Bone-Marrow-Failure by GerardLum

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									                                                                                                                                               jslum.com | Medicine
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
                                                                                                                        Hypocellular
 Normal BM                                  BM Failure – Appears empty
                                                                                                                        > 90% Intertubucular space occupied by Fat
                                                                                     Classification
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
Clinical
                                                                                       Hemoglobinuria (PNH)
Anaemia – Tiredness, Weakness, Pallor, Breathlessness, Tachycardia
                                                                                       Pregnancy
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
                                                                                     Severity
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




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

 Short Stature
 Microcephaly
 Microphtalmia
 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
                                child

								
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