AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The word polycythemia indicates increased red blood cells, white blood cells, and platelets. Most of the time, it is used in place of erythrocythemia, or pure red blood cell increase, such as in secondary polycythemia.

The term polycythemia is reserved for the myeloproliferative disorder called polycythemia vera, in which all 3 peripheral blood cell lines can be increased.

Erythrocytosis or erythrocythemia is a more specific term to denote increased red blood cells.

Pathophysiology

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

Relative polycythemia, or erythrocythemia, results from decreased plasma volume (Gaisbock syndrome). 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 also be acquired or congenital; however, they are driven by circulating factors independent of the function of hematopoietic stem cells.

Frequency

United States

Frequency depends on the underlying disease.

Mortality/Morbidity

• Mortality and morbidity depend on the underlying condition.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Increased red blood cell mass increases blood viscosity and decreases tissue perfusion, potentially predisposing the patient to thrombosis.
• Symptoms due to high red blood cell mass usually manifest as plethora or a ruddy complexion.
• If the condition is secondary to hypoxia, as in venous-to-arterial shunts or compromised lung and oxygenation, patients can also appear cyanotic.
• Symptoms may result from impaired circulation to the central nervous system, and patients present with headaches, lethargy, and confusion or more serious presentations such as stroke and obtundation.
• 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 with 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 rather than secondary polycythemia.

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 caused by enhanced stimulation of red blood cell production. In contrast, polycythemia vera is characterized by bone marrow with an inherent increased proliferative activity. Enhanced erythroid stimulation results from the following:

• Acquired polycythemia due to a physiologic response to generalized or localized tissue hypoxia
• • Generalized inadequate tissue oxygenation or hypoxia can be due to the following:
  • • 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 met-hemoglobin. These conditions are usually familial.
    • Exposure to carbon monoxide by smoking or working in automobile tunnels results in an acquired condition. 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
• • 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 of high EPO levels are as follows:
  • • 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 factor1-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 hypoxia sensing 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 the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels.
• Low EPO-dependent polycythemias
• • These are called primary familial and congenital polycythemias.
  • The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels.
  • These conditions can be acquired from (1) insulinlike growth factor-1, a well-known stimulator of erythropoiesis, and (2) cobalt toxicity, which can induce erythropoiesis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Dehydration
Gaisbock syndrome (spurious polycythemia)
Relative polycythemia
Renal arteriovenous aneurysm

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Measure red blood cell mass and plasma volume when repeated hematocrit levels exceed 52% in males and 47% in females. However, data from the Polycythemia Vera Study Group showed that if the hematocrit value is equal to or greater than 60%, the red blood cell mass is always increased; formal red blood cell mass and plasma volume studies are unnecessary in these cases. As a practical note, most nuclear medicine departments perform these tests very infrequently, which may raise questions about the reliability and validity of red blood cell mass and plasma volume measurements.
• • To measure red blood cell mass, calculate total red blood cell mass from the dilution factor and a known volume of radiolabeled (chromium Cr 51) autologous red blood cells.
  • The red blood cell mass is increased if it exceeds 35 mg/kg in males and 31 mg/kg in females.
  • Documentation of an increased red blood cell mass is essential to demonstrate true erythrocytosis.
• To measure plasma volume, use radiolabeled albumin (iodine I 131), similar to with the red blood cell mass measurement. Plasma volume can also be calculated indirectly using total red blood cell mass and the hematocrit value.
• Decreased plasma volume with a normal red blood cell mass indicates a relative polycythemia or erythrocytosis, similar to the increased hemoglobin and hematocrit levels associated with severe dehydration.
• Measuring arterial oxygen saturation is important to exclude generalized hypoxemia as a cause. Further investigation may require performing the test while the patient is sleeping. Measured arterial oxygen saturations of less than 92% may be associated with the development of a secondary polycythemia.
• Carboxyhemoglobin levels of greater than 8% in individuals who smoke or those who may have an occupational exposure to carbon monoxide may be associated with the development of polycythemia.
• The hemoglobin-oxygen dissociation curve may be determined in patients with a lifelong history (particularly a familial history) of erythrocytosis with normal oxygen saturation and normal levels of 2,3-diphosphoglycerate.
• • Formulas are available in which the measured arterial and venous oxygen saturations can be used to calculate the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen.
  • This partial pressure value is a good estimate of the entire oxygen dissociation curve because the shape of the dissociation curve varies only minimally, even with very high and very low oxygen affinity hemoglobins.
• Endogenous serum levels of EPO may be helpful to determine inappropriate production of EPO. Serum EPO levels also may be very helpful in distinguishing between primary and secondary polycythemias.
• • In polycythemia vera and congenital/familial primary polycythemias, EPO levels are usually low to low-normal.
  • In secondary physiologic or nonphysiologic polycythemias, EPO levels are usually normal or elevated.

Imaging Studies

• An abdominal CT scan or an intravenous pyelogram to investigate the kidneys and their function may be indicated in a minority of patients who may have a tumor or renal abnormalities that may be causing the polycythemia.

Histologic Findings

Increased total red blood cell mass determines true polycythemia. Secondary causes must be identified individually.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The development of secondary erythrocytosis in response to tissue hypoxia is physiologic and probably beneficial to many patients. The expanded red blood cell mass may partially or totally compensate for the lack of oxygen delivery and result in tissue oxygenation to its normal level. However, limitation of compensatory increased red blood cells compromises circulation because of hyperviscosity when the hematocrit reaches levels higher than 60-65%. The latter leads to greater tissue hypoxia and EPO secretion, a continued increase in red blood cells, and further impairment of circulation.

• To restore viscosity and maintain circulation at its optimal level, phlebotomize or remove the offending red blood cells.
• Some patients with extreme secondary polycythemia have impaired alertness, dizziness, headaches, and compromised exercise tolerance. They also may be at increased risk for thrombosis, strokes, myocardial infarction, and deep vein thrombosis. These are the patients who require phlebotomy.
• The optimal level of hematocrit is one that is as close as possible to normal without impairing the compensatory benefit of increased oxygen delivery.
• • This may be determined individually by symptom relief or decompensation, depending on the viscosity level.
  • Repeated phlebotomies result in iron deficiency that can cause other symptoms. This may limit or retard further erythropoiesis so that additional phlebotomies may not be necessary.
• Proper treatment of the underlying condition, when possible, is important.
• • Provide oxygen supplementation to patients with chronic obstructive pulmonary disease.
  • Recommend weight loss in patients with obesity and hypoventilation.
  • Recommend smoking cessation for patients with carboxyhemoglobin.
  • Surgically correct arteriovenous shunts.

Surgical Care

Some cases are caused by conditions that can be ameliorated by surgical removal or correction.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medications are available to treat the blood disorder. Treat the underlying health problem.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Excessive polycythemia, usually defined as hematocrit levels of higher than 65-70%, may result in increased whole blood viscosity. This, in turn, may lead to impaired blood flow locally, resulting in thrombosis. Hyperviscosity also may 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.

Prognosis

• The prognosis of patients with secondary polycythemia is generally related to the prognosis of the underlying disorder. However, the polycythemia itself, when physiologic and not sufficiently extreme to cause significant hyperviscosity, is generally associated with a normal lifespan. However, emerging evidence suggests that at a minimum, patients with congenital or familial primary polycythemia may have an increased risk of thrombosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Distinguishing between polycythemia vera/primary polycythemia and secondary polycythemias is important because patients with untreated polycythemia vera have a very high risk of thrombotic problems and, to a lesser degree, hemorrhagic problems, which may be fatal or severely disabling. In contrast to most patients with secondary polycythemia, patients with polycythemia vera must be phlebotomized and/or treated with myelosuppressive therapy to maintain their hematocrit values at no higher than 45-47%.
• In patients with secondary polycythemia that is physiologic, determining the optimal hematocrit level for a given patient may be very difficult. Phlebotomies that keep very high hematocrit values (>65%) at a level low enough to prevent hyperviscosity problems may result in impaired tissue oxygenation. On the other hand, allowing the hematocrit value to remain at a higher level in order to provide better oxygen delivery capacity may result in thrombosis or general impaired tissue oxygenation due to sluggish blood flow secondary to hyperviscosity.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Balcerzak SP, Bromberg PA. Secondary polycythemia. Semin Hematol. Oct 1975;12(4):353-82. [Medline].
• Calverley PM, Leggett RJ, McElderry L, Flenley DC. Cigarette smoking and secondary polycythemia in hypoxic cor pulmonale. Am Rev Respir Dis. May 1982;125(5):507-10. [Medline].
• Kershenovich S, Modiano M, Ewy GA. Markedly decreased coronary blood flow in secondary polycythemia. Am Heart J. Feb 1992;123(2):521-3. [Medline].
• Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood. Sep 1 1997;90(5):2057-61. [Medline].
• Lubarsky DA, Gallagher CJ, Berend JL. Secondary polycythemia does not increase the risk of perioperative hemorrhagic or thrombotic complications. J Clin Anesth. Mar-Apr 1991;3(2):99-103. [Medline].
• Menon D, York EL, Bornstein RA, et al. Optimal hematocrit and blood viscosity in secondary polycythemia as determined from cerebral blood flow. Clin Invest Med. 1981;4(2):117-21. [Medline].
• Patakas DA, Christaki PI, Louridas GE, Sproule BJ. Control of breathing in patients with chronic obstructive lung diseases and secondary polycythemia after venesection. Respiration. 1986;49(4):257-62. [Medline].
• Percy MJ, Beard ME, Carter C, Thein SL. Erythrocytosis and the Chuvash von Hippel-Lindau mutation. Br J Haematol. Oct 2003;123(2):371-2. [Medline].
• Prchal JF, Prchal JT. Molecular basis for polycythemia. Curr Opin Hematol. Mar 1999;6(2):100-9. [Medline].
• Remacha AF, Montserrat I, Santamaria A, et al. Serum erythropoietin in the diagnosis of polycythemia vera. A follow-up study. Haematologica. Jul-Aug 1997;82(4):406-10. [Medline].
• Schwarcz TH, Hogan LA, Endean ED, et al. Thromboembolic complications of polycythemia: polycythemia vera versus smokers'' polycythemia. J Vasc Surg. Mar 1993;17(3):518-22; discussion 522-3. [Medline].
• Sondel PM, Tripp ME, Ganick DJ, et al. Phlebotomy with iron therapy to correct the microcytic polycythemia of chronic hypoxia. Pediatrics. May 1981;67(5):667-70. [Medline].
• Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. May 1 2004;69(9):2139-44. [Medline].
• Van Maerken T, Hunninck K, Callewaert L, et al. Familial and congenital polycythemias: a diagnostic approach. J Pediatr Hematol Oncol. Jul 2004;26(7):407-16. [Medline].
• York EL, Jones RL, Menon D, Sproule BJ. Effects of secondary polycythemia on cerebral blood flow in chronic obstructive pulmonary disease. Am Rev Respir Dis. May 1980;121(5):813-8. [Medline].

Article Last Updated: May 17, 2006