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Bone Marrow Failure

Definition Aplastic Anaemia

Disorders of hematopoietic stem cell Multipotent Myeloid Stem Cells are suppressed
Can involve 1 or all cell line(s) Marrow Failure
Erythroid – Red cells Pancytopenia
Myeloid – White blood cells Characteristics
Megakaryocytic – Platelets Peripheral Pancytopenia
Pancytopenia/ Single Cytopenia – Due to failure of BM to produce blood cells Marrow Hypoplasia
Red cells – Normocytic, Normochromi c (slight Macrocytosis may present)

Normal BM Aplastic Anaemia BM

Normal BM BM Failure – Appears empty
> 90% Intertubucular space occupied by Fat
Pathophysiol ogy (General)
Acquired Inherited
Causes of ↓/ Damaged to HSC (Hematopoietic Stem Cells), Microenvironment
Radiation – Marrow aplasmia Fanconi’s Anaemia
• Acquired stem cell injury – Viruses, Toxins, Chemicals
(Stems, Progenitor cells, Stroma Dyskeratosis Congenita
(Quantitative, Qualitative abnormality)
may all be damaged) Shwachman Syndrome
• Abnormal Humoral or Cellular Control of Haematopoiesis
Drugs & Chemicals Amegakaryocytic
• Abnormal or Hostile Marrow Microenvironment
• Regular effects (Cytotoxic Thrombocytopenia
• Immunologic Sup pression of Hematop oiesis
agents, Benzene)
(eg. Mediated by Antibodies, T cells (or cellularly) or Lymphokines)
• Idiosyncratic reactions
• Mutations in Genes (Inherited BM Failure syndromes)
(Chloramphe nicol, NSAIDs)
Mechanisms of Action
Viruses – Epstein-Barr Virus,
• Damage to HSC, Microenvironment – results in Hypoplastic/ Aplastic BM
Hepatitis, HIV
• Maturation Defects – B12, Folate deficiency
Immune Disease
• Differentiation Defects - Myelodysplasia
(Hypoimmun oglobulinemia)
Paroxysmal Nocturnal
Hemoglobinuria (PNH)
Anaemia – Tiredness, Weakness, Pallor, Breathlessness, Tachycardia
Granulocytopenia – Recurrent/ Severe Bacterial Infections
Signs & Symptoms
Thrombocytopenia – easy Bruising, Petechiae, Bleeding from Nose/ Gums
Bleeding – Easy Bruising, Nose Bleed, Heavy/Irregular Menses
Dark Urine (presence of Hb may accompany PNH)
Forms of BM Failure
Non-spe cific symptoms of Chronic Anaemia – Fatigue, SOB, Ringing in Ears
Aplastic anaemia (AA)(can develop to MS, PNH) Fever
Myelodysplastic Syndrome (MS) Loss of Appetite, Loss of Weight
Paroxysmal Nocturnal Hemoglobinuria (PNH) Clinical
• Expansion of 1 or several cell clones (abnormal stem cell) that can grow in Cachexia
BM environment where normal BM have difficulty/ cannot grow at all Petechiae – located over dependant region
• PNH cells - Deficient in all protein that use glycosylphosphatidylinositol (Pretibial surface, dorsal aspect of Ankles, Wrists)
(GPI) mole cule for attachment to cell surface Pallor – Mucous membranes, Nail beds
• Diagnosis made when GPI-anchored Proteins from cell surface Absent Lymphadenopathy & Splenomegaly are Not Seen
Classification Platelet (/uL) Reticulocyte (/uL) Neutrophil (/uL)
Congenital Acquired Moderate < 80000 < 60000 < 1200
Fanconi’s Anaemia Acquired Aplastic Anaemia (AAA) Severe < 20000 < 60000 * < 500
Dyskeratosis Congenita Virus Infection Very Severe < 100
Diamond Blackfan Anaemia (Hepatitis B, Epstein-Barr, Parvovirus B19) * = Or Transfusion Dependant
Scwachman-Diamon d Syndrome Treatment
BM Transplantation
Pancytopenias Single Cytopenias Immunosuppression
Aplastic Anaemia Diamond-Black fan Anaemia (Antithymocyte, Antilymphocyte Globulins, Androgens, Corticosteroids)
Fanconi Anaemia Transient Erythroblastopenia (Effe ctive alternative for non-candidate for BM Transplant)
Dyskeratosis Congenita Congenital Dyserythropoietic Anaemia Supportive Treatment – Blood Transfusion
Scwachman-Diamon d Syndrome Congenital Sideroblastic Anaemia

Scwachman – Diamond Syndrome Amegakaryocytic Thrombocytopenia
Autosomal recessive disorder Autosomal recessive disorder
Mutated SBDS gene Biallelic Mutations
(Scwachman Bodian Diamond Syndr.) Thrombopoietin receptor
Pancytopenia Single Cytopenia
Congenital Congenital
Exocrine Pancreatic Insufficien cy &
BM Failure
Cartilage, Hair Hypoplasia occur
(Short stature, Dysostosis) | Medicine

Myelodysplastic Syndromes (MS) (=Preleukaemia) Dyskeratosis Congenita

Can Develop to Acute Myeloid Leukaemia (Minority) Inherited Genetic Skin condition
(↑ Difficult to Treat than 1° AML) X-linked Recessive disorder
BM ↑ Active (compared to Normal) Mutation of
Numbers of Bl ood Cells in Circulation ↓ DKC1 (Dyskerin) gene
Cells produced in BM are Defective & Destroyed before leaving BM to enter TERC (Telomerase Reverse Transcriptase RNA template) gene
blood stream (DKC1, TERC – Involved in Maintenance of Telomerase length)
Pathophysiol ogy Characteristics (3 Triad of Events)
1° 2° Nail dystrophy
No known exposure Aggressive Treatment of other Mucosal Leukoplakia
Cancers with exposure to Pigmentation of Upper Body
• Radiation Haematological Features
• Alkylating Agents Anaemia
• Topoisomerase II Inhibitors Leucope nia
Initial HSC (Hematopoietic Stem Cell) injury can be from Thrombocytopenia
• Cytotoxic Chemotherapy
• Radiation Exposure
• Viral Infection
• Chemical exposure to Genotoxins (eg. Ben zene)
• Genetic Predisposition
Clonal mutation predominates over BM, suppress healthy stem cells
In early stages, main cause of Cytopenias is ↑ Apoptosis
As disease progress & convert to Leukaemia
• Gene mutation occur
• Proliferation of Leukemic cells (overwhelms the Healthy marrow)
Chemotherapy (rarely cure the disease)
(Intensive/ ↓ Dose Chemotherapy – Worsen the disease)
↑ Risk ↓ Risk
General support Blood Transfusion
Single agent chemotherapy Antibiotic
(Hydroxyurea, Etopoxides, Epo, GCSF
Mercaptopurine, ↓ Dose Cytosine
Arabinoxide)(Demethhylating agent
5’ Azacytidine/ Decitabine)
Intensive Chemotherapy Abnormal Skin Pigmentatio n Abnormal Skin Pigmentatio n Abnormal Skin Pigmentatio n
Stem cell Transplantation Premature Greying of Hair

Fanconi’s Anaemia (FA)

BM Disorder
Features of Aplastic Anaemia, Congenital Physical Anomalies
Leukoplakia Nail Dystrophy Nail Dystrophy
Autosomal recessive
Premature Loss of Teeth
X-linked pattern of Inheritance Dyskeratosis Co ngenita l
Fanconi anaemia (FANC) genes Hypocellular BM Fragment
Encode for Proteins involved in FA pathway
Responsible for repair of DNA damage
FANCD 1 – Identical to Breast/ Ovarian susceptibility gene (BRCA2)
Mutations in gene is responsible for FA
Clinical Diamond-Bla ckfan Anaemia
Pancytopenia Fail to make enough RBC (Inherited Erythroblastopenia)
Hyper/ Hypopigmented skin lesions
Congenital, Single Cytopenia
Short Stature
Anaemia apparent during 1st year of life
Skeletal Malformation (Thumb, Radial Anomalies)
(Fatigue, Weakness, Pallor)
Structural Renal Abnormalities Clinical
Birth Marks Microcephaly Small, Low-set Ears Hand abnormalities
Microcephaly Low Frontal Hairline Micrognathia Malformed/ Absent
Hypertelorism Cleft Palate Thumb
Ptosis Short, Webbed Neck Slowed growth –
Broad, Flat bridge of Shoulder Blades – Leading to Short
Nose Smaller, Higher than Stature

Short Stature
Epicanthal folds
Dangling thumbs Abnormal Thumbs Hyperpigmented
Site of Ureter area
reimplantation Treatment
Congenital Dislocated Hips Hematopoietic Stem Cell Transplantation
Rocker Bottom Feet (1st line therapy) Diamond-Bla ckfan Anaemia
Androgen Hb – 46g/L
(used when Transplantation is not an option) MCV – 124 fl
Preimplantation Genetic Diagnosis (PGD) –
For HLA matching to give rise to a sibling
(free of the disease) & d onate for the sick