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polycythaemia

introduction

excessive concentration of RBCs in the peripheral blood
increased RBC mass enlarges the vascular bed, decreases peripheral resistance and increases cardiac output and improves oxygen transport
HOWEVER, an excessively high RBC mass causes high viscosity and this may increase the risk of stroke (CVA), deep venous thrombosis (DVT), and other thrombotic events in various patient subgroups, particularly in those with Chuvash erythrocytosis (in CE) and polycythemia vera, although viscosity itself may not be the causal factor, and in CE patients, it may be more related to upregulation of HIF-controlled prothrombotic genes such as tissue factor and thrombospondin.
- In PRV patients, 50-75% of thrombotic events are arterial, most frequently causing strokes and TIAs and less so, AMIs and venous thromboses ¹⁾
  - the majority of “idiopathic” Budd-Chiari syndrome patients have the JAK2 mutation despite a normal hematocrit
  - it may be that the proportion of activated neutrophils may be an important factor in PRV-associated thrombosis as the studies seem to show variable results regarding haematocrit vs thrombosis risk and environmental hypoxia such as mild altitude living may be a risk factor perhaps by reducing protein S levels via an HIF-1-mediated mechanism ²⁾

studies are far from conclusive that it is the high haematocrit and resultant viscosity that increases thrombotic events in certain patient subgroups as there are likely to be other more important factors
the routine practice of phlebotomy for elevated hematocrit needs to be re-evaluated as it does have adverse effects such as iron deficiency (which leads to inhibition of PHD2, increased HIF, and increased erythropoietin) and potential detrimental paradoxic thrombotic effects ³⁾

artefactual due to dehydration
“apparent polycythemia” due to reduced amount of plasma in the blood with a normal red cell count
- obesity
- smoking
- excessive alcohol intake
- diuretics
- phaeochromocytoma
“absolute polycythemia”
- primary (results in reduced erythropoietin secretion):
  - polycythaemia rubra vera - raised haematocrit often with raised neutrophils, basophils and platelets and JAK2 mutations
  - familial erythrocytosis due to:
    - SH2B3 mutations
    - EPOR mutations
- secondary:
  - due to increased erythropoietin secretion:
    - chronic hypoxia:
      - chronic obstructive pulmonary disease (COPD)
      - obstructive sleep apnoea
      - high altitude
      - carboxyhaemoglobinaemia
    - erythropoietin-secreting renal tumours
    - renal artery stenosis
    - erythropoietin doping
    - familial:
      - left shifted oxygen dissociation curve:
        
        2,3 diphosphoglycerate deficiency
        
        high oxygen affinity haemoglobins
      - methaemoglobinaemia
      - mutations in hypoxia-sensing pathway genes;
        
        EGLN1 (PHD2) mutations
        
        EPAS1 (HIF-2alpha) mutations
        
        VHL mutations
      - gain of function mutation of erythropoietin gene
  - due to other exposures:
    - cobalt
    - insulin growth factor 1
    - manganese
    - post-renal transplant (increased angiotensin signalling)
    - testosterone

red cell mass and plasma volume measurements
- normal red cell mass, decreased plasma volume:
  - “apparent polycythemia”
- elevated red cell mass:
  - oxygen sats < 93%:
    - hypoxic erythrocytosis eg COPD
  - oxygen sats > 93%:
    - JAK2 mutation +ve ⇒ polycythaemia rubra vera
    - JAK2 mutation -ve:
      - serum erythropoietin level:
        
        normal or low, then consider:
        
        polycythaemia rubra vera
        
        EPO-receptor mutation
        
        renal disease
        
        tumours
        
        high affinity haemoglobins
        
        raised, then consider:
        
        renal disease
        
        tumours
        
        VHL mutation
        
        high affinity haemoglobins

ruddy complexion
may cause lethargy, SOB
may cause headaches and tinnitus
- appear to be related to increased viscosity of blood resulting from the expanded red cell mass and elevated hematocrit
Polycythemia vera and secondary polycythemia have been implicated in reduced cerebral blood flow and focal cerebral ischaemia ⁴⁾ and may cause cardiac micro-emboli
increased risk of thrombotic events such as ischaemic stroke however, this may not be due to the raised RBC mass itself but to other factors

¹⁾ , ²⁾ , ³⁾

⁴⁾