Secondary Polycythemia Clinical Presentation

Updated: Dec 20, 2018
  • Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
  • Print
Presentation

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. [3]

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. [5]

Chronic pruritus in the absence of a rash is more indicative of a primary myeloproliferative disorder than of secondary polycythemia.

Next:

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.

Previous
Next:

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. [1, 2, 6, 7, 8, 9]  Approximately two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not lymphocyte) counts and platelet counts. [10] 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, [11] 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. [12]

  • Chronic obstructive pulmonary disease is commonly due to a large amount of ventilation in poor gas exchange units (high ventilation-to-perfusion ratios). [13]

  • 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.

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 renal 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 opponent 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.

A 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. [16]

Low EPO-dependent polycythemias

These are called primary familial and congenital polycythemias. [17] The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels. [18] 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. [19]

Previous