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Hypoplastic bone marrow syndromes

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  • 1.  
  • 2. Bone Marrow Failure Syndromes Ahmed Elshebiny University of Menoufyia
  • 3. Blood is continuously renewed
  • 4. The Bone Marrow is the blood Factory May be exposed to damage or failure
  • 5. 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
  • 6. Bone Marrow Failure
    • May involve one or more cell lines
    • Lymphocytes are usually spared
  • 7. Venn Diagram AML APLASTIC ANEMIA MDS PNH
  • 8. Bone Marrow Failure Syndromes
  • 9.  
  • 10. Pathophysiology of Bone marrow Failure
    • A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow
    • Maturation defects, such as vitamin B-12 or folate deficiency
    • Differentiation defects, such as myelodysplasia.
  • 11. Aplastic Anemias Aplastic Anemias Acquired Conistituitional Single line Agranulocytosis Pure Red Cell Aplasia Multilineage
  • 12. 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
  • 13.  
  • 14. Aplastic Anemia
  • 15. Drugs associated with AA
    • NSAIDs(Butazones, Indomethacin,Piroxicam, Diclofenac)
    • Antibiotics( e.g sulfonamides)
    • Furosemide
    • Phenothiazines
    • Corticosteroids
    • Penicillamine
    • Gold
    • Allopurinol
  • 16. 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
  • 17. Severity of AA
    • 2 of 3 peripheral blood count criteria
    • ANC < 500 / µL
    • Plat count< 20 000 / µL
    • Retics (Automated) < 60 000 / µL
  • 18. Pancytopenia
    • Pancytopenia has many causes of which AA is not the most common
  • 19. 1-Pancytopenia with hypocellular bone marrow
    • Acquired Aplastic Anemia
    • Inherited Aplastic Anemia
    • Some MDS
    • Rare aleukemic leukemia
    • Some acute lymphoblastic leukemia
    • Some lymphomas of bone marrow
  • 20. 2-Pancytopenia with cellular bone marrow
    • Primary bone marrow disease
    • MDS
    • PNH
    • Myelofibrosis
    • Mylophthisis
    • Hairy cell leukemia
    • Aleukemic leukemia
    • Secondary to systemic disease
    • SLE
    • alcoholism
    • B12 or folate difficiency
    • Hypersplenism
    • Overwhelming infection
    • Brucellosis
    • Sarcoidosis
    • T.B.
  • 21. 3- Hypocellular marrow with or without cytopenia
    • Q fever
    • Ligionaires
    • Toxoplasmosis
    • Anorexia Nervosa
    • T.B.
    • Hypothyroidism
  • 22. 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
  • 23. Iron Studies
    • SI
    • TIBC
    • Transferrin Saturation
    • Ferritin
  • 24. Bone marrow aspiration and biopsy Hypocellular but there may be pockets of cellularity ( hot spots)
  • 25. 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
  • 26. 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)
  • 27. Management of Acquired AA
    • HSCT using histocompatible sibling donor
    • 75% may lack matched sibling
    • Matched unrelated donor ( MUD) from large donor registries
    • Combined immunosuppression
  • 28. 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.
  • 29. 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.
  • 30. Agranulocytosis (direct toxicity or Immune mediated)
    • Heavy metals
    • Analgesics
    • Antiepliptics ( Carbamazepine, phenytoin)
    • Antipsycotics
    • Cardiovascular drugs ( Captopril, Methyldopa, thiazides,..)
    • Sulfa
    • Antibiotics
    • Levamisole, Fluconazole, Ranitidine, Metclopramide, allopurinol
    • Chinese herbs
    • Insecticides
    • Hair dyes
  • 31. Constitutional Bone Marrow Failure Syndromes
    • Fanconi anemia
    • Dyskeratosis congenita
    • Shwachman-Diamond syndrome
    • Amegakaryocytic thrombocytopenia
    • Diamond-Blackfan anemia
    • Severe congenital neutropenia
    • Thrombocytopenia absent radii syndrome
  • 32. 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
  • 33.  
  • 34.  
  • 35. Fanconi Anemia (ttt)
    • SCT
    • Androgens
    • Growth factors
  • 36. Copyright ©2010 Ferrata Storti Foundation Dokal, I. et al. Haematologica 2010;95:1236-1240 Table 1. Characteristics of the inherited bone marrow failure syndromes
  • 37. Dyskeratosis Congenita
    • Abnornal skin pigmintation
    • Nail Dystrophy
    • Leukoplakia
    • AA
  • 38. 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
  • 39. PNH
    • Hemolysis
    • Venous thrombosis
    • Aplastic anemia
  • 40. P.N.H
  • 41. 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.
  • 42.  
  • 43. 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.
  • 44. Approaches to treatment of Bone Marrow Failure Syndromes
    • Transfusions
    • Growth Factors
    • Immunosuppression
    • SCT
    • Others drugs
  • 45. References
    • Bethesda Handbook of Clinical hematology 2010
    • Hamilton et al : Hematology in Clinical practice 2005
    • E-medicine online textbook, Hematology
    • Other web resources
  • 46. THANK YOU

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