Myeloproliferative, myelodysplastic and aplastic anaemia Flashcards Preview

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Flashcards in Myeloproliferative, myelodysplastic and aplastic anaemia Deck (47):
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Haemopoesis Definition

The production of blood cells

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Where does haemopoesis occur in the foetus?

0-2 months - yolk sac
2-7 months - liver, spleen
5-9 months - bone marrow

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Where does haemopoesis occur in infants

Bone marrow - all bones

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Where does haemopoesis occur in adults

Bone marrow
(vertebrae, ribs, sternum, skull, sacrum, pelvis, ends of femur)

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Haemopoesis hierarchy

DRAW

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Pluriopotent stem cell

Numbers diminish with age, committed to divide

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Colony forming unit

commited to divide

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Where are haemopoetic stem cells found?

BM
Peripheral blood after treatment with G-CSF
Umbillical cord blood

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Haempoetic stem cell characteristics

-self renewal
-unspecialised
- ability to differentiate (mature)
-quescent (non in cell cycle)
-rare cell

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Control of stem cell fate

HSC can
a. undergo self-renewal (identical copy)
b. Apoptosis (programmed cell death)
c. Differentations (Matureation and specialisation)

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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

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Stroma definition

BM microenviroment that supports the developing haemopoetic stem cell

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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)

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Pre-malignant and malignant conditions are termed clonal because..?

They arise from a single ancestral cells

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Examples

1. over-production = Myeloproliferative disorder
2. Under production = Aplastic anaemia (e.g fanconis)
3. Abnormal cells produced
= myelodysplasia, leukaemia

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Myeloproliferative disorders

Polycythaemia rubra vera
Essential thrombocytosis
Myelofibrosis

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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

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Myelofibrosis definition

Marrow scarring due to hyperplasia of megakarocytes which causes increased production of PDGF

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Causes of myelofibrosis

50% JAK2, 50% calreticulin

Increased PDGF leads to myeloid metaplasia

Massive hepatomegaly

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Presentation of myelofibrosis

constitutional symptoms

Abdominal discomfort - massive spleenn

BM failure (Anaemia, Infection, bleeding)

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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

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Treatment of myelofibrosis

Under 50
- myeloblative SCT

50-65
- non-myeloblative BMT

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Prognosis of myelofibrosis

can be curative with transplant

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Essential thrombocytosis definition

Clonal proliferation of megakaryocytes leads to increased platelets (thrombocytosis) with impaired function

Pt >600x 10 9 peristently

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Cause of Essential thrombocytosis

50% calreticulin mutation
50% JAK2

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Clinical features of essential thrombocytosis

microvascular occlusion
-headaches
-dizziness
-erythomegaly
-splenomegaly
-thombosis
-bleeding

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Investigations of essential thrombocytosis

exclude other causes (bleeding, infection, malignancy)
FBC (+ repeat)
Pt >600 x109 persistently
ESR, CRP, Fibrinogen

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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

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Polycythaemia rubra vera definition

increase in RBC volume due to a clonal malignancy of a marrow stem cell

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Causes of Polycythaemia rubra vera

Jak2 mutation is present in more than 90%

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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

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Investigations of Polycythaemia rubra vera

bloods
-increased RCC
-increased packed cell volume
- increased Hb
Blood film
JAK2 mut
Serum ferritin

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Management of Polycythaemia rubra vera

no cure
venesection
low dose aspirin
-cytotoxic drugs e.g hydroxycarbamine if symptomatic
-splenomegaly
- radioactive phosphorus

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Prognosis of Polycythaemia rubra vera

Most remain well
-thrombosis/ haemorrhage main complocation

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Classification of myeloproliferative disorders based on the cell type

RBC - polycythaemia rubra vera
WBC - chronic myeloid leukaemia
Platelets - Essential thrombocytopenia
Fibroblasts - myelofibrosis

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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

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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

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Myelodysplastic syndrome (MDS) definition

Dysplasia and ineffective haemooesis in >1 o the myeloid series (RBC, Pts, Neutrophils)

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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

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CFs Myelodysplastic syndrome (MDS)

20% present with infections
70-80% present with fatigue due to anaemia

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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

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Types of Myelodysplastic syndromes (MDS)

Multiple sub-types based on morphology and % blasts

1. refractory anaemia
or
2. refractory anaemia with sideroblasts (perinuclear ring of iron granules)
3. refractory anaemia with excessive blasts

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Fanconis anaemia features

10-20% of aplastic anaemia cases
Autosomal recessive inheritance
BONE MARROW FAILURE

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Fanconis anaemia characteristics

-somatic abnormalites
-bone marrow failure
-short telomeres
-malignancy
-chromosome instability

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Types of Fanconis anaemia

7 genetic FANCA to FANC-G

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Clinical features of Fanconis anaemia

micropthalmia
GU malformations
GI malformations
mental retardation
Hearing loss
CNS e.g hydrocephalus

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Treatment of Fanconis anaemia

Gold standard- allogenc stem cell transplant
Other options are:
-supportive care
-corticosteroids
-androgens

Life time surveillance for secondary tumours