Maj Gen (R) Masood Anwar

Bone marrow failure syndromes can be defined as a group of diseases in which occurs failure on the part of bone marrow to produce mature and functional blood cells in required quantities. In peripheral blood it will manifest as pancytopenia, bicytopenia or some times monocytopenia.

 Suppression of normal bone marrow maturation (ineffective haemopoiesis)  Destruction or suppression of stem cells and/or microenvironment  Replacement of normal bone marrow with abnormal tissue or cells  Destruction of bone marrow with disease

 Most common cause is ineffective haemopoiesis because of Vitamin B12 and/or Folate deficiency – 29%  Aplastic anaemia – 22-27%  All other causes for remaining <50%

Aplastic Anaemia is defined as pancytopenia in the peripheral blood with hypoplastic bone marrow and no evidence of any primary disease infiltrating, replacing or suppressing active haematopoiesis.

APLASTIC ANAEMIA

 Abnormalities of Stem cell  Abnormalities of Stroma  Abnormalities of cytokines

◦ Failure of stem cells to grow in normal culture ◦ Failure of normal stem cells to grow in patient stromal cell culture ◦ High CSF releaser levels ◦ Decreased response of stem cells to CSF and EPO

EXTRINSIC AGENT INTRINSIC DEFECT SILENT IMMUNE MILD TO MODERATE AUTOREACTIVITY ACUTE DESTRUCTION

 Direct Injury (Secondary or Acquired) ◦ Drugs (Iatrogenic), radiation, viruses ◦ Drug toxicity is through intermediate metabolites ◦ Bind covalently to marrow cell proteins and DNA leading to DNA damage and apoptosis ◦ Radiation causes direct damage to DNA ◦ Viruses intercalate with DNA

 Immune Mediated (idiopathic) ◦ Improvement in pancytopenia after failed allogeneic BMT  Immunosuppressive conditioning (ALG or Cyclophosphamide) intended to allow engraftment of donor marrow might have promoted the function of host marrow*  BMT of an identical twin also requires immunosuppression

 Immune Mediated (idiopathic) ◦ Improvement in pancytopenia after failed allogeneic BMT  Immunosuppressive conditioning (ALG or Cyclophosphamide) intended to allow engraftment of donor marrow might have promoted the function of host marrow*  BMT of an identical twin also requires immunosuppression

 Immune Mediated (idiopathic) ◦ Trials of IST (Immunosuppressive Therapy) ◦ Most successful regimens have been multi-drug combinations ◦ Effectiveness of such trials strongly suggest immune mediated cause of the disease

 Congenital  Acquired

 Skeletal ◦ Short stature ◦ Microcephaly ◦ Radial anamolies ◦ Hip and spine anamolies  Skin ◦ Hyperpigmentation ◦ Hypopigmentation  Genitiurinary tract ◦ Renal tract anamolies ◦ Hypogonadism  Craniofacial  Gastrointestinal  Cardiac  No associated abnormalities

SHORT STATURE

RADIAL ABNORMALITIES

RENAL ANAMOLIES

 Primary Idiopathic  Secondry ◦ PNH ◦ Radiation ◦ Chemicals ◦ Viruses ◦ Drugs  Regularly causing – cytotoxic  Probably causing – chloramphenicol  Rarely causing – Quinine etc ◦ Stroma and growth factors

 Low Hb/Hct, TLC and platelet count defined for the age and sex together with hypocellular marrow  Conveniently divided into three groups for therapeutic decisions  Non Severe Aplastic Anaemia (NSAA)  Severe Aplastic Anaemia (SAA)  Very Severe Aplastic Anaemia (VSAA)

 Presenting complaints – anaemia, infection, bleeding  History – family, personal, occupational, drugs  Physical examination – liver, spleen, lymph nodes  Blood counts ◦ Hb <10 g/dl ◦ Neutrophil count <1.0 X 10^9/l ◦ Platelet count <100 X 10^9/l ◦ Reticulocyte count (corrected) <1% ◦ MCV ~100 fl  Bone marrow ◦ Aspirate ◦ Biopsy