Erythrocytosis

What every physician needs to know:

Erythrocytosis, also known as secondary polycythemia or secondary erythrocytosis to distinguish it from the chronic myeloproliferative disease, polycythemia vera, is an increase in the number of circulating red cells above the gender-specific normal level.

Erythrocytosis can be either relative (pseudoerythrocytosis) or absolute.

Relative erythrocytosis occurs when there is plasma volume contraction without any change in circulating erythrocyte number; absolute erythrocytosis represents an increase in circulating red cell number, regardless of the size of the plasma volume. Since there is no simple clinical assay for plasma volume size, the two types of erythrocytosis, whether defined by an increase in the red cell count, hematocrit or hemoglobin level, cannot be distinguished from each other.

Furthermore, because the red cell count, hematocrit or hemoglobin measure different properties of the total circulating red cell mass, they may not congruently indicate the presence of erythrocytosis, and since the size of the red cell mass and plasma volume can vary independently of each other, measurements of red cell number, hematocrit or hemoglobin can only suggest the presence of erythrocytosis but not its type or extent.

Importantly, although the gender-specific norms for red cell number, hematocrit or hemoglobin have declined over the past several decades, presumably as tobacco use has waned, these changes have not been widely incorporated into clinical laboratory standards. Thus, the current criteria for erythrocytosis underestimate its prevalence.

A single elevation of red cell number, hematocrit or hemoglobin, unless extreme (red cell count greater than 6 x 106 /µL; hematocrit greater than 60%; hemoglobin greater than 18.0gm%), is not sufficient evidence for the presence of an absolute erythrocytosis, because plasma volume contraction can do this as well. Therefore, by definition, the presence of erythrocytosis requires a persistent elevation of the red cell count, hematocrit or hemoglobin level. In this regard, prior measurements of red cell number, hematocrit or hemoglobin are extremely helpful in assessing not only the persistence but the duration of the erythrocytosis.

Once the presence of erythrocytosis has been established, the distinction between relative and absolute needs to be made for both diagnostic and therapeutic purposes, and this can only be done by a direct measurement of both the red cell mass and the plasma volume.

What features of the presentation will guide me toward possible causes and next treatment steps:

The symptoms and signs associated with erythrocytosis in part reflect its cause and in part are a consequence of the increased blood viscosity associated with the increase in red cell mass or decrease in the plasma volume. If the onset of erythrocytosis is gradual or it is not severe, there may be no symptoms.

The most common symptoms include headache, blurred vision, tinnitus, dizziness, vertigo, scotomata, anorexia, weakness, and reduced mental acuity. Cough or dyspnea point to a respiratory or cardiac cause; insomnia, snoring and daytime somnolence suggest sleep apnea. Paresthesias, extremity pain, epigastric distress or abdominal fullness and aquagenic pruritus frequently accompany polycythemia vera. Cyanosis or clubbing suggest hypoxia due to cardiac or pulmonary right to left shunts as a cause for the erythrocytosis; splenomegaly suggests polycythemia vera though a left upper quadrant mass could be due to a hypernephroma.

Hypertension is common to all forms of erythrocytosis if red cell mass expansion is extreme but may also point to a renal cause. 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.

If the erythrocytosis is extreme, a cerebrovascular accident, myocardial infarction or venous thromboembolism can be its presenting manifestation; intra-abdominal venous thrombosis in particular, is a presenting manifestation of polycythemia vera in women.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Once persistent elevation of the red cell count, hematocrit or hemoglobin level has been established, the next step is to determine if the erythrocytosis is relative and due to plasma volume contraction, or absolute.

Acute causes of plasma volume contraction such as diarrhea, emesis, diuretics, diaphoresis, hypodipsia, ethanol abuse, or a capillary leak syndrome are usually clinically obvious. However, chronic causes such as hypertension, tobacco use, sleep apnea or androgen therapy are often not considered. Furthermore, neither a normal serum erythropoietin level nor a normal arterial oxygen saturation, exclude the presence of absolute erythrocytosis.

A further obstacle recently to the differential diagnosis of erythrocytosis, has been the assumption that this should begin with exclusion of polycythemia vera, when in fact, in contrast to every other cause of absolute erythrocytosis, polycythemia vera is not only an intrinsic bone marrow disorder but also most commonly involves changes in white cell and platelet production. Finally, recently the distinction between relative and absolute erythrocytosis has been made more complicated by the decrease in the number of Nuclear Medicine Laboratories offering these essential measurements.

In some instances, measurement of the plasma volume or red cell mass alone has been employed with extrapolation of the other value; these approaches have been shown to be inaccurate because the plasma volume and red cell mass can vary independently of each other. In the event that a red cell mass and plasma volume measurement cannot be obtained, a simple expedient is diagnostic phlebotomy.

An absolute red cell mass elevation is defined as present when the red cell mass is greater than 125% of normal. Thus, an absolute erythrocytosis implies an increase in the red cell mass of at least 600ml in an 80 kg man. Therefore, a single phlebotomy after equilibration should reduce the hematocrit by at least 10%. If the decrement in hematocrit is equal to or less than this, absolute erythrocytosis is present. If, however, the hematocrit falls below the patient’s baseline, absolute erythrocytosis is not present.

What conditions can underlie erythrocytosis:

Erythrocytosis can be caused by the following:

Chronic hypoxia

- Whether due to the low ambient oxygen tension that occurs at high altitude, impaired ventilation due to neurologic disease or anatomic pulmonary disease.

Inability of hemoglobin to appropriately release its oxygen at ambient tissue pO2

Right to left cardiac and vascular shunting

Including the hepatopulmonary syndrome associated with liver disease.

Sleep apnea

Impaired oxygen carriage with carbon monoxide intoxication

Inappropriate erythropoietin production

- As may occur with familial VHL mutations (Chuvash polycythemia) or cobalt poisoning, tumors, particularly with those associated with the von Hippel-Lindau syndrome (cerebellar, renal, liver, adrenal and pheochromocytoma) as well as meningioma and uterine fibromyoma.

Familial mutations in the erythropoietin receptor or 2,3-bisphosphoglycerate (2,3-BPG)

Certain drugs such as testosterone and its congeners and the recombinant erythropoietins

The type of erythrocytosis dictates the diagnostic process. For relative erythrocytosis, the diagnosis relies primarily on a careful history with respect to diuretic, tobacco or androgen use, sleep apnea and the possibility of a pheochromocytoma, and for the latter, a 24 hour urine for fractionated catecholamines and metanephrines is the diagnostic test of choice.

For absolute erythrocytosis, direct measurement of the arterial oxygenation saturation is the next step. A value greater than 93% excludes a hypoxic cause with the exception of high oxygen affinity hemoglobins and carbon monoxide intoxication. If the latter is suspected, because of the short half-life of carboxyhemoglobin, its measurement can be misleading if performed remotely with respect to the time of exposure.

If the arterial oxygen saturation is greater than 93%, JAK2 V617F and JAK2 Exon 12 assays are appropriate, since a positive assay for either implicates autonomous marrow erythropoiesis as the cause of the erythrocytosis. It is important in this regard, to emphasize that a positive assay is not proof that the patient has polycythemia vera, since it well documented that these mutations can be associated with erythrocytosis alone, without ever evolving into polycythemia vera.

Furthermore, a bone marrow examination is of no diagnostic assistance in this instance and cannot be recommended, despite the World Health Organisation (WHO) recommendations, because these recommendations have never been prospectively validated, while it has also been well established that there are no bone marrow abnormalities specific for polycythemia vera.

A serum erythropoietin assay is only helpful if elevated, since this excludes polycythemia vera as a cause for erythrocytosis; a normal erythropoietin level does not exclude hypoxia or polycythemia vera as a cause for erythrocytosis. If the JAK2 mutation assays are negative, polcythemia vera is unlikely, and consideration must be given to renal lesions, solid tumors, high affinity hemoglobins and mutations in the erythropoietin receptor, or the genes involved in erythropoietin production, including VHL and HIF.

The P50 is the best test for a high oxygen affinity hemoglobin, since many of the mutations involved because of their location fail to influence hemoglobin electrophoretic behavior; a low P50 is diagnostic for a high oxygen affinity hemoglobin.

Renal ultrasound and a urinalysis are good screening tests for renal lesions associated with erythrocytosis.

When do you need to get more aggressive tests:

As indicated above, the laboratory evaluation of suspected erythrocytosis relies on only a minimum of laboratory tests, in addition to careful history taking to uncover most of its causes. Invasive testing is almost never necessary unless a tumor is suspected. Certainly, contrary to the dictates of the WHO, a bone marrow examination is never indicated, since this test cannot distinguish one form of erythrocytosis from another or from polycythemia vera.

What imaging studies (if any) will be helpful?

Imaging studies, usually computed axial tomography of the head, chest and abdomen or pulmonary angiography, are only necessary if there is an indication that the erythrocytosis is being caused by a tumor, or a right to left vascular shunt.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

The treatment of secondary erythrocytosis depends in part on its cause and in part on whether the erythrocytosis is causing symptoms due to increased blood viscosity. In this regard, the need for phlebotomy varies. For example, many patients with life-long erythrocytosis due a high oxygen affinity hemoglobin will be asymptomatic because of the mild degree of erythrocytosis, but a few will not.

Patients with cyanotic congenital heart disease or chronic obstructive pulmonary disease may benefit from limited phlebotomy but this must be evaluated on an individual basis. For other causes, with removal of the stimulus for erythrocytosis, such as tobacco or androgen use, sleep apnea, renal artery stenosis or tumor resection, the need for phlebotomy will be limited. At the same time, the presence of comorbidities such as hypertension or heart failure may dictate a more aggressive phlebotomy approach until the underlying cause is corrected.

In some patients, such as those with polycythemia vera or with an uncorrectable form of erythrocytosis, phlebotomy therapy will need to be chronic, with the goal to induce and maintain sufficient iron deficiency to prevent significant elevation of the red cell mass. In this regard, it needs to be emphasized that in the adult, iron deficiency in the absence of anemia does not impair aerobic performance.

The treatment of plasma volume contraction causing a pseudoerythrocytosis is the same as for an absolute erythrocytosis since they share in common the same abnormality, increased blood viscosity. Phlebotomy results in a rapid expansion of the plasma volume, alleviating the symptoms associated with the contracted plasma volume and, as in the case of uncorrectable erythrocytosis, periodic phlebotomy therapy may also be necessary in this situation as well.

What other therapies are helpful for reducing complications?

It needs to be recognized that chronic hypoxemia can lead to systemic and pulmonary hypertension, impairment of renal function, proteinuria and hyperuricemia regardless of its cause. Therefore, correction of hypoxia should be a principal concern in those situations in which it is the cause of the erythrocytosis. Phlebotomy assists with this, since it alleviates hypertension, improves cardiac, pulmonary and cerebral hemodynamics and renal function by expanding the plasma volume and reducing blood viscosity. It also improves hemostasis.

Liver transplantation is the only remedy for the hepatopulmonary syndrome. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor antagonists are useful for correcting post renal transplant erythrocytosis. Patients with familial erythrocytosis may rarely develop exceedingly painful splenomegaly due to extramedullary hematopoiesis for which splenectomy may be required.

What should you tell the patient and the family about prognosis?

With the exception of tumor-associated erythrocytosis, for which prognosis will depend on the tumor type, and structural disorders of the heart, lungs, liver and kidneys, the prognosis for erythrocytosis patients is good, as long as care is taken to ensure that blood viscosity is controlled by phlebotomy, since this eliminates the risk of thromboembolic disease. As mentioned above, rarely extramedullary hematopoiesis may necessitate splenectomy but otherwise, most patients do well.

“What if” scenarios.

The use of chemotherapy to control erythropoiesis when a secondary form of erythrocytosis was confused with polycythemia vera, has led to the development of acute leukemia. Since chemotherapy is an inefficient and slow method for controlling erythrocytosis in polycythemia vera, while JAK2 V617F or JAK2 exon 12-associated erythrocytosis may never evolve into polycythemia vera, the use of hydroxyurea or any other chemotherapeutic agent in an erythrocytosis patient in place of phlebotomy cannot be condoned. It is a myth that phlebotomy stimulates the bone marrow in polycythemia vera, because marrow function in this disease is autonomous and independent of physiologic stimuli.

Pathophysiology

Erythropoiesis is tightly regulated because red cell production is an exponential process, which left uncontrolled can produce a dangerous increase in blood viscosity. Erythropoiesis is regulated by the hormone erythropoietin, which acts as a mitogen to trigger dormant immature erythroid precursors into cell cycle and a viability factor to maintain these precursors as they develop into mature erythrocytes.

Hypoxia is the only physiologic stimulus for erythropoietin production, which is regulated at the level of gene transcription by the transcription factors HIF-1? and HIF-2?. They partner with HIF-1? to activate the erythropoietin gene and a variety of other genes useful to hypoxic tissues. HIF-1? is constitutively produced while HIF-1? and HIF-2? are rapidly metabolized by prolyl hydroxylation and ubiquitination if tissue oxygenation is adequate. When there is tissue hypoxia, the HIF proteins cannot be hydroxylated on proline and bind with HIF-1? to stimulate erythropoietin gene transcription.

Erythropoietin is produced primarily in the kidneys, but to a small extent in the liver, and acts on erythroid progenitor cells in the bone marrow. When tissue hypoxia is corrected, HIF-1 protein catabolism increases, erythropoietin production is curtailed and the plasma erythropoietin level falls to its constant baseline. Erythrocytosis, therefore, with the exception of polycythemia vera, where the erythroid progenitor cells do not require erythropoietin, can be caused by abnormalities anywhere in the erythropoietin regulatory pathway, from disorders preventing access of oxygen to the blood, to mutations in the key proteins involved in erythropoietin production or in the response to the hormone.

An essential feature associated with the induction of erythrocytosis, is the body’s attempt to maintain the total blood volume constant. Thus, as the number of red cells increases, the plasma volume is reduced, leading eventually to an increase in peripheral vascular resistance. This is in contrast to the autonomous erythropoiesis associated with polycythemia vera, where erythropoietin is not involved and the plasma volume expands as the red cell mass increases, resulting in a reduction in peripheral vascular resistance and a greater initial tolerance of the erythrocytosis.

As a corollary, with plasma volume expansion, the extent of the erythrocytosis will be masked, which is why direct determination of the red cell mass and plasma volume is necessary to document the presence of erythrocytosis when polycythemia vera is a diagnostic consideration, a concept not understood by the WHO. Conversely, since many of the causes of secondary erythrocytosis can also contract the plasma volume, in addition to stimulating erythropoietin production, direct determination of the red cell mass and plasma volume is usually necessary to document the presence of erythrocytosis in this situation as well.

The plasma erythropoietin level is not a sensitive indicator of the presence of hypoxic erythrocytosis unless the hypoxia is extreme, not only because of its wide normal range (4-24 mU/mL) but because erythropoietin is metabolized by its target cells in the bone marrow, the erythroid progenitor cells. Thus, as the marrow erythroid progenitor cell pool expands, plasma erythropoietin is usually down regulated into the normal range.

What other clinical manifestations may help me to diagnose erythrocytosis?