What is Markiafavi-Micheli Disease?
Markiafavi-Micheli’s disease is a rather rare form of acquired hemolytic anemia, characterized by a violation of the structure of erythrocytes, neutrophils and platelets, accompanied by signs of intravascular erythrocyte destruction. An increase in hemoglobin, hemosiderinuria (hemosiderin in the urine), and an increase in free plasma hemoglobin are often observed. The disease is often complicated by thrombosis of peripheral veins and blood vessels of internal organs.
The disease was described in detail in 1928 by Markiafava under the name “hemolytic anemia with persistent hemosiderinuria”, then in the same year Micheli and was called Markiafavi-Micheli’s disease.
The common name for the disease is paroxysmal nocturnal hemoglobinuria (PNH).
This name does not correspond to the essence of the disease, since with this disease there are neither real paroxysms, nor obligatory hemoglobinuria.
Intravascular destruction of erythrocytes with hemosiderinuria, except Markiafavi-Micheli’s disease, is observed in a number of other diseases. It is found in many forms of autoimmune hemolytic anemia with both thermal and cold antibodies, especially in forms with thermal hemolysins; Permanent intravascular destruction of erythrocytes is detected in some forms of hereditary hemolytic anemia associated with a violation of the structure of the erythrocyte membrane.
Markiafavi-Micheli’s disease is one of the rare forms of hemolytic anemia.
Causes of Disease Markiafavi-Micheli
Currently, there is no doubt that in Markiafavi-Micheli’s disease, the defect in red blood cells is the cause of the increased destruction of red blood cells. This has been proven in the transfusion of donor erythrocytes to patients and erythrocytes from patients with healthy people.
Pathogenesis during Markiafavi-Micheli Disease
With the disease Markiafavi – Mikeli affects not only red blood cells, but also leukocytes and platelets. The decrease in the number of these shaped elements is connected, on the one hand, with a certain decrease in their production, on the other – with a violation of their structure and accelerated destruction. It has been proven that platelets and leukocytes of patients with Markiafah-Mickey syndrome are hypersensitive to the effects of complement. They are many times more sensitive to the action of isoagglutinins than donor platelets and white blood cells. In other words, platelets and white blood cells have the same membrane defect as erythrocytes.
On the surface of erythrocytes, leukocytes and platelets, it is not possible to detect immunoglobulins using the most sensitive methods and thus show the belonging of the Markiafav-Micheli disease to the group of auto-aggressive diseases.
Convincingly proved the existence of two independent populations of erythrocytes in Markiafavi Mikeli’s disease. The most resistant cells in a healthy person, the reticulocytes, turn out to be the most fragile in Markiafavi-Micheli disease.
The identity of the erythrocyte, neutrophil and platelet membrane lesions indicates that the cell following the stem cell most likely receives pathological information: the common cell is the precursor of myelopoiesis.
Described isolated cases of rapid leukemia in the background of this disease.
The main role in the mechanism of development of thrombotic complications is attributed to the intravascular breakdown of red blood cells and stimulation of coagulation by factors released from cells during their breakdown. It has been proven that reticulocytes contain a large number of factors contributing to blood coagulation.
In case of disease Markiafavi-Michels are mainly destroyed reticulocytes; perhaps this should explain the high incidence of thrombotic complications in Markiafavi-Micheli’s disease and the relative rarity of such complications in other forms of hemolytic anemia with marked intravascular hemolysis.
Symptoms of Disease Markiafavi-Micheli
The disease often begins suddenly. The patient complains of weakness, malaise, dizziness. Sometimes patients pay attention to a small yellow sclera. Usually the most common first complaint is a pain complaint: severe headaches, abdominal pain. Perhaps asymptomatic course of the disease, and then only the tendency to increased thrombosis causes the patient to consult a doctor. Hemoglobinuria is rarely the first symptom of the disease.
Attacks of pain in the abdomen – one of the characteristic signs of the disease Markiafavi -Micheli. Localization of pain can be very different. Operations are described in connection with suspected acute appendicitis, gastric ulcer, cholelithiasis, up to the removal of a part of the stomach in such patients. Outside the crisis of pain in the abdomen, as a rule, does not happen. Often vomiting is associated with pain in the abdomen. Probably, abdominal pain is associated with thrombosis of small mesenteric vessels. Peripheral thrombosis is often observed. Thrombophlebitis occurs in 12% of patients with Markiafavi-Micheli disease, as a rule, affects the veins of the extremities. Thrombosis of the renal vessels is described. Thrombotic complications are the most common cause of death in Markiafavi-Micheli disease.
When examining a patient, pallor with a slight icteric tinge, puffiness of the face, and sometimes excessive fullness are detected. A slight enlargement of the spleen is possible, but not necessary. The liver is often enlarged, although it is also not a specific symptom of the disease.
Markiafavi-Micheli’s disease is accompanied by signs of intravascular hemolysis, primarily an increase in free plasma hemoglobin, observed in almost all patients. However, the severity of this increase is different and depends on the period during which the disease was conducted. During the crisis, this indicator increases significantly, and the amount of plasma metalbumin also increases. The level of free hemoglobin depends on the content of haptolobin, the filtration of hemoglobin in the kidneys, the rate of destruction of the hemoglobin-haptoglobin complex.
When passing through the tubules of the kidneys, hemoglobin is partially destroyed, is deposited in the epithelium of the tubules, which leads to the excretion of hemosiderin in urine in most patients. This is an important symptom of the disease. Sometimes hemosiderinuria is not detected immediately, only in the process of dynamic observation of the patient. It should also be noted that hemosiderin is excreted in the urine in a number of other diseases.
Diagnosis of Disease Markiafavi-Micheli
The content of hemoglobin in patients with Markiafavi-Micheli disease ranges from 30 to 50 g / l in the period of exacerbation, to the norm – in the period of improvement. The content of erythrocytes is reduced accordingly to a decrease in hemoglobin. The color indicator remains close to one for a long time. If the patient loses a lot of iron in the urine in the form of hemosiderin and hemoglobin, then the iron content gradually decreases. Low color index is observed in approximately half of the patients. Sometimes hemoglobin F levels are elevated, especially during exacerbations.
In a significant proportion of patients, the content of reticulocytes is elevated, but relatively low (2-4%). Sometimes point defects are found in red blood cells. The number of leukocytes in Markiafavi-Micheli disease is reduced in most cases. In many patients, the number of leukocytes is 1.5-3.0 H 109 / l, but sometimes decreases to very low numbers (0.7-0.8 H 109 / l). Leukopenia in most patients is due to a decrease in the number of neutrophils. However, sometimes with Markiafavi-Micheli disease, the content of leukocytes is normal and rarely elevated to 10-11 × 109 g / l.
In case of Markiafavi-Micheli disease, phagocytic activity of neutrophils decreases. Thrombocytopenia is also common, but there is no decrease in aggregation. Probably, the rarity of hemorrhagic complications is connected with this, although the number of platelets sometimes falls to very low numbers (10-20 × 109 / l). Usually in most patients the platelet count ranges from 50 to 100 hours 109 / l. A normal platelet count does not exclude Markiapha-Micheli’s disease.
The study of bone marrow reveals mainly signs of hemolytic anemia, an irritation of the red sprout with a normal number of myelokaryocytes. In a number of patients, the number of megakaryocytes is somewhat reduced.
The level of serum iron in Markiafavi-Micheli disease depends on the stage of the disease, the severity of intravascular erythrocyte destruction and hematopoietic activity. In some cases, the disease Markiafara – Mikeli begins with signs of hypoplasia. The iron stores in the body of the patient depend, on the one hand, on the loss
iron with urine, on the other – from the intensity of blood formation. In particular, it does not allow to consider the iron deficiency as a diagnostic sign of the disease Markiafavi-Micheli.
Markiafavi-Micheli disease may proceed in different ways. P-and this state of health of patients outside the crisis does not suffer, the hemoglobin content of about 8090 g / l.
Often, after an infection, acute hemolytic crises occur with the release of black urine; during this period, severe abdominal pain appears, the temperature rises to 38-39 ° C and the hemoglobin content drops sharply. In the future, the crisis passes, the hemoglobin content rises to the usual numbers for the patient.
In another, also typical, variant, the general condition of patients outside the crisis is disturbed much more. Hemoglobin level is constantly low – 40-50 g / l. For all the time the disease may not be black urine, and if it happens, after the transfusion of plasma or fresh unwashed red blood cells. In addition to these two options, there are a number of transitional forms, when at first there are hemolytic crises, and then with the progression of anemia, they are smoothed out. In some patients, severe hemolytic crises follow one after another, leading to severe persistent anemia. Crises are often accompanied by thrombotic complications. In some patients, the picture of the disease is mainly determined by thrombosis, and the hemoglobin level is maintained at about 9.5-100 g / l.
In some patients, the Markiafavi-Micheli disease begins with aplastic anemia.
Differential diagnosis is carried out with a number of diseases depending on what symptom of the disease the doctor has noticed.
If a patient has black urine, and in the laboratory it does not cause difficulties to identify hemosiderin in the urine, then the diagnosis is facilitated. The range of diseases with intravascular destruction of red blood cells is limited, so the correct diagnosis is made fairly quickly.
More often, however, other symptoms of the disease attract the doctor’s attention: abdominal pain, peripheral vascular thrombosis, anemia. Often it makes suspect a malignant neoplasm of the gastrointestinal tract. In such patients, x-ray studies of the stomach, intestines are performed, and if they see red urine, then the kidneys are examined.
Often, doctors pay attention to high protein in the urine and suggest any kidney disease. It does not take into account that pronounced proteinuria, dark urine color and the absence of red blood cells in it are more common in hemoglobinuria, since hemoglobin is also a protein.
In these cases, it is advisable to perform a gregersen benzidine test with urine if it does not contain red blood cells. In addition to hemoglobin, a positive sample of Gregersen may cause myoglobin, but myoglobinuria is much less common than hemoglobinuria, and with them the hemoglobin content does not decrease.
Severe pancytopenia in Markiafavi-Micheli’s disease leads to a diagnosis of aplastic anemia. However, this group of diseases is not characterized by an increase in the number of reticulocytes, irritation of the red sprout of the bone marrow, intravascular destruction of red blood cells.
It is much more difficult to distinguish from autobiopathic hemolytic anemia from Markiafavi-Michele’s disease with a hemolysin form. They almost do not differ in
the clinical picture, however, the number of leukocytes in Markiafavi-Micheli disease is often reduced, and prednisone is practically ineffective, whereas in autoimmune hemolytic anemia, leukocytes are often elevated, and in its hemolysin forms, prednisolone often gives a good effect.
Diagnosis is assisted by the detection of serum hemolysins by the standard method and by modifications of the sucrose test, as well as the detection of anti-erythrocyte antibodies on the surface of erythrocytes.
Excretion of hemosiderin with urine in combination with abdominal pain, hypochromic anemia, and thrombocytopenia is sometimes observed with severe lead intoxication. However, in these cases there is a polyneuritic syndrome, which is absent in Markiafavi-Micheli’s disease. In addition, for the disease Markiafavi-Micheli is characterized by a positive sucrose test and Hema test. When lead poisoning they are negative. Lead poisoning is accompanied by a sharp increase in the content of 6-aminolevulinic acid and coproporphyrin in the urine.
Treatment of Disease Markiafavi-Micheli
There are no methods of treatment aimed at the mechanism of the development of the disease. The depth of anemia in Markiafavi-Micheli’s disease is determined by the severity of hypoplasia, on the one hand, and the destruction of red blood cells, on the other. The patient’s severe general condition and low hemoglobin levels are indicative of blood transfusions.
The number of blood transfusions is determined by the patient’s condition, the rapidity of hemoglobin level increase. Many patients constantly need blood transfusions at intervals of 3-4 days to several months. Initially, patients tolerate procedures well, but after months or years of illness, they often develop severe reactions even to thoroughly washed red blood cells. This requires the selection of red blood cells from an indirect Coombs test.
Some patients received nerobol 5 mg 4 times a day with some effect. Nerobol should be used for several months under the control of liver function in connection with the possibility of cholestatic hepatitis. The action of the drug prolonged action (retabolila) weaker.
Oxymetalone is significantly less toxic than non-shock, prescribed at 150-200 mg / day; cholestatic effect of large doses of the drug is significantly less than that of nerobol. Anadrol is applied on 150-200 mg / day. within 3-4 months.
Due to the increased ability to form unsaturated fatty acid peroxides in the erythrocyte membrane of patients with Markiafavi-Micheli disease, the question arises about the use of tocopherol preparations. Vitamin E has antioxidant properties and is able to resist the action of oxidizing agents. At a dose of 3-4 ml / day. (0.15-0.2 μg of tocopherol acetate) The drug has a certain antioxidant effect. In particular, it can be used for the prevention of hemolytic crisis in the use of iron preparations.
Iron preparations are shown with its significant loss and severe deficiency.
To combat thrombosis in Markiafavi-Micheli disease uses heparin, more often in small doses (5,000 IU, 2–3 times a day in the skin of the abdomen), as well as indirect anticoagulants.
The life expectancy of patients ranges from 1 to 7 years, described patients who lived 30 years. Improvement and even recovery are possible. Complete clinical improvement in patients suggests the fundamental possibility of reversing the process.