits of hematin hydrochloride. In the structures of the bone marrow, there are signs of aplasia - a decrease in the number of sprouts of blood formation.

Classification

The main criteria that underlie the classification of Markiafava disease - Mikeli - the detection of pathological clones in the blood, the absence or presence of hemolysis, as well as the accompanying pathological processes accompanied by bone marrow failure - myelodysplastic syndrome, aplastic anemia, myelofibrosis. In medicine, there are three types of this disease:

1. The classic form. There are laboratory and clinical signs of hemolysis without bone marrow failure.
2. Subclinical form. It is diagnosed in patients in whose blood cells with an PNH phenotype are detected, but there are no signs of hemolysis.
3. Markiafava syndrome - Mikeli with blood pathologies. Such a diagnosis is made in cases when hemolysis symptoms are noted in people, a clone of cells with a PNH phenotype is determined in the blood.

Symptomatology

In most cases, the pathology develops gradually. The main symptoms of Markiafava disease - Mikeli are directly related to hemolysis. First, the patient has severe general weakness, dizziness, and malaise. The skin, sclera and oral mucosa sometimes turn yellow. Many patients have difficulty breathing and swallowing. About a quarter of patients notice that the urine becomes excessively dark or even black (most often in the morning or night). In men, erectile dysfunction is possible.

Thrombosis

The reason for the development of pain with paroxysmal nocturnal hemoglobinuria is thrombosis. Blood clots can form in any area, but their most common localization is the lumbar region and abdominal cavity. With thrombosis of mesenteric vessels, attacks of abdominal pain are observed, with blockage of the renal vessels, lower back pain. Liver vein thrombosis (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 fluid accumulation in the peritoneum. With the development of bone marrow failure, hemorrhagic syndrome occurs - bleeding gums, nosebleeds, petechial rashes.

Diagnosis of Markiafava-Miqueli disease

Hematologists observe patients with this pathology. On examination, they evaluate the color of the skin and mucous membranes. Palpation of the abdomen is also carried out, circumstances are established that preceded the onset of symptoms (colds, hypothermia, stress).

The diagnostic examination program includes:

1. A biochemical blood test that shows signs of hemolysis is an increased level of lactate dehydrogenase and indirect bilirubin, a low concentration of haptoglobin, ferritin and serum iron. Often there is an excess of reference indicators of urea, liver transaminases and creatinine.
2. General blood and urine tests, where a decrease in the level of red blood cells and hemoglobin, an increase in the concentration of reticulocytes is detected. In some cases, a decrease in the number of granulocytic leukocytes and platelets is detected. In the analysis of urine, a high amount of hemosiderin, iron and free hemoglobin is observed.
3. A verification test, which is the most accurate method to confirm the presence of a pathological process, is flow cytometry. Using monoclonal antibodies, they can detect a decrease or absence on the membranes of erythrocytes, granulocytes and monocytes of the expression of protective proteins.
4. Instrumental studies that are used for suspected arterial or venous thrombosis. Such studies include echocardiography, electrocardiography, CT of the brain, organs of the abdominal cavity and chest, sometimes with contrast.
   

Treatment

Patients with Markiafava disease - Mikeli are hospitalized in the hematology department, and with severe anemia - in the intensive care and resuscitation department. To avoid death, doctors should start targeted (specific) treatment as soon 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 parameters are indicated. Clinical recommendations for paroxysmal nocturnal hemoglobinuria should be strictly observed.

Conservative therapy

Effective conservative methods that completely eliminate the manifestations of the disease do not yet exist. Therapeutic measures are being taken to maintain the patient’s normal condition, reduce hemolysis intensity, and the likelihood of complications (renal failure, thrombosis). Conservative therapy of paroxysmal nocturnal hemoglobinuria (PNH) includes the following areas:

1. Targeted treatment. The main drug with high efficiency and affecting the main link in the pathogenesis of the disease is eculizumab. It is a monoclonal antibody that is capable of binding to the C5 component of complement and blocking its cleavage into C5a and C5b. As a result of this, the formation of pro-inflammatory cytokines and the membrane-attacking complex, which cause hemolysis, platelet aggregation, and neutrophil destruction, are suppressed.
2. Symptomatic treatment. To enhance the stability of red blood cells, folic acid and vitamin B ₁₂ are prescribed, with iron deficiency, oral forms of iron medications with vitamin C. Anticoagulants are prescribed for the treatment and prevention of thrombosis.
3. Immunosuppressive treatment of Markiafava disease - Mikeli. In order to restore and stabilize the processes of hematopoiesis, cytostatics (cyclosporin, cyclophosphamide) are used. In a small number of patients, the use of antithymocytic globulin is effective.
4. Other methods of eliminating hemolysis. In order to stop hemolysis, glucocorticosteroids, androgens are also used, however, the effectiveness of these medications is very low. Whole blood transfusion may be used as the main treatment.
   

Surgical treatment

The only way to achieve a cure for Markiaphava disease, Mikeli, is through 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 rarely resorted to, since they are associated with the occurrence of a large number of complications incompatible with life (veno-occlusive liver disease, transplant versus host disease). Surgery is recommended for resistance to traditional 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 a stroke, myocardial infarction, pulmonary embolism. Due to the toxic effects of hemoglobin on the tubules of the kidneys, about 65% of patients have chronic kidney diseases, which cause death in 8-18% of cases. In approximately 50% of patients, thrombosis of small vessels in the lungs provokes pulmonary hypertension. Less commonly, as a result of bone marrow failure, people die from infections and massive bleeding.