Aplasia of the bone marrow

Aplasia of the bone marrow (or aplasia of hematopoiesis) are bone marrow deficiency syndromes that include a group of disorders in which the function of the hematopoiesis performed by the bone marrow is abruptly suppressed. The consequence of this disorder is the development of pancytopenia (there is a deficit of all blood cells: leukocytes, erythrocytes, and also platelets). Deep pancytopenia is a life-threatening condition.

[1], [2], [3]

Epidemiology

Aplasia of the bone marrow occurs in people with a frequency of 2.0 / 1 000 000 people per year. This indicator varies depending on the country, so there may be a spread of between 0.6-3.0 + / 1 000 000 people per year.

[4], [5], [6], [7], [8]

Causes of the bone marrow aplasia

Among the causes of bone marrow aplasia are the following:

• Chemotherapy and radiation therapy.
• Autoimmune disorders.
• Environmentally hazardous working conditions.
• Various viral infections.
• Contact with herbicides and insecticides.
• Some medicines, for example, drugs that treat rheumatoid arthritis, or antibiotics.
• Nocturnal hemoglobinuria.
• Hemolytic anemia.
• Diseases of connective tissue.
• Pregnancy - the bone marrow is affected by the perverse response of the immune system.

[9], [10], [11], [12], [13], [14], [15], [16]

Risk factors

Among the risk factors for bone marrow aplasia are those described below.

• chemical compounds: cytostatics - they contribute to the cessation of cell division, they are usually used for the therapy of tumors. A certain dosage of such drugs can damage the bone marrow, violating the formation of blood cells; immunosuppressants - suppress the immune system of the body, they are used when there is excessive activation of immunity, in which their own healthy tissues are damaged. If to cancel their reception, a hemopoiesis often is restored;
• substances that affect the body, if the patient has an individual hypersensitivity to them. These are antibiotics (antibacterial drugs), gasoline, mercury, various dyes, chloramphenicol, and also gold preparations. Such substances can cause both reversible and irreversible destruction of bone marrow function. They can enter the body through the skin, when breathing by aerosol, orally - along with water and food;
• irradiation with ionic particles (radiation) - for example, if safety rules are violated at nuclear power plants or in medical institutions where tumors are treated with radiotherapy;
• viral infections - such as influenza, hepatitis virus, etc.  

[17], [18], [19], [20], [21], [22], [23]

Pathogenesis

The pathogenesis of bone marrow aplasia has not yet been fully studied. Nowadays several different mechanisms of its development are considered:

• Bone marrow is affected through a polypotent stem cell;
• The hematopoietic process is suppressed because of the influence of humoral or cellular immune mechanisms on it;
• Components of the microenvironment start to function incorrectly;
• Development of a deficiency of factors that contribute to the hematopoietic process.
• Mutations in genes that cause hereditary bone marrow deficiency syndromes.

In this disease, the content of the components (vitamin B12, iron, and protoporphyrin) that directly participate in hematopoiesis does not decrease, but at the same time, the hematopoietic tissue can not use them.

[24], [25], [26], [27], [28], [29]

Symptoms of the bone marrow aplasia

Aplasia of the bone marrow manifests itself depending on which cellular element of the blood was affected:

• If there is a decrease in the level of erythrocytes, dyspnea and general weakness and other symptoms of anemia appear;
• If the level of leukocytes decreases, a fever occurs and the susceptibility of the organism to infections increases;
• If the level of platelets is reduced, there is a tendency to develop hemorrhagic syndrome, the appearance of petechiae, as well as bleeding.

With partial red cell aplasia of the bone marrow, a sharp decrease in erythrocyte production, deep reticulocytopenia, and also isolated normochromic anemia are observed.

There is a congenital and acquired form of the disease. The second manifests itself under the guise of acquired primary erythroblastrophy, as well as a syndrome that occurs in other diseases (it can be lung cancer, hepatitis, leukemia, infectious mononucleosis or pneumonia, as well as sickle cell anemia, parotitis or ulcerative colitis, etc.).

[30], [31]

Complications and consequences

Among the complications of bone marrow aplasia:

• An anemic coma, in which there is a loss of consciousness, the development of a coma. There is no reaction to any external stimuli, since oxygen does not enter the brain in the right amount - this is due to the fact that the level of erythrocytes in the blood quickly and significantly decreases;
• Various hemorrhages begin (hemorrhagic complications). The worst option in this case is a hemorrhagic stroke (some part of the brain is soaked with blood and therefore dies);
• Infections - microorganisms (various fungi, bacteria or viruses) cause infectious diseases;
• Disturbance of the functional state of some internal organs (such as the kidney or heart), especially with accompanying chronic pathology.

[32], [33], [34], [35], [36]

Diagnostics of the bone marrow aplasia

In the diagnosis of bone marrow aplasia, a history of the disease is examined, as well as the patient's complaints: how long the symptoms of the disease have appeared, and what the patient associates with their appearance.

Further, an anamnesis of life is revealed:

• Presence of concomitant chronic diseases in the patient.
• Presence of hereditary diseases.
• Does the patient have bad habits.
• It is specified whether a recent long-term use of any medication has been carried out.
• Presence of tumors in the patient.
• Was contact with various toxic elements.
• Was the patient exposed to radiation exposure or other radiation factors?  

After this, a physical examination is carried out. The color of the skin is determined (with aplasia of the marrow, paleness is observed), the pulse rate is determined (most often it is frequent) and the indices of blood pressure (it is lowered). The mucous membranes and skin are examined for hemorrhages and purulent vesicles, etc. 

[37], [38]

Analyzes

During the diagnosis of the disease, some laboratory tests are also carried out.

A blood test is performed - if a patient has a bone marrow aplasia, a decrease in the level of hemoglobin, as well as the number of red blood cells, will be revealed. The color index of the blood remains in this state. The number of platelets with leukocytes decreases, and besides this the correct ratio of white blood cells is violated, because the content of granulocytes decreases.

Urine is also analyzed to determine the presence of erythrocytes in the urine - this is a sign of hemorrhagic syndrome, or the presence of leukocytes and microorganisms, which is a symptom of the development of infectious complications in the body.

A biochemical blood test is also performed. Thanks to him, the parameters of glucose, cholesterol, uric acid (to identify the concomitant defeat of any organs), creatinine, as well as electrolytes (sodium, potassium and calcium) are elucidated. 

[39], [40], [41], [42], [43], [44], [45]

Instrumental diagnostics

With instrumental diagnostics the following procedures are carried out.

For the purpose of examination of the bone marrow, a puncture is performed (piercing, in which the inner contents are extracted) of some bone, usually a sternum or hip bone. With the help of a microscopic examination, the replacement of the hematopoietic tissue by cicatricial or fatty is determined.

Trepanobiopsy, which examines the bone marrow, as well as its relationship with the nearby tissues. During this procedure, a special device called trepan is used - with it, the bone marrow, together with the periosteum, and bone, is taken from the iliac bone.

Electrocardiography, which allows you to identify problems with the nutrition of the heart muscle, heart rhythm.

Differential diagnosis

Differential diagnosis is carried out with such diseases:

• Night paroxysmal hemoglobinuria;
• Hypoplastic anemia  (and transient erythroblastopenia in children);
• Hyperplenism;
• Myelodysplastic syndrome;
• Acute as well as hairy cell leukemia;
• SLE;
• DIC-syndrome;
• Developed as a result of hypopituitarism, hypothyroidism or liver disease anemia.

Treatment of the bone marrow aplasia

It is almost impossible to eliminate the disease with etiotropic treatment (affecting its cause). The elimination of a provoking factor (for example, cancellation of the drug taken, exit from the radiation zone, etc.) can help, but in this case only the rate of bone marrow death decreases, but stable hematopoiesis can not be restored by this method.

Immunosuppressive treatment is performed if transplantation can not be performed (there is no suitable donor for the patient). In this case, drugs from the groups of cyclosporin A or antilymphocytic globulin are used. Sometimes they are used together.

The use of GM-CSF (drugs that stimulate the production of leukocytes). This treatment is used if the number of white blood cells drops to less than 2 x 109 g / l. Also in this case, corticosteroid drugs can be used.

Anabolic steroids are used that stimulate protein production.

In the process of treating bone marrow aplasia, the following methods are used:

• Transfusion of blood elements.

The transfusion is carried out by washed red blood cells (these are donor red blood cells that release from proteins) - this method reduces the severity and the number of negative reactions to the transfusion procedure. Do such a transfusion only if there is a threat to the life of the patient. These are the following states:

• the patient falls into anemic coma;
• Anemia of severe severity (in this case, the hemoglobin level falls below 70 g / l).

Transfusion of donor platelets is performed if the patient has bleeding and an evident decrease in the number of platelets.

Hemostatic therapy is carried out depending on the area in which bleeding began.

In the event of infectious complications, the following methods of therapy are conducted:

• antibacterial treatment. It is performed after taking swabs from the nasopharynx, as well as urine and blood on the sowing, to determine which microorganism was the cause of the infection, and to reveal its sensitivity to antibiotics;
• necessarily performed systemic antifungal treatment;
• local treatment with antiseptic sites that can become entry gates of infection (these are the places through which bacteria, fungi or viruses enter the body). Under such procedures, it is usually meant to rinse the mouth using different drugs in turn.

Medications

When aplasia of the bone marrow is necessarily used medicamentous treatment. The most commonly used drugs are 3 medicinal groups: cytostatics (6-mercaptopuril, cyclophosphamide, methotrexate, cyclosporin A, and also imarant), immunosuppressants (dexamethasone, as well as methylprednisolone) and antibiotics (macrolides, cephalosporins, chlorocrinolones, as well as azalides ). Sometimes drugs that correct intestinal microflora disorders and problems with blood pressure, enzyme drugs, etc., can be used.

Methylprednisolone is prescribed by mouth. When transplanting organs - in dosage not more than 0,007 g / day.

Side effects of the drug: water, as well as sodium can stay in the body, increases blood pressure, can be observed loss of potassium, osteoporosis, muscle weakness, drug gastritis; the resistance to different infections may decrease; suppression of the adrenal glands, some mental disorders, problems with the menstrual cycle.

The drug is contraindicated in the severe stage of hypertension; at stage 3 of circulatory failure, and also in pregnancy and acute endocarditis, as well as nephritis, various psychoses, osteoporosis, ulcers of the duodenum or stomach; after a recent operation; with the active stage of tuberculosis, syphilis; elderly people, and also children under 12 years old.

Methylprednisolone with caution prescribed in the presence of diabetes, only if there are absolute indications, or for treatment in patients with insulin resistance, with high titers of anti-insulin antibodies. With tuberculosis or infectious diseases, you can use the medicine, only combining it with antibiotics or drugs that treat tuberculosis.

Imuran - on the first day it is allowed to apply a dose of not more than 5 mg per 1 kg of a person's weight per day (to be consumed in 2-3 doses), but the dosage as a whole depends on the immunosuppression regimen. The size of the maintenance dose is 1-4 mg / kg of body weight per day. It is established depending on the tolerance of the patient's organism and its clinical state. Studies indicate that treatment with Imuran should be carried out a long course, even by applying small doses.

In case of an overdose, sores in the throat, bleeding and bruising, and infections may appear. Such symptoms are more typical for a chronic overdose.

Side effects - after bone marrow transplantation in the treatment of azathioprine in combination with other immunosuppressors, bacterial, fungal or viral infections are often observed in patients. Among other adverse reactions are arrhythmia, signs of meningism, headaches, lesions of the lips and mouth, paresthesia, etc.

Cyclosporine A is used intravenously - the daily dose is divided into 2 doses and injected for 2-6 hours. For the initial daily dose, 3-5 mg / kg is enough. Intravenous application is optimal in the treatment of patients who underwent bone marrow transplantation. Before transplanting (4-12 hours once before the operation), the patient is given a dose of 10-15 mg / kg, and then the same daily dose is used for the next 1-2 weeks. Later the dose is reduced to the usual maintenance dose (approximately 2-6 mg / kg).

Symptoms of overdose are drowsiness, severe vomiting, tachycardia, headaches, the development of severe kidney failure.

When taking Cyclosporine, the following precautions should be followed. Therapy should be carried out in a hospital by doctors who have extensive experience in treating patients with immunosuppressants. It should be remembered that, as a result of taking Cyclosporine, a predisposition to the development of malignant lymphoproliferative tumors increases. That is why you need to decide before the beginning of the procedure whether all the risks associated with it justify the positive effect of its treatment. At pregnancy the preparation is authorized to use only in view of strict indications. Since there is a risk of anaphylactoid reactions as a result of intravenous administration, antihistamines should be taken for prophylaxis, and the patient should be transferred to the oral route of the drug as soon as possible.

Vitamins

If the patient has bleeding, in addition to gemotherapy, you should take 10% calcium chloride solution (inside), as well as vitamin K (15-20 mg per day). In addition, ascorbic acid is administered in large amounts (0.5-1 g / day) and vitamin P (in a dosage of 0.15-0.3 g / day). It is recommended to take folic acid in high doses (maximum 200 mg / day), as well as vitamin B6, preferably in the form of injections (50 mg of pyridoxine daily).

Physiotherapeutic treatment

To activate the work of the bone marrow, the physiotherapeutic treatment is used - the diathermy of tubular bones in the region of the legs or sternum. The procedure should be done every day for 20 minutes. It should be noted that this option is only possible if there is no marked bleeding.

Operative treatment

Bone marrow transplantation is performed in case of a severe stage of aplasia. The effectiveness of such an operation increases if the patient is at a young age, and also he has performed a small number of transfusions of elements of donor blood (no more than 10).

With such treatment, the bone marrow is extracted from the donor and further transplanted to the recipient. Before the suspension of stem cells will be introduced, they are treated with cytostatics.

After the transplant, the patient will have a long course of immunosuppressive treatment, which is necessary to prevent possible rejection of the transplant by the body, as well as to prevent other negative immune responses.

Prevention

The primary preventive measures for bone marrow aplasia are as follows: the external negative factors must be prevented. To do this, you must follow safety techniques when working with dyes or objects that can be sources of ionizing radiation, as well as monitor the application of drugs.

Secondary prevention, which is necessary to prevent a possible deterioration in a person with an already developed disease or to prevent relapse, is in such measures:

• Dispensary records. Observation should continue even if there are signs of recovery;
• Long-term supportive lekartsvennaya therapy.

[46], [47], [48], [49], [50], [51], [52],

Forecast

Aplasia of the bone marrow usually has an unfavorable prognosis - if the treatment is not timely, the patient dies in 90% of cases.

Thanks to transplantation of the donor bone marrow, 9 out of 10 patients can live more than 5 years. Therefore, this method is considered the most effective method of treatment.

Sometimes it is not possible to perform a transplant, but modern medication therapy is also capable of giving results. About half of the patients thanks to it can live more than 5 years. But in this case, in most cases, survive patients who are ill at the age of no more than 40 years.

[53], [54], [55], [56],