Secondary Polycythemia

Updated: Jun 07, 2022
  • Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Sara J Grethlein, MD, MBA, FACP  more...
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Practice Essentials

In secondary polycythemia, the number of red blood cells (RBCs) is increased as a result of an underlying condition. Secondary polycythemia would more accurately be called secondary erythrocytosis or erythrocythemia, as those terms specifically denote increased red blood cells. The term polycythemia is used appropriately in the myeloproliferative disorder called polycythemia vera, in which there are elevated levels of all three peripheral blood cell lines—RBCs, white blood cells, and platelets. [1, 2]

Secondary polycythemia most often develops as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys. The most common causes of secondary polycythemia include obstructive sleep apnea, obesity hypoventilation syndrome, and chronic obstructive pulmonary disease (COPD). [3] Other causes include testosterone replacement therapy [4] and heavy cigarette smoking. Patients who have arteriovenous or intracardiac shunting can present with polycythemia without hypoxemia. Erythropoietin-secreting tumors (eg, hepatocellular carcinoma, renal cell carcinoma, adrenal adenoma) cause some cases.

Secondary polycythemia must be differentiated from primary polycythemia and relative polycythemia (in which RBC numbers are normal but plasma volume is contracted. The reduction in plasma volume may be due to dehydration or to reduced venous compliance; the latter is also termed stress polycythemia or Gaisböck syndrome, and is typically seen in obese middle-aged men who are receiving a diuretic for treatment of hypertension. See Presentation and Workup.

To the extent that the increased RBCs alleviate tissue hypoxia, secondary polycythemia may in fact be beneficial. However, treatment with phlebotomy is indicated for patients with hematocrits higher than 60%-65%, who may experience symptoms such as  impaired alertness, dizziness, headaches, and compromised exercise tolerance, and who may face increased risk for thrombosis, strokes, myocardial infarction, and deep venous thrombosis. Otherwise, secondary polycythemia is addressed by treating the underlying condition. See Treatment.




Increased hemoglobin and hematocrit values reflect an increase in the ratio of red blood cell mass to plasma volume. Any change in either the hemoglobin or the hematocrit can alter test results.

Relative polycythemia, or erythrocythemia, results from decreased plasma volume. A true polycythemia or erythrocythemia results from increased red blood cell mass. Therefore, hemoglobin and hematocrit levels alone cannot accurately help make this distinction. Direct measurement of red blood cell mass is necessary to differentiate these conditions.

In primary polycythemia, the disorder results from a mutation expressed within the hematopoietic stem cell or progenitor cells, which drives the overproduction and accumulation of red blood cells. The secondary polycythemic disorders may be acquired or congenital; however, they are driven by factors that are independent of the function of hematopoietic stem cells. Elevated hemoglobin levels due to chronic hypoxia in patients with chronic lung disorders such as COPD or sleep apnea are the result of an increased production of erythropoietin, which in turn causes increased production of red blood cells.



Secondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. In contrast, polycythemia vera is characterized by bone marrow with an inherent increased proliferative activity. [1, 2, 5, 6, 7]   Approximately two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not lymphocyte) counts and platelet counts. [8]  No other causes of polycythemia/erythrocytosis are associated with elevated granulocyte or platelet counts.

Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia, [9]  as in the following settings:

  • Because of the decreased ambient oxygen concentration at high altitudes, people living in those locales can develop compensatory erythrocytosis as a physiologic response to tissue hypoxia. [10]

  • Chronic obstructive pulmonary disease is commonly due to a large amount of ventilation in poor gas exchange units (high ventilation-to-perfusion ratios). [11]

  • Alveolar hypoventilation can result from periodic breathing and oxygen desaturation (sleep apnea) or morbid obesity (Pickwickian syndrome).

  • Cardiovascular diseases associated with a right-to-left shunt (arteriovenous malformations) can result in venous blood mixing in the arterial system and delivering low oxygen levels to tissues.

  • Hemoglobin abnormalities associated with high oxygen affinity and congenital defects can lead to oxidized or methemoglobin. These conditions are usually familial.

  • Exposure to carbon monoxide, such as by smoking or working in automobile tunnels, results in an acquired condition. [12, 13]  Carboxyhemoglobin has a strong affinity for oxygen.

Impaired perfusion of the kidneys, which may lead to stimulation of erythropoietin [EPO] production, is usually due to local renal hypoxia in the absence of systemic hypoxia. Conditions include the following:

  • Arteriosclerotic narrowing of the renal arteries or graft rejection of a transplanted kidney can lead to impaired kidney perfusion.

  • Aneurysms affecting the aorta and renal vessels can lead to kidney infarction and hypoxia.

  • Focal glomerulonephritis has been associated with secondary polycythemia, although the mechanism for stimulation of EPO secretion in this condition remains unknown.

  • Polycythemia occurring after kidney transplantation is not a rare event. The mechanisms involved have not been clearly demonstrated.

Inappropriate stimulation of EPO production

Inappropriate stimulation of EPO production may occur in the following settings:

  • Benign renal lesions, such as hydronephrosis and cysts, can stimulate EPO production, possibly due to compromised renal blood flow by compressive or vasoconstrictive mechanisms.

  • Malignant and benign tumors that secrete EPO have been observed in patients with renal carcinomas, cerebellar hemangioblastomas, adrenal carcinomas, adrenal adenomas, hepatomas, and uterine leiomyomas.

  • Blood doping is an illegal practice. Competitive athletes have been known to attempt to maintain an advantage over their opponents by autologous blood transfusions or self-administration of recombinant EPO. Several deaths have been attributed to excessive blood doping.

  • Illicit use of androgenic steroids to build muscles and strength can also increase red blood cell mass by stimulating endogenous serum EPO levels.

Congenital causes

Hemoglobin mutants associated with tight binding to oxygen and a failure to deliver oxygen in the venous blood can cause high EPO levels. The high level of EPO is compensatory to elevate hemoglobin levels to deliver an optimal amount of oxygen to the tissues. Hypoxia-inducible factor 1-alpha (HIF1-alpha) binds to the hypoxia-responsive element, which is downstream of the gene for EPO. The activity of HIF1-alpha is increased by a lowered oxygen tension.

von Hippel-Lindau gene mutation results in polycythemia by altering the von Hippel-Lindau protein, which plays an important role in sensing hypoxia and binds to hydroxylated HIF1-alpha to serve as a recognition site of an E3-ubiquitin ligase complex. In this condition, and in hypoxia, the undegraded HIF1-alpha forms a heterodimer with HIF-beta and leads to increased transcriptions of the gene for EPO.

Chuvash polycythemia is caused by an autosomal recessive gene mutation on the von Hippel-Lindau gene, which results in the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels. [14]

Low EPO-dependent polycythemias

These are called primary familial and congenital polycythemias. [15]  The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels. [16]  These conditions can be acquired from (1) insulinlike growth factor-1 (IGF-1), a well-known stimulator of erythropoiesis, and (2) cobalt toxicity, which can induce erythropoiesis.

Testosterone-associated polycythemia

The administration of androgen esters to hypogonadal men can lead to polycythemia. However, the incidence of testosterone-associated polycythemia may be lower in men receiving pharmacokinetically steady-state delivery of testosterone formulations, as occurs following the subcutaneous implantation of testosterone pellets, than it is in men receiving intramuscular injections of shorter-acting androgen esters.

Ip and colleagues found that in men receiving long-acting depot testosterone treatment, the development of polycythemia (hematocrit >50%) was predicted by higher trough serum testosterone concentrations but not by the duration of treatment. [17]


Secondary polycythemia has been reported as a paraneoplastic phenomenon in patients with testicular cancer. The mechanism is not clear. 

A case of pazopanib-related secondary polycythemia has been reported in a patient receiving treatment for myxofibrosarcoma. [18]



The frequency of secondary polycythemia depends on the underlying disease. The mortality and morbidity of secondary polycythemia depend on the underlying condition.



The prognosis of patients with secondary polycythemia is driven by the underlying disorder. The polycythemia itself, when physiologic and not sufficiently extreme to cause significant hyperviscosity, generally has no effect on life span. However, patients with secondary polycythemia generally have a shorter survival following diagnosis than patients with polycythemia vera. This is believed to reflect the dire conditions that underlie many cases of secondary polycythemia.

At extreme levels of secondary polycythemia, patients can be at risk for thrombosis. Excessive polycythemia, usually defined as hematocrit levels higher than 65-70%, may result in increased whole blood viscosity. This, in turn, may lead to impaired blood flow locally, resulting in thrombosis. The risk is lower than with primary erythrocytosis but data are too sparse for accurate quantification. 

Hyperviscosity may also lead to generalized sluggish blood flow, resulting in impaired tissue oxygenation in multiple organs, which may lead to decreased mentation, fatigue, generalized weakness, and poor exercise tolerance.