Bone Marrow  Failure Syndromes Ahmed Elshebiny University 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 Dia...
Bone Marrow Failure <ul><li>May involve one or more cell lines </li></ul><ul><li>Lymphocytes are usually spared </li></ul>
Venn Diagram AML APLASTIC ANEMIA MDS PNH
Bone Marrow Failure Syndromes
 
Pathophysiology of Bone marrow Failure <ul><li>A decrease in or damage to the hematopoietic stem cells and their microenvi...
Aplastic Anemias Aplastic Anemias Acquired Conistituitional Single line Agranulocytosis Pure Red Cell Aplasia Multilineage
Aplastic Anemia <ul><li>Named so in 1904 </li></ul><ul><li>The theoretical basis for marrow failure includes primary defec...
 
Aplastic Anemia
Drugs associated with AA <ul><li>NSAIDs(Butazones, Indomethacin,Piroxicam, Diclofenac) </li></ul><ul><li>Antibiotics( e.g ...
Clinical and laboratory features <ul><li>symptoms due to pancytopenia </li></ul><ul><li>No lymphadenopathy or splenomegaly...
Severity of AA <ul><li>2 of 3 peripheral blood count criteria </li></ul><ul><li>ANC < 500 / µL </li></ul><ul><li>Plat coun...
Pancytopenia <ul><li>Pancytopenia has many causes of which AA is not the most common </li></ul>
1-Pancytopenia with hypocellular bone marrow <ul><li>Acquired Aplastic Anemia </li></ul><ul><li>Inherited Aplastic Anemia ...
2-Pancytopenia with cellular bone marrow <ul><li>Primary bone marrow disease </li></ul><ul><li>MDS </li></ul><ul><li>PNH <...
3- Hypocellular marrow with or without cytopenia <ul><li>Q fever </li></ul><ul><li>Ligionaires </li></ul><ul><li>Toxoplasm...
CBC and Blood film <ul><li>Decreased numbers </li></ul><ul><li>Decreasd retics usually to less than 1 % </li></ul><ul><li>...
Iron Studies <ul><li>SI </li></ul><ul><li>TIBC </li></ul><ul><li>Transferrin Saturation </li></ul><ul><li>Ferritin </li></ul>
Bone marrow aspiration and biopsy Hypocellular but there may be pockets of cellularity ( hot spots)
Other lab studies <ul><li>Chromosomal analysis and cytogenetic studies </li></ul><ul><li>Chromosomal breakage analysis wit...
Imaging studies of bone marrow function <ul><li>Ferrokinetic studies have been conducted using a radioactive label, such a...
Management of Acquired AA <ul><li>HSCT using histocompatible sibling donor </li></ul><ul><li>75% may lack matched sibling ...
Prognosis <ul><li>With current BMT regimens, most patients with severe aplastic anemia have a 60-70% long-term survival ra...
Pure Red Cell Aplasia (PRCA) <ul><li>May be caused by a thymoma.  </li></ul><ul><li>It may occur transiently, resulting fr...
Agranulocytosis (direct toxicity or Immune mediated) <ul><li>Heavy metals </li></ul><ul><li>Analgesics </li></ul><ul><li>A...
Constitutional Bone Marrow Failure Syndromes <ul><li>Fanconi anemia  </li></ul><ul><li>Dyskeratosis congenita  </li></ul><...
Fanconi Anemia <ul><li>Autosomal Recessive in 99% </li></ul><ul><li>FANCB is x-linked recessive </li></ul><ul><li>Birth de...
 
 
Fanconi Anemia (ttt) <ul><li>SCT </li></ul><ul><li>Androgens </li></ul><ul><li>Growth factors  </li></ul>
Copyright ©2010 Ferrata Storti Foundation Dokal, I. et al. Haematologica 2010;95:1236-1240 Table 1. Characteristics of the...
Dyskeratosis Congenita <ul><li>Abnornal skin pigmintation </li></ul><ul><li>Nail Dystrophy </li></ul><ul><li>Leukoplakia <...
Other constituitional  <ul><li>Diamond-Blackfan anemia (DBA) is a pure red cell aplasia and usually manifests in early inf...
PNH <ul><li>Hemolysis </li></ul><ul><li>Venous thrombosis </li></ul><ul><li>Aplastic anemia </li></ul>
P.N.H
PNH and Aplastic Anemia <ul><li>PNH is caused by an acquired genetic defect limited to the stem-cell compartment affecting...
 
Prognosis <ul><li>The prognosis of bone marrow failure depends on the duration of the marrow function abnormality.  </li><...
Approaches to treatment of Bone Marrow Failure Syndromes <ul><li>Transfusions </li></ul><ul><li>Growth Factors </li></ul><...
References <ul><li>Bethesda Handbook of Clinical hematology 2010 </li></ul><ul><li>Hamilton et al : Hematology in Clinical...
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Hypoplastic bone marrow syndromes

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Hypoplastic bone marrow syndromes

  1. 2. Bone Marrow Failure Syndromes Ahmed Elshebiny University of Menoufyia
  2. 3. Blood is continuously renewed
  3. 4. The Bone Marrow is the blood Factory May be exposed to damage or failure
  4. 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
  5. 6. Bone Marrow Failure <ul><li>May involve one or more cell lines </li></ul><ul><li>Lymphocytes are usually spared </li></ul>
  6. 7. Venn Diagram AML APLASTIC ANEMIA MDS PNH
  7. 8. Bone Marrow Failure Syndromes
  8. 10. Pathophysiology of Bone marrow Failure <ul><li>A decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow </li></ul><ul><li>Maturation defects, such as vitamin B-12 or folate deficiency </li></ul><ul><li>Differentiation defects, such as myelodysplasia. </li></ul>
  9. 11. Aplastic Anemias Aplastic Anemias Acquired Conistituitional Single line Agranulocytosis Pure Red Cell Aplasia Multilineage
  10. 12. Aplastic Anemia <ul><li>Named so in 1904 </li></ul><ul><li>The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment </li></ul><ul><li>Distinction between congenital or acquired may be difficult </li></ul><ul><li>80 % of patients have acquired cause which is an autoimmune disease </li></ul>
  11. 14. Aplastic Anemia
  12. 15. Drugs associated with AA <ul><li>NSAIDs(Butazones, Indomethacin,Piroxicam, Diclofenac) </li></ul><ul><li>Antibiotics( e.g sulfonamides) </li></ul><ul><li>Furosemide </li></ul><ul><li>Phenothiazines </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Penicillamine </li></ul><ul><li>Gold </li></ul><ul><li>Allopurinol </li></ul>
  13. 16. Clinical and laboratory features <ul><li>symptoms due to pancytopenia </li></ul><ul><li>No lymphadenopathy or splenomegaly or cachexia </li></ul><ul><li>Anemia is usually normocytic </li></ul><ul><li>Hypocellular marrow is the hallmark </li></ul><ul><li>Need to rule out other disorders </li></ul>
  14. 17. Severity of AA <ul><li>2 of 3 peripheral blood count criteria </li></ul><ul><li>ANC < 500 / µL </li></ul><ul><li>Plat count< 20 000 / µL </li></ul><ul><li>Retics (Automated) < 60 000 / µL </li></ul>
  15. 18. Pancytopenia <ul><li>Pancytopenia has many causes of which AA is not the most common </li></ul>
  16. 19. 1-Pancytopenia with hypocellular bone marrow <ul><li>Acquired Aplastic Anemia </li></ul><ul><li>Inherited Aplastic Anemia </li></ul><ul><li>Some MDS </li></ul><ul><li>Rare aleukemic leukemia </li></ul><ul><li>Some acute lymphoblastic leukemia </li></ul><ul><li>Some lymphomas of bone marrow </li></ul>
  17. 20. 2-Pancytopenia with cellular bone marrow <ul><li>Primary bone marrow disease </li></ul><ul><li>MDS </li></ul><ul><li>PNH </li></ul><ul><li>Myelofibrosis </li></ul><ul><li>Mylophthisis </li></ul><ul><li>Hairy cell leukemia </li></ul><ul><li>Aleukemic leukemia </li></ul><ul><li>Secondary to systemic disease </li></ul><ul><li>SLE </li></ul><ul><li>alcoholism </li></ul><ul><li>B12 or folate difficiency </li></ul><ul><li>Hypersplenism </li></ul><ul><li>Overwhelming infection </li></ul><ul><li>Brucellosis </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>T.B. </li></ul>
  18. 21. 3- Hypocellular marrow with or without cytopenia <ul><li>Q fever </li></ul><ul><li>Ligionaires </li></ul><ul><li>Toxoplasmosis </li></ul><ul><li>Anorexia Nervosa </li></ul><ul><li>T.B. </li></ul><ul><li>Hypothyroidism </li></ul>
  19. 22. CBC and Blood film <ul><li>Decreased numbers </li></ul><ul><li>Decreasd retics usually to less than 1 % </li></ul><ul><li>Normo or macrocytosis </li></ul><ul><li>Increased platelet hetrogenicity in size </li></ul><ul><li>Microspherocytes and giant platelets are absent </li></ul><ul><li>Relative lymphoctosis </li></ul>
  20. 23. Iron Studies <ul><li>SI </li></ul><ul><li>TIBC </li></ul><ul><li>Transferrin Saturation </li></ul><ul><li>Ferritin </li></ul>
  21. 24. Bone marrow aspiration and biopsy Hypocellular but there may be pockets of cellularity ( hot spots)
  22. 25. Other lab studies <ul><li>Chromosomal analysis and cytogenetic studies </li></ul><ul><li>Chromosomal breakage analysis with MMC/DEB </li></ul><ul><li>h TERC screen for DC and other tests </li></ul><ul><li>Difficient GPI- anchored proteins on flow- cytometry </li></ul><ul><li>Ham test </li></ul>
  23. 26. Imaging studies of bone marrow function <ul><li>Ferrokinetic studies have been conducted using a radioactive label, such as iron-59 or indium-111 </li></ul><ul><li>Magnetic resonance imaging (MRI) </li></ul><ul><li>Positron emission tomography (PET) </li></ul>
  24. 27. Management of Acquired AA <ul><li>HSCT using histocompatible sibling donor </li></ul><ul><li>75% may lack matched sibling </li></ul><ul><li>Matched unrelated donor ( MUD) from large donor registries </li></ul><ul><li>Combined immunosuppression </li></ul>
  25. 28. Prognosis <ul><li>With current BMT regimens, most patients with severe aplastic anemia have a 60-70% long-term survival rate. </li></ul><ul><li>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% </li></ul><ul><li>Cyclosporine therapy at 200-400 mg/d (maintain serum trough levels at 100-250 ng/mL) has a reported 85% hematologic remission rate. </li></ul>
  26. 29. Pure Red Cell Aplasia (PRCA) <ul><li>May be caused by a thymoma. </li></ul><ul><li>It may occur transiently, resulting from a viral infection such as with parvovirus B19. </li></ul><ul><li>Pure red cell aplasia also may be permanent, as a result of viral hepatitis. </li></ul><ul><li>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. </li></ul>
  27. 30. Agranulocytosis (direct toxicity or Immune mediated) <ul><li>Heavy metals </li></ul><ul><li>Analgesics </li></ul><ul><li>Antiepliptics ( Carbamazepine, phenytoin) </li></ul><ul><li>Antipsycotics </li></ul><ul><li>Cardiovascular drugs ( Captopril, Methyldopa, thiazides,..) </li></ul><ul><li>Sulfa </li></ul><ul><li>Antibiotics </li></ul><ul><li>Levamisole, Fluconazole, Ranitidine, Metclopramide, allopurinol </li></ul><ul><li>Chinese herbs </li></ul><ul><li>Insecticides </li></ul><ul><li>Hair dyes </li></ul>
  28. 31. Constitutional Bone Marrow Failure Syndromes <ul><li>Fanconi anemia </li></ul><ul><li>Dyskeratosis congenita </li></ul><ul><li>Shwachman-Diamond syndrome </li></ul><ul><li>Amegakaryocytic thrombocytopenia </li></ul><ul><li>Diamond-Blackfan anemia </li></ul><ul><li>Severe congenital neutropenia </li></ul><ul><li>Thrombocytopenia absent radii syndrome </li></ul>
  29. 32. Fanconi Anemia <ul><li>Autosomal Recessive in 99% </li></ul><ul><li>FANCB is x-linked recessive </li></ul><ul><li>Birth defects </li></ul><ul><li>Bone marrow failure </li></ul><ul><li>Oncogenesis ( hematological and solid) </li></ul><ul><li>Mutations in 13 genes </li></ul><ul><li>10% develop leukemia and 6% MDS </li></ul>
  30. 35. Fanconi Anemia (ttt) <ul><li>SCT </li></ul><ul><li>Androgens </li></ul><ul><li>Growth factors </li></ul>
  31. 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
  32. 37. Dyskeratosis Congenita <ul><li>Abnornal skin pigmintation </li></ul><ul><li>Nail Dystrophy </li></ul><ul><li>Leukoplakia </li></ul><ul><li>AA </li></ul>
  33. 38. Other constituitional <ul><li>Diamond-Blackfan anemia (DBA) is a pure red cell aplasia and usually manifests in early infancy. ( responds to steroids) </li></ul><ul><li>Schwachman-Diamond syndrome is a syndrome of bone marrow failure (classically neutropenia), exocrine pancreatic insufficiency, and metaphyseal dysostosis that also manifests in early childhood </li></ul>
  34. 39. PNH <ul><li>Hemolysis </li></ul><ul><li>Venous thrombosis </li></ul><ul><li>Aplastic anemia </li></ul>
  35. 40. P.N.H
  36. 41. PNH and Aplastic Anemia <ul><li>PNH is caused by an acquired genetic defect limited to the stem-cell compartment affecting the PIGA gene. </li></ul><ul><li>Mutations in the PIGA gene render cells of hematopoietic origin sensitive to increased complement lysis. </li></ul><ul><li>Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation, as detected by means of flow cytometry. </li></ul><ul><li>Furthermore, patients whose disease responds after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH. </li></ul>
  37. 43. Prognosis <ul><li>The prognosis of bone marrow failure depends on the duration of the marrow function abnormality. </li></ul><ul><li>Most inherited forms of bone marrow failure, such as Fanconi anemia, are associated with transformation into leukemia several years later. </li></ul><ul><li>Viral causes, such as parvoviruses, are usually self-limiting. </li></ul><ul><li>Acquired idiopathic aplastic anemia is usually permanent and life threatening. Half the patients die during the first 6 months. </li></ul>
  38. 44. Approaches to treatment of Bone Marrow Failure Syndromes <ul><li>Transfusions </li></ul><ul><li>Growth Factors </li></ul><ul><li>Immunosuppression </li></ul><ul><li>SCT </li></ul><ul><li>Others drugs </li></ul>
  39. 45. References <ul><li>Bethesda Handbook of Clinical hematology 2010 </li></ul><ul><li>Hamilton et al : Hematology in Clinical practice 2005 </li></ul><ul><li>E-medicine online textbook, Hematology </li></ul><ul><li>Other web resources </li></ul>
  40. 46. THANK YOU

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