OVERVIEW: What every practitioner needs to know

Are you sure your patient has polycythemia? What are the typical findings for this disease?

Polycythemia is defined as an increase in red cell mass as evidenced by increase in hemoglobin, hematocrit and number of circulating erythrocytes (RBCs). In relative polycythemia there is increase in hemoglobin due to reduced plasma volume without increase in red cell mass (e.g., dehydration). In polcythemia vera (PV, primary polycythemia) there is an absolute increase in red cell mass. PV is a myeloproliferative disease caused by abnormal proliferation of a clone of erthroid proginators that proliferate even in absence of erythropoietin (EPO). Secondary polycythemia is caused by factors other than abnormal clone of erythroid proginators.

Typical findings for polycythemia:

In many children the only manifestation will be plethora. Alternatively, polycythemia may be discovered inadvertently on a routine CBC.

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Other symptoms may include headache, pruritus, dizziness and sweating. Other less common presentations include cyanosis, respiratory distress, numbness, tingling, weakness, tiredness, confusion, syncope, GI bleeding. Thrombotic manifestations such as stroke, myocardial infarction can occur. Patients can also have other manifestations of an underlying disease that led to polycythemia.

PV commonly presents after the sixth decade, but other conditions that cause polycythemia and PV can present at any age.

Polycythemia Vera (PV)

PV needs special mention here. It is the most common cause of primary polycythemia and yet is quite uncommon in children. It presents in the sixth decade of life and is commonly associated with splenomegaly. It belongs to a group of clonal disorders including chronic myeloproliferative disorder, essential thrombocythemia, primary myelofibrosis and chronic myelogenous leukemia.

Polycythemia Vera – molecular basis for disease and therapy

Most patients with PV have a somatic mutation in the pluripotent stem cell that leads to overproduction of functionally normal erythrocytes and may also have overproduction of other blood cells. The mutation, JAK2 V617F, in the Janus-type tyrosine kinase-2 gene (JAK2) on chromosome 9 is demonstrated in less than 25% at diagnosis but develops later in most cases.

Arterial and venous thrombosis are the most important serious complications and are prevented by myelosuppressive therapy such as Hydroxyurea and Busulfan. Newer treatments include pegylated interferon alpha and targeted therapy with JAK2 kinase inhibitors are being evaluated at this time. In familial cases presence of germline mutation is followed by an acquired mutation that uncovers the disease, a fact that is suspected to be underreported in literature.

What other disease/condition shares some of these symptoms?

Polycythemia can be the presenting feature of a wide variety of conditions in children. These include:

1) Renal disease: Polycythemia may be caused by excessive erythropoietin which is produced in kidneys. Polycythemia may be seen in hydronephrosis, and less commonly with nephrotc syndrome, nepnrosclerosis, chronic glomerulonephritis, pyelonephritis, renal transplantation.

2) Neonatal conditions: Maternofetal and twin to twin (recipient twin) transfusions, infant of diabetic mother, intrauterine hypoxia such as due to maternal smoking, intrauterine growth retardation, maternal cyanotic heart disease, maternal hypertension, severe alcoholism, delayed cord clamping, “stripping” of umbilical cord (with intention of giving ‘more’ blood to baby), Beckwith syndrome and perinatal asphyxia are among the common causes of neonatal polycythemia.

3) Biphosphoglycerase mutase (2,3 BPGM) deficiency leads to lower levels of 2,3 DPG (2,3 biphosphoglycerate) and shifts the oxygen curve to the left, effectively increasing the hemoglobin’s oxygen affinity leading to polycythemia without any other manifestations even in carriers.

4) Polycythemia is among the commonest hematologic abnormality of Downs syndrome even in the absence of cardiac disease. Other genetic syndromes being trisomy 13, 18 and 21 (Downs).

5) Congenital cyanotic heart disease can lead to secondary polycythemia due to hypoxia.

6) Smoking increases carboxyhemoglobin and is the commonest cause of secondary polycythemia in adults.

7) High affinity hemoglobins – e.g., Hb Moke and Hb Osler – may have no other presenting feature except polycythemia.

8) A number of pulmonary diseases that lead to hypoxia can cause secondary polycythemia.

9) Polycythemia vera – see above.

What caused this disease to develop at this time?

Primary polycythemia is usually due to germline mutations, very significant among them being those in the JAK2 gene. Shedding light on etiology of secondary polycythemia needs detailed history and physical examination with special attention to areas such as smoking by patient or exposure to smoke at home, living in high altitudes, congenital cyanotic heart disease, high oxygen affinity hemoglobins (family history), renal conditions (hydronephrosis {most common}, chronic glomerulonephritis, pyelonephritis, nephrotic syndrome, renal transplant).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Polycythemia is defined be a Hgb> 18.5 gm% in males or >16.5 gm% in women.

  • Polycythemia is also considered when the Hgb is >17 gm% in males or >15 gm% in females and there has been a sustained increase in Hgb of >2gm% over the patient’s baseline that cannot be attributed to correction of iron deficiency.

  • It is important to note that by definition, 95% of all patients have an hematocrit that is ‘normal’, and thus 2.5% may have an hematocrit that is higher than 95% of individuals, but possibly still normal for that particular child. Confirming a high hemoglobin and hematcrit level is imperative before embarking on a major workup for polycythemia since a high value may return to normal without any intervention. Physiologically, children have a quite varied levels of Hemoglobin that vary with the child’s age. Normal levels of hemoglobin are higher in newborns, higher as later stages of sexual development progress during adolescence, higher in males compared to females, higher in those who participate in vigorous physical activity, and higher in those who live at higher altitude.

  • Carboxyhemoglobin >5% is a very common cause of polycythemia. This is confirmed when the Hgb returns to normal after carboxyhemoglobin returns to normal after intervention.

  • Bone marrow may show hyperplasia in beginning, myelofibrosis, in later course of disease.

  • Determination of RBC mass is the gold standard diagnostic test, but is very expensive and not routinely available.

  • A definitive diagnosis of PV can be made genetically by demonstrating the presence of JAK2 V617F or a similar mutation.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not very helpful for diagnosing polycythemia. They are however especially helpful in secondary polycythemia, e.g., 2D echocardiogram for Cyanotic Congenital Heart Disease.

If you are able to confirm that the patient has polycythemia, what treatment should be initiated?

  • Phelbotomy can be used to decrease headaches, ‘fullness’ and many other symptoms of polycythemia. Aspirin, Cyproheptadine, psoralens, reducing the frequency of bathing, interferon-alpha, and allopurinol are all used to help reduce pruritis.

  • Phlebotomy is used to keep the hematocrit under 55 in PV. Myelosuppressive therapy is also commonly used for PV. JAK2 inhibitors, Pegylated interferon, Aspirin (to prevent bleeding), are also useful. Radioactive phosphorus, Chlorambucil are also used in some cases.

  • Splenectomy can help fatigue and severe secondary cytopenias.

  • Anagrelide decreases thrombocytosis that may accompany polycythemia.

  • Bone marrow transplant has been found to be successful.

Definition of response to therapy in PV – Hematocrit under 45 without phlebotomy, and platelet count <400,000, and leukocyte count <10,000, and absence of splenomegaly and disease related symptoms.

What are the adverse effects associated with each treatment option?

Interferon can cause diarrheas, fatigue, allergic reactions.

Aspirin can casue gastric bleeding and other bleeding complications.

Splenectomy can increase risk of sepsis by polysaccharide encapsulated bacterial organisms (particularly pneumococcus and H. influenzae).

Regarding phlebotomy, it should be remembered that iron deficiency (caused by phlebotomy), though debated, may increase the risk of stroke in this setting. It does not decrease itching.

What are the possible outcomes of polycythemia?

Thrombosis can occur in 30% to 50%, bleeding in 25-33%, leukemic transformation, myelofibrosis, are also known to occur frequently.

What causes this disease and how frequent is it?

PV is more common in males than females (2.8 per 100,000 versus 1.3/100,000). It has a much higher incidence in Ashkenazi Jews. It can also occur secondary to various cardiac, pulmonary, renal conditions.

How do these pathogens/genes/exposures cause the disease?

In primary polycythemia presence of JAK2 mutation leads to proliferation of the progenitor erythropoietic precursor even in absence of erythropoietin leading to uncontrolled production of RBCs.

In secondary polycythemia there is either increased erythropoietin production (in kidneys) or the hypoxic state (due to cardiac, pulmonary or high affinity hemoglobins) fuels erythropoietin production.

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

About a third to half of the patients get thrombosis while a third will have significant bleeding episodes when followed for a decade after their diagnosis. It must be remembered that iron deficiency complicating polycythemia carries a higher risk of stroke than polycythemia alone. Stroke, myocardial infarction, deep vein thrombosis, hepatic vein thrombosis are common manifestations. Itching, erythromelalgia (warm extremities), angina, congestive heart failure, bleeding/clotting at surgery (3/4 of the cases) is well known.

Are additional laboratory studies available; even some that are not widely available?

Sequencing the JAK2 gene, looking for various rare mutations in JAK2 gene are not routinely performed.

How can polycythemia be prevented?

Prevention is based on etiology. Stopping smoking, avoiding second hand smoke would be helpful. In case of presence of familial polycythemia (JAK2), genetic counselling would be helpful.

What is the evidence?

Polycythemia, especially PV, manifest much more commonly in adults, and there is much more data in adult literature.

Orkin, SH, Nathan, DG, Ginsburg. “Nathan and Oski's Hematology of infancy and childhood”. 2009. pp. 521-570. (Multiple chapters related to polycythemia. Very high quality textbook of pediatric hematology.)

Beutler, E, Kaushansky, K, Lichtman, M, Beutler, E, Kipps, T, Prchal, J, Seligsohn, U. “Disorders of iron metabolism”. Williams Hematology. 2010. (Very high quality textbook of Adult Hematology. Since the disease is far more manifest in adults there is a preponderence of high quality adult literature.)

Hoffman, R, Benz, E, Shattil, S. Hematology, Basic principles and practice. (Another very high quality adult textbook.)

Remon, J, Raghavan, A, Maheshwari, A. “Polycythemia in the newborn”. NeoReviews. vol. 12. 2011. pp. e12-28. (An excellent recent review of neonatal polycythemia.)

Ongoing controversies regarding etiology, diagnosis, treatment

There is controversy about etiology, diagnosis and therapy. JAK2 mutation is sometimes absent in the peripheral cells and also in the blasts. Hence, it is believed to be expressed in the somewhat mature marrow precursors.

In many cases, at many levels, the diagnosis is not easy to make. While venous Hct >65 in newborns and > in adults is considered polycythemia, a study showed that a FU without any intervention resulted in resolution of polycythemia in half the patients.