Today in morning report we talked about polycythemia. 

The first step when you see a patient with an elevated hemoglobin (Hb > 160 in women or > 165 in men) is to confirm the diagnosis of polycythemia (as opposed to a concentration problem). To do this, you look at the other measures on your CBC to confirm the diagnosis:

• Hematocrit > 49% (in men) or 48% in Women.
• RBC count > 5×10⁶ cells/microL (Least useful measure) in addition to an elevated Hb.

The differential diagnosis for polycythemia includes:

Primary Polycythemia – EPO Independent (low EPO)

• Polycythemia Vera (JAK2 mutation)
• Idiopathic Erythrocytosis
• Activating mutations of EPO receptor

A word on JAK2 (and a biochemistry review):

Janus-Kinase 2 (JAK2) is a non-receptor tyrosine kinase, which is an enzyme located in the cytosol (not on the cellular surface) responsible for transfer of a phosphate from ATP to a tyrosine residue in protein.  The other class of tyrosine kinases are receptor tyrosine kinases, which may be familiar from therapies like VEGF inhibitors in lung cancer, or PDGFR inhibitors (like Gleevec) for CML.

A vast majority of patients with polycythemia vera will have activating mutations in the JAK2 gene that make their red blood cells more sensitive to erythropoietin. This is why it is an EPO independent form of polycythemia.  JAK2 mutations are also implicated in other myeloproliferative disorders such as essential thrombocythemia (ET).  Interestingly, JAK2 mutations are also implicated in myelofibrosis, where patients often present with pancytopenia.

Unlike the receptor tyrosine kinase inhibitors, we do not have developed ways of targeting non-receptor tyrosine kinase inhibitors. Therefore the treatment of PV is to manage complications through phlebotomy, low dose ASA and through cytoreductive agents like hydroxyurea.

The differential diagnosis of secondary polycythemia – Erythropoietin Dependent (Normal/High EPO):

• Chronic Hypoxia
  • Smoking
  • Poorly Controlled OSA
  • COPD
  • Carbon Monoxide
  • Cyanotic heart disease
• Endogenous EPO
  • Tumor
• Exogenous EPO
• Androgens – Testosterone, Anabolic Steroids
• Transfusion of blood products (sports performance enhancement) (may have low EPO)

Organize your history into three components: 

Erythromelalgia (Courtesy of Wikipedia)

1. Symptoms due to the underlying polycythemia: Think about hyperviscosity syndromes (like sickle cell anemia crisis) to remember the symptoms of polycythemia. These include: chest and abdominal pain, myalgia and weakness, fatigue, headache, blurred vision, transient loss of vision, paresthesias, slow mentation and/ora sense of depersonalization
2. Symptoms suggesting the presence of a secondary cause of polycythemia (such as underlying pulmonary disease):
   • Ask a comprehensive review of symptoms including shortness of breath, dyspnea on exertion, chronic cough, history of cyanosis, OSA symptoms.
   • Does your patient have a history of congenital heart disease, chronic kidney disease? Are they using any exogenous substances such as EPO or testosterone?
3. Symptoms suggesting the diagnosis of primary polycythemia (i.e. polycythemia vera):
   • Pruritus after bathing
   • Erythromelalgia  (intense burning of the hands and feet associated with erythema)
   • Gout
   • Arterial or venous thrombosis
   • Hemorrhage
   • Early satiety due to the presence of splenomegaly.

What should you do if you suspect a patient has polycythemia?

1. Confirm the diagnosis by repeating the lab when the patient is well hydrated and look at the other markers of RBC (Hct, RBC mass, MCV).
2. Order an erythropoietin level and a JAK2 level, a reticulocyte level may also be helpful if it is high
3. Screen the patient for thrombosis, splenomegaly with an abdominal ultrasound if symptomatic
4. Consider referral to Hematology for phlebotomy and definitive management.

The bottom line:

• Polycythemia is a blood condition characterized by elevated Hb and RBC mass/hematocrit that makes patients prone to hyper viscosity syndromes.
• The differential includes primary and secondary causes (which are much more common)
• Polycythemia Vera is a mutation of the JAK2 signalling pathway which makes RBCs and other bone marrow cells more sensitive to EPO/Thrombopoeitin and other stimulatory molecules.