Bone marrow aplasia
Introduction
Hello, welcome to this 9th class of the Hematology course provided by the University of Guanajuato. In this class we are going to review some basic concepts of bone marrow aplasia.
A failure in the bone marrow can be defined as pancytopenia.
PAN = All
CYTO = Cells
PENIA = Decrease
It is the result from poor hematopoiesis. The levels considered for this condition are the following:
Anemia: Hemoglobin less than 10mg/dL, low or absent reticulocytes.
Leukopenia: Leukocytes less than 4000/uL
Thrombocytopenia: platelets less than 150 000/uL
Or combinations.
This cytopenia are different from cytopenia caused by peripheral destruction.
Hypo proliferative anemias are characterized by being normocytic and normochromic with an inappropriate reticulocyte response (<2.5). It Is known as NON-REGENERATIVE ANEMIA.
The causes of pancytopenia can be acquired or hereditary. In this class we are going to review basic characteristics about bone marrow aplasia as well as some of the treatments available for this condition.
Content development
Bone marrow aplasia. Also known as aplastic anemia
Ehrlich described it in 1888 in a pregnant woman. Affection of the 3 cell lines.
Gradual disappearance without being able to be replaced.
PARTIAL APLASIA: Moderate disappearance of stem cells
SEVERE APLASIA: Total disappearance of hematopoietic cells
It can be congenital or acquired.
It affects to a greater or lesser extent the three hematopoietic series.
The disappearance of hematopoietic tissue in the bone marrow is replaced by fat, leading to peripheral pancytopenia: anemia, leukopenia, and thrombocytopenia.
The alteration can be of both the stem cell and the micro-environment that sustains it.
The condition is not sexually predominant and can appear at any age.
Typical patient: a young person who was previously well.
Symptoms: anemia and predisposition to profuse bleeding.
Laboratory tests: pancytopenia and hypocellular and fatty bone marrow.
Depending on the etiology, the following forms are recognized:
- Unavoidable aplastic anemia: after exposure to cytotoxic drugs or radiation at a dose that is considered very high.
- Idiosyncratic aplastic anemia: occurs rarely and unexpectedly in individuals who have been exposed to drugs/chemicals such as NSAIDs, thyro-statics, psychotropics, anticonvulsants, antidiabetics, chloramphenicol, sulfonamides, antimalarials, cardiovascular agents, benzene, aromatic hydrocarbons, heavy metals, etc., without a clear dose relationship.
- Idiopathic aplastic anemia: It occurs spontaneously and without a known cause.
- Infections that cause aplastic anemia: hepatitis, Epstein-Barr virus infection, parvovirus B19, etc.
- Immune aplastic anemia: short-lived and sometimes associated with circulating antibodies as seen in lupus erythematosus or transfusion rejection reactions.
- Malignant aplastic anemia: it is observed transiently in the evolution of acute leukemias and myelodysplasias.
Parvovirus B19 infection
Erythema infectious, is not usually a severe infection. Its most noticeable symptom is a bright red patch or rash on children’s cheeks.
It is caused by a virus called parvovirus B19 and can be transmitted from one person to another through droplets or secretions (e.g., saliva, sputum). It can also be transmitted from a pregnant woman to her fetus.
Parvovirus infections can worsen sickle cell anemia and other hemolytic anemias. This complication can lead to an aplastic crisis in which blood counts drop to dangerously low levels.
Pathophysiology
Pancytopenia reflects a failure in the hematopoietic process manifested as a severe decrease in the number of all hematopoietic progenitor cells.
Two mechanisms have been suggested for bone marrow failure.
- Direct damage by chemical agents (benzene), drugs, or radiation to both quiescent and proliferating hematopoietic cells.
- Immune suppression of bone marrow cells
* Absence or defect of hematopoietic precursors.
Presence of fat, decrease in CD34 + cells, reduction in telomere size
* Involvement of the medullary microenvironment.
An alteration in the microenvironment could be responsible for low cell replication in OM, although its role as the sole pathophysiological mechanism is unlikely. Serum levels of colony-stimulating factors are generally elevated in AA, as a biological response to pancytopenia.
* Immune reaction against hematopoietic tissue
The destruction of hematopoiesis by the immune system plays a central role in the pathophysiology of AA.
Mechanisms:
- Alterations in T lymphocytes with production of interferon-gamma and tumor necrosis factor that act on mitosis increase the expression of the Fas antigen in CD34 + cells and apoptosis in hematopoietic cells
- Observation of a clone of CD34 + cells capable of destroying hematopoietic cells
- Inhibition of monocyte and macrophage-mediated hematopoietic colony formation
- Production by B lymphocytes of antibodies that inhibit marrow activity.
- Altered drug metabolism
Mechanism of idiosyncratic aplastic anemia.
Many drugs and chemical agents’ mechanisms involve enzymatic degradation of highly reactive electrophilic compounds toxic to cellular macromolecules.
The excessive generation of these toxic intermediaries or the failure to purify them is genetically determined and can occur when exposed to the drug in question.
Diagnosis
It can be difficult because it overlaps with other entities, particularly bone marrow disorders.
Peripheral blood:
-Cell count:
-Pancytopenia
-Reticulocytopenia
-Macrocytosis
-Lymphocyte count is generally maintained
-In the early stages, there are isolated cytopenia, particularly thrombocytopenia
-Monocytopenia
Presence of fetal hemoglobin in children
The smear should be carefully examined to rule out:
-Dysplastic neutrophils
-Abnormal platelets
-Blasts and other abnormal cells
Peripheral blood:
◦RDW is normal (normocytic anemia).
◦The size of the platelets is average, without the presence of macro plates or other dysplastic features.
◦The number of granulocytes is decreased, but their phagocytic and bactericidal function is normal.
*Others:
-Erythropoietin levels: high in AA.
-Iron:
+ Serum ferritin may be elevated, and the level of serum transferrin receptors is average unless there is iron deficiency.
-The study of hemoglobin (Hb) may show an increase in fetal hemoglobin that shows compensatory spinal stress.
-There is an increase in the expression of antigen I in erythrocytes, which increases their risk of lysis by cold antibodies.
Bone marrow exam:
-Hypocellularity (<25%)
-«Hot spots» with dominant erythropoiesis
-Few or no megakaryocytes
-Mast cells (connective tissue, hematopoietic cells, inflammation, allergies, share precursor cell with basophil)
-Lymphoid hyperplasia
-Plasma cells (from B lymphocytes, antibody production)
-Macrophages
-Dyserythropoiesis (rule out).
Bone marrow studies:
They are performed to determine the bone marrow’s cellularity to study the types and amounts of cells produced in the marrow.
Study the iron levels in the bone marrow and look for chromosome abnormalities.
Marrow biopsy A. Marrow biopsy in a young adult. B. Marrow biopsy in a young adult with very severe aplastic anemia. Few hematopoietic cells and few lymphocytes and stromal cells are found. The hematopoietic space is replaced by reticular cells (pre-adipocytic fibroblasts) converted into adipocytes.
Patients with aplasia present clinical manifestations derived from the decrease in the blood cells of the three hematopoietic series.
Clinically it presents the following triad:
- Anemic syndrome: paleness, weakness, dyspnea, and fatigue.
- Recurrent infections, a consequence of neutropenia and monocytopenia
- Hemorrhagic phenomena due to thrombopenia (petechiae, bruising, epistaxis, vaginal bleeding, and unexpected bleeding).
Congenital form: Fanconi’s anemia
Areas of hyperpigmentation of the skin (café-au-lait spots), low body size
Skeletal abnormalities: the absence of the thumb, absence, or hypoplasia of the first metacarpal, thumbs with three phalanges, decreased number of ossification points, lack of the radius of one or both arms, etc.
Renal malformations: renal agenesis and horseshoe kidney.
Nervous system disorders, microcephaly, microphthalmia, mental retardation, palpebral ptosis, deafness, strabismus, nystagmus, and hyperreflexia.
Hypogonadism and atrophy of the spleen.
There is a defect in DNA stability, DNA repair, and increased sensitivity to oxygen free radicals in peripheral blood lymphocytes or bone marrow cells.
The cells of patients with FA show a tendency to present spontaneous chromosomal breaks.
They have overexpression of TNF-α and TNF-ϒ in the bone marrow.
Excess TNF- α plays an essential role in suppressing erythropoiesis. HLA-identical related bone marrow transplantation provides 80% survival.
Uncommon inherited disorder.
It is distinguished by reticulated hyperpigmentation of the skin, oral leukoplakia, and nail dystrophy.
It is often associated with hematologic abnormalities and multisystemic expressions; It has also been called Zinsser-Cole-Engman syndrome and Cole-Rauschkolb-Toomey syndrome.
It predominates in the male sex. It is transmitted by a recessive inheritance pattern linked to the X chromosome.
It usually affects the face, neck, shoulders, chest, armpits, and thighs; It begins with the manifestation of thin and dystrophic nails.
Prognosis
The prognosis is conditioned by the bone marrow insufficiency, pulmonary complications, and the appearance of malignant tumors; the patients rarely survive past 50 years of age.
As there is no specific treatment, prescribed steroids, androgens, and transplantation of bone marrow to improve the patient’s conditions.
Pure red cell aplasia
It is a rare syndrome defined by anemia, reticulocytopenia, and a significant decrease or absence of erythroid precursors in the bone marrow. Cellularity is expected concerning the other hematopoietic series.
Erythropoietin is elevated to try to compensate for this erythroid deficiency.
How are erythroblastopenias classified?
* Congenital
1.Blackfan-Diamond anemia (erythrogenesis imperfecta).
* Acquired
1. Idiopathic
2. Secondary
– Thymoma (30-50% of secondaries).
– Neoplasms.
– Connective diseases (systemic lupus erythematosus, rheumatoid arthritis, etc).
– Parvovirus B19 infection (mainly affects patients with hemolytic anemia).
– Drugs (antiepileptics, isoniazid, sulfa drugs, etc).
Leukocyte aplasia
Shwachman-Diamond syndrome: selective white series aplasia: neutropenia, which associates exocrine pancreatic insufficiency with secondary steatorrhea and skeletal abnormalities (metaphyseal dysplasia).
Hereditary, autosomal recessive disease that induces accelerated cell apoptosis in the FAS pathway.
The resulting hypo proliferation may be due to the documented telomere shortening in leukocytes of people with this condition.
The prognosis of the patients is determined by the recurrent bacterial infections, secondary mainly to the alteration of the neutrophils and the spinal dysfunction and leukemia.
Treatment:
- Supplementation of pancreatic enzymes and fat-soluble vitamins.
- Prevention and treatment of invasive infectious diseases with early treatment of febrile illness.
- Correction of hematological abnormalities when possible.
- Monitoring and treatment of orthopedic deformities.
Severe neutropenia or recurrent infections can be treated with granulocyte colony stimulating factor (G-CSF). However, there is controversy about the possibility of accelerating the development of myeloproliferative syndromes.
Transfusions may be necessary for patients with anemia or symptomatic thrombocytopenia. Erythropoietin may also help treat anemia.
Kostmann syndrome:
- Severe congenital neutropenia.
- It is characterized by marked neutropenia, although eosinophils and monocytes may be increased.
- In the bone marrow, conserved cellularity is observed with the absence or decrease of myeloid progenitors or an arrest of maturation in myelocytes or promyelocytes.
- The pathogenesis of KS remains poorly understood today; the latest research suggests that neutropenia is due to low levels of a granulocyte-stimulating factor (G-CSF) or to a defect in the receptors for it
- Currently, the treatment of choice is the use of G-CSF, with which a significant increase in neutrophil numbers has been observed, which has increased the survival of these patients.
Megacariocytes pure aplasia
Congenital Amegakaryocytic Thrombocytopenia or ART (thrombocytopenia with absent radii)
- Rare autosomal recessive inherited disease characterized by isolated severe hypomegakaryocytic thrombocytopenia during the first years of life develops into bone marrow failure and pancytopenia.
- About 50% progress to aplastic anemia.
- The myelogram shows normal cellularity with a decrease or absence of megakaryocytes.
The most affected individuals present with hematomas at birth, petechiae, and may present with severe bleeding (gastrointestinal and, rarely, intracerebral) during the neonatal period and the first years of life.
The number of platelets gradually increases during childhood, and in adulthood, the platelet count is almost normal or completely normal.
There is no specific treatment.
Prevention of bleeding in the first years of life is essential to reduce morbidity.
If the patient has very low platelet counts, platelet transfusions may be required.
Treatment
Initiate AA treatment immediately after diagnosis and should be aimed at identifying and eliminating possible etiological factors, treating complications secondary to pancytopenia, and restoring normal hematopoiesis.
Eliminating the cause is useful because 50% of the cases are acquired.
Monitoring for symptoms consists of performing tests from time to time, giving transfusions, giving antibiotics, or some other treatment that may be necessary. This strategy is the right decision for avoiding complicating the patient’s life to have an everyday life.
Long-term transfusion treatment is not recommended because frequent red blood cell transfusions can lead to iron overload (liver and heart damage). Although there are chelating agents to remove excess iron, they are difficult to administer and poorly tolerated in patients.
Bone marrow transplant
BMT is the curative treatment of choice in young patients, as it replaces hematopoietic progenitor cells with average OM.
A minority of patients have an identical HLA sibling who may be a donor, and severe complications related to this procedure such as infections, interstitial pneumonitis, and graft versus host disease can occur.
Graft failure occurs more frequently than in other pathologies, especially in Poly transfused patients.
Immunosuppression
Efficient in AA, with a 40 to 80% response to a drug or a combination of these.
Unlike BMT, in general, normal hematopoiesis is not fully restored, and mild or moderate anemia, leukopenia and/or thrombocytopenia persist, but without transfusion requirements or severe risk of infections.
This only partial recovery is believed to be due to sustained OM inhibition by lymphocytes or an irreversible loss of progenitor cells.
The most widely used immunosuppressants are purified immunoglobulins from the plasma of animals immunized with childhood thymocytes for antithymocyte gamma globulin (GAT) and thoracic duct lymphocytes for antilymphocyte gamma globulin (GAL).
Both produce lysis of human T lymphocytes, although they also act on B lymphocytes, natural killer cells, monocytes, adhesion cells.
Cyclosporine and corticosteroids are also used.
GAT can cause allergic reactions.
Cyclosporine: can cause kidney dysfunction or hypertension and interact with other drugs.
Intense immunosuppression mixing GAT and cyclosporine: recovery of 70 to 80% of patients.
Hematopoietic growth factors
Endogenous hematopoietic growth factors are normal or elevated in most patients with AA.
The administration of pharmacological granulocytic colony-stimulating factors (G-FEC) and/or granule-macrophage (GM-FEC) can increase the number of neutrophils, but generally in patients with residual myelopoiesis and without severe neutropenia.
The combined use of factors with synergistic mechanisms and multilinear effect (interleukin 3, GM-FEC, thrombopoietin, and erythropoietin) could improve the therapeutic response in some patients.
- Erythropoietin (Anaresp, Epogen, and Procit)
- G-CSF (Filgrastima and Neupogen)
- GM-CSF (Leukine, Sargamostima)
Conclusion
Bone marrow aplasia is characterized by cytopenia, when the three cell lines are decreased, pancytopenia is stablished. Peripheral cells are decreased but normal, with no dysplastic alterations.
In bone marrow aplasia, an Increased number of fat cells are observed within this tissue, replacing hematopoietic cells.
It can be acquired or hereditary. There are some xenobiotics which can Induce bone marrow failure, as well as some hereditary diseases.
There are some Immunological treatments, bone marrow transplant and growth factors In order to restore proper bone marrow function.