Authors :

Srikanth Nagalla, MBBS, MS, FACP Associate Professor of Medicine, Division of Hematology and
Oncology, UT Southwestern Medical Center
https://emedicine.medscape.com/article/205039-overview

Secondary Polycythemia
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.
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). Other causes testosterone replacement therapy and
heavy cigarette smoking. 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.

Pathophysiology
Increased hemoglobin and hematocrit values reflect 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 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 eventual accumulation of red blood
cells. The secondary polycythemic disorders may be acquired or congenital; however, they are
driven by circulating factors that are independent of the function of hematopoietic stem cells.

History
Patients with a high red blood cell mass usually have plethora or a ruddy complexion. However,
if the polycythemia is secondary to hypoxia, as in venous-to-arterial shunts or compromised lung
and oxygenation, patients can also appear cyanotic.
Increased red blood cell mass increases blood viscosity and decreases tissue perfusion. With
impaired circulation to the central nervous system, patients may present with headaches,
lethargy, and confusion or more serious presentations, such as stroke and obtundation. In
addition, polycythemia potentially predisposes patients to thrombosis.
Congenital heart diseases manifest at birth or in early childhood. In some cases, a family history
of congenital heart disease may be present.
Patients with familial hemoglobinopathies that result in increased oxygen affinity usually have a
family history of similar problems in several family members, although significant numbers of
patients with congenital polycythemia have no family history of similar disorders.
Chronic pruritus in the absence of a rash is more indicative of a primary myeloproliferative
disorder than of secondary polycythemia.

*V/Q Ratio = V̇ or V – ventilation – the air that reaches the alveoli. Q̇ or Q – perfusion – the blood
that reaches the alveoli via the capillaries.
*Plethora = Hypervolemia / blood increase

Physical
Plethora manifests as increased redness of the skin and mucosal membranes. This finding is
easier to detect on the palms or soles, where the skin is light in dark-skinned individuals. Some
patients may have acrocyanosis caused by sluggish blood flow through small blood vessels.
The presence of splenomegaly supports a diagnosis of polycythemia vera rather than secondary
polycythemia. Cardiac murmurs and clubbing of the fingers may suggest a congenital heart
disease.

Causes
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. Approximately
two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not
lymphocyte) counts and platelet counts. 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, as in the following settings:

 Decreased ambient oxygen concentration, as occurs in people living at high altitudes, can
result in compensatory erythrocytosis as a physiologic response to tissue hypoxia.
 Chronic obstructive pulmonary disease is commonly due to a large amount of ventilation
in poor gas exchange units (high ventilation-to-perfusion ratios)
 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 by smoking or working in automobile tunnels results in an
acquired condition. [14, 15] Carboxyhemoglobin has a strong affinity for oxygen.
Orphanet : Secondary polychitaemia
https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=98428
Expert reviewer(s): Pr Jean BRIERE - Last update: July 2010

Secondary polycythemia may be congenital and caused by defects in the oxygen sensing
pathway due to autosomal recessive mutations in the VHL, EGLN1 and EPAS1 genes (3p26-p25,
1q42-q43 and 2p21-p16 respectively) which result in enhanced erythropoietin (EPO)
production in hypoxic conditions, or by other autosomal dominant congenital defects including
high oxygen-affinity hemoglobin and biphosphoglycerate mutase deficiency, which result in
tissue hypoxia and a secondary erythrocytosis. Alternatively, secondary polycythemia may be
acquired and caused by increased amounts of EPO. This may be due to tissue hypoxia that may
be central and caused by pulmonary or cardiac disease or high altitude, or local and caused by
hypoxia in the kidney such as renal artery stenosis. EPO production may be pathologic and caused
by EPO secreting tumors such as renal cell cancer, hepatocellular carcinoma, cerebellar
hemangioblastoma, meningioma and parathyroid carcinoma/adenoma (see these terms). In
addition EPO may be administered deliberately to produce erythrocytosis and enhance
performance.

Secondary Erythrocytosis
(Secondary Polycythemia)
https://www.msdmanuals.com/professional/hematology-and-oncology/myeloproliferative-
disorders/secondary-erythrocytosis
Last full review/revision December 2016 by Jane Liesveld, MD; Patrick Reagan, MD

In secondary erythrocytosis, only RBCs are increased, whereas in polycythemia vera, RBCs, WBCs, and
platelets may be increased. Any elevation of Hb or Hct above normal values for age and sex is considered
erythrocytosis.