Haem - Polycythaemia & Myeloproliferative disorders Flashcards
Define polycythaemia
Raised haemoglobin concentration and raised haematocrit
What are the types of polycythaemia
Relative (lack of plasma)/ pseudopolycythaemia: alcohol, obesity, diuretics
True:
Primary (myeloproliferative neoplasm): philadelphia Chr -ve or +ve
Secondary (non-malignant)
What are dilution studies
Measures RBC mass and plasma volume
1. Take components out
2. Radiolabel them (51Cr-RBCs, 131I-Albumin)
3. Reinfuse and measure dilution
Red cell mass N, plasma volume reduced → relative
Red cell mass high, plasma volume N → true polcythaemia
What are the causes of true primary polycythaemia
Primary (myeloproliferative neoplasm): suppressed EPO
Philadelphia Chr -ve:
- essential thrombocythaemia (megakaryocyte)
- Polycythaemia vera (erythroid)
- Primary myelofibrosis
Philadelphia chromosome +ve:
CML
What are the causes of secondary true polcythaemia
Raised EPO
Appropriate (JAK2 wild type/V617F/Exon12):
- High altitude
- Hypoxic lung disease (COPD)
- Cyanotic heart disease
- High affinity Hb
Inappropriate:
- Renal disease (cysts, tumours, inflammation)
- Uterine myoma
- Other tumours (liver, lung)
What is the role of tyrosine kinase
Transmit cell growth signals from surface receptors to nucleus
Activated by transferring phosphate groups
Normally held tightly in inactive state
Promote cell growth but do NOT block maturation
Which gene mutations are associated with myeloproliferative disorders
JAK2: single point mutation in polycythaemia vera (100%), essential thrombocythaemia and primary myelofibrosis
Calreticulin:
MPL
Describe idiopathic erythrocytosis
a JAK2 V617F -ve (sometimes JAK 2 exon 12) version of PV where there is an isolated expansion of RBCs (not pseudopolycythaemia) / not plts
What is the epidemiology of polycythaemia vera
M > F
Mean age at diagnosis = 60yo (5% <40yo)
What are the clinical features of polycythaemia vera
Hyperviscosity: headaches, light-headedness, visual disturbances, fatigue, dyspnoea
Histamine release: aquagenic (hot water) pruritus, peptic ulceration
Plethoric (red nose)
Thrombosis, stroke
Retinal vein engorgement
Splenomegaly
What are the features of polcythaemia vera on investigation
Blood count: high RBC, Hb, plts, WCC
JAK2 V617F mutation
What is the treatment for polycythaemia vera
reduce HCT <45% + reduce risk of thrombosis:
- Venesection (only suitable in younger/healthy patients)
- Hydroxycarbamide (cytoreductive therapy → less DNA synthesis in RBCs): Keep plts <400 x 109/L and Hct <45%
- Aspirin
Define essential thrombocythaemia
Chronic myeloproliferative disorder involving megakaryocytic lineage
What is the epidemiology for essential thrombocythaemia
Bimodal age distribution: 30 years (minor peak); 55 years
30yo (M = F); 55 years (F > M)
What are the clinical features of essential thrombocythaemia
Incidental (50% of cases)
Thrombosis (arterial or venous) – CVA, gangrene TIA, DVT/PE
Bleeding (mucous membrane and cutaneous)
Hyperviscosity (headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea)
Splenomegaly (modest)
What are the features of essential thrombocythaemia on investigation
Blood count: high plts (Sustained thrombocytosis >600 x 109/L)
Mutations (JAK2, calreticulin, MPL) - 50%
Blood film – large platelets and megakaryocyte fragments
Increased BM megakaryocytes (not reactive)
Note: the Hb is NOT that elevated (differentiates from PV)
What is the treatment for essential thrombocythaemia
Aspirin (thrombosis prevention)
Hydroxycarbamide (antimetabolite that suppresses cell turnover)
Anagrelide (inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing)
What is the prognosis for essential thrombocythaemia
Normal life span in many patients
Leukaemic transformation in about 5% over 10 years
Myelofibrosis is also UNCOMMON, unless there is fibrosis at the beginning
Define primary myelofibrosis and what is it characterised by
a clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Characterised by extramedullary haematopoiesis (i.e. in liver and spleen)
Other MPD (ET and PV) may transform into PMF
What is the cause and epidemiology of primary myelofibrosis
Expansion of the clone → produces fibroblast growth stimulating factor → proliferation and collagen deposition in the bone marrow → bone marrow scarring
Epidemiology = 60-70yo, M=F, 0.5-1.5/100,000/year
What are the clinical features of primary myelofibrosis
Incidental in 30%
Presentations related to:
- Cytopaenias (anaemia, thrombocytopaenia)
- Thrombocytosis
- Splenomegaly (MASSIVE) → Budd-Chiari syndrome
- Hepatomegaly (extra-medullary haematopoiesis)
- Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia)
What are the features of primary myelofibrosis on investigation
Blood film:
- Leucoerythroblastic picture
- Tear drop poikilocytosis (dacrocytes)
- Giant platelets
- Circulating megakaryocytes
Bone marrow:
- DRY TAP
- Trephine biopsy: increased reticulin/collagen fibrosis, increased clustering and megakaryocytes, new bone formation
JAK2/CALR mutation
Evidence of extramedullary haematopoeisis (liver, spleen)
What is the treatment for primary myelofibrosis
Supportive: transfusion of RBC or platelets (often ineffective due to splenomegaly → rapid break down RBCs)
Cytoreductive Therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
HSCT: potentially curative (reserved for high risk eligible cases)
Splenectomy: symptomatic relief but a dangerous operation, often followed by worsening of condition
Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)
What is the prognosis for myelofibrosis
Prognostic scoring system = DIPPS (1-6)
Median 3-5 years survival (however, very variable)
BAD prognostic signs:
- Severe anaemia < 100 g/L
- Thrombocytopaenia < 100 x 109/L
- Massive splenomegaly
- High DIPPS score (score 4-6: 1.3 years)
