BONE MARROW FAILURE SYNDROMES Maj Gen R Masood

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.

CAUSES � 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 IN PAKISTAN � Most common cause is ineffective haemopoiesis because of Vitamin B 12 and/or Folate deficiency – 29% � Aplastic anaemia – 22 -27% � All other causes for remaining <50%

DEFINITION 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

PATHOPHYSIOLOGY � Abnormalities of Stem cell � Abnormalities of Stroma � Abnormalities of cytokines

PATHOGENESIS Experimental findings ◦ 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

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

PATHOPHYSIOLOGY � 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 allogeneic BMT pancytopenia after failed �Immunosuppressive conditioning (ALG or Cyclophosphamide) intended to allow engraftment of donor marrow might have promoted the function of host marrow* �BMT of an identical immunosuppression twin also requires

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

AETIOLOGY � Congenital � Acquired

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

FANCONI ANAEMIA SHORT STATURE

FANCONI ANAEMIA RADIAL ABNORMALITIES

FANCONI ANAEMIA RENAL ANAMOLIES

CHROMOSOMAL FRAGMENTATION

ACQUIRED APLASTIC ANAEMIA � Primary Idiopathic � Secondry ◦ ◦ ◦ PNH Radiation Chemicals Viruses Drugs �Regularly causing – cytotoxic �Probably causing – chloramphenicol �Rarely causing – Quinine etc ◦ Stroma and growth factors

DIAGNOSTIC CRITERIA �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)

DIAGNOSIS � 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

BONE MARROW ASPIRATE

BONE MARROW TREPHINE BIOPSY