Case 116 – Summary!

Thank you for everyone’s involvement in the case this week. We discussed a 56 year old man who presented with an acute stroke. This was managed with oral aspirin as his NIHSS score was low at 3 and he presented at 4.5 hours after his symptoms developed.

His initial investigations revealed polycythaemia with iron deficient picture (Hb 122, HCT 0.52, MCV low) and mild thrombocytosis (480).

We took a thorough history to assess for potential secondary causes and cardiovascular risk factors. The only identifiable factors were a renal transplant 6 months ago (no prior dialysis and acute renal disease necessitating need for transplant) and smoking history. However he only smoked 5 cigarettes per day and had normal saturations so it wasn’t felt this was a significant contributory cause although he has obviously been recommended to stop. We also assessed cardiovascular risk status.

An important learning point from our case is the need to repeat the FBC/look back at previous results to ensure it is not just an erroneous result. Doing so highlighted that his polycythaemia was longstanding and pre-dated his renal disease and transplant. This prompted us to perform JAK2 V617F mutation analysis which was present confirming the diagnosis of polycythaemia vera.

Our patient was stratified as high risk due to his acute stroke and underwent venesection to try promptly reduced his HCT as well commencing hydroxycarbamide therapy. We discussed the importance of optimizing other cardiovascular risk factors and continuing anti-platelet therapy.

Below is a summary of polycythaemia and post-renal transplant erythrocytosis.

Polycythaemia

Polycythaemia is a frequent finding in general medicine and general practice. The vast majority of causes are due to relative/apparent polycythaemia (reduced plasma volume making the blood more concentrate) or secondary or reactive to other causes.

Causes

PV causes

Investigations

Those with a persistently raised venous haematocrit (male >0.52; females >0.48) should be reviewed and investigated. However, if there is a clear secondary cause no further investigations may be necessary.

 BSH guidelines recommend using the following investigative algorithm: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15648

Polycythaemia algorithm

 Stage 1 Investigations:

  • History and examination
  • FBC/film (NB film not generally helpful in diagnosing polythaemia but needed to look for signs of myelofibrosis)
  • Ferritin, U&E, LFT (frequently patients are iron deficient)
  • Serum erythropoietin
  • ABG (or Sp02 but beware if at risk of carbon monoxide poisoning, sleep apnoea or high affinity haemoglobins as may be normal). An SaO2 <92% is associated with absolute erythrocytosis
  • JAK2V617F mutation (allele burden equivalent in bone marrow and peripheral blood)

Stage 2 investigations (if JAK2 negative):

  • Red cell mass
  • Abdominal USS (splenomegaly, renal pathology etc)
  • JAK2 exon 12 analysis (can have discrepancy between allele burden in bone marrow and peripheral blood)
  • Marrow aspirate/trephine/cytogenetics
    • – Marked increased erythropoiesis, moderate increase in granulopoiesis and megakaryopoiesis. Highly variable megakrycocyte including hyperlobulated nuclei, absent iron stores.
    • – Abnormal karyotype, SH2B3 mutation, TET2, DNMT3A

 

Polycythaemia Vera

 Polycythaemia vera is a clonal haematopoietic neoplasm which presents usually in the 60s with a slight male predominance. The substitution of phenylalanine for valine at position 617 of the JAK2 gene is responsible for approximately 95% of cases of polycythaemia vera and costs approximately £50. Progenitor cells have increased sensitivity to growth factors as the V617F mutation allows the JAK protein to become active even when no growth factor is bound leading to increased cell survival and proliferation. The incidence is approximately 2-3 per 100 000 per year.  When the V617F mutation is not found, mutations in exon 12 should be looked for as these account for a further 2-4% of cases of polycythaemia vera.

Clinical features:

  • Night sweats
  • Weight loss, lethargy
  • Splenomegaly
  • Aquagenic pruritis
  • Thrombosis (venous/arterial/microvascular) and bleeding
  • Arterial thrombosis more common (75%)
  • Abdominal vein thrombosis should be investigated for the JAK2v617F and exon 12 mutations even with a normal FBC.
  • Headache/visual disturbance
  • Dizziness
  • Erythromelalgia

 

Diagnostic criteria

JAK2-positive polycythaemia vera (requires both criteria)

  • High HCT (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
  • Mutation in JAK2

JAK2-negative polycythaemia vera (requires A1-A4) plus another A or two B criteria)

  • A1 Raised red cell mass (>25% above predicted) OR HCT >0.6 in men; >0.56 in women
  • A2 Absence of mutation in JAK2
  • A3 No cause of secondary erythrocytosis
  • A4 Bone marrow histology consistent with PV
  • A5 Palpable splenomegaly
  • A6 Presence of an acquired genetic abnormality (excluding BCR-ABL1) in the haemopoietic cells
  • B1 Thrombocytosis (Plts >450 x 109/l)
  • B2 Neutrophil leukocytosis (neutrophil count >10 x 109/l in non-smokers, >12.5 x 109/l in smokers)
  • B3 Radiological evidence of splenomegaly
  • B4 Low serum erythropoietin

 

Risk stratification (of thrombotic risk based on ECLAP data):

  • Low risk: <65 years and no PV-associated thrombotic history
  • High risk: >65 years and/OR prior PV-associated arterial or venous thrombosis
  • NB: other factors contributing to thrombotic risk include: WCC >15 x 109/l, smoking, diabetes mellitus, hypertension, hypercholesterolaemia. Patients with these features even if stratified as low risk should be considered as high risk.
  • Mortality is predominantly based on thromboembolic events

 

Factors associated with an increased risk of transformation to myelofibrosis

~Incidence of transformation 5-10% in 10 years

  • Longer disease duration
  • Splenomegaly
  • Raised LDH
  • Presence of reticulin fibrosis at diagnosis
  • JAK2 V617F allele burden >50%

Factors associated with an increased risk of transformation to AML

  • Age
  • WCC >15 x 109/l
  • Splenomegaly
  • Abnormal karyotype

Management

 All Patients

  • HCT target <0.45
    • based on CYTO-PV data on reduction of major thrombosis/cardiovascular death
  • Aspirin 75mg – 100mg per day (+ PPI if high bleeding risk including age >75)
  • Optimisation of other cardiovascular risk factors e.g hypertension
  • Avoid excess of dietary iron

Low risk patients

  • Venesection alone to achieve target HCT
  • In the acute setting this may be needed frequently e.g. alternate days and concomitant fluid replacement may be necessary
  • ≥3 venesections per year is associated with higher thrombotic risk. If maintenance venesection frequency high cytoreductive treatment should be considered.
  • Patients otherwise catergorised as low risk should be managed with cytoreductive therapy if extreme thrombocytosis (>1500 – haemorrhage risk), progressive splenomegaly/progressive leukocytosis. Or marked constitutional symptoms.

High risk patients

  • Require use of cytoreductive therapy
  • Hydroxycarbamide or interferon are first line

 

  • Hydroxycarbamide
    • No definitive evidence that it increases risk of transformation to leukaemia.
    • Advise to stop 3 months prior to conception

European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance:

  1. Need for phlebotomy to keep haematocrit <0·45 after 3 months of at least 2 g/day of hydroxycarbamide OR
  2. Uncontrolled myeloproliferation, i.e. platelet count >400 × 109/l AND white blood cell count >10 × 109/l after 3 months of at least 2 g/day of hydroxycarbamide OR
  3. Failure to reduce massiveasplenomegaly by more than 50% as measured by palpation OR failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of hydroxycarbamide OR
  4. Absolute neutrophil count <1·0 × 109/l OR platelet count <100 × 109/l OR haemoglobin <100 g/l at the lowest dose of hydroxycarbamide required to achieve a complete or partial clinico‐haematological response OR
  5. Presence of leg ulcers or other unacceptable hydroxycarbamide ‐related non‐haematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide.

 

  • Interferon
    • Safe in pregnancy

 

  • Other cytoreductive agents
    • Ruxolitinib (JAK2 inhibitor)
      • Second/third line if HC intolerant/resistant
    • Radioactive phosphorus / busulfan
      • Increased risk of leukaemia transformation so should only be administered to thse with a limited life expectancy.
    • Anagrelide
      • Can be used in combination if plt count not controlled with hydroxycarbamide

 

Post renal transplant erythrocytosis

  • Incidence ~5-20%
  • Various definitions ranging from HCT >0.50 -0.52 persisting for between 1 and 6 months.
  • It typically occurs within the first year post transplant
  • The erythrocytosis is related to EPO levels. Risk factors for developing post transplant erythrocytosis include:
    • Male > female
    • Native kidney in situ
    • Renal artery stenosis
    • Reduced need for EPO pre-transplant or transfusions
    • Poor allograft function
  • It is usually considered to be a benign condition as it is not associated with thrombosis or increased mortality. It can also spontaneously resolve over 1-4 years.
  • Management:
    • ACEi or ARB as these suppress the renin-angiotensin system
    • Treat hypertension
    • No benefit of aspirin
    • Consider venesection if persistent symptoms to target HCT 0.5 (no evidence of benefit)

References

  1. McMullin MF. A guideline for the diagnosis and management of polycythaemia vera. A Britich Society for Haematology Guideline. 184(2):176-191. 2019.
  2. Landolfi R et al. European Collaboration on Low-dose aspirin in polycythaemia vera (ECLAP): A randomised trial. Seminars in Thrombosis and haemostasis. 23(5):473-8. 1997.
  3. Marchioli R et al. Cardiovascular events and intensity of treatment in polycythaemia vera. New England Journal of Medicien. 368:22-33. 2013
  4. McMullin MF. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis. A Britich Society for Haematology Guideline. 184(2):161-175. 2019.

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