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Haematology & Transfer Practice > Myeloproliferative Disorders > Flashcards

Myeloproliferative Disorders Flashcards

1
Q

Myeloproliferative Disorders

A
  • Clonal disorders of haemopoiesis with increased progeny of one or more cells
  • Can include Chronic Myeloid Leukaemia but regarded as a separate disease
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2
Q

Myeloproliferative Disorder examples

A

-Polycythaemia rubra vera (PRV)
-Essential thrombocytosis (ET)
-Idiopathic myelofibrosis (IMF)

Can tranform into one another
All can terminate as acute myeloid leukaemia
Clonal pluripotent stem cell, hence transformation

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3
Q

Polycythaemia - Clinical Characteristics

A

An absolute increase in red cell volume or mass
Raised Hb
Raised PCV/Hct
When associated with a reduced plasma volume then a relative polycythaemia

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4
Q

Primary and Secondary Polycythaemia

A

Primary polycythaemia – clonal disorder
Secondary – driven either by increased erythropoietin (epo) production with or without hypoxia

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5
Q

Polycythaemia ruba vera (PRV) Clinical Characteristics

A
  • Increased red cell mas with/without increase in platelets or neutrophils
  • Stem cell disorders hyperplasia can give increase in three cell lines
  • Autonomous erythropoiesis: normal or reduced epo concentration
  • Red cell progenitors in PRV can survive in vitro without addition of epo
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6
Q

Myeloproliferative disorders associated cytogenetics

A
  • No specific chromosome abnormaility but 20-30% have some abnormalities in karyotype. Not known if this is cuasative
  • Deletion of part of long arm of chromosome 20
  • Trisomy 8
    Trisomy 9
    Duplication of part of the long arm of chromosome 1
    Duplication of part of the long arm of chromosome 13
    -Abnormalities of chromosomes 5 and 7 are associated with disease progression - May be due to prior therapy
    -Over expression of the gene PRV-1 is found on the neutrophils in PRV
    -Decreased thrombopoietin receptor expression
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7
Q

Clinical Features of Myeloproliferative Disorders

A

2-3 cases per 100,000
Male:female ratio 0.3-1.2
55-60 years of age
Rare in childhood but can occur at any age

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8
Q

Thrombotic Complications of Myeloproliferative Disorders

A
  • Most common feature
  • Increased risk of arterial, venous and microvascular thrombosis
  • Increased PCV causes an increase in the plasma viscosity, rheological abnormalities and abnormal platelet endothelial contact
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9
Q

Arterial Occulsions associated with Myeloproliferative Disorders

A

Myocardial infarction
Cerebro- vascular –accidents
Transient ischaemic attacks
Amaurosis-vision loss reducedblood flow
Scotomata- areas of lost vision
Mesenteric/limb ischaemia
Budd-Chiari- occlusion of hepatic vein

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10
Q

Neurological Factors associated with Myeloproliferative Disorders

A

-Headaches
-Drowsiness
-Insomnia
-Amnesia
-Tinitus
-Vertigo
-Chorea- abnormal jerky movements

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11
Q

Pruritis (itching) associated with Myeloproliferative Disorders

A
  • Found in 25% of cases
  • Can be severe
    -Aquagenic
    -Relieved by a reduction in the PCV
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12
Q

Skin conditions/ changes associated with myeloproliferative disorders

A

-Plethora – red-rosy complexion
-Dilated conjunctivial vessels
-Rosacae-like skin changes
-Sweet’s Syndrome- acute febrile neutrophilic dermatosis

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13
Q

Other associated complications of Myeloprolfierative Disorders

A

Splenomegaly – 30-50% of cases… ? Associated with myelofibrosis
Gout found in 5% of cases
Hypertension- common

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14
Q

Myeloproliferative Disorders and Disease transformation

A
  • 1-3% of cases treated by venesection will transform into acute leukaemia
  • 10-30% of cases treated with radioactive phosphorus, chlorambucil or irradiation will develop acute leukaemia in 5-8 years from diagnosis
  • 10-20% of cases will develop myelofibrosis 15 years after diagnosis.

-Gradual transformation and is associated with the development of leukamia.

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15
Q

PRV/ PV - Diagnostic Criteria

A

A1: increased red cell mass or PCV > 0.60 in men or > 0.56 in women
A2: normal arterial O2 concentration (>92%) and no increase in epo
A3: palpable splenomegaly
A4 :acquired clonal genetic abnormality in haemopoietic cells ( not BCR/ABL)

B1: platelet count > 400
B2: neutrophils > 10.0 > 12.5 in smokers
B3: radiological splenomegaly
B4: endogenous erythroid colonies or low serum epo
A1 plus A2 and either another A or another two Bs establishes the diagnosis

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16
Q

PRV/PV: JAK2 mutation

A
  • 95% of PRV are Janus Kinase 2 positive.
  • JAK2; tyrosine kinase
  • Important role in growth factor signalling
  • Mutation causes activation of kinase with cell proliferative independent of normal growth factor control
  • JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera
    50-70% of patients with essential thrombocythemia
    40-50% of cases of idiopathic myelofibrosis
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17
Q

Prv/PV Treatment

A

-In the absence of thrombocytosis- regular venesection target PCV 0.45: Higher PCVs associated with thrombosis, Repeated venesection can cause Fe deficiency but then can cause a reactive thrombocytosis

  • Hydroxyurea- free radical nitrous oxide reduces DNA replication: Well tolerated oral therapy can cause painful leg ulcers, gastro-intestinal side-effects and photosensitivity. ? Leukaema-genic
  • Interferon alpha- good for younger patients, expensive, sub-cut injection. Flu like symptoms, fatigue and depression
  • Anagrelide – used for thombocytosis- inhibits megakaryocyte differentiation. Used in conjunction with hydroxurea- lower doses of each. Can depend on the combination of factors being treated.
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18
Q

PRV Prognosis

A

Adequately treated PRV has a relatively benign natural history with life expectancy of 11 years

Average age of onset is 60

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19
Q

Myelofibrosis

A
  • Agnogenic myeloid metaplasia
    -Idiopathic myelofibrosis (IMF)
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20
Q

Primary Myelofibrosis - Clinical Characteristics/ Microscopy

A

-reticulin deposition in BM
-ineffective BM haematopoiesis, extramedullary haematopoiesis in spleen and liver, associated with anaemia and splenomegaly
-fibrosis is secondary to megakaryocyte dysplasia
-dysplastic megakaryocytes produce pro-inflammatory cytokines which stimulate fibroblasts to produce collagen fibres

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21
Q

Pathophysiology and cytogenetics of Myelofibrosis

A

-clonal myeloproliferative disorder of the pluripotent haemopoietic stem cell
-Multiple cell lineages with progressive fibrosis
-Secondary to release of pro-inflammatory cytokines from the clonal cells- primarily megakaryocytes

-Increased numbers of CD34+ cells in the peripheral circulation
-Colony formation without exogenous growth factors
-No specific cytogenetic abnormalities, commonest deletion of 20q, 13q, Trisomy 8 and abnormalities of chromosomes 1,5,7,9
-Oncogene mutations are rare but include point mutations in N-Ras, c-KIT and p53
-Deletion/ down-regulation of retinoic acid receptor.

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22
Q

Patient Distribution of Myelofibrosis

A
  • Predominantly over 50 years old
  • Median ago 67 years old
  • 1 in 500,000
  • Rare in the young
  • No sex prevalence
23
Q

Causes of Myelofibrosis

A
  • Essentially unknown
  • Linked to exposure to benzene and radiation
  • Acquired mutation of genetic material
24
Q

Symptoms of Myelofibrosis

A

Anaemia
Splenomegaly
Bone pain-especially lower legs
Lethargy
Bruising/bleeding
Night sweats
Infections

25
Q

Pathophysiology of Myelofibrosis

A
  • Bone marrow infiltration/replacement with fibrous tissue
  • Extra-medulary haemopoiesis- liver and spleen
26
Q

Organomegaly associated with Myelofibrosis

A

Oranomegaly: Enlargement of organs
Splenomegaly due to extra-medullary haemopoiesis
Splenic infarction
Hepatomegaly due to extra-medullary haemopoiesis
Portal hypertension
Ascites
Oesophageal varices

27
Q

Diagnosis of Myelofibrosis

A

-Abnormal FBC
-Leuco-erythroblastic picture
-Tear drop poikilocytes
-Bone pain
-Splenomegaly
-General symptoms associated with haematological malignancy
- Bone marrow aspirate
- Trephine biopsy

28
Q

Treatment of Myelofibrosis

A

-Transfusion to support anaemia
-Erythropoietin
-Hydroxyurea with steroids, can improve haemopoiesis
-Andreogens- testosterone, oxymetholone can improve haemopoiesis
-Radiotherapy t0 reduce spleen
-Thalidomide with steroids- reduces spleen size, improves anaemia and better haemopoiesis: Experimental

29
Q

Essential Thrombocythaemia (ET)

A

-Persistent elevation of the platelet count above 600 x10 9/l
-Poorly understood- lack of positive diagnostic criteria

30
Q

Pathophysiology of ET

A

Clonality is difficult to establish-heterogeneous disease
-Thrombopoietin (TPO) mutations not found, whereas in congenital thrombocytosis they have
-TPO levels similar to reactive thrombytosis and therefore not diagnostic

31
Q

Clinical features of ET

A

1.5 – 2.0 cases per 100,000
Median age of onset 50-55 years
Rare in childhood but can occur at any age

32
Q

Thrombotic Complications of ET

A

-15-20% of cases present with a thrombosis, arterial or venous

-Risk factors include age >60, platelet count >1000 x 10 9/l, hyperlipidaemia, hypertension and smoking

33
Q

Adverse prognostic indicators of ET

A

-Males
-Monoclonal haemopoiesis
-Anti-phospholipid antibodies
-Spontaneous megakryocyte or erythroid colonies
-Factor V Leiden

34
Q

Haemorrhagic Complications of ET

A

-More common with platelet count >1000 x10 9/L
-No risk predictors
-Acquired von Willebrands disease decrease in HMW multimers

35
Q

Splenomegaly and hyposplenism associated with ET

A

-20-25% of cases
-Rarely more than moderate
-Progressive splenomegaly- suspicious of development of myelofibrosis
-May develop splenic atrophy due to micro-infarctions

36
Q

Leukaemic Transformation seen in ET

A

-Evolve into myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) but only rarely ( small risk)

-Increased risk associated with cytogenetic abnormalities and treatment with alkylating agents

-3% treated with hydroxurea will develop AML or MDS

37
Q

Myeloproliferative disorders transformation to PRV and Myelofibrosis

A

-Less than 10% transform to myelofibrosis
-1-2% transform to PRV

38
Q

Investigations and diagnostic criteria of Myelofibrosis

A

-Diagnosis of exclusion
-Persistent raised platelet count (>600)
-Other clonal disorders must be ruled out
-Platelet count >600 for a minimum of 2 months
-No evidence of PRV
-No reactive cause for thrombocytosis
-No evidence of iron deficiency
-No evidence of CML
-No evidence of MDS; no significant dysplasia, no cytogenetic abnormalities associated with MDS
-No evidence of myelofibrosis; no collagen fibrosis, minimal or no reticulin fibrosis

39
Q

Causes of reactive thrombocytosis ( Secondary thrombocytosis)

A

Iron deficiency
Blood loss acute or chronic
Hyposplenism/splenectomy
Surgery
Malignancies
Drugs; vincristine

40
Q

What is reactive thrombocytosis

A

Reactive thrombocytosis, also known as secondary thrombocytosis, is a condition characterized by an elevated platelet count in response to an underlying cause or stimulus.

41
Q

Treatment of reactive thrombocytosis

A

-High-risk over 60 >1500 platelet count, previous history of thrombosis, diabetes and hypertension. Hydroxyurea, anagrelide and aspirin have been used.

-Intermediate risk – none of above risks usually aspirin alone and some Hydroxyurea. 40-60 years old

-Low risk- less than 40 years old, no risk factors, low dose aspirin, some platelet inhibitors

42
Q

Prognosis of reactive thrombocytosis

A

-Some studies suggest mortality at 10 years is the same as matched controls but some studies contrary
-In high risk patients Hydroxyurea reduces the risk of vaso-occlusive events from 10.7 to 1.6 per 100 patient years

43
Q

ET and Pregnancy

A

-Most common MPD encountered in pregnant women

-Commonest complication is miscarriage in the first trimester in up to 30% of pregnancies.

-Secondary to placental infarcts

-Greater risk of maternal thrombosis/haemorrhage

-Treat with aspirin and interferon

-Not Hydroxyurea or anagrelide as they can be teratogenic

44
Q

Myelodysplastic Syndrome Definition

A

clonal disorder of haematopoietic stem cells characterised by production of abnormal (dysplastic) cells in 1 or more lineages

45
Q

Myelodysplastic Syndrome (MDS)Subtypes

A

refractory anaemia (RA)
refractory anaemia with ring sideroblasts (RARS)
del(5q) syndrome
refractory neutropaenia (RN)
refractory thrombocytopaenia (RT)
refractory cytopaenia with multilineage dysplasia (RCMD)
refractory anaemia with excess blasts type 1 (RAEB-1)
refractory anaemia with excess blasts type 2 (RAEB-2)

46
Q

Clinical features / symptoms of MDS

A

vague symptomology – often found by chance on a routine FBC
lethargy
bruising and bleeding
susceptibility to infection

47
Q

MDS Diagnosis

A

most patients are >70 years old at diagnosis

diagnosis dependent on both quantitative (eg FBC) and qualitative (eg dysplasia on blood films) abnormalities

48
Q

Common dysplastic ( change in size and shape of cells) features in MDS

A
  • RBC poikilocytosis
  • Pseudo-Pelger Nucleus
  • Ringer Sideroblast (erythroblast with iron laden mitochondria
  • Macropolycyte (giant neutrophils)
  • Excess blasts (RAEB-2)
49
Q

WHO classification/ Diagnosis of MDS

A

classification based on:
blood count
morphological appearance
percentage of blast cells in blood/bone marrow

MDS are pre-leukaemic disorders and highly prone to transformation to AML - higher blast % is associated with poorer prognosis

> 20% blast percentage is considered AML

revised WHO criteria tries to streamline MDS diagnosis by focusing on:
number of dysplastic lineages (SLD vs MLD)
number of cytopaenias
percentage of ring sideroblasts
percentage of blast cells in blood/bone marrow

50
Q

Genetic Aetiology of MDS ( pathogenesis and cytogenetics)
Risk factors for mutations

A
  • pathogenesis is unclear but thought to be due to accumulation of driver mutations in key genes in a multipotent haematopoietic progenitor cell
  • chromosome abnormailities and mutations are frequent, commonly effecting these across all MDS subtypes:
    -RNA splicing (SRSF2, SF3B1, U2AF1)
    -epigenetic regulators (DNA methylation, histone modification)
    -transcription factors (RUNX1, GATA2)
    -cytokine signaling (JAK2, KIT)
    -chromatin architecture (cohesin, mediator)
  • Risk factors for mutations :smoking, ionising radiation, pesticides and chemicals e.g. benzene.
  • usually primary and can be secondary to chemotherapy and radiotherapy ( called therapy-related MDS or t-MDS)
51
Q

Prognosis of MDS. Scoring system.

A

-Prognosis is variable - depends on MDS type

-Scoring systems help predict prognosis e.g. International Prognostic Scoring System (IPSS) e,g:
–degree of cytopaenia influences the incidence of complications and treatment
–% blast cells is a predictive risk of developing leukaemia
–some cytogenetic groups indicate good prognosis (eg. Del(5q) syndrome) or indicate poor prognosis (MDS with complex cytogenetic changes)

  • Death may be caused by infection, hemorrhage, iron overload from multiple transufsion or transformation into AML
52
Q

Treatment of MDS

A

For Low Risk MDS (low grade):
(less than 5% of blasts in the marrow, only one cytopaenia and favourable cytogenetics)
Treatment may not be necessary
Haemopoietic growth factors e.g. Eythropoietin, G-CSF, to correct cytopaenias
Antibiotics/anti-fungals etc
Transfusions e.g. platelets, red cells
Iron Chelation
Lenalidomide in MDS associated with del(5q)

Treatment for High Risk MDS:
Chemotherapy (azacytidine, decitabine)
DNA methyl-transferase inhibitors (hypomethylating agents)
Stem cell transplantation
Supportive care only

53
Q

MDS with del (5q)

A

-characterized by deletion of q arm of chromosome 5

– total deletion in most cases are ~70Mb which results in haploinsufficiency of up to 40 genes

-one crucial gene in del(5q) region is CSNK1A1 which encodes a protein casein kinase 1a

Haematology & Transfer Practice (13 decks)

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