Table of Contents
- Polycythemia Vera
- Etiology and Epidemiology of Polycythemia Vera
- Symptoms and Complications of Polycythemia Vera
- Diagnosis of Polycythemia Vera
- Treatment and Prevention of Polycythemia Vera
- Secondary Polycythemia
- Etiology and Symptoms of Secondary Polycythemia
- Treatment and Prevention of Secondary Polycythemia
Polycythemia is charactised by an increased production of red blood cells (RBCs). This is accompanied by a rise in the packed cell volume (PCV) as well as haemoglobin (Hb). The extra red blood cells increase the viscosity of blood and may cause complications, such as blood clots or bleeding.
Depending on the cause, polycythemia can be classified into two types:
- Polycythemia vera (PV): also called primary polycythemia, this condition is characterized by 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.
PV is considered as one of the myeloproliferative disorders, the others being essential thrombocythemia, myelofibrosis and chronic myelogenous leukemia.
Myeloproliferative disorders are characterised by an abnormal development and thus functioning of the bone marrow cells. A key feature seen is trilineage myeloid bone-marrow dysplasia associated with peripheral cytopenias.
PV, also known as polycythemia rubra vera, Osler’s disease, is a chronic disease that may be life-threatening. It is characterized by trilineage bone-marrow hyperplasia (polycythemia, granulocytosis, thrombocythemia) with low erythropoietin.
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. This gene encodes a protein that is essential for RBC production. Its full role is not entirely understood but it may be instrumental in the onset of this disease.
- A family history of this disease is usually lacking. However, due to certain unknown genetic mechanisms, more than one family member may have the disease occasionally.
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.
PV is generally not seen in the younger age group and 60-65 years is the most common age for diagnosis.
Symptoms and Complications of Polycythemia Vera
PV may remain asymptomatic for years owing to the extremely slow development of this disease.
An increase in RBCs leads to the formation of thick, viscous blood that interferes with oxygen delivery to the cells. Because of this lack of oxygen, the normal functioning is hampered thus leading to symptoms.
PV presents with a wide spectrum of clinical and hematological findings. The trilineage expansion (polycythemia, granulocytosis, thrombocythemia) mainly leads to the occurrence of symptoms.
The clinical features typically include the following:
- Fatigue, headache, dizziness
- Visual disturbances
- Itching, more prominent after a warm bath
- Bleeding from multiple sites and gums
- Abnormal sensations in hands and feet
- Weight loss
- In rare cases, osteopathic pain
The higher viscosity of blood in PV poses serious health hazards. Blood clots are formed easily and can cause heart attacks or stroke. They also can lead to enlargement of the liver and spleen. Formation of blood clots within the liver and spleen can give rise to intense pain.
There is also an increased risk of gastric ulcers, gout or renal stones due to the rise in RBCs.
In rare cases, myelofibrosis can develop, wherein there is replacement of the bone marrow by scar tissue.
AML may occur occasionally because of uncontrolled growth of the undifferentiated marrow cells.
Diagnosis of Polycythemia Vera
Table 1: Proposed revised WHO criteria for polycythemia vera
|Major criteria||Haemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume|
|Presence of JAK2V617F 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|
Polycythemia vera is an incidental diagnosis, often detected during testing for other medical conditions. The diagnosis of PV is based on past medical history, physical examination, the age of the patient and after certain diagnostic tests.
Once the diagnosis of polycythemia is confirmed, it is essential to find out whether it is primary or secondary.
Primary or secondary polycythemia can be differentiated based on the past medical history and clinical examination of the patient. The level of erythropoetin (EPO) helps in differentiation the two types of polycythemia. In polycythemia vera, the level of EPO is very low whereas in secondary polycythemia the level of EPO is normal or raised.
The tests done for PV include the following:
- CBC: a rise in Hb or hematocrit can be indicative of PV. The counts of RBCs, WBCs and platelets may show an abnormal increase or decrease and hence, it becomes important to exclude other blood disorders, infections etc.
- Blood smear: a blood smear may show an increased RBC count and any abnormal blood cell types, found more frequently in PV associated with AML or myelofibrosis.
- Measurement of the level of EPO is significant in diagnosis, especially to differentiate between primary and secondary polycythemia as described above.
- Bone marrow examination: normal production of blood cells can be confirmed using a bone marrow biopsy. If on bone marrow examination an increase in the RBC production is evident, it is highly suggestive of PV.
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 like medicines, procedures and other methods may be needed for effective management of the disease. Patients undergoing treatment usually lead a normal life. However for prevention as well as treatment of complications, medical supervision is necessary.
The various modalities used in the treatment of PV lead to a decrease in the RBC count as well as Hb. Thus, the viscosity of blood becomes near normal and the subsequent chances of a myocardial infarction or stroke are reduced. It also ensures adequate oxygen supply to all the tissues.
The treatment modalities that help in the reduction of red blood cell count are:
- Medications: the commonly used drugs are hydroxyurea or interferon-alpha. Their primary action is to decrease RBC overproduction by the bone marrow. Hydroxyurea is an anti-cancer drug that improves blood flow by decreasing the RBC and platelet 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.
- Phlebotomy: in this procedure, venous blood is removed from the patient’s body. This blood is then passed through an airtight tube and collected in a sterile container. This helps in the reduction of RBCs as well as a reduction in the viscosity of blood. Usually, one unit of blood per week is extracted until normal hematocrit values are reached. It needs to be repeated every few months.
- Radiation treatment: overactivity of the marrow cells can be suppressed by radiation. This causes a reduction in the RBCs and thus reduces the viscosity of blood.
- Use of low-dose aspirin for its anti-thrombotic effect has been found to be beneficial in various studies. It is a blood-thinner that decreases the chances of blood coagulation. It is also helpful in treatment of bone pain and burning sensation of hands as well as 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 pruritis 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.
- Pruritis has also been experimentally treated with paroxetine (20 mg/day), an antidepressant that is a selective serotonin reuptake inhibitor (SSRI). Other treatment options for PV-associated pruritus are JAK inhibitors, interferon-α (IFN- α) and narrow-band ultraviolet B phototherapy.
- Imatinib mesylate is a drug approved for use in leukemia. It has been shown to reduce the number of phlebotomies in patients with PV. It may also help in reversing splenomegaly. Current research is focused on limiting the damage caused by the abnormal JAK2 gene.
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 is a polycythemia with no association with the JAK2 gene. It is so called because the polycythemia occurs secondary to certain underlying causes which increase the demand for oxygen of our body. These hypoxic conditions cause our bodies to release erythropoietin, a hormone that increases the RBC count and, hence, the blood viscosity. Secondary polycythemia is, thus, characterized by increased erythropoietin levels.
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 apnoea 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 is a prominent feature of 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 haemangioblastoma and pheochromocytomas. 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 very low whereas in secondary polycythemia EPO is normal or raised.
Treatment and Prevention of Secondary Polycythemia
In contrast to polycythemia vera, secondary polycythemia has a potential cure. In cases of chronic tissue hypoxia, treating the cause of hypoxia cures the polycythemia. In these situations, there is a very low risk of thrombosis 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.
Secondary polycythemia is triggered by conditions causing long-standing hypoxia. These include smoking, high altitudes, mountain climbing etc. It thus becomes necessary to avoid such situations in order to prevent secondary polycythemia. In secondary polycythemia, treatment for the underlying diseases such as severe lung or heart diseases may also lead to improvement.