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.

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