IOD Bone Marrow Failure

Question 1

What are all cells made from?

Answer 1

stem cells

Question 2

Which cells are made?

Answer 2

Erythrocyte, platelets, macrophages, neutrophils, eosinophils, basophils, B cells, T cells

Question 3

What does BM need?

Answer 3

cytokines
EPO, TPO, GCSF and many others
Haematinics: B12, folate, iron

Question 4

do WCC need iron?

Answer 4

no

Question 5

What should be in peripheral blood?

Answer 5

Should be mature red cells, white cells and platelets

In abnormal cases, often reflects problems of BM

Question 6

Reasons for cytopenias and examples?

Answer 6

Reduced cell production
B12, folate, iron deficiency
Epo deficiency in CKD

Excess loss of cells, or destruction
Single cell line affected
Pancytopenia – all 3 cell lines

Failure of appropriate utilisation
Anaemia of chronic disease

Question 7

signs of red cell cytopenia?

Answer 7

Lethargy, poor concentration, loss of appetite, pale skin, shortness of breath, tachycardia, reduced exercise tolerance

Question 8

signs of white cells cytopenia?

Answer 8

Fevers and infections – esp urine, chest, sinus and skin, sore mouth

Question 9

signs of platelets cytopenia?

Answer 9

Easy bruising and bleeding, menorrhagia, epistaxis, petechiae, gum bleeding

Question 10

Inherited single lineage

Answer 10

Anaemia [Diamond-Blackfan]
Neutropenia [Congenital]
Thrombocytopenia [Congenital amegakaryocytic & thrombocytopenia with absent radii-TAR]

Question 11

inherited pancytopenia?

Answer 11

Fanconi Anaemia
Dyskeratosis Congenita
Shwachman-Diamond Pearson

Question 12

acquired single lineage?

Answer 12

Pure red cell aplasia [viral, immune, drugs]

Question 13

acquired pancytopenia?

Answer 13

Aplastic anaemia [drugs, viral, immune]
Bone marrow infiltration [leukaemia, MDS]
Paroxysmal nocturnal haemoglobinuria

Question 14

Diamond-blackfan anaemia?

Answer 14

: inherited PRCA. Skeletal abnormalities [craniofacial, thumb & upper limb, cardiac and urogential malformation, cleft palate, increased risk of leukaemia

Question 15

Thrombocytopenia with absent radii?

Answer 15

: low platelet count with no radius bone. Associated with lactose intolerance, cardiac and kidney problems

Question 16

fanconi anaemia?

Answer 16

pancytopenia, short stature, endocrine problems, skin pigmentation, abnormalities of arms, eyes, kidneys, ears. Increased risk of cancer, especially AML

Question 17

Dyskeratosis congenita?

Answer 17

skin pigmentation, nail dystrophy and oral leukoplakia, with progressive BMF

Question 18

Scwachman-Diamond Pearson?

Answer 18

predominantly a neutropenia, but all 3 cell lines affected, exocrine pancreatic dysfunction, growth retardation

Question 19

myelodysplastic syndrome?

Answer 19

abnormal cells in the BM which do not mature properly

Question 20

paroxysmal nocturnal haemoglobinuria?

Answer 20

defective blood cells, especially RBCs very susceptible to destruction by the complement system; haemolysis, haemoglobinuria. A degree of bone marrow dysfunction and risk of life threatening blood clots

Question 21

Signs of aplastic anaemia?

Answer 21

Hypocellular bone marrow
No abnormal cells
No fibrosis

At least 2 of the following:
Hb <100 g/L
Plt <50x109/L
Neut <1.5x109/L

Question 22

Severity of AA?

Answer 22

RBCs less than 20 , platelets less than 20, neutrophils less than 0.5 -severe
very severe-neutrophils less than 0.2

Question 23

Appearance of AA?

Answer 23

fat, no cancer cells , no BM cells

Question 24

Info AA?

Answer 24

Rare (2-3 cases per million per year)
Wide age range (peak ~25 yrs, >65 yrs) Oriental+

Diagnosed by absence of cells
no characteristic presence or diagnostic test

Thorough history of viruses, travel, occupation, vaccinations, childhood history, skeletal abnormalities, medications – including over the counter

Marked neutropenia leads to risk of overwhelming infection; may be life threatening. Signs and symptoms related to cytopenias

Question 25

Causes of AA?

Answer 25

PREDICTABLE Radiation, high dose chemotherapy - dose dependent Predictable recovery course IDIOSYNCRATIC Drug induced – not dose related Many small case reports – evidence unclear Chloramphenicol VIRAL Hepatitis ( 5-10% of cases) ? EBV/CMV/ HIV IDIOPATHIC Majority of cases (60-70%)

Question 26

Pathogenesis AA?

Answer 26

Unclear, probably autoimmune component-T cell reaction BM environment and stromal cells may have a role Demonstrated increased progressive shortening of the terminal restriction fragments of chromosomes – telomere shortening

Question 27

Diagnosis AA?

Answer 27

FBC, blood film, retics, BM, Viral studies, LFTs

Question 28

how to exclude PNH?

Answer 28

PIG-A gene mutation causing absence of GPI anchored proteins Disregulated complement leads to intravascular haemolysis (thromboses) NO depletion leads to smooth muscle contraction & vasoconstriction - pain

Question 29

how to exclude malignant hypocellular disease?

Answer 29

Immunophenotyping, cytogenetics

Question 30

how to exclude late presentation of congenital forms

Answer 30

Chromosomal breakage analysis for Fanconi anaemia | X-rays, Autoimmune studies

Question 31

Complications?

Answer 31

``` Risk of infection – life threatening Blood transfusion support Antibodies, reactions Iron overload Reduced quality of life ``` Evolution to PNH ~7% Transformation to acute leukaemia ~10%

Question 32

Treatment AA?

Answer 32

``` Supportive treatment: Blood product support, antibiotics, general advice Immunosuppression: Ciclosporin ATG (rabbit or horse) Growth factors: Eg GCSF in combination with the above Haemopoietic Stem Cell Transplant: Sibling donor first line treatment now if pt <40yrs ```

Question 33

Fanconi anaemia?

Answer 33

``` AR disorder with progressive pancytopenia High frequency of chromosome breakages Can isolate breakage points Increased predisposition to malignancies Most (60%) patients have somatic abnormalities Skin – cafe au lait Skeletal – eg absent thumbs GU – horseshoe kidneys Cardiac Neurological ```

Question 34

Porgression?

Answer 34

``` Very rare and varied presentations Difficult diagnosis Normal FBC at birth Usually presents between 5 and 10 yrs Progresses with age BM failure in 90% by 40 yrs ``` Acute Leukaemia: 33% cumulative incidence by 40yrs Solid tumours: 28% cumulative incidence by 40 yrs

Question 35

Treatment FA?

Answer 35

Risk of death from disease is from BM failure BMT if possible: Definitive treatment Prior to BMT – supportive treatment, steroids and androgens but life expectancy mid-20s-growth factors

Question 36

Dyskeratosis congenita?

Answer 36

Abnormal skin pigmentation, nail dystrophy, mucosal leucoplakia BM failure cause of early mortality Pulmonary complications, risk of malignancy X linked, dyskerin gene

Question 37

Transient red cell aplasia?

Answer 37

Infection with Parvovirus B19 ‘Slapped cheek’ syndrome Specifically infects & destroys erythroid precursor cells Erythropoiesis ceases for 5-10 days Unconcerning in normal people (RBCs live for 120 days) Can be life-threatening in those with an underlying chronic anaemia

Question 38

Diagnosis of tca?

Answer 38

Parvo B19 serology testing | (IgM positive shows acute infection) and PCR

Question 39

treatment of TCA?

Answer 39

Supportive (isolation – saliva, respiratory spread) RBC transfusion if necessary Keep away from pregnant women: crosses placenta

Question 40

Diagnosis of BMF?

Answer 40

Low blood counts (pancytopenia) Refer for urgent evaluation Repeat FBC and blood film

Question 41

other tests?

Answer 41

LFT's, RBCs, B12, folate, ferritin, Coag screen Viral serology Autoimmune profile

Question 42

history and exam?

Answer 42

sepsis, bleeding, splenomegaly, jaundice, lymphadenopathy

Question 43

Approach to neutropenic sepsis?

Answer 43

This is a medical emergency!! (ABC approach to a sick patient) A life threatening complication of chemotherapy Suspect in anyone who is hypotensive and tachycardic They may not have a fever Neutrophil count <1.0 x109/L Give broad spectrum IV antibiotics without delay

Question 44

Classification of thrombocytopenia?

Answer 44

Characterised by purpura, easy bruising and overt bleeding - such as menorrhagia, epistaxis and gastrointestinal bleeds. Reduced production Congenital Acquired – marrow infiltration eg myelofibrosis, aplastic anaemia, drugs eg omeprazole Increased destruction Immune – idiopathic, viral, drugs Microangiopathic disease – TTP, DIC, HUS Septicaemia – usually secondary to Gram-negative organisms

Question 45

Thrombocytopenia therapy?

Answer 45

If actively bleeding: Intravenous immunoglobulin & steroids +/- TXA In very severe cases eg intracranial haemorrhage give platelets May require red cell transfusion & correction of clotting abnormalities. In chronic cases: Immunosuppressants & steroid sparing agents eg azathioprine, MMF, Rituximab, TPO receptor agonists: romiplostim/ eltrombopag, splenectomy Always look for the underlying cause, and treat it!