Mild to moderate cases of SP are usually asymptomatic. A slight erythema may be noted but generally does not prompt patients to seek medical attention.

In contrast, patients presenting with severe SP generally show symptoms triggered by the underlying disease. If polycythemia is induced by general hypoxia, patients may be cyanotic. Hypoxia is also related to lethargy and headaches. Furthermore, pulmonary and cardiac disorders may manifest in dyspnea, rales, cough, chest pain, reduced tolerance to exercise and syncopes. Lower back and abdominal pain as well as oliguria or anuria may indicate renal causes of polycythemia.

Rarely, SP patients may initially present with thrombosis, thromboembolism or stroke.

• Hypoxemia

  Introduction In adult defined by a Hct > 55% Most common cause is chronic hypoxemia secondary to lung disease Causes of Secondary Polycythemia Hypoxemia COPD Restrictive lung disease Cyanotic congenital heart High altitude Ectopic erythopoeitin Renal [step2.medbullets.com]

  In this article the authors describe a young boy from Thailand with plethora, hypoxemia, and aggravated respiratory distress following a chest infection. [ncbi.nlm.nih.gov]

  Common causes of secondary erythrocytosis include Smoking Chronic arterial hypoxemia Tumors (tumor-associated erythrocytosis) Use of androgenic steroids Surreptitious erythropoietin use Less common causes include certain congenital disorders such as High [merckmanuals.com]

  The increased production may be an appropriate (compensatory) physiologic response to hypoxemia, which may result from: chronic obstructive pulmonary disease hemoglobin abnormalities (such as carboxyhemoglobinemia, which occurs in heavy smokers) heart [doctor-clinic.org]

• Pathologist

  […] medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists [emedicine.medscape.com]

  Typically, the diagnosis can be confirmed based on hematocrit/ hemoglobin values, JAK2V617F testing, and bone marrow examination by a pathologist. [clinicaladvisor.com]

• Diarrhea

  […] the VHL gene affects the hypoxia-sensing pathway) Right to left arteriovenous shunts in the lungs Proline hydroxylase 2 and hypoxia-inducible factor 2 alpha (HIF-2α) mutations Spurious erythrocytosis may occur with hemoconcentration (eg, due to burns, diarrhea [merckmanuals.com]

  Causes of spurious polycythemia include: burns diarrhea hemoconcentration (higher-than-normal concentration of cells and solids in the blood, usually due to becoming dehydrated or taking diuretics ) stress Weakness, headaches, and fatigue are usually [medical-dictionary.thefreedictionary.com]

  Relative polycythemia may be the consequence of abnormally lowered fluid intake or of marked loss of body fluid, such as occurs in persistent vomiting, severe diarrhea, or copious sweating or when water is caused to shift from the circulation into the [britannica.com]

• Erythema

  A slight erythema may be noted but generally does not prompt patients to seek medical attention. In contrast, patients presenting with severe SP generally show symptoms triggered by the underlying disease. [symptoma.com]

  Findings consistent with polycythemia vera include hemoglobin >18.5 gm/dL, persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and erythromelalgia (dysesthesia and erythema involving the distal extremities). [mayomedicallaboratories.com]

  Fewer than 5% of patients have erythromelalgia: This is erythema, warmth, pain and even sometimes infarction of the distal extremities. The hands and feet have a painful burning sensation. [patient.info]

  Facial, conjunctival and mucous membrane plethora, and palmar erythema are other nonspecific consequences of erythrocytosis. Spider angiomata suggest that the erythrocytosis is due to the hepatopulmonary syndrome. [oncologynurseadvisor.com]

• Flushing

  If the skin is flushed or itchy, particularly after a hot bath, it may indicate a diagnosis of polycythemia. The doctor may also check for a history of smoking or alcohol abuse or a family history of kidney disease. [chealth.canoe.com]

  Symptoms include: fast or irregular heartbeat, diarrhea, wheezing and facial flushing, along with others. carcinoma [car-sin-o-ma] Cancer that starts in the lining layer of an organ. [cancersmoc.com]

• Suggestibility

  These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. [keio.pure.elsevier.com]

  History suggestive of sleep apnoea like snoring loudly in sleep, day time sleepiness, poor sleep, morning headache and reduced performance. [explainmedicine.com]

• Hematuria

  Patients with elevated erythropoietin levels (and no indication of hypoxia) or microscopic hematuria should undergo abdominal imaging, central nervous system imaging, or both to seek a renal lesion or other tumor sources of erythropoietin. [merckmanuals.com]

  For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom. [mdedge.com]

  On initial laboratory investigation, hemoglobin was 22.8 g/dL; packed cell volume was 68.5%; serum albumin was low (1.8 g/L); urinalysis showed 3+ proteinuria without hematuria; blood urea was 46 mg/dL; serum creatinine was 2.0 mg/L; complement levels [sjkdt.org]

• Microscopic Hematuria

  Patients with elevated erythropoietin levels (and no indication of hypoxia) or microscopic hematuria should undergo abdominal imaging, central nervous system imaging, or both to seek a renal lesion or other tumor sources of erythropoietin. [merckmanuals.com]

• Burning Sensation

  For example, antihistamines can alleviate itching, and aspirin can soothe burning sensations and bone pain. [medical-dictionary.thefreedictionary.com]

  Your doctor may advise you to take aspirin to relieve bone pain and the burning sensation in hands or feet that you may experience as a result of PV. Aspirin also reduces the chance of blood clots. [daviddarling.info]

  The hands and feet have a painful burning sensation. It also occurs in thrombocythaemia, suggesting that high platelets are important. [patient.info]

  Erythromelalgia can also cause a painful, burning sensation or swelling of the affected areas. [rarediseases.org]

  Erythromelalgia, which is an acute onset of a burning sensation that affects the four limbs and is usually accompanied by a reddish or bluish colouration, is a rare but classic symptom of both PV and essential thrombocythaemia 10. [ncbi.nlm.nih.gov]

• Somnolence

  Cough or dyspnea point to a respiratory or cardiac cause; insomnia, snoring and daytime somnolence suggest sleep apnea. [oncologynurseadvisor.com]

  As soon as they return to bed, however, they will go to sleep again and display the characteristic somnolent cyanosis. In inappropriate polycythemia the laboratory findings will be those of the underlying defect. [medtextfree.wordpress.com]

  […] demonstrated a response (increase in hemoglobin, or reduction or elimination of blood transfusion requirements) in 29% of patients with moderate or severe anemia. 37 However, a large number of patients stopped the drug secondary to side effects (neuropathy, somnolence [clevelandclinicmeded.com]

Polycythemia is often diagnosed after measuring an elevated serum hemoglobin level and augmented hematocrit in a routine blood analysis. And although these findings imply an increase in erythrocyte counts, they are not reliable indicators of polycythemia. Indeed, they only reveal hemoconcentration and this condition is most commonly provoked by insufficient hydration. This applies particularly to slight elevations above the reference range. Moreover, diuresis, diarrhea and burns may cause considerable loss of fluids and thus induce hemoconcentration.

Severe hemoconcentration is associated with an increased risk of thrombosis and cardiovascular events and thus requires further clarification. This also holds true for moderate increases of hemoglobin concentration and hematocrit that are confirmed in subsequent blood analyses.

Thorough anamnesis including an inquiry regarding the medical history of the patient and their family concerning pulmonary or cardiovascular disorders, micturition problems, place of domicile, occupation, trips to foreign countries and altitude, may already indicate a congenital disease, an underlying disorder or SP due to exposure to certain environmental factors.

Evaluation of serum erythropoietin levels may be helpful to distinguish primary polycythemia and SP [11]. Results should be interpreted considering data obtained during anamnesis since elevated erythropoietin concentrations are not necessarily pathological.

During physical examination, special attention should be paid to pulmonary and cardiac function. If doubts remain regarding the condition of these organs, diagnostic imaging, pulmonary function tests and electrocardiography may be required. While plain radiography is very helpful to diagnose lung disorders, magnetic resonance imaging and computed tomography are more sensitive and should be applied to assess renal function.

Genetic screens are indicated to confirm genetic disorders triggering SP and primary forms of polycythemia such as polycythemia vera, although these diseases are generally related with more extensive hematological alterations. Polycythemia vera, for instance, is associated with erythrocytosis, leukocytosis and thrombocytosis. The latter are not characteristic for SP unless induced by comorbidities.

Coagulation tests may be realized to assess the patient's individual risk of cardiovascular accidents.

• Hemoglobin Increased

  There is increased hemoglobin concentration above the upper limit of normal. Criteria to label polycythemia are : RBCs = count increased. [labpedia.net]

• Hepatocellular Carcinoma

  carcinoma Cerebellar hemangio-blastoma Uterine leiomyomas Smokers polycythemia Carbon monoxide causes tissue hypoxemia and release of EPO; for unknown reasons there is a decrease in plasma volume Stress polycythemia Looks like dehydration and found in [step2.medbullets.com]

  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). [orpha.net]

  Matsuyama M, Yamazaki O, Horii K, Higaki I, Kawai S, Mikami S, Higashino M, Oka H, Nakai T, Inoue T (2000) Erythrocytosis caused by an erythropoietin-producing hepatocellular carcinoma. J Surg Oncol 75:197–202 CrossRef PubMed Google Scholar 3. [link.springer.com]

  In hepatocellular carcinoma there is an increased erythropoietin in blood as hepatocellular carcinomal cells leads to erythropoietin production. [explainmedicine.com]

Physiological SP does not require any treatment and is rarely associated with detrimental hemoconcentration and hyperviscosity. However, any condition provoking hematocrit levels that exceed 60% lead to a vicious circle: Alterations of the rheological properties of the blood interfere with circulation and oxygen supply to peripheral tissues, independent of the initial trigger of erythropoietin stimulation. Aggravated hypoxia, however, further enhances erythropoietin synthesis and leads to even stronger hemoconcentration. This vicious circle needs to be interrupted to avoid serious complications of polycythemia.

Thus, treatment of severe SP consists in adequate therapy of the underlying disorder and remediation of hemoconcentration. The latter may be achieved with phlebotomy and subsequent restitution of fluids. This procedure is not recommended for mild to moderate cases of SP; limited awareness, lethargy, headaches and a tendency towards thrombosis indicate this approach. While hemoglobin concentration and hematocrit should ultimately near reference ranges, mild polycythemia may be beneficial and may compensate for generally reduced oxygen supply. Of note, repeated phlebotomy may cause iron deficiency, impair erythropoiesis and further reduce red blood cell counts.

Therapy of pulmonary, cardiac and renal disorders that may induce SP is described elsewhere.

Prognosis of SP largely depends on the underlying disease. In this context, chronic obstructive pulmonary disease, heart failure, renal failure and malignant neoplasms may significantly reduce life expectancy. While there is no causative treatment for polycythemia due to genetic disorders, hydronephrosis is generally curable.

SP itself is associated with minor morbidity and mortality, but if hemoconcentration causes thromboembolism or stroke, consequences are generally detrimental. According to current knowledge, such events rarely occur in patients suffering from SP and are more frequently related to primary congenital polycythemia and polycythemia vera.

Erythropoietin is the main regulator of erythropoiesis. About 90% of the total amount of erythropoietin are synthesized by renal fibroblasts; a minor share of this hormone is produced by hepatocytes. An increase in red blood cell formation may be required if those cells circulating are unable to assure sufficient oxygen supply to peripheral tissues. Thus, hypoxia induces erythropoietin production. However, the body does not distinguish between hypoxia due to pulmonary, cardiovascular or renal pathologies and a true need for more red blood cells to adjust to an external reduction of oxygen concentrations, e.g., while staying at altitude. The latter induces physiological SP [3].

Accordingly, SP may be associated with any of the following diseases:

• Hypoventilation
• Sleep apnea
• Chronic bronchitis
• Chronic obstructive pulmonary disease
• Pulmonary hypertension and cor pulmonale
• Heart failure
• Hydronephrosis [4]
• Nephrotic syndrome [5]
• Congenital 2,3-bisphosphoglycerate deficiency / 2,3-BPG deficiency
• Chuvash polycythemia
• Any other condition reducing ventilation, pulmonary oxygen assimilation, cardiac function, release of oxygen from hemoglobin and renal blood flow

Additionally, neoplasms may release erythropoietin and stimulate erythropoiesis. Renal, adrenal, hepatic and uterine tumors are most frequently associated with SP [6]. Cerebellar hemangioblastomas as those seen in von Hippel-Lindau disease may also produce erythropoietin.

Certain lifestyle decisions may interfere with oxygen supply and erythropoietin synthesis, too. Smoking, for instance, causes saturation of hemoglobin with carbon monoxide. The latter has a much higher affinity to hemoglobin than oxygen and thus disturbs oxygen assimilation in pulmonary alveoli. Of note, chronic exposure to carbon monoxide may affect non-smokers as well [7] [8].

SP may be asymptomatic and may only be diagnosed incidentally during blood sample analyses conducted for any other reason. Thus, it is presumably underdiagnosed. Additionally, there is a broad spectrum of diseases acting as possible triggers of this condition and prevalence of SP among patients suffering from any of these underlying diseases varies largely. Therefore, overall incidence and prevalence rates of SP cannot be provided.

SP changes the rheological properties of the blood, evokes a condition that is also referred to as hemoconcentration. Considerable hemoconcentration, in turn, causes both reversible red blood cell aggregation and thrombosis. The former leads to formation of rouleaux, i.e., of erythrocyte aggregates that look like a roll of coins. These rouleaux are primarily found in capillaries and interfere with microcirculation. They may diminish oxygen supply to peripheral tissues. Thrombus formation, thromboembolism and stroke account for morbidity and mortality directly associated with polycythemia. Indeed, cerebrovascular accidents may be the first symptom of hemoconcentration [5] [9].

Athletes who dope with erythropoietin or who train in high altitude to realize autologous blood transfusions before partaking in a competition accept the above described risks. Additionally, doping may reveal previously undiagnosed cardiovascular pathologies and thus, serious adverse events or even sudden death may not only be triggered by an overdose of erythropoietin but also by presumable safe doses [10].

Any measure aiming at prevention of pulmonary, cardiac and renal diseases may also be considered useful for prevention of SP. In this context, patients should avoid smoking and prolonged exposure to carbon monoxide, maintain a healthy diet and lose overweight; they should exercise regularly. Comorbidities contributing to failure of the above mentioned organs, e.g., hypertension and diabetes mellitus, should be tightly controlled.

Neither intake of recombinant erythropoietin nor realization of autologous blood transfusions can be recommended to improve athletic performance.

Erythropoiesis, i.e., differentiation of multipotent hematopoietic stem cells into red blood cells, takes place in the bone marrow. Unless a patient suffers from any comorbidities, pathological stimulation of erythropoiesis results in increased red blood cell counts, an augmented serum concentration of hemoglobin and an alteration of the overall ratio of blood cells to blood fluids, an increased hematocrit. This condition is generally referred to as polycythemia.

Erythropoietic disorders may result from degeneration of stem cells and loss of their ability to differentiate into erythrocytes or from uncontrolled division of any intermediate cell stage, whereby the former would cause anemia and the latter would provoke primary polycythemia. Erythropoiesis is regulated by a number of external factors, mainly by serum concentrations of erythropoietin, a hormone mainly produced by renal fibroblasts. Gene defects or acquired metabolic alterations may render myeloid precursors more sensitive to erythropoietin. Because in such cases, the problem is still intrinsic to erythropoietic processes occurring in the bone marrow, these patients are also diagnosed with primary polycythemia.

In contrast, erythropoiesis itself is unaltered in secondary polycythemia (SP). Here, an enhanced production of erythropoietin accounts for increases in red blood cell formation. In general, erythropoietin secretion is stimulated by hypoxia, which is the body's way to adjust to reduced oxygen supply [1]. Consequently, any pathological condition leading to renal hypoxia may lead to enhanced release of erythropoietin and SP.

Polycythemia is often diagnosed during routine analyses of blood samples. However, slight elevations of hemoglobin or hematocrit may result from a variety of factors and are most frequently provoked by insufficient hydration. Thus, only significant and repeated exceeding of reference values should prompt a thorough workup. The following values a considered significantly altered [2]:

• Hemoglobin concentrations > 180 g/L and/or hematocrit > 0.55 in adult males
• Hemoglobin concentrations > 165 g/L and/or hematocrit > 0.50 in adult females

Polycythemia is the medical term for an increase in red blood cell counts or mass. Red blood cells - also designated erythrocytes - originate from the bone marrow, where multipotent stem cells differentiate into a variety of intermediate cell stages and finally into erythrocytes. This process is called erythropoiesis and is regulated by distinct external factors, mainly by erythropoietin. This hormone is primarily produced by the kidneys, although minor quantities are also released by hepatic cells. Erythropoietin is best known as an illegal doping agent and it is used to this end particularly because it increases red blood cell production and thus improves oxygen supply to peripheral tissues. If elevated serum levels of erythropoietin cause polycythemia, i.e., if there is no pathological alteration of erythropoiesis, the patient will be diagnosed with secondary polycythemia (SP).

Causes

Erythropoietin synthesis is stimulated by hypoxia. If tissues are not supplied with sufficient oxygen, the body reacts, increases erythropoietin levels and consequently erythrocyte formation, and thus tries to improve that situation. This is a physiological process that takes place, for instance, while staying at high altitudes.

However, if insufficient oxygen supply is caused by pulmonary or cardiac disorders, if the kidneys are poorly irrigated or damaged, erythropoietin levels also rise. Such diseases cause pathological SP.

Symptoms

Mild SP is usually asymptomatic. Here, hypoxia may cause a bluish discoloration of the skin, lethargy and headaches.

Symptoms related to the underlying disease generally predominate in patients suffering from severe SP due to chronic obstructive pulmonary disease, heart failure or renal disorders. Such symptoms may comprise breathing difficulties, rales, cough, reduced tolerance to exercise, syncopes and pain.

Diagnosis

Routine analyses of blood samples may reveal hemoconcentration, i.e., increased levels of hemoglobin and an elevated hematocrit. However, these are unspecific findings. Additional hematological alterations as well as the results of a physical examination will indicate which diagnostic measures are required to identify the underlying disease. Diagnostic imaging, pulmonary function tests and electrocardiography may become necessary.

Treatment

Mild cases of SP don't require specific treatment.

Treatment of severe cases of SP consists in adequate therapy of the underlying disorder and remediation of hemoconcentration. The latter may be achieved with phlebotomy and subsequent restitution of fluids.

1. Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013; 27(1):41-53.
2. Fairbanks VF, Tefferi A. Normal ranges for packed cell volume and hemoglobin concentration in adults: relevance to 'apparent polycythemia'. Eur J Haematol. 2000; 65(5):285-296.
3. Jedlickova K, Stockton DW, Chen H, et al. Search for genetic determinants of individual variability of the erythropoietin response to high altitude. Blood Cells Mol Dis. 2003; 31(2):175-182.
4. Sung CC, Lin SH. Images in clinical medicine. Nonobstructive hydronephrosis with secondary polycythemia. N Engl J Med. 2011; 365(1):e1.
5. Nagaraju SP, Bairy M, Attur RP, Sambhaji CJ. Cerebral venous thrombosis and secondary polycythemia in a case of nephrotic syndrome. Saudi J Kidney Dis Transpl. 2016; 27(2):391-394.
6. Wiesener MS, Munchenhagen P, Glaser M, et al. Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia. Int J Cancer. 2007; 121(11):2434-2442.
7. Meyer G, Boissiere J, Tanguy S, et al. Carbon monoxide pollution impairs myocardial perfusion reserve: implication of coronary endothelial dysfunction. Cardiovasc Toxicol. 2011; 11(4):334-340.
8. Nakamura T, Setsu K, Takahashi T, et al. Chronic exposure to carbon monoxide in two elderly patients using a kotatsu, a traditional Japanese charcoal-based heater. Psychogeriatrics. 2015.
9. Crespo AM, Abraira L, Guanyabens N, et al. Recurrent Stroke with Rapid Development of Intracranial Stenoses in Polycythemia Vera. J Stroke Cerebrovasc Dis. 2016; 25(4):e41-43.
10. Piloto N, Teixeira HM, Teixeira-Lemos E, et al. Erythropoietin promotes deleterious cardiovascular effects and mortality risk in a rat model of chronic sports doping. Cardiovasc Toxicol. 2009; 9(4):201-210.
11. Patnaik MM, Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired. Leukemia. 2009; 23(5):834-844.