Polycythemia


Polycythemia is a laboratory finding that the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.
Polycythemia has many causes. It can describe an increase in the number of red blood cells or a decrease in the volume of plasma. Absolute polycythemia can be due to genetic mutations in the bone marrow, physiological adaptations to one's environment, medications, and/or other health conditions. Laboratory studies such as serum erythropoeitin levels and genetic testing might be helpful to clarify the cause of polycythemia if the physical exam and patient history do not reveal a likely cause.
Mild polycythemia on its own is often asymptomatic. Treatment for polycythemia varies, and typically involves treating its underlying cause. Treatment of primary polycythemia could involve phlebotomy, antiplatelet therapy to reduce risk of blood clots, and additional cytoreductive therapy to reduce the number of red blood cells produced in the bone marrow.

Definition

Polycythemia is defined as serum hematocrit or hemoglobin exceeding normal ranges expected for age and gender, typically Hct >49% in healthy adult men and >48% in women, or HgB >16.5 g/dL in men or >16.0 g/dL in women. The definition is different for neonates and varies by age in children.

Differential diagnoses

Polycythemia in adults

Different diseases or conditions can cause polycythemia in adults. These processes are discussed in more detail in their respective sections below.
Relative polycythemia, also known as pseudopolycythemia, is not a true increase in the number of red blood cells or hemoglobin in the blood, but rather an elevated laboratory finding caused by reduced blood plasma. Relative polycythemia is often caused by loss of body fluids, such as through burns, dehydration, and stress. A specific type of relative polycythemia is Gaisböck syndrome; in this syndrome, primarily occurring in obese men, hypertension causes a reduction in plasma volume, resulting in a relative increase in red blood cell count. If relative polycythemia is deemed unlikely because the patient has no other signs of hemoconcentration and has sustained polycythemia without clear loss of body fluids, the patient likely has absolute or true polycythemia.
Absolute or true polycythemia can be split into two categories:
  • Primary polycythemia, that is the overproduction of red blood cells due to a primary process in the bone marrow. These can be familial or congenital, or acquired later in life.
  • Secondary polycythemia, whenever additional red blood cells may have been received through another process — for example, being over-transfused.

    Polycythemia in neonates

Polycythemia in newborns is defined as hematocrit > 65%. Significant polycythemia can be associated with blood hyperviscosity, or thickening of the blood. Causes of neonatal polycythemia include:
  • Hypoxia: Poor oxygen delivery in utero resulting in compensatory increased production of red blood cells. Hypoxia can be either acute or chronic. Acute hypoxia can occur as a result of perinatal complications. Chronic fetal hypoxia is associated with maternal risk factors such as hypertension, diabetes and smoking.
  • Umbilical cord stripping: delayed cord clamping and the stripping of the umbilical cord towards the baby can cause the residual blood in the cord/placenta to enter fetal circulation, which can increase blood volume.
  • The recipient twin in a pregnancy undergoing twin-to-twin transfusion syndrome can have polycythemia.

    Pathophysiology

The pathophysiology of polycythemia varies based on its cause. The production of red blood cells in the body is regulated by erythropoietin, which is a protein produced by the kidneys in response to poor oxygen delivery. As a result, more erythropoietin is produced to encourage red blood cell production and increase oxygen-carrying capacity. This results in secondary polycythemia, which can be an appropriate response to hypoxic conditions such as chronic smoking, obstructive sleep apnea, and high altitude. Furthermore, certain genetic conditions can impair the body's accurate detection of oxygen levels in the serum, which leads to excess erythropoietin production even without hypoxia or impaired oxygen delivery to tissues. Alternatively, certain types of cancers, most notably renal cell carcinoma, and medications such as testosterone use can cause inappropriate erythropoietin production that stimulates red cell production despite adequate oxygen delivery.
Primary polycythemia, on the other hand, is caused by genetic mutations or defects of the red cell progenitors within the bone marrow, leading to overgrowth and hyperproliferation of red blood cells regardless of erythropoeitin levels.
Increased hematocrit and red cell mass with polycythemia increases the viscosity of blood, leading to impaired blood flow and contributing to an increased risk of clotting.

Evaluation

History and physical exam

The first step to evaluate new polycythemia in any individual is to conduct a detailed history and physical exam. Patients should be asked about smoking history, altitude, medication use, personal bleeding and clotting history, symptoms of sleep apnea, and any family history of hematologic conditions or polycythemia. A thorough cardiopulmonary exam including auscultation of the heart and lungs can help evaluate for cardiac shunting or chronic pulmonary disease. An abdominal exam can assess for splenomegaly, which can be seen in polycythemia vera. Examination of digits for erythromelalgia, clubbing or cyanosis can help assess for chronic hypoxia.

Laboratory evaluation

Polycythemia is often initially identified on a complete blood count. The CBC is often repeated to evaluate for persistent polycythemia. If an etiology of polycythemia is unclear from history or physical, additional laboratory evaluation might include:

Primary polycythemia

Primary polycythemias are myeloproliferative diseases affecting red blood cell precursors in the bone marrow. Polycythemia vera occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. A hallmark of polycythemia vera is an elevated hematocrit, with Hct > 55% seen in 83% of cases. A somatic mutation in the JAK2 gene, also present in other myeloproliferative disorders, is found in 95% of cases. Symptoms include headaches and vertigo, and signs on physical examination include an abnormally enlarged spleen and/or liver. Studies suggest that mean arterial pressure only increases when hematocrit levels are 20% over baseline. When hematocrit levels are lower than that percentage, the MAP decreases in response, which may be due, in part, to the increase in viscosity and the decrease in plasma layer width. Furthermore, affected individuals may have other associated conditions alongside high blood pressure, including formation of blood clots. Transformation to acute leukemia is rare. Phlebotomy is the mainstay of treatment.
Primary familial polycythemia, also known as primary familial and congenital polycythemia, exists as a benign hereditary condition, in contrast with the myeloproliferative changes associated with acquired PCV. In many families, PFCP is due to an autosomal dominant mutation in the EPOR erythropoietin receptor gene. PFCP can cause an increase of up to 50% in the oxygen-carrying capacity of the blood; skier Eero Mäntyranta had PFCP, which is speculated to have given him an advantage in endurance events.

Secondary polycythemia

Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes.
Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic polycythemia. Conditions which may result in physiologic polycythemia include:
  • Altitude related – Polycythemia can be a normal adaptation to living at high altitudes. Many athletes train at high altitude to take advantage of this effect, which can be considered a legal form of blood doping, although the efficacy of this strategy is unclear.
  • Hypoxic disease-associated – for example, in cyanotic heart disease where blood oxygen levels are reduced significantly; in hypoxic lung disease such as COPD; in chronic obstructive sleep apnea; conditions that reduce blood flow to the kidney e.g. renal artery stenosis. Chronic carbon monoxide poisoning and rarely methemoglobinemia can also impair oxygen delivery.
  • Genetic – Heritable causes of secondary polycythemia include abnormalities in hemoglobin oxygen release, which results in a greater inherent affinity for oxygen than normal adult hemoglobin and reduces oxygen delivery to tissues.
Conditions where the secondary polycythemia is not caused by physiologic adaptation, and occurs irrespective of body needs include: