Myeloproliferative, myelodysplastic and aplastic anaemia Flashcards
Haemopoesis Definition
The production of blood cells
Where does haemopoesis occur in the foetus?
0-2 months - yolk sac
2-7 months - liver, spleen
5-9 months - bone marrow
Where does haemopoesis occur in infants
Bone marrow - all bones
Where does haemopoesis occur in adults
Bone marrow
vertebrae, ribs, sternum, skull, sacrum, pelvis, ends of femur
Haemopoesis hierarchy
DRAW
Pluriopotent stem cell
Numbers diminish with age, committed to divide
Colony forming unit
commited to divide
Where are haemopoetic stem cells found?
BM
Peripheral blood after treatment with G-CSF
Umbillical cord blood
Haempoetic stem cell characteristics
- self renewal
- unspecialised
- ability to differentiate (mature)
- quescent (non in cell cycle)
- rare cell
Control of stem cell fate
HSC can
a. undergo self-renewal (identical copy)
b. Apoptosis (programmed cell death)
c. Differentations (Matureation and specialisation)
Types of stem cell division
Types of division
Symmetrical - both daughter cells mature leading to a contraction in stem cell numbers
Assymetrical division- one new daughter cell (maintenance of numbers), one differentiations
Symmetrical stem cell - Expansion
of stem cell number
Balance is influencced by complex interplay of micro-environment (the niche) and internal ques
Stroma definition
BM microenviroment that supports the developing haemopoetic stem cell
Stroma/ bone marrow microenvironment features
Stromal cells + ECM
Stromal cells - macrophages, fibroblasts, endothelial cells, fat cells, reticulum cells
Surrounded by ECM
-laminin, fibronectin, collagen, Proteoglycans
Sinusoids: network of BVs lined by a singel layer of endothelial cells, support haemopoetic cells, allow passage of newly formed cells into the circulation
Haemopoetic cords/islands
- site of haemopoesis
Macrophages
- found within haemopoetic cords
- contain stored iron (haemosiderrin + ferritin)
Pre-malignant and malignant conditions are termed clonal because..?
They arise from a single ancestral cells
Examples
- over-production = Myeloproliferative disorder
- Under production = Aplastic anaemia (e.g fanconis)
- Abnormal cells produced
= myelodysplasia, leukaemia
Myeloproliferative disorders
Polycythaemia rubra vera
Essential thrombocytosis
Myelofibrosis
Myeloproliferative disorders definition
Uncontrolled proliferation of one or more of the myeloid stem cell line. While the cells proliferate the also retain the ability to differntiate into RBCs, WBCs or platelets
Myelofibrosis definition
Marrow scarring due to hyperplasia of megakarocytes which causes increased production of PDGF
Causes of myelofibrosis
50% JAK2, 50% calreticulin
Increased PDGF leads to myeloid metaplasia
Massive hepatomegaly
Presentation of myelofibrosis
constitutional symptoms
Abdominal discomfort - massive spleenn
BM failure (Anaemia, Infection, bleeding)
Investigations of myelofibrosis
BM
- aspirate- dry
- trephone - shows fibrosis
FBC
- pts in high then thrombocytopenia
- decreased RBC
- WCC increased or decreased
Blood fillm
- tear drops RBCs
- leucoerythroblastic cells
Treatment of myelofibrosis
Under 50
- myeloblative SCT
50-65
- non-myeloblative BMT
Prognosis of myelofibrosis
can be curative with transplant
Essential thrombocytosis definition
Clonal proliferation of megakaryocytes leads to increased platelets (thrombocytosis) with impaired function
Pt >600x 10 9 peristently
Cause of Essential thrombocytosis
50% calreticulin mutation
50% JAK2
Clinical features of essential thrombocytosis
microvascular occlusion
- headaches
- dizziness
- erythomegaly
- splenomegaly
- thombosis
- bleeding
Investigations of essential thrombocytosis
exclude other causes (bleeding, infection, malignancy)
FBC (+ repeat)
Pt >600 x109 persistently
ESR, CRP, Fibrinogen
Treatment of essential thrombocytosis
Stratification into risk groups
Low risk
- (60
- one or more high risk features plt >1500 x109/l previous thrombosis or thrombotic risk factors e.g diabetes or hypertension
Polycythaemia rubra vera definition
increase in RBC volume due to a clonal malignancy of a marrow stem cell
Causes of Polycythaemia rubra vera
Jak2 mutation is present in more than 90%
Clinical features of Polycythaemia rubra vera
due to hyperviscosity and hypervolaemia
- headaches
- dizziness
- visual disturbances
- tinnitus
- pruritis (after hot bath)
- erythromyalgia
- gout (increased urate)
- plerothic complexion
- splenomegaly
- thrombosis
- haemorrhage
Investigations of Polycythaemia rubra vera
bloods -increased RCC -increased packed cell volume - increased Hb Blood film JAK2 mut Serum ferritin
Management of Polycythaemia rubra vera
no cure venesection low dose aspirin -cytotoxic drugs e.g hydroxycarbamine if symptomatic -splenomegaly - radioactive phosphorus
Prognosis of Polycythaemia rubra vera
Most remain well
-thrombosis/ haemorrhage main complocation
Classification of myeloproliferative disorders based on the cell type
RBC - polycythaemia rubra vera
WBC - chronic myeloid leukaemia
Platelets - Essential thrombocytopenia
Fibroblasts - myelofibrosis
High risk ET treatment
First line = apsirin + hydroxycarbamide
(ribonucelotide reductase inhibitor resulting in reduced production of deoxyribonucleotides
Second line therapy = anagrelide + aspiring
- inhibits megakaryocyte differentiation
Inf-a useful in management of ET in pregnancy
JAK2 inhbitrs e.g ruxoltinib
JAK 2 inhibitors mechanism of action
JACK2 mutations result in continuous activatio of JAK receptor regardless of ligand binding
Specifically ruxotilinib
Inhibits JAK1 and 2
-70% of pts reduuced splenomegaly and functional improvement
Myelodysplastic syndrome (MDS) definition
Dysplasia and ineffective haemooesis in >1 o the myeloid series (RBC, Pts, Neutrophils)
Features of Myelodysplastic syndrome (MDS)
Common in elderly
25% transform to AML
de novo or secondary to previous chemo/rx
associated with acquired cytogenetic abnormalities
CFs Myelodysplastic syndrome (MDS)
20% present with infections
70-80% present with fatigue due to anaemia
Management of Myelodysplastic syndrome (MDS)
Depends on age of patient
- supportive care- blood and plt transfusion
- Growth factors - erythropoetin + granucolcyte colony stimulating factor (not much success as stimulating cells produces more dysplastic cells)
- Low dose chemo e.g hydroxycarbamide, low dose cytarabine
- immunosuppression
- high dose chemo - only in selected patients (AML-type)
- Allogenic stem cell transplantation only in selevted patients
Types of Myelodysplastic syndromes (MDS)
Multiple sub-types based on morphology and % blasts
- refractory anaemia
or - refractory anaemia with sideroblasts (perinuclear ring of iron granules)
- refractory anaemia with excessive blasts
Fanconis anaemia features
10-20% of aplastic anaemia cases
Autosomal recessive inheritance
BONE MARROW FAILURE
Fanconis anaemia characteristics
- somatic abnormalites
- bone marrow failure
- short telomeres
- malignancy
- chromosome instability
Types of Fanconis anaemia
7 genetic FANCA to FANC-G
Clinical features of Fanconis anaemia
micropthalmia GU malformations GI malformations mental retardation Hearing loss CNS e.g hydrocephalus
Treatment of Fanconis anaemia
Gold standard- allogenc stem cell transplant Other options are: -supportive care -corticosteroids -androgens
Life time surveillance for secondary tumours
