hypoplastic bone marrow syndromes
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Bone Marrow Failure Syndromes
Ahmed ElshebinyAhmed ElshebinyUniversity of MenoufyiaUniversity of Menoufyia
Blood is continuously renewed
The Bone Marrow is the blood Factory
May be exposed to damage or failure
Bone Marrow Failure Syndromes
Bone Marrow Failure Syndromes
AA PNH MDS
Acquired Constitutional
Autoimmune Fanconi
DC
Diamond-Blackfan
others
Toxic, Irradiation, Infection
Pure Red Cell Aplasia
Agranulocytosis
Bone Marrow Failure May involve one or more cell lines Lymphocytes are usually spared
Venn Diagram
APLASTIC ANEMIA
MDSPNH
AML
Bone Marrow Failure Syndromes
Pathophysiology of Bone marrow Failure
1. A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
2. Maturation defects, such as vitamin B-12 or folate deficiency
3. Differentiation defects, such as myelodysplasia.
Aplastic Anemias
Aplastic Anemias
Acquired Conistituitional
Single line
Agranulocytosis
Pure Red Cell Aplasia
Multilineage
Aplastic Anemia Named so in 1904 The theoretical basis for marrow failure
includes primary defects in or damage to the stem cell or the marrow microenvironment
Distinction between congenital or acquired may be difficult
80 % of patients have acquired cause which is an autoimmune disease
Aplastic Anemia
Drugs associated with AA NSAIDs(Butazones, Indomethacin,Piroxicam,
Diclofenac) Antibiotics( e.g sulfonamides) Furosemide Phenothiazines Corticosteroids Penicillamine Gold Allopurinol
Clinical and laboratory features symptoms due to pancytopenia No lymphadenopathy or splenomegaly or
cachexia Anemia is usually normocytic Hypocellular marrow is the hallmark Need to rule out other disorders
Severity of AA 2 of 3 peripheral blood count criteria
1. ANC < 500 /µL
2. Plat count< 20 000 /µL
3. Retics (Automated) < 60 000 /µL
Pancytopenia
Pancytopenia has many causes of which AA is not the most
common
1-Pancytopenia with hypocellular bone marrow
1. Acquired Aplastic Anemia
2. Inherited Aplastic Anemia
3. Some MDS
4. Rare aleukemic leukemia
5. Some acute lymphoblastic leukemia
6. Some lymphomas of bone marrow
2-Pancytopenia with cellular bone marrow
Primary bone marrow disease1. MDS2. PNH3. Myelofibrosis4. Mylophthisis5. Hairy cell leukemia6. Aleukemic leukemia
Secondary to systemic disease1. SLE2. alcoholism3. B12 or folate difficiency4. Hypersplenism5. Overwhelming infection6. Brucellosis7. Sarcoidosis8. T.B.
3 -Hypocellular marrow with or without cytopenia
1. Q fever
2. Ligionaires
3. Toxoplasmosis
4. Anorexia Nervosa
5. T.B.
6. Hypothyroidism
CBC and Blood film Decreased numbers Decreasd retics usually to less than 1 % Normo or macrocytosis Increased platelet hetrogenicity in size Microspherocytes and giant platelets are
absent Relative lymphoctosis
Iron Studies SI TIBC Transferrin Saturation Ferritin
Bone marrow aspiration and biopsy
Hypocellular but there may be pockets of cellularity ( hot spots)
Other lab studies Chromosomal analysis and cytogenetic
studies Chromosomal breakage analysis with
MMC/DEB h TERC screen for DC and other tests Difficient GPI- anchored proteins on flow-
cytometry Ham test
Imaging studies of bone marrow function
Ferrokinetic studies have been conducted using a radioactive label, such as iron-59 or indium-111
Magnetic resonance imaging (MRI) Positron emission tomography (PET)
Management of Acquired AA HSCT using histocompatible sibling donor 75% may lack matched sibling Matched unrelated donor ( MUD) from large
donor registries Combined immunosuppression
Prognosis With current BMT regimens, most patients with severe
aplastic anemia have a 60-70% long-term survival rate. Patients with severe aplastic anemia who receive
antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) but do not receive BMT have a 41% response rate and a 1-year survival rate of 55%.4 The addition of androgens increases response rates to 70%, with a 1-year survival rate of 76%
Cyclosporine therapy at 200-400 mg/d (maintain serum trough levels at 100-250 ng/mL) has a reported 85% hematologic remission rate.
Pure Red Cell Aplasia (PRCA) May be caused by a thymoma. It may occur transiently, resulting from a viral
infection such as with parvovirus B19. Pure red cell aplasia also may be permanent, as a
result of viral hepatitis. Finally, it may be the result of lymphoproliferative
diseases (eg, lymphomas, chronic lymphocytic leukemia) or collagen vascular diseases (eg, systemic lupus erythematosus, refractory anemia), or it may occur during pregnancy.
Agranulocytosis (direct toxicity or Immune mediated)
1. Heavy metals2. Analgesics3. Antiepliptics ( Carbamazepine, phenytoin)4. Antipsycotics5. Cardiovascular drugs( Captopril, Methyldopa, thiazides,..)6. Sulfa7. Antibiotics8. Levamisole, Fluconazole, Ranitidine, Metclopramide,
allopurinol9. Chinese herbs10. Insecticides11. Hair dyes
Constitutional Bone Marrow Failure Syndromes
1. Fanconi anemia
2. Dyskeratosis congenita
3. Shwachman-Diamond syndrome
4. Amegakaryocytic thrombocytopenia
5. Diamond-Blackfan anemia
6. Severe congenital neutropenia
7. Thrombocytopenia absent radii syndrome
Fanconi Anemia Autosomal Recessive in 99% FANCB is x-linked recessive Birth defects Bone marrow failure Oncogenesis ( hematological and solid) Mutations in 13 genes 10% develop leukemia and 6% MDS
Fanconi Anemia (ttt) SCT Androgens Growth factors
Copyright ©2010 Ferrata Storti Foundation
Dokal, I. et al. Haematologica 2010;95:1236-1240
Table 1. Characteristics of the inherited bone marrow failure syndromes
Dyskeratosis Congenita
Abnornal skin pigmintation
Nail Dystrophy Leukoplakia AA
Other constituitional Diamond-Blackfan anemia (DBA) is a pure
red cell aplasia and usually manifests in early infancy. ( responds to steroids)
Schwachman-Diamond syndrome is a syndrome of bone marrow failure (classically neutropenia), exocrine pancreatic insufficiency, and metaphyseal dysostosis that also manifests in early childhood
PNH Hemolysis Venous thrombosis Aplastic anemia
P.N.H
PNH and Aplastic Anemia PNH is caused by an acquired genetic defect limited
to the stem-cell compartment affecting the PIGA gene.
Mutations in the PIGA gene render cells of hematopoietic origin sensitive to increased complement lysis.
Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation, as detected by means of flow cytometry.
Furthermore, patients whose disease responds after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.
Prognosis The prognosis of bone marrow failure depends on
the duration of the marrow function abnormality. Most inherited forms of bone marrow failure, such
as Fanconi anemia, are associated with transformation into leukemia several years later.
Viral causes, such as parvoviruses, are usually self-limiting.
Acquired idiopathic aplastic anemia is usually permanent and life threatening. Half the patients die during the first 6 months.
Approaches to treatment of Bone Marrow Failure Syndromes
1. Transfusions
2. Growth Factors
3. Immunosuppression
4. SCT
5. Others drugs
References Bethesda Handbook of Clinical hematology
2010 Hamilton et al : Hematology in Clinical
practice 2005 E-medicine online textbook, Hematology Other web resources