Polycythemia is defined as an increased red blood cell mass of the blood. This is accompanied by a rise in the packed cell volume (PCV), as well as hemoglobin (Hb). The extra red blood cells increase the viscosity of blood and may cause thromboembolic and ischemic complications.
Depending on the cause, polycythemia can be classified into two major types:
- Primary Polycythemia: It is also called Polycythemia Vera (PV). This condition is an acquired stem cell disorder characterized by unregulated de novo synthesis of RBCs by the bone marrow cells.
- Secondary polycythemia: There is an increased production of RBCs due to a physiologic increase in the demand for oxygen by the body.
Polycythemia vera, also called polycythemia rubra vera or primary polycythemia, is one of the four myeloproliferative disorders; the others being essential thrombocytosis (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML). Myeloproliferative disorders are acquired clonal stem cell disorders characterized by an abnormal development and functioning of the bone marrow cells.
In polycythemia vera, all three cell lineages (red blood cells, granulocytes and platelets) is increased, most prominently the red blood cells.
Etiology and Epidemiology of Polycythemia Vera
The etiology of polycythemia vera is not fully understood.
This disease is presumed to have a genetic basis. Most patients have a mutation in the JAK2 (Janus kinase 2) gene, located on chromosome 9. This gene encodes a protein that is essential for RBC production and its mutation is instrumental in the onset of PV.
The prevalence of PV is higher amongst the Eastern European Jews than amongst other European or Asian populations. The incidence of PV is 2.8 per 100,000 males and 1.3 per 100,000 females. Several small studies have shown that PV is prevalent in 22 of 100,000 people.
The incidence of PV increases with age and is more common in the 50-70 years age group.
Clinical Features and Complications of Polycythemia Vera
Many patients with PV remain asymptomatic for years owing to the extremely slow development of this disease, and are found incidentally on routine blood counts revealing increased hemoglobin levels.
Most of the symptoms of PV occur due to the increased blood viscosity, secondary to increased red blood cell mass. The thick, viscous blood causes sluggish circulation, blocks vessels, and interferes with oxygen delivery to the cells that may result in the following symptoms:
- Headache, dizziness and fatigue
- Visual disturbances
- Itching, more prominent after a warm bath
- Bleeding from multiple sites and gums
- Abnormal sensations in the hands and feet
- Angina pectoris
- Weight loss
- In rare cases, osteopathic pain
The blood hyperviscosity may result in thromboembolic complications such as myocardial ischemia, transient ischemic attack, stroke, or hepatic vein thrombosis. The bleeding complications such as epistaxis, ecchymosis and gum bleeding occur due to platelet dysfunction.
The prominent itching after a warm bath occurs due to the increased histamine release from increased basophils and mast cells. Peptic ulcers and gastritis symptoms also occur in these patients due to an increased histamine release and may lead to gastrointestinal bleeding.
The patients with PV have a ruddy complexion. Splenomegaly is a common physical finding, present in 75% of cases. Hepatomegaly is also present in one-third of patients. Epigastric tenderness may occur due to gastritis or a peptic ulcer.
In rare cases, PV may progress to acute myeloblastic leukemia (AML) or myelofibrosis.
Diagnosis of Polycythemia Vera
As previously mentioned, polycythemia vera is often an incidental diagnosis detected during routine blood counts. Once the diagnosis of polycythemia is confirmed, it is essential to find out whether it is a primary or secondary polycythemia.
Primary or secondary polycythemia can be differentiated based on the past medical history and clinical examination of the patient. The serum erythropoietin (EPO) level helps in the differentiation of these two types of polycythemia.
In primary polycythemia (PV), the level of EPO is subnormal, whereas, in secondary polycythemia, the level of EPO is normal or raised.
The tests done for PV include the following:
- CBC: Raised Hb or hematocrit can be indicative of PV. The counts of RBCs, granulocytes and platelets may also be increased.
- Blood smear: An increased RBC number and abnormal blood cell types may be seen, especially in PV associated with AML or myelofibrosis.
- Serum Erythropoietin: Measurement of the EPO level helps to differentiate between primary and secondary polycythemia, as described above.
- Bone marrow examination: An increase in the RBC production is highly suggestive of PV.
- JAK2 mutation analysis: The presence of the JAK2 mutation (along with low EPO) confirms the diagnosis of polycythemia vera.
The World Health Organisation (WHO) has proposed the following diagnostic criteria for polycythemia vera.
Table 1: WHO Criteria for Polycythemia Vera
|Major criteria||Hemoglobin > 18.5 g/dL in men, > 16.5 g/dL in women or other evidence of increased red cell volume|
|Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation|
|Minor criteria||Bone marrow biopsy showing hypercellularity for age with trilineage expansion|
|Serum erythropoietin level below the reference range for normal|
|Endogenous erythroid colony formation in vitro|
According to WHO criteria, the diagnosis of polycythemia vera requires:
(i) The presence of both major criteria plus one minor criterion (Or)
(ii) The presence of first major criterion plus two minor criterion.
Treatment and Prevention of Polycythemia Vera
PV is a chronic disease which has no cure. However, patients with PV can be managed efficiently for many years. Multiple modalities may be needed for the effective management of the disease. Their goal is to lower the RBC mass, decreasing blood viscosity, and the subsequent risks of myocardial infarction, stroke and other thromboembolic complications. It also ensures an adequate oxygen supply to all the tissues. Patients undergoing treatment usually lead a normal life. However, for prevention, as well as treatment of complications, medical supervision is necessary.
The treatment modalities that help in the reduction of red blood cell count are:
- Phlebotomy: It is the treatment of choice. In this procedure, about one unit of venous blood (approximately 500 ml) is removed from the patient’s body at regular intervals until the hematocrit is maintained at less than 45%.
- Medications: Hydroxyurea and interferon-alpha are the commonly used cytoreductive drugs. Hydroxyurea is an anti-cancer drug that improves blood flow by decreasing the RBC counts. Interferon- α (IFN- α) is a substance normally produced by our body. It prompts the immune system to suppress RBC production and thereby reduces the effects of polycythemia.
- JAK inhibitors: Ruxolitinib is a newer drug that inhibits JAK 1 and 2 enzyme subtypes. It is used in patients with PV who have failed to respond to hydroxyurea and alpha-interferon.
- Radiation therapy: Over-activity of the bone marrow cells can be suppressed by radiation therapy. This causes a reduction in the RBCs and thus reduces the blood viscosity.
- Low-dose aspirin: Low-dose aspirin is used for its anti-thrombotic effect that decreases the chances of blood coagulation. It is also helpful in the treatment of bone pain and the burning sensation of hands and feet. However, aspirin can cause gastric and intestinal hemorrhage and thus should only be taken under supervision.
- The use of antihistaminics in the treatment of pruritus is not very promising. The itching may be brought under control by avoiding the use of warm water and vigorous rubbing after bathing. Starch baths may also help soothe the skin. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is used experimentally to treat pruritus.
There are no known preventive strategies for primary polycythemia. It is, however, possible to control the symptoms and complications of this disease by adequate treatment.
Secondary polycythemia, as the name indicates, occurs secondary to certain underlying causes, which increase the oxygen demand of our body. These hypoxic conditions cause our bodies to release excess erythropoietin, a hormone that increases the RBC count to increase the oxygen carrying capacity of blood. Secondary polycythemia is, thus, characterized by increased erythropoietin levels. It has no association with the JAK2 gene.
Etiology and Symptoms of Secondary Polycythemia
Chronic hypoxia is the primary cause of secondary polycythemia. The causes of chronic hypoxia are chronic respiratory diseases, sleep apnea syndrome, residence at high altitude levels and congenital heart diseases with a right-to-left cardiac shunt. Such conditions increase the oxygen demand of the body.
Kidneys are the major site of erythropoietin (EPO) production and, hence, polycythemia may be a prominent feature of some renal diseases such as single or multiple cysts, hydronephrosis or renal artery stenosis.
EPO and erythropoietin-like substances are also secreted by malignancies including renal cell carcinoma, hepatoma, uterine fibroids, cerebellar hemangioblastoma and pheochromocytoma. Erythrocytosis is reported in up to 5% of patients with renal cell carcinoma.
Symptoms of secondary polycythemia are similar to those of PV. The only difference is in the level of EPO. In primary polycythemia, EPO is subnormal whereas, in secondary polycythemia, EPO is normal or raised.
Treatment and Prevention of Secondary Polycythemia
In contrast to polycythemia vera, secondary polycythemia is triggered by conditions causing long-standing hypoxia. Hence, treating the underlying cause of hypoxia cures the polycythemia. Smoking, high altitudes, mountain climbing etc. should be avoided to prevent secondary polycythemia.
The risk of thromboembolic complications is very low in secondary polycythemia, as compared to primary polycythemia, although some thrombotic events were reported in patients with a right-to-left cardiac shunt. Competitive athletes may indulge in blood doping with recombinant human EPO in certain scenarios.