Polycythemia Rubra Vera

Clonal myeloproliferative disorder that originates from transformation of mulitipotent hematopoietic progenitors and causes the overproduction of erythroid cells often accompanied by elevated platelets, leucocytosis, or both.

Most common Philadelphia chromosome negative myeloproliferative neoplasm with an estimated prevalence of approximately 50 per 100,000 people in the US.

More common in the sixth and seventh decades of life.

Chronic clonal myeloproliferative neoplasm with increasedred cell mass, elevated white cell and platelet counts are also common.

Median age approximately 60 years.

Affects about 100,000 people in the US.

Estimated incident is 2.8 cases per hundred thousand patients per year.

Incidence increases as a fourth power of age with a peak incidence of 10.5 x 10 to the 5th/year at ages 75-80 years.

Incidence is approximately 2 in 100,000, with a slight male predominance.

Median survival greater than 10 years in treated patients and about 18 months in untreated patients.

In large series median survival 19 years.

Incidence close to 20-fold in individuals exposed to radiation.

Often culminates in acute leukemia or myelofibrosis.

The risk of transformations to acute leukemia is about 3-5%.

About 15% of patients transform to myelofibrosis.

The rate of myelofibrosis may be higher among younger patients, who will have a longer duration of disease.

The longer patient has polycythemia vera the greater likelihood of disease progression.

Incidence of acute leukemia is about 5.3 x 1000 person years.

About 6000 to 7000 new cases annually in the United States.

40% of patients have some degree of leukocytosis and thrombocytosis.

Thromboembolism occurs in 15-60% and causes 10-40% of the mortality.

The risk of thrombosis is increased and the survival is worse in patients who additionally have a leukocytosis.

Leukocytosis at the time of diagnosis is associated with adverse prognostic implications, including the risk of thrombosis, progression of disease, and reduced overall survival.

Activated leukocytes, have procoagulant factors, tissue factors and cytokines,  including IL1beta and TNF, alpha contributing to the risk of thrombosis and promoting fibrotic changes in the bone marrow.

Age and thrombotic history are the only two factors included in risk stratification tools for patients with PV.

Signs of progressive disease include the elimination in the elevation of red blood count or even the presentation of anemia.

Progressive disease can manifest by a markedly enlarging spleen, unintentional weight loss, fevers, bone pain and presence of immature cells in the circulation.

Hepatic vein thrombosis common in polycythemia and is most common in women.

Thrombosis, including myocardial infarction and stroke, is the leading cause of death and his attributed to increased blood viscosity.

Higher viscosity displaces platelets towards the vessel walls, leading to platelet interaction with endothelium, causing emdy damage and upregulating soluble procoagulant factors.

Incidence may be as high as 2.3 per 100,000 with a slight male preponderance.

The incidence is higher among men than among women in all races and ethnicities.

Incidence approximately 2.8 cases per 100,000 men and approximately 1.3 cases per 100,000 women.

Prevalence is approximately 2 cases per 100,000 population.

Relatively uncommon among individuals younger than 30 years.

More common among Jews of European descent than among other European populations and Asians.

Women present at a younger age than males.

Serum erythropoeitin levels are low or low normal at presentation, and remain low after normalization of the hematocrit by treatment.

Erythroid progenitors are capable of growing in vitro in the absence of erythropoietin.

The major criterion is a hemoglobin level greater than 18.5 g/dL in men, and greater than 16.5 g in women, or evidence of increased red blood cells volume.

The second major criteria is the presence of JAK2 or other functionally similar mutations.

JAK2 gene is seen on nearly all patients with PV.

Phosphorylation of JAK2 results in cellular proliferation in the absence of external growth factors, and leads to clonal proliferation of hematopoetic cells.

JAK2 V617F is the most common JAK2 mutation.

JAK2 results in activation of the JAK/signal transducers and activators of trancsription (STAT) pathway.

The activation of the cellular signaling cascade results in erythropoietin independent clonal proliferation of erythroid precursors, increasing red cell volume, extra medullary, hematopoiesis, and inflammatory cytokine production.

JAK-STAT mutations cause hematopoietic progenitors cells, and stem cells to secrete IL –1beta, tumor necrosis factor alpha, IL – 12 and IL, and interferon gamma, among other pro inflammatory cytokines,which provide a survival advantage to the mutated hematopoeitic stem cells and serve as promoters of mutagenesis.

In addition to causing an overproduction of red blood cells, the inflammatory cytokines drive the production of other myeloid cell lines, often leading to thrombocytosis and leukocytosis.

102 genes are integrally involved in the pathogenesis of the disease and are involved in the production of collagen, inflammatory cytokines, procoagulants, enhancement of hematopoietic stem cell expansion, and the process of leukemic transformation.

There is a lack of social, genetic testing at the time of diagnosis due to the relatively low frequency of abnormal karyotypes.

Diagnosis requires three major criteria or 2 major criteria +1 minor criterion.

Major criteria:

Hemoglobin greater than 16.5 g/dL in men, greater than 16 g/dL in women

Hematocrit greater than 49% in men, greater than 48% in women

Increased red cell mass

Minor criteria for diagnosis bone marrow biopsy evidence of hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation, serum EPO level below the normal range, and endogenous erythroid colony formation in vitro.

For diagnosis the patient must have two major and one minute criteria, or the first major criterion with 2 minor criteria.

Most of P Vera’s disease related morbodities are  related to increase risk of arterial and venous thrombosis.

PV is a progressive disease with 20 year rates ranging from 11 to 45% in terms of progressiondo myelofibrosis.

Progression to myeloproliferative neoplasm-blast phase occurs at a rate of 2-4%.

Patients are asymptomatic for many years, but then may experience fatigue, pruritus, night sweats, and bone pain.

EPO level may be normal in 36% of patients with PV

Bone marrow examination is often not necessary to diagnose PV.

Baseline bone marrow fibrosis is present in about 14 to 48% of patients at presentation and is independently associated with increased risk of disease progression to post polycythemia vera myelofibrosis.

Splenomegaly at presentation in about 30-40% of patients.

Splenomegaly rarely massive:defined as either palpable splenomegaly greater than 5 cm below, the left costal margin, what the emergence of newly palpable splenomegaly.

Splenomegaly is a risk factor for fibrotic transformation, and for leukemic evolution as well as reduced overall survival.

Disease related symptoms present in up to 85% of patients.

Bleeding occurs in 15-35% of patients and causes death in 6-30% of cases.

Patients can present as isolated erythrocytosis, leucocytosis, or myelofibrosis.

10-20% of patients have karyotypic abnormalities including 20q-, trisomy 8, trisomy 9, 13q- and deletions of chromosome 5 or 7.

Low ferritin levels and absence of stainable iron in the marrow regarded as hallmarks of polycythemia vera.

Vitamin B12 levels may be increased due to transcobalamin release from an increased granulocytic mass.

Approximately 40% present with trilineage hyperplasia, 20% present with erythrocytosis alone.

Elevated RBC mass, normal arterial oxygen saturation, splenomegaly, leucocytosis, thrombocytosis, elevated LAP, and elevated B12 or unbound B12 binding capacity.

Multiple studies have shown that there is no association with either  venous or arterial thrombotic events or disease progression with elevated platelet counts.

Measurement of red blood cell mass and plasma volume were mandatory studies but more relevant biological tests, serum erythropoeitin levels and bone marrow histologic examinations have made them unnecessary.

Plasma volume increases with red blood cell mass, while in hypoxic erythrocytosis the plasma volume decreases as the red blood cell mass increases.

Associated with impaired expression of the thrombopoietin receptor c-mpl, increased PTP-MEG2 phosphatase and elevated granulocyte expression of the PRV-1 receptor.

JAK2 mutations, V617F and exon 12 mutations, seen in virtually all patients and peripheral blood analysis for this mutation and erythropoietin level followed by bone marrow examination associated indicated for diagnosis.

A high JAK2 allele burden is associated with pruritus, myelopoeisis splenomegaly and venous thrombosis.

Diagnosis can be made by chance following routine hematologic evaluation, after presentation of a thrombotic event approximately 30% of cases, or based on the presence of symptomatology.

Diagnostics criteria: Hemoglobin greater than 18 g/dL in men and greater than 16.5 g/dL women, with evidence of increased volume of red blood cells, and the presence of a JAK2 mutation, bone marrow showing hypercellularity, below normal EPO level.

JAK2 gene is involved directly the intracellular signaling in PV progenitor cells, a process that occurs after exposure to cytokines to which the cells are rendered hypersensitive.

Clinical course highly variable, from few symptoms to serious illness.

Patients may experience a variety of symptoms and complications related to vascular processes, cytokine associated symptoms, splenomegaly or evolution of the disease process.

The disease may persist for many years without change in stage or clinical progression, and than of his can evolve to myelofibrosis or acute myelogenous leukemia.

Transformation to acute myelogenous leukemia is observed in approximate 5% of patients, after 10 years.

Underlying vascular disease common in older patients.

Thrombotic complications include cerebrovascular accidents, myocardial infarction, deep vein thrombosis, pulmonary embolus Are frequent.

Blood clots occur in approximately 30% of patients prior to diagnosis.

Rates of thrombosis decline after the first decade of disease.

Thrombosis can be observed as microvascular or macrovascular processes.

Microvascular complications P vera are caused by platelet hypersensitivity intransigent inclusion of small blood vessels.

Macrovascular complications are caused by The development of thrombotic enlarged arteries and veins, causing major thrombotic events.

Arterial events are more common than venous events.

Younger women with PV are at greater risk for unusual thrombotic events such as hepatic vein occlusion.

Major events as the primary causes of mortality are thrombotic events, accounting for 45% of all deaths.

Additional major causes of death include emergence of solid tumors, 19.5% and leukemic transformation 13%.

Associated symptoms driven by circulating pro-inflammatory cytokines, resulting from abnormal activation of JAK2 leads to fatigue, pruritus early satiety, inability to concentrate, and inactivity.

Approximately 85% of patients with PV develop fatigue.

Pruritus is present at some point in the course of PV in approximately 65% of patients and is generally localized to the trunk and proximal extremities and classically occurs following a hot shower.


Main goal of treatment is to prevent thrombotic events while avoiding iatrogenic harm, and minimizing the risk of transformation to the post polycythemia vera myelofibrosis or acute myeloid leukemia.

The goals of treatment are to maintain the hematocrit below 45%, normalize counts of white blood cells and platelets, control splenomegaly, reduce symptoms, and improve quality of life, prolong survival by preventing thrombotic complications, progression to myelofibrosis, and leukemic transformation.

Cornerstone of treatment has been phlebotomy to maintain hematocrit values a lesson 45%.

Maintaining a hematocrit below 45% by phlebotomy or hydroxyurea, or both, significantly reduces the risk of thrombosis compared to maintaining it in the 45 to 50% range.

Most patients receive low dose aspirin.

All patients, without a contraindication, should take prophylactic low dose aspirin for prevention of thrombotic events.

Low dose aspirin results in the relative risk reduction of 40% for a combined end point that includes nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes with a mean follow up of three years.

Therapeutic phlebotomy plus low-dose aspirin recommended for low risk patients less than 60 years old and no history of thrombosis, while cytoreduction is required in patients in addition to phlebotomy and low-dose aspirin for high-risk patients age 60 years a greater or a history of thrombosis.

Presently incurable.

Aggressive management of keeping the hematocrit below 45% lowers the risk of major thrombosis and desths from cardiovascular causes.

Cytoreductive therapy is recommended for patients with high risk of thrombosis in those with persistent or progressive hematologic abnormalities, splenomegaly, or symptoms

Cytoreductive therapy is also recommended for patients who cannot undergo phlebotomy or who require frequent phlebotomies.

High  burden of erythrocytosis contributes to thrombotic risk by increasing blood’s viscosity.

Phlebotomy induced iron deficiency can lead to complications of restless leg syndrome and cognitive impairment.

Iron supplementation should not given for phlebotomy induced iron deficiency to effectively control polycythemia.

Treatment is recommendations are that the hematocrit be kept below 45% and platelet count below 400,000 for cubic millimeter, otherwise the rates of thrombotic events will be proportionally increased.

However, randomized clinical trials do not show significant increase in the incidence of major thrombosis when the hematocrit of 45-50% was maintained (Di Nisio M et al, Berk PD et al, Fruchtman SM et al).

Phlebotomies decrease blood-iron levels, which controls the amount of hemoglobin that can be produced, which in turn lowers the hematocrit.

Use of alpha-interferon eliminates the need for phlebotomy.

Interferons induce sustained reduction in mutant JAK2 alleles and induce high rates of clinical, hematological and ,molecular responses.

In the PEGINVERA  trial a mono pegylated interferon administered every two weeks was found at the 7.5 years to have a 61% complete hematological response with control of RBC, platelet, white cell counts and spleen size.

Decreased iron levels decrease the incidence of heart disease, and a state of chronic iron deficiency that limits erythropoiesis is the ultimate goal of phlebotomy therapy in polycythemia vera.

Low dose aspirin has antithrombotic value.

Hydroxyurea is most commonly used first line cytoreductive agent.

Hydroxyurea can decrease thrombotic risk in high risk patients.

Some patients treated with hydroxyurea have an inadequate response or develop unacceptable side effects: 11% of patients become resistant to, or intolerant to  (13%) treatment.

In the study of PRV patients with hydroxyurea for a median of 4.4 years demonstrates a response rate of 90%, with 24% complete responders and 69% partial response after a median of 4.6 months of therapy.

Median overall survival with hydroxyurea treatment in this study was 19 years.

In a study of 55 patients with polycythemia rubra vera previously treated with phlebotomy with without hydroxyurea and followed for a median of 13 years after the initiation of interferon therapy revealed hematologic response normalization of platelet count in all patients by one year, decreased spleen size in 27 of 30 patients who had baseline splenomegaly.

About 25% of patients treated with hydroxyurea have unacceptable side effects or in inadequate response.

Patients who have resistance or intolerance to hydroxyurea have a shorter survival than other patients with polycythemia vera.

Patients are treated with hydroxyurea as long as they derive benefit.

More than 1 in 4 patients have hematocrit levels greater of 45%or greater, despite treatment.

In treated patients who do not maintain hematocrit levels consistently less than 45%, have approximately 4 times higher risk of cardiovascular death or thromboses.

In a observational prospective study with polycythemia in patients who received either interferon or hydroxyurea calling the overall hematological response was similar in both groups at 70%.

In the above study a molecular response with a decreased JAK2 allele burden was more common in the interferon group than in the Hydrea group 54.7% versus 19.4%

The interferon group demonstrated decreased phlebotomy needs and greater improvement in systemic symptoms.

In the above study patients with JAK2 mutation had a better five-year progression free survival in the interferon group than in the hydroxyurea group, 75.9% versus 47.6%.

Pegylated interferon has similar results compared to hydroxyurea in PV.

For patients intolerant to hydroxyurea, ruxolitinib is available.

Ruxolitinib 10 mg twice a day is an effective starting dose.

In a study of patients with inadequate response to or unacceptable side effects from hydroxyurea treated with ruxolitinib had superior response in controlling the hematocrit, reducing the spleen size, and improving symptoms associated with polycythemia vera (Vannuchi AM et al).

RESPONSE trial established the efficacy and safety of Ruxolitinib vs best supportive therapy in patient resistant or intolerant of hydroxyurea.

Upon finding of myelofibrosis, patients are stratified by risk with younger patients with high-risk disease being candidates for stem cell transplant.

JAK 1/2 inhibitors can eliminate the underlying malignant clone.

Ruxolitinib is front-line therapy for patients who developed myelofibrosis, reducing by 30% the risk of death compared to a control arm.

Studies revealed a connection between an elevated WBC count and poor outcomes in patients with PV,  including a higher risk of thrombosis as well as increase symptom burden.

Rusfertide is an injectable peptide mimetic of the iron regulatory hormone hepcidin, which restricts the ability of iron for erythropoiesis.

Rusfertide treatments was associated with the mean hematocrit of less than 45% during a 28 week period.

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