MYELOPROLIFERATIVE DISORDERS Flashcards
[POLYCYTHAEMIA VERA (PV)]
What is the definition of polycythaemia?
: increase in Hb, HCT (red cell mass) and RCC.
[POLYCYTHAEMIA VERA (PV)]
What is the definition of absolute erythrocytosis?
true increase in red cell volume
[POLYCYTHAEMIA VERA (PV)]
What is the definition of relative erythrocytosis?
normal red cell volume but decrease in plasma volume e.g. burns, dehydration
[POLYCYTHAEMIA VERA (PV)] What are the causes of secondary polycythaemia?
Due to an appropriate (hypoxic) increase in erythropoietin (e.g. high altitude, lung disease, CVS disease etc.) OR
Due to an inappropriate increase in erythropoietin (e.g. renal cell carcinoma, Wilm’s tumour, Chuvasch polycythaemia)
[POLYCYTHAEMIA VERA (PV)]
- Clonal stem cell disorder leading to excessive proliferation of __________________ progenitor cells
- Hence, we will expect to see both ________________
- Over 95% of patients with PV have acquired mutations of the gene ________________ mutation which causes tyrosine kinase to be constantly switched on, leading to cell proliferation.
- Aka there is increased sensitivity to EPO, with absolute EPO levels being LOW due to -ve feedback
erythroid (predominant), myeloid and megakaryocytic
leucocytosis, thrombocytosis and erythrocytosis (predominant finding)
Janus Kinase 2 (JAK2) 🡪 V617F
[POLYCYTHAEMIA VERA (PV)]
What are the symptoms of PV?
Symptoms of hyperviscosity
- Headache, light-headedness, stroke
- Visual disturbances
- Fatigue, dyspnoea
Increased histamine release (due to increased Basophils and Mast cells produced)
- Aquagenic pruritus (pruritic following warm bath or shower)
- Peptic ulceration (due to activation of H2 receptor on parietal cells 🡪 abdominal pain)
[POLYCYTHAEMIA VERA (PV)]
What are the signs of PV?
Extramedullary Haematopoiesis
- Variable splenomegaly due to increased RBC turnover and production
- Hepatomegaly
Hyperviscosity
- Plethora (flushing) of the face and deep dusky cyanosis
- Retinal vein engorgement 🡪 causing transient visual disturbance
- Injected conjunctiva (due to engorged veins)
Thrombotic Risk
- Erythromelalgia (red painful extremities): Burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis, in the presence of palpable pulses
- Thrombosis – DVT, PE, Stroke, AMI
Others
- Haemorrhage
- Gout due to increased red cell turnover and overproduction of uric acid
[POLYCYTHAEMIA VERA (PV)]
What are the investigations performed for PV?
- Increased haemoglobin and haematocrit
- May be masked by Fe Def Anemia – check Fe and ferritin levels!
- Thrombocytosis (Platelets are increased in both PV and ET)
- White cells normal or moderately increased
- Increased red cell mass and plasma volume
[POLYCYTHAEMIA VERA (PV)]
How is PV diagnosed?
Raised haematocrit (normal = 40-50%)
Normal Plasma Volume
Mutation in JAK2
If JAK2 negative but other features suggestive:
- Low serum erythropoietin
- Splenomegaly clinically or US
- Red cell mass studies
- Bone marrow biopsy
[POLYCYTHAEMIA VERA (PV)]
How is PV managed?
Aim to reduce viscosity: Keep HCT <45%
- Venesections
- Chemotherapy
Aim to reduce risk of thrombosis
- Aspirin
- Keep platelets < 400,000 x 109
[POLYCYTHAEMIA VERA (PV)]
What is the prognosis of patients with PV?
PV develops into myelofibrosis in 30% of cases and into acute myeloblastic leukaemia in 5% as part of the natural history of the disease.
[ESSENTIAL THROMBOCYTHAEMIA (ET)]
- Essential thrombocythaemia (ET) is a chronic MPN mainly involving megakaryocytic lineage.
- There is sustained thrombocytosis >__________.
- The incidence is 1.5 per 100000 and there are 2 peaks: 55 years + minor peak 30 years.
600x109/L
[ESSENTIAL THROMBOCYTHAEMIA (ET)]
What are the clinical features of ET?
Thrombosis: arterial or venous
- CVA, gangrene, TIA
- DVT or PE
Bleeding: mucous membrane and cutaneous (platelets count raised but may not be effective)
Findings a/w increased cellular proliferation
- +/- Symptoms of hyperviscosity: Headaches, dizziness, visual disturbances
- +/- Splenomegaly (usually modest)
[ESSENTIAL THROMBOCYTHAEMIA (ET)]
What are the investigations performed for ET?
No gold standard for diagnosis
Platelet count consistently above 600x109/L
Megakaryocyte abnormalities & clustering in BM
JAK 2 V617F mutation (50%)
Splenomegaly – slight, may even be non-palpable
Spontaneous erythroid/ megakaryocytic colonies independent of growth factors
Normal ESR and CRP – no signs of infection
[ESSENTIAL THROMBOCYTHAEMIA (ET)]
What is the management of ET?
Aspirin to prevent thrombosis
- High risk of thrombosis:
age>60, thrombosis/ haemorrhagic/ ischemic symptoms, platelets >1000x109
Hydroxycarbamide (aka Hydroxyurea)
- Antimetabolite
- Suppresses the platelet count
- Myelosuppressive: can also suppress white blood cell count and haemoglobin 🡪 Possibly mildly leukaemogenic
- Also used in Sickle Cell Disease to increase HbF
[MYELOFIBROSIS]
Myelofibrosis is a clonal myeloproliferative disease with proliferation mainly of _________& __________, associated with reactive _____________& _________
Primary myelofibrosis has an incidence of 0.5-1.5/100000 and peaks in the 7th decade.
megakaryocytes & granulocytic cells
bone marrow fibrosis & extramedullary haematopoiesis.
[MYELOFIBROSIS]
What are the clinical features of myelofibrosis?
Clinical Features
- Hypermetabolic state:
- Weight loss
- Fatigue and dyspnoea
- Night sweats
- Thought to be due to increased inflamm markers (IL6) released due to abnormal blood cells
Changes in other cell lines:
- Anaemia
- Thrombocytopenia OR Thrombocytosis
- Leucocytosis OR Leukocytopenia
Splenomegaly: may be massive
Hepatomegaly
[MYELOFIBROSIS]
What are the stages of myelofibrosis?
1) Prefibrotic Stage
- Presence of Leucocytosis and Thrombocytosis
- Neutrophils are left shifted + Abnormal large platelets due to fibrotic BM pushing out the immature cells
- There may be presence of immature nucleated RBC in PBF
- Blood changes mild, but may be confused with ET
- Marrow hypercellular
Fibrotic Stage
- Fibrosis occurs due to the PDGF released by abnormal platelets that stimulate fibroblasts in BM
- Splenomegaly & blood changes (very hard to predict the ultimate changes in WCC and Platelet count. However, there is definitely anemia)
- Anemia
- Dry tap (difficult to aspirate bone marrow aspirate) – hypocellular and fibrotic
- Prominent collagen fibrosis
- Osteosclerosis (later)
[MYELOFIBROSIS]
What are the investigations performed in patients with myelofibrosis?
Peripheral blood film
- Leucoerythroblastic picture (immature RBC and WBC normally only found in the bone marrow.)
- Tear Drop Poikilocytes (poikilocytes = abnormally shaped RBC) 🡪 also seen in Beta Thalassemia major
Bone marrow
- Dry tap
- Fibrotic bone marrow (on bone marrow trephine)
Cytogenetics:
- Absent Philadelphia chromosome (differentiates from CML)
- JAK2 mutation in 50%
FBC: High platelet count, but thrombocytopenia in later stages
[MYELOFIBROSIS]
What is the prognosis of myelofibrosis?
Median survival 3-5 years but very variable
Bad prognostic signs:
- Severe anaemia <10g/dL
- Thrombocytopenia <100x109/l
- Massive splenomegaly
