Hypoplastic bone marrow syndromes

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