Secondary polycythemia refers to ploycythemia caused due to elevated serum erythropoietin levels. 

They are also at slightly higher risk of developing stroke and venous thromboembolism.

Refer to “Polycythemia” section in “Approach to diagnosis”.  Click here

In secondary polycythemia phlebotomies are done only if patient is symptomatic. Use of Aspirin and amount of phlebotomy are generally done as per discretion of treating physician (in secondary polycythemia therapeutic goal of PCV is a fine balance between adequate tissue oxygenation and hyperviscosity. Usual target is 60%)

Myelosuppressive therapy is generally avoided.

Always try to treat the underlying cause.

Ex: Stop smoking or change diuretics to other medications or Stop use of androgens or Low flow oxygen for patients with COPD or weight loss for patients with hypoventilation syndrome or surgical removal of EPO producing tumors

Hypoxic pulmonary disease related polycythemia

• These patients have increased risk of cor-pulmonalae
• Long term oxygen therapy/ continuous positive pressure ventilation improves survival and also decreases hemoglobin level
• Non invasive ventilation or continuous positive airway pressure at night for type II respiratory failure
• Smokers must be strongly to stop smoking
• Do venesection if Hct>0.56 and try to maintain it between 0.50- 0.52.
• Phlebotomy helps in decreasing pulmonary arterial resistance and improving right ventricular function.

Polycythemia due to cyanotic congenital heart disease

• Advice corrective/ palliative surgery or catheter intervention to decrease cyanosis and erythrocytosis
• Children are at increased risk of cerebral venous sinus thrombosis, that is particularly linked to iron deficiency
• In adults there is increased risk of cerebral arterial and microarterial thrombi
• Venesection is recommended if there are symptoms of hyperviscosity and Hct>0.65
• Adequate iron stores must be maintained prior to venesection, as symptoms of hyperviscosity could be due to iron deficiency. Also, iron deficiency lead to microcytic RBCs which are less deformable, and hence is associated with high risk of thrombosis.
• Avoid antiplatelet agents and anticoagulation for prevention of stroke, as there is increased risk of bleeding.
• Hydroxyurea may be used to decrease venesection requirement. This increases the size of RBCs and hence decreases the risk of thrombosis.

Primary familial and congenital polycythemia

• They include
  • Chuvash polycythemia
    • Autosomal recessive inheritance. Associated with mutation of von HippelLindau gene which leads to impaired interaction between VHL protein and HIF1alpha. This leads to decreased ubiquitation of HIF. Increased HIF levels lead to upregulation of EPO and subsequent polycythemia.
  • Erythropoietin receptor mutation leading to augmented response to EPO (which occurs through JAK pathway)
    • Loss of negative regulatory domain of EPO receptor
    • Failure to internalize EPO and EPO receptor
    • Deficiency of PHD (Prolinehydroxylase) which normally combines with HIF alpha and enhances its degradation
  • High oxygen affinity hemoglobins
• Low dose aspirin can be given in these cases
• Venesection with target Hct- 0.52.
• Ruxolitinib can be considered in Chuvash polycythemia

Renal polycythemia

• Post renal transplant- 
  • Hb>17g/dL or PCV- >51% for more than 6 months after renal transplant
  • Seen in 8-15% renal transplant recipients
  • Usually occurs 8-24 months after transplantation
  • If untreated, patient may develop venous thrombosis
  • Affects patients with well preserved graft function
  • Most of the patients show elevated EPO levels
  • Probable mechanism- Activation of rennin angiotensin system with elevated levels of angiotenisn II and hypoxia inducible factor.
  • Treated with ACE inhibitors or Angiotensin receptor blocker (Enalapril/ Losartan). 
  • Phlebotomy with target PCV- 50%
  • If both these are not possible or are contraindicated or fail, then may use theophylline or antiproliferative agent (Ex: MMF, Sirolimus, Azathioprine etc)
  • As native kidneys are the sources of EPO, some need removal of native kidneys.
  • If risk of cardiovascular disease is high, use Aspirin.
• No benefit of giving aspirin
• Phlebotomy with target Hct- 0.5
• Solitary renal cyst, Polycystic kidney disease, hydronephrosis, renal artery stenosis- Surgical correction

Chronic mountain sickness

• It is pathological loss of adaptation to altitude by highlanders
• Seen in those who live above 2500 meters
• Develop cyanosis, pulmonary hypertension later leading to CCF
• Treatment
  • Descend to lower altitudes or sea level
  • Phlebotomies
  • Respiratory stimulants such as Medroxyprogesterone acetate (60mg/day), Almitrine, Enalapril (10mg/day)

Gaisbock’s syndrome

• It is also called stress polycythemia/ pseudopolycythemia
• Seen in obese, hypertensive males who smoke
• Probably occurs because of excessive catecholamines
• Polycythemia is because of decreased plasma volume
• Treatment- Correct cardiovascular risk factors

Benign/ Idiopathic erythrocytosis

• Increased red cell mass, who on investigation, do not have any form of primary or secondary erythrocytosis.
• Frequently seen in men.
• EPO levels are variable (Low in 1/3^rd and elevated in 2/3^rd patients)
• Associated with lower incidence of vascular complications
• Venesection must be done if Hct is >0.54 and there is risk of thrombosis (If previous thrombosis, peripheral vascular disease, DM, Hypertension, then target must be to reduce Hct to <0.45).
• Aspirin should be given if otherwise clinically indicated for primary or secondary prevention.
• Need rirorous control of vascular risk factors such as diabetes mellitus, hypertension and smoking.
• Avoid cytoreductive agents

Recent advances:

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak–Zhuang Syndrome 

Pacak–Zhuang syndrome is charectorised by polycythemia and multiple paragangliomas. It is caused due to somatic mosaicism for activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. 

https://doi.org/10.1056/NEJMoa2110051