A. Introduction. A hematocrit greater than 48% in women or 52% in men constitutes polycythemia. Likewise a hemoglobin of >16.5 g/dL in women or >18.5 g/dL in men raises the suspicion for polycythemia.
a. Absolute polycythemia is characterized by an increase in red blood cell (RBC) mass due to either primary or secondary causes.
b. Relative polycythemia is characterized by a decrease in plasma volume.
B. Clinical Manifestations of Polycythemia
a. Patients are often asymptomatic if the hematocrit is lower than 60%. Higher hematocrits may cause:
i. Symptoms of hyperviscosity (e.g., headaches, dizziness, blurred vision, chest pain, abdominal pain, paresthesias, fatigue), facial plethora (ruddy cyanosis).
ii. Both thrombosis and bleeding may result from abnormalities in platelet function as the hematocrit rises.
b. Symptoms specific to polycythemia vera are described in Chapter 70.
C. Causes of Polycythemia. Polycythemia may be a secondary, physiologic response to another disorder (e.g., chronic hypoxemia), or it may herald a primary myeloproliferative neoplasm like polycythemia vera.
a. Absolute polycythemia. There are five common causes of absolute polycythemia. Remember, “Hypoxemia Can Cause Polycythemia Every Time.”
MNEMONIC: Causes of Absolute Polycythemia (“Hypoxemia Can Cause Polycythemia Every Time”)
Cushing’s syndrome or Corticosteroids
Erythropoietin-secreting Tumors or after renal Transplantation
i. Hypoxemia. Chronic hypoxemia, as a result of cardiopulmonary disease, sleep apnea, or high altitude, can lead to a secondary polycythemia.
ii. Carboxyhemoglobinemia or methemoglobinemia. Carboxyhemoglobin and methemoglobin reduce the oxygen-carrying capacity of RBCs, resulting in tissue hypoxia, which induces a secondary polycythemia. Smoking is a common cause of carboxyhemoglobinemia. Alternatively, high-affinity hemoglobin variants also cause a leftward shift of the hemoglobin oxygen dissociation curve, decrease oxygen delivery to the tissues, and induce a compensatory polycythemia.
iii. Cushing’s syndrome or corticosteroid therapy. Corticosteroids have an erythropoietic effect, which can lead to polycythemia. Moreover, supplemental testosterone use can induce a secondary polycythemia by stimulating erythrocytosis through unclear mechanisms.
iv. Polycythemia vera is a clonal myeloid neoplasm (myeloproliferative neoplasm) in which hematopoietic progenitor cells expand, leading to elevated RBC indices (RBC count, hemoglobin, and hematocrit). JAK2 mutations are the leading drivers of this neoplasm.
v. Erythropoietin-secreting tumors are primarily renal cell carcinomas, hemangioblastomas (of the cerebellum), uterine fibroids, or hepatocellular carcinomas.
vi. After renal transplantation. Due to unclear mechanisms, erythrocytosis can occur in up to 15% of patients after a renal transplant.
b. Relative polycythemia. There are two main causes of relative polycythemia.
i. Dehydration (e.g., from vomiting, diarrhea, excessive sweating, or diuretics) can deplete plasma volume, leading to a relative polycythemia.
ii. Stress erythrocytosis (Gaisböck’s polycythemia) results from contraction of plasma volume and is therefore a misnomer. This benign disorder is seen most often in hypertensive, obese men.
D. Approach to the Patient
a. Rule out hypoxemia, carboxyhemoglobinemia, and methemoglobinemia. These are relatively easy to evaluate. If abnormalities significant enough to result in polycythemia are found, the need for additional workup may be eliminated. An arterial blood gas with oxygen saturation, carboxyhemoglobin, and methemoglobin levels is necessary for all patients and is more accurate than pulse oxygen saturation measurements (carbon monoxide values in excess of 5% are suggestive of this diagnosis as the cause of the polycythemia). While oxygen saturations may be adequate during the day, sleep apnea may be severe enough to lead to a secondary polycythemia, so consider a formal sleep study if clinical suspicion of sleep apnea exists.
b. Family history. If there is an associated family history of elevated blood counts, consider either polycythemia vera (see Chapter 70) or a high-affinity hemoglobin moiety, which may be evaluated by an oxygen dissociation curve.
c. Stratify approach based on hematocrit
i. Hematocrit greater than 60% in men or 55% in women
1. Rules out steroid excess, which usually causes a mild polycythemia. Furthermore, because an elevated RBC mass is found in 99% of these patients, decreased plasma volume is unlikely, and an RBC mass study is not necessary.
2. Reduces the list of possible diagnoses to either polycythemia vera (more common) or an erythropoietin-secreting tumor (less common). The following characteristics may provide clues to differentiating polycythemia vera from other secondary causes (see also Chapter 70 for the diagnostic criteria of polycythemia vera).
a. Polycythemia vera
i. Presence of splenomegaly, leukocytosis, or thrombocytosis.
ii. A history of bleeding or thrombotic complications may be present.
iii. Concomitant iron deficiency in the setting of elevated RBC indices.
iv. Decreased erythropoietin level (usually less than 20mU/mL).
v. Molecular testing positive for a Janus kinase (JAK2) gene mutation. Note, this is present in approximately 98% of patients with polycythemia vera, but does not exclude or confirm the diagnosis alone.
b. Erythropoietin-secreting tumors
i. An abdominal computed tomography (CT) scan may help rule out renal pathology (including cancer) and hepatic malignancies.
ii. Brain imaging (preferably with magnetic resonance imaging [MRI]) may be performed if clinical suspicion of a cerebellar lesion exists.
ii. Hematocrit less than 60% in men or 55% in women
1. An RBC mass study should be performed to rule out a decreased plasma volume, which is responsible for polycythemia in approximately 50% of cases. In general, secondary causes will account for far more cases than polycythemia vera.
E. Treatment. Treatment is aimed at the underlying disorder. Stress erythrocytosis requires no treatment other than encouraging weight loss and oral hydration. General therapeutic measures include the following:
a. Oxygen therapy is useful in patients with an arterial oxygen tension (PaO2) lower than 60 mm Hg.
b. Smoking cessation is highly encouraged (especially in patients with carboxyhemoglobinemia).
c. Hydration is recommended for patients with evidence of dehydration.
d. An angiotensin-converting enzyme inhibitor is used to treat post–renal transplantation polycythemia.
e. Surgical consultation is appropriate if an erythropoietin-secreting tumor is suspected.
f. Therapeutic phlebotomy to lower the hematocrit is usually only indicated for patients with polycythemia vera (see Chapter 70).
Suggested Further Readings
McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005;130:174–95.Find this resource:
Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017;129:680.Find this resource: