BONE MARROW FAILURE SYNDROMES
Maj Gen (R) Masood Anwar
BONE MARROW FAILURE SYNDROMES
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
CAUSES
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%
CAUSES IN PAKISTAN
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.
DEFINITION
APLASTIC ANAEMIA
Abnormalities of Stem cell Abnormalities of Stroma Abnormalities of cytokines
PATHOPHYSIOLOGY
◦ 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
PATHOGENESISExperimental findings
EXTRINSIC AGENT
INTRINSIC DEFECT
SILENT IMMUNE MILD TO MODERATE
AUTOREACTIVITY
ACUTE DESTRUCTION
PATHOGENESIS
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
PATHOPHYSIOLOGY
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
PATHOPHYSIOLOGY
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
PATHOPHYSIOLOGY
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
PATHOPHYSIOLOGY
Congenital Acquired
AETIOLOGY
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
FANCONI ANEMIA
FANCONI ANAEMIA
SHORTSTATURE
FANCONI ANAEMIA
RADIAL ABNORMALITIES
FANCONI ANAEMIA
RENALANAMOLIES
CHROMOSOMAL FRAGMENTATION
Primary Idiopathic Secondry
◦ PNH◦ Radiation◦ Chemicals◦ Viruses◦ Drugs
Regularly causing – cytotoxic Probably causing – chloramphenicol Rarely causing – Quinine etc
◦ Stroma and growth factors
ACQUIRED APLASTIC ANAEMIA
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)
DIAGNOSTIC CRITERIA
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
DIAGNOSIS
BONE MARROW ASPIRATE
BONE MARROW TREPHINE BIOPSY