MYELOPROLIFERATIVE disorders describe a group of 3 disorders with similar biologic components. These include polycythemia vera (PV), essential thrombocytopenia, and primary myelofibrosis.1 Each of these disorders is characterized by increased hematopoiesis, overproduction of blood elements, and the potential for conversion to acute leukemia.1 Polycythemia vera is distinguished by excessive red blood cell production.

Primary polycythemia, or PV, is not triggered by another illness, but is acquired and is a progressive disorder of bone marrow, growing over a period of 10 to 20 years. Typically, the affected people are unaware of the disease until they develop a complication or are diagnosed because of other unrelated medical problems. Polycythemia vera affects one person in 200 000, usually more men than women, and occurs mostly among people aged 50 to 70 years.2 If the patient undergoes treatment after diagnosis, their life expectancy is about 10 to 15 years; if not treated, they usually only live about 18 months after diagnosis.3 Most patients will die from complications of thrombosis, heart failure, leukemia, or hemorrhage.4 The last phase, or spent phase, of PV occurs in approximately 20% of patients and includes myeloid metaplasia with myelofibrosis, splenomegaly, and cytopenia.5

In the late 1960s and early 1970s, a PV study group was formed to develop diagnostic criteria and recommendations for treatment. Several studies performed after the group's recommendations narrowed the cause of PV to a clonal transformation of a single hematopoietic stem cell. In 2001, The World Health Organization further refined the diagnostic criteria using evidence-based information from ongoing studies.2

PATHOPHYSIOLOGICAL COMPONENTS OF PV

Polycythemia vera is caused by an increased cell growth and decreased cell death of erythroid progenitors. Polycythemia vera can develop from a proliferative phase to a metastatic and then spent or malignant phase that can develop into acute leukemia.4 Polycythemia vera is acquired from a genetic mutation recently identified in the JAK2 protein called JAK2 V617F.2 Two key aspects of PV are the ability to form clones and erythropoietin independence. In PV, a single clonal population of erythrocytes, granulocytes, platelets, and variable clonal B cells arise when a hematopoietic stem cell undergoes a rapid growth and the cell gains an advantage over other stem cells.6

Erythropoietin independence is the ability of erythroid colonies formed from the PV hematopoietic stem cell to grow without erythropoietin. Although the colonies do not require erythropoietin, they continue to respond to it and the erythropoietin receptor remains normal. Endogenous erythroid colony formation has been found in 100% of PV patients. This is due to a hypersensitivity of erythropoietin causing erythroid progenitors to grow in vitro in the absence of cytokines.1 Several research studies examining the effects of endogenous erythroid colonies formation have identified the presence of the JAK2 V617F protein mutation in myeloproliferative disorders. The mutated gene has been found in approximately 95% of patients with PV.1 The mutated protein interferes with the signaling pathways in the place of cytokines. The mutated cells encourage rapid cell growth and resist cell death, which leads to increased growth and lifespan of the JAK2 mutation.

DIAGNOSTIC CRITERIA

Patients are often diagnosed with PV after incidental laboratory findings for other reasons. After the World Health Organization revised the diagnostic criteria for PV, testing includes a combination of laboratory values and criteria where the patient exhibits multiple symptoms. This includes an "increased red blood cell mass greater than 25% of normal values, absence of causes of secondary Polycythemia, palpable splenomegaly, a clonality marker, thrombocytosis with platelets greater than 400,000/mcl, neutrophil count greater than 10,000/mcl, splenomegaly diagnosed by ultrasound, or decreased serum erythropoietin."2^(p1127) Bone marrow biopsy is often performed to examine and confirm primary PV diagnosis from secondary PV. Bone marrow will demonstrate many abnormal cells, an abnormal increase of erythroids, and increased clusters of multiple structural forms of megakaryocytes with nuclei containing multiple lobules.2

CLINICAL MANIFESTATIONS AND COMPLICATIONS OF PV

Patients will demonstrate symptoms of PV in the erythrocytotic phase because of the excessive growth of red blood cells and platelets. These symptoms include pruritus after being in hot water, headache, weakness, shortness of breath, visual problems, abnormal tingling, itching or burning of the skin, and gastric pains.4

Patients may seek health care complaining of hemorrhage and other unknown symptoms related to an unknown diagnosis of PV. The thrombotic complications include development of deep vein thrombosis, stroke, myocardial ischemia, or mesenteric ischemia.2 Common hemorrhagic complications include nosebleed, oral mucosa bleeding, gastrointestinal bleeding, or bruising. Frequent complications caused by PV include splenomegaly, skin problems, open sores inside the mouth, peptic ulcers, gout, uric acid, kidney stones, and possible development of other blood disorders such as acute leukemia.7 Polycythemia vera has the ability to progress to an inactive phase where patients may not require phlebotomy or chemotherapy treatment. Polycythemia vera can develop into the last phase where patients will develop postpolycythemic myeloid metaplasia that can include developing splenomegaly, anemia, thrombocytopenia, and fever or weight loss.

CURRENT EVIDENCE-BASED TREATMENT FOR PV

Treatment of patients diagnosed with PV is tailored to each individual's current needs and laboratory findings. There are several types of treatment that can be used alone or together to alleviate symptoms and the disorder. Treatments include phlebotomy, myelosuppressive therapies, interferon alpha, and medications to treat the symptoms associated with PV.

Phlebotomy is still a standard of practice to help decrease the hematocrit levels to a goal of 42% to 47%. Initially the patient may have phlebotomy every 2 to 4 days to decrease hematocrit levels. Once the levels are lowered, patients may come in for phlebotomy every 2 to 3 months depending on the rate of red blood cell regeneration. Each phlebotomy session requires that 450 to 500 ml of blood are removed from the patient.4 Important teaching points for the patient are to hydrate with fluids before and after phlebotomy and to slowly rise from a sitting to standing position to avoid orthostatic hypotension. Common adverse effects of phlebotomy are headache, weakness, hypotension, chest pain, and a vasovagal response. Low-dose aspirin has been used to help lower platelet levels and for its antithrombotic effects in the blood through platelet aggregation inhibition.4

Treatment for patients in the spent phase include steroids, myelosuppressive agents, splenectomy, and red blood cell or platelet transfusions as needed. These treatments are aimed at treating the symptoms caused in the spent phase and are mostly palliative. The negative outcome of myelosuppressive therapies is a 5% chance of causing acute leukemia in patients.4

Myelosuppressive therapy is used when the patient has had a previous thrombotic event, requires frequent phlebotomy, and has uncontrolled adverse effects from PV, such as pruritus and weight loss.7 This therapy works to slow down red blood cell production and medications include alkylating agents and nonalkylating agents.4 Another myelosuppressive agent is radioactive phosphorous, which is an intravenous treatment generally given to patients older than 70 years.7 This therapy should not be considered for long-term treatment because it can cause progression to acute leukemia.

Hydroxyurea, a nonalkylating myelosuppressive agent, is commonly administered in a pill form. The mechanism of action is to inhibit the rapid growth of cells by preventing DNA synthesis of ribonucleoside reductase.8 Hydroxyurea is the drug of choice for most PV patients, but it has short-term effects, so it needs to be taken twice daily. It can also cause thrombocytopenia and leucopenia.4

Interferon alpha is given to patients who do not respond to the myelosuppressive agents. It suppresses production of hematopoietic progenitors and obstructs bone marrow fibroblast progenitor cells. It can be given in conjunction with phlebotomy and aspirin and works best in patients with myeloid metaplasia and splenomegaly but is costly.8 Patients may be prescribed medications to help control the adverse effects of PV. Antihistamines or H2 receptor blockers are prescribed to help with pruritus. Patients with high levels of uric acid will be prescribed Allopurinol.3

JAK2 inhibitors

The JAK2 mutation is found in 90% to 97% of all PV patients.9 Because of the potentially fatal complications and poor prognosis, research has begun to examine medications and treatments to stop the gene mutation. A group of 4 different medications have been identified to stop the mutation, change the pathway, or inhibit the proliferation of the mutated cells. The medications are separated into 2 categories, JAK2-selective or JAK2-nonselective.9

JAK2-selective drugs look at binding to the JAK2 site and suppress hematopoietic colony growth when the mutation gene is present.9 So far, the research demonstrates that this is not only effective in stopping the mutation but also in affecting the cells when the mutation is not present. JAK2-nonselective drugs inhibit the tyrosine kinase receptors that inhibit the cell lines causing the JAK2 V617F mutation.9 Several clinical drug trials are in effect utilizing the selective and nonselective JAK2 inhibitors. These drugs are showing promising results in decreasing the myeloproliferation and disease symptoms and manifestations. Research is still in the early stages to understand the ability of the drugs to prevent disease progression and increase survival. Some of the limitations of the JAK2 inhibitors found so far are the development of thrombocytopenia and drug toxicities.9

Imatinib

Clinical studies are examining the effects of an antineoplastic agent called imatinib. It is a tyrosine kinase inhibitor that acts by inhibiting intracellular pathways that develop into malignancies.10 In small groups of polycythemia patients, it has been shown to reduce the need for phlebotomy, lower platelet counts, and reduce the size of the spleen. In 2 cases evaluated by researchers, using imatinib placed the patients into a hematologic remission and there was a threefold reduction in the amount of mutated JAK2 V617F cells seen on laboratory specimens.8

STEM CELL TRANSPLANTATION

Hemopoietic stem cell transplantation has been used successfully in other myeloproliferative disorders. Stem cell transplantation has been researched in late phase of PV patients since 1988. From 1988 to 2000, the Fred Hutchinson Cancer Research Center in Washington conducted a trial utilizing 10 PV patients undergoing stem cell transplantation. These patients had developed marrow fibrosis and acute leukemia with no other treatment options available. At the end of the research study, 5 of the original PV patients were in remission.5 Stem cell research has lent valuable information for possible increase in survival when patients are diagnosed with spent phase PV.

PATIENT EDUCATION

As nurses, we have the opportunity to educate patients who have been diagnosed with PV. Education should focus on disease process, adverse effects of treatment, how to recognize thrombosis or bleeding, and how to best follow treatment to assure compliance. Weight reduction and cessation of smoking can decrease risk of thrombosis. Patients can be encouraged to eat frequent small meals to help with feelings of fullness associated with splenomegaly.3 Patients are also encouraged to use electric razors and soft toothbrushes to help prevent bleeding.4 With a good understanding of the treatment plan, it is hoped that patients can have an improved quality of life.

CONCLUSIONS

Polycythemia vera is a hematopoietic stem cell disorder characterized by clonal dominance and unregulated increase in erythrocytes, leukocytes, or platelets. This leads to an increase in red blood cell production causing blood to thicken and leads to complications. Patients often do not know they carry this disorder until they seek medical care with complaints from symptoms such as thrombosis, bleeding, fatigue, and weakness. Until recently, diagnosing PV has been difficult because it is similar to the other 2 myeloproliferative disorders, essential thrombocytopenia and primary myelofibrosis. Because of ongoing research, the gene mutation JAK2 V617F has been identified in all PV patients and has led to more research focusing on stopping this mutation. It is important for patients to receive education regarding management of symptoms and treatment so that compliance and a better quality of life can be achieved.

REFERENCES

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