What is polycythemia vera? What are the symptoms of polycythemia vera? How is polycythemia vera diagnosed? What are the treatment options for polycythemia vera?

Understanding Polycythemia Vera

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an increased red blood cell mass (RCM), or erythrocytosis. This leads to hyperviscosity of the blood and an increased risk of thrombosis. Patients with PV may present with a variety of symptoms, including pruritus after bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such as weakness, headaches, or dizziness. Some patients are diagnosed incidentally when an elevated hemoglobin and/or hematocrit level is detected on a complete blood count.

Epidemiology of Polycythemia Vera

The median age of patients diagnosed with PV is 60 years, although it can occur in persons of all age groups. PV occurs with a slight predominance in men. The incidence of PV is reported to be 2.3 per 100,000 persons per year, so a typical family physician can expect to diagnose PV once or twice during their career and will often have at least one patient in their panel who carries the diagnosis.

Importance of Diagnosis and Treatment

The seriousness of PV is underscored by the fact that the median survival in untreated symptomatic patients after diagnosis is six to 18 months. However, with appropriate treatment, the median survival is more than 10 years. Therefore, it is crucial to accurately diagnose and manage PV to improve patient outcomes.

Diagnosing Polycythemia Vera

PV should be suspected when hemoglobin and/or hematocrit levels are elevated, defined as a hemoglobin level greater than 18 g per dL (180 g per L) in white men and 16 g per dL (160 g per L) in blacks and women, and a hematocrit level greater than 52 percent (0.52) in white men and 47 percent (0.47) in blacks and women. PV should also be suspected in patients with portal venous thrombosis and splenomegaly, with or without thrombocytosis and leukocytosis.

Excluding Secondary Erythrocytosis

When making the diagnosis of PV, the physician must first exclude a secondary erythrocytosis, such as those caused by heavy smoking, chronic pulmonary disease, or renal disease. Once a secondary cause is ruled out, the diagnosis of PV is made using a combination of major and minor criteria defined by the Polycythemia Vera Study Group (PVSG).

PVSG Diagnostic Criteria

The major diagnostic criteria for PV include an increased RCM, normal oxygen saturation, and the presence of splenomegaly. The test for RCM is a nuclear medicine study involving autologous infusion of radio-labeled red blood cells followed by serial phlebotomy to determine distribution. Physicians may refer patients to a specialty laboratory for this study.

Atypical Presentation: Normal Hemoglobin and Hematocrit

In rare cases, patients with PV may present with normal hemoglobin and hematocrit levels, a phenomenon known as the “PV variant.” This atypical presentation can make the diagnosis more challenging, and clinicians should be aware of this possibility to avoid missed or delayed diagnoses.

Treatment Strategies for Polycythemia Vera

Treatment for PV typically includes phlebotomy, with the possible addition of myelosuppressive agents based on a risk-stratified approach. Agents under investigation for PV treatment include interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist is recommended for the management of PV.

Prognosis and Survival

Untreated patients with PV may survive for only six to 18 months after diagnosis. However, with appropriate treatment, the median survival is more than 10 years. This highlights the importance of early diagnosis and effective management of PV to improve patient outcomes.

Conclusion

Polycythemia vera is a serious chronic myeloproliferative disorder that requires prompt diagnosis and treatment to extend patient survival. Clinicians should be aware of the typical presentation of PV, as well as the rare variant where patients may present with normal hemoglobin and hematocrit levels. By understanding the diagnostic criteria and treatment options for PV, healthcare professionals can ensure timely and effective management of this condition.

Polycythemia Vera | AAFP

BRIAN J. STUART, LT, MC, USNR, AND ANTHONY J. VIERA, LCDR, MC, USNR

Polycythemia vera is a chronic myeloproliferative disorder characterized by increased red blood cell mass. The resultant hyperviscosity of the blood predisposes such patients to thrombosis. Polycythemia vera should be suspected in patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal venous thrombosis. Secondary causes of increased red blood cell mass (e.g., heavy smoking, chronic pulmonary disease, renal disease) are more common than polycythemia vera and must be excluded. Diagnosis is made using criteria developed by the Polycythemia Vera Study Group; major criteria include elevated red blood cell mass, normal oxygen saturation, and palpable splenomegaly. Untreated patients may survive for six to 18 months, whereas adequate treatment may extend life expectancy to more than 10 years. Treatment includes phlebotomy with the possible addition of myelosuppressive agents based on a risk-stratified approach. Agents under investigation include interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist is recommended.

Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an increased red blood cell mass (RCM), or erythrocytosis, which leads to hyperviscosity and an increased risk of thrombosis. Patients may present with complaints of pruritus after bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such as weakness, headaches, or dizziness. Other patients are diagnosed after an incidental finding of an elevated hemoglobin and/or hematocrit level on a complete blood count.

The median age of patients diagnosed with PV is 60 years, although it can occur in persons in all age groups. ¹ PV occurs with a slight predominance in men. A comprehensive review¹ reported the incidence of PV to be 2.3 per 100,000 persons per year. Therefore, a typical family physician can expect to make a diagnosis of PV once or twice during his or her career, and will often have at least one patient in his or her patient panel who carries the diagnosis. The seriousness of PV is underscored by the fact that the median survival in untreated symptomatic patients after diagnosis is six to 18 months.² With treatment, the median survival is more than 10 years.²

Diagnosis

PV should be suspected when hemoglobin and/or hematocrit levels are elevated (i.e., hemoglobin level greater than 18 g per dL [180 g per L] in white men and 16 g per dL [160 g per L] in blacks and women; hematocrit level greater than 52 percent (0.52) in white men and 47 percent (0.47) in blacks and women).³ PV also should be suspected in patients with portal venous thrombosis and splenomegaly with or without thrombocytosis and leukocytosis. Other signs and symptoms are listed in Table 1.^1,4

In making the diagnosis of PV, the physician must first exclude a secondary erythrocytosis.^5,6 Once a secondary cause is ruled out (Table 2⁷), the diagnosis of PV is made using a combination of major and minor criteria defined by the Polycythemia Vera Study Group (PVSG). Although new diagnostic modalities have been developed, these criteria remain the standard method to diagnose PV.⁸

Major diagnostic criteria include increased RCM, normal oxygen saturation, and the presence of splenomegaly. The test for RCM is a nuclear medicine study involving autologous infusion of radio-labeled red blood cells followed by serial phlebotomy to determine distribution. Physicians may refer patients to a specialty laboratory for this study.

More Common

Hematocrit level > 52 percent (0.52) in white men, > 47 percent (0. 47) in blacks and women

Hemoglobin level > 18 g per dL (180 g per L) in white men, > 16 g per dL (160 g per L) in blacks and women)

Plethora

Pruritus after bathing

Splenomegaly

Weight loss

Weakness

Sweating

Less Common

Bruising/epistaxis

Budd-Chiari syndrome

Erythromelalgia

Gout

Hemorrhagic events

Hepatomegaly

Ischemic digits

Thrombotic events

Transient neurologic complaints (headache, tinnitus, dizziness, blurred vision, paresthesias)

Atypical chest pain

Changes to these diagnostic criteria have been proposed. For example, determinations of RCM, classically given in milliliters per kilogram (mL per kg), can be misleading if the patient is obese, because body fat is relatively avascular. The International Council for Standardization in Haematology (ICSH) has amended the RCM assessment, recommending the use of formulas incorporating body surface area, weight, gender, and plasma volume.^8–10 [Level of evidence: C, consensus opinion] A patient with PV could have low oxygen saturation levels, because it is possible to have both PV and an unrelated hypoxic disorder.¹ Palpable splenomegaly is an important physical finding and major criterion. However, palpation is only 58 percent sensitive for diagnosis¹¹ (i.e., if present, it will not be detected by examiners in 42 percent of cases). Specificity is much better. This lack of sensitivity has led to some discussion about the use of imaging techniques to answer the question, although such a finding by imaging might be relegated to the status of a minor criterion. ¹⁰ In addition, the minor criteria of leukocyte alkaline phosphatase (LAP) and serum vitamin B₁₂ and B₁₂ binding capacity may be dropped in the future because of inter-laboratory error regarding LAP and the unavailability of vitamin 10 B₁₂ binding capacity. Furthermore, neither of these criteria is sensitive nor specific.¹ Nonetheless, the PVSG criteria remain the diagnostic standard.

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Serum erythropoietin (EPO), bone marrow histopathology and karyotype, and the presence of endogenous erythroid colonies (EEC) have been proposed as diagnostic tests for PV. Because PV is an autonomous (i.e., EPO-independent) erythroid proliferation, serum EPO levels in PV are low or normal.^1,5 Low-serum EPO levels for PV have a sensitivity of 70 percent and a specificity of 90 percent. ¹

In PV, bone marrow displays characteristic histologic findings,¹⁰ and clonal cytogenetic abnormalities can be detected.⁵ Use of this test requires the availability of a histologist who is specially trained in marrow histology. Finally, EEC growth is based on the ability of erythroid cells from peripheral blood and bone marrow samples in PV to grow in vitro without the addition of EPO.^12,13 This unique finding, along with serum EPO levels, forms the basis for a new diagnostic approach,⁵ but has the disadvantages of expense and limited availability.¹⁰

Although serum EPO levels and marrow biopsies may become a routine diagnostic option, the PVSG criteria remain the standard of diagnosis. Consultation with a hematologist is appropriate to aid in diagnosis, and serum EPO levels and bone marrow biopsy should be considered if available. An algorithm summarizing the evaluation and management of PV is presented in Figure 1.

Treatment

No single treatment is available for PV. Thrombosis accounts for the majority of morbidity and mortality. The major goal of treatment is to prevent thrombotic events. Examples of thrombotic events include arterial and venous thrombosis, cerebrovascular accident, deep venous thrombosis, myocardial infarction, peripheral arterial occlusion, and pulmonary infarct.¹⁴ Of additional importance to the family physician is the symptomatic treatment of the bothersome microvascular sequelae, such as pruritus and distal extremity erythromelalgia (Table 3^1,15–17). Because PV is a rare condition, it has been difficult to assemble patients for well-designed, randomized controlled trials with long- term follow-up. Therefore, recommendations for treatment are based on lower quality evidence from case series and uncontrolled trials.

The PVSG and Gruppo Italiano Studio Policitemia (GISP) are two prospective trials that have unearthed a therapeutic dilemma regarding the two basic treatment approaches—phlebotomy alone and phlebotomy plus myelosuppressive agents. A number of new therapeutic agents have been developed. In addition to interferon alfa-2b (Intron A) therapy, agents that target platelet number (e.g., anagrelide [Agrylin]), and platelet function (e.g., aspirin) are being investigated as potential therapies.

The mainstay of treatment for PV is phlebotomy, which is aimed at reducing hyperviscosity by decreasing the venous hematocrit level to less than 45 percent (0. 45) in white men and 42 percent (0.42) in blacks and women.^1,14,18 The PVSG reported the best median survival, 12.6 years, for this type of treatment.¹⁴ Some features of using phlebotomy alone are attractive, primarily because it is a simple procedure without many risks, except for the eventual development of iron deficiency.⁸ Some experts have cast doubt on the PVSG findings regarding median survival, noting that up to 50 percent of patients treated with phlebotomy alone had to switch to other treatments by the fifth year.¹⁹ The PVSG found a statistically significant increase in the number of thrombotic events within the first three years of initiating treatment, compared with the use of myelosuppressive agents.¹⁴ After this period, however, the rate of thrombosis remained the same for both treatment approaches. Furthermore, the GISP found an added independent dimension to the risk of thrombosis—rates increase with age and a history of thrombotic events. ²⁰ Despite these concerns, a recent survey of physicians who were members of the American Society of Hematology showed that 69 percent use phlebotomy as first-line therapy for PV.²¹

The use of myelosuppressive agents such as radioactive phosphorus (³²P), chlorambucil (Leukeran), busulfan (Myleran), pipobroman (Vercyte), and hydroxyurea (Hydrea) in conjunction with phlebotomy has been studied. Chlorambucil, busulfan, and pipobroman, all alkylating agents, have fallen out of favor because of concerns about rates of iatrogenic leukemia.¹⁹ The agent ³²P remains in use with supplemental phlebotomy and has a reported median survival similar to that of phlebotomy alone—10.9 years according to PVSG data¹⁴ and 11.8 years according to GISP.²⁰ The myelosuppressive drugs such as ³²P had an initial advantage over phlebotomy alone regarding thrombosis rates during the first three years of treatment. However, this effect disappeared after three years, and rates of thrombosis thereafter were equivalent.^8,14,19 Unfortunately, prospective data have revealed the mutagenic potential of myelosuppressive agents such as ³²P, with a relative risk for malignancy of 2.3 to four times that of the control groups after about six years of treatment. Patients treated with phlebotomy alone had the same rate of cancer as patients in the control groups. ^2,14,20

The nonalkylating myelosuppressive agent hydroxyurea is widely used in the treatment of PV, because it is less leukemogenic.²² PVSG data have established this agent to be an effective bone marrow suppressant. Hydroxyurea is associated with a lower risk of thrombosis compared with solely phlebotomized patients. Concern regarding the safety of long-term use of hydroxyurea has been noted.^14,19

Recombinant interferon alfa-2b reduces myeloproliferation and splenomegaly, and alleviates the symptom of pruritus.²³ It has no established mutagenic potential, and thus may prove a valuable option for younger patients and those with impressive splenomegaly.¹⁹ A small case series of 11 patients found that the patients’ red cell indices could be normalized over six to 12 months with interferon therapy alone, and without evidence of thrombosis.²⁴ However, many patients discontinue interferon because of side effects, and the cost of treatment is high. ^23,25 Myelosuppressive treatment options are summarized in Table 4.^1,26,27

Reduction of platelet counts with anagrelide has been proposed as a treatment option for PV, as with other myeloproliferative disorders, but this option has not been thoroughly studied.^19,25 Targeting platelet function with aspirin remains another possibility. One PVSG protocol found that 300 mg of aspirin daily in conjunction with phlebotomy and dipyridamole (Persantine) was associated with an increased risk of gastrointestinal bleeding.¹⁴ However, a small GISP study randomized patients to low-dose aspirin (40 mg per day) or placebo and found no increased rates of bleeding or complications.¹ The use of low-dose aspirin is being investigated by the European Collaboration on Low-Dose Aspirin.^19,22,25

A risk-stratified approach to the management of PV is currently recommended (Table 5).¹ [Level of evidence: C, expert opinion] Patients treated with phlebotomy alone benefit from low rates of malignancy but experience more thrombosis events during the first few years of treatment. Patients treated with myelosuppressive agents and supplemental phlebotomy avoid this early thrombotic risk but in turn have significant rates of malignant transformation after about six years of therapy. Therefore, stratifying patients by age and risk of thrombosis is useful. High-risk patients are those 60 years or older, or those with a history of thrombosis. A myelosuppressive agent with supplemental phlebotomy is reasonable in this group. This group’s generally shorter life expectancy lessens the threat of eventual iatrogenic malignancy. Patients in this group stand to gain from the benefit of lower early thrombosis rates with myelosuppressive medications. Those considered at indeterminate risk are younger than 60 years and have no history of thrombocytosis, but do have cardiovascular or other risk factors.¹ Therapy in this group should be individualized, possibly with the addition of agents acting on platelet function or number. Finally, those considered low risk are younger than 60 years and have no thrombosis-related risk factors. Phlebotomy alone may be the treatment of choice with the goal of reducing the hematocrit level to less than 45 percent (0.45) or lower based on gender and race.^1,14,19,25 Consultation with a hematologist is recommended to apply such strategies, and newer agents may be tailored to patients on an individualized basis.

PV produces microvascular sequelae whose symptoms, while not life threatening, can be bothersome to patients (Table 1).^1,4 Because PV is rare, high-quality evidence supporting treatment is lacking. Pruritus, particularly after bathing (aquagenic pruritus) is a common symptom and various treatment options are available (Table 3^1,15–17). Symptoms such as transient neurologic disturbances may respond to low-dose aspirin therapy. Erythromelalgia is rare, occurring in approximately 3 percent of patients with PV. Low-dose aspirin typically is used, with myelosuppressive therapy reserved for those patients who do not respond.¹

Polycythemia | Boston Children’s Hospital

Polycythemia is a blood disorder occurring when there are too many red blood cells, which carry oxygen from the lungs through the blood stream to the rest of the body. The excess red blood cells cause the blood to increase in volume and thicken, keeping it from flowing easily.

Polycythemia can be divided into two overarching categories:

• Primary polycythemia, caused by overproduction of red blood cells by the bone marrow due to mutation or biological factor in the body.
• Secondary polycythemia, which is caused by factors that reduce the amount of oxygen reaching the body’s tissues, such as smoking, high altitude, or congenital heart disease. The red blood cells in some patients with secondary polycythemia may carry an abnormal form of hemoglobin that does not release oxygen readily (high-affinity hemoglobin).

There are three forms of primary polycythemia:

• polycythemia vera or primary bone marrow polycythemia, an adult disease of the blood-forming hematopoietic stem cells
• primary familial and congenital polycythemia, caused by genetic abnormalities or inappropriate levels of a hormone called erythropoietin (which triggers red blood cell production)
• newborn polycythemia, which is detected before or at birth and treated in a neonatal intensive care unit

Polycythemia | Symptoms & Causes

What are the symptoms of polycythemia?

Infants and children with polycythemia often have no visible symptoms. When they do appear, the most common symptoms include:

• deep reddish-purple coloring
• poor feeding
• tiredness or fatigue
• shortness of breath or breathing difficulty
• low blood sugar
• headache
• dizziness
• itchiness, especially following a warm bath or shower
• numbness, tingling, burning, or weakness in your hands, feet, arms, or legs

What causes polycythemia?

Polycythemia may be caused by an increase in a baby’s red cell production due to:

• chronically lowered oxygen levels
• some chromosomal abnormalities

Or it can be the result of extra blood cells entering the baby’s circulation due to:

• delay in clamping the umbilical cord after delivery
• twin-twin transfusion

Polycythemia is rare. Some babies may be at increased risk, including those born:

• at high altitudes (greater demand for blood to carry oxygen)
• after 42 weeks gestation
• small for gestational age or with intrauterine growth restriction (poor growth of the baby while in the womb)
• identical twins, who share a placenta and develop twin-twin transfusion syndrome
• to diabetic mothers
• with chromosomal abnormalities, including trisomy 18 and 13, and trisomy 21 (Down syndrome)

Polycythemia | Diagnosis & Treatments

How is polycythemia diagnosed?

In addition to a complete medical history and physical examination, diagnostic procedures for polycythemia may include:

• high red blood cell counts or hemoglobin levels
• genetic tests to determine what is causing increased red blood cell production

After all tests are completed, doctors will be able to outline the best treatment options.

How is childhood polycythemia treated?

Treatments for polycythemia can include:

• phlebotomy (withdrawal of blood through the veins)
• medication such as hydroxyurea to reduce blood cells
• low-dose aspirin

With secondary polycythemia, treatment usually focuses on the underlying cause.

How we care for polycythemia

Children with polycythemia are treated at the Blood Disorders Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, where children and young adults receive care from some of the world’s most experienced hematologists with deep experience in the conditions they treat.

Polycythemia | Research & Innovation

Our areas of research for polycythemia

New medications for adult polycythemia vera are currently in development. The results of these efforts, as well as of studies of the biology of adult polycythemia vera, may one day benefit children with other forms of polycythemia.

Clinical trials

For many children with rare or hard-to-treat conditions, clinical trials provide new options. Search our clinical trials database. If you’re not sure which clinical trials might be right for your child, email us at [email protected]. We can help you navigate your options.

Polycythemia | Programs & Services

Centers

Programs

Polycythemia | Contact Us

Diagnosis of latent polycythemia vera (clinician’s view)

WHO – World Health Organization

PI – polycythemia vera

KM – bone marrow

MPN – myeloproliferative neoplasm/neoplasia/tumor

OCE — volume of circulating erythrocytes

TO – thrombotic complications

EPO – erythropoietin

ET – essential thrombocythemia

BCSH – British Committee for Standards in Haematology; British Committee for Standardization in Hematology

Polycythemia vera (PV), or erythremia, Wakez’s disease, polycythemia vera is a clonal myeloproliferative neoplasm (neoplasia, tumor) – MPN, which is characterized by the proliferation of erythroid, granulocytic, megakaryocytic sprouts of myelopoiesis (panmyelosis), with predominant proliferation of the erythroid sprout of hematopoiesis, an increase the number of erythrocytes and hemoglobin, thrombocytosis, leukocytosis in peripheral blood (pancytosis), independence of erythropoiesis from normal regulatory mechanisms. Almost all patients are carriers of the JAK2V617 °F mutation or another functionally similar mutation [1].

According to the classification of the World Health Organization (WHO) of 2008, the diagnosis of PV should be established on the basis of a comprehensive assessment of the clinical picture and laboratory parameters. The leading diagnostic criterion is the hemoglobin content >165 g/l in women and >185 g/l in men [2]. In accordance with the criteria of the British Committee for Standards in Haematology (BCSH), in cases with borderline hemoglobin levels, the diagnosis of PV involves an assessment of hematocrit: >52% in men and >48% in women [3].

Hemoglobin concentrations and hematocrit serve as markers to indirectly determine the volume of circulating erythrocytes. As you know, the hemoglobin content and hematocrit are determined by the volume of circulating erythrocytes (OCE) and the volume of circulating plasma. The definition of OCE makes it possible to distinguish absolute erythrocytosis from relative erythrocytosis, the cause of which is a decrease in plasma volume. However, the importance of determining the BCE in the differential diagnosis of erythrocytosis cannot be overestimated. In I.P., in contrast to erythrocytosis caused by excessive production of erythropoietin (EPO), plasma volume is often increased. Because of this, the hemoglobin content and hematocrit increase to a lesser extent than OCE. In both men and women, an increase in hemoglobin concentration is not always associated with absolute erythrocytosis and, conversely, a low hemoglobin content can be observed with absolute erythrocytosis [4, 5]. Ignorance of this leads to the fact that the true cause of thrombosis of the hepatic and portal veins in patients with so-called myeloproliferative neoplasia, unclassified, remains unidentified [6].

The only reliable method for the differential diagnosis of absolute and relative erythrocytosis is to determine the mass of circulating erythrocytes – isotope dilution using the patient’s own erythrocytes labeled with ⁵¹ Cr [7]. However, this technique is not used in daily clinical practice, as it is laborious, expensive and has insufficient diagnostic accuracy.

The WHO classification presents the following model of the clinical course of PV [2].

The first stage of polycythemia (initial) is characterized by moderate erythrocytosis, low hemoglobin content and hematocrit. In some cases, PI can mimic essential thrombocythemia (ET). The spleen is slightly enlarged, but it usually cannot be palpated (the enlargement of the spleen is due to increased sequestration of platelets and erythrocytes in it).

The second stage of polycythemia (deployed, proliferative) is characterized by severe plethora, hepato- and splenomegaly. Erythrocytosis, thrombocytosis, leukocytosis with a shift of the leukocyte formula to the left are found in the blood.

The third stage of polycythemia (postpolycythemic myelofibrosis) is characterized by hepato-, splenomegaly, foci of extanodal hematopoiesis are found in them. Pancytopenia increases in the blood, and fibrosis of varying severity in the bone marrow (BM).

A number of researchers distinguish the initial stage of PV as a separate form of the disease: masked, in the process of evolution, latent, subclinical, smoldering, prepolycythemic, unrecognized / undiagnosed IP. Latent I.P. characterized by the presence of the JAK2V617 °F mutation, CM morphological features that meet the 2008 WHO criteria for PI, and a hemoglobin content below the diagnostic level (<185 g/l in men and <165 g/l in women). It is with this form of PV that diagnostic problems arise, since the disease proceeds with moderate erythrocytosis, without splenomegaly. About 30% of patients at diagnosis do not have leukocytosis and thrombocytosis. Differential diagnosis of latent PV is carried out with all nosological forms in the group of classical Ph-negative MPNs [8, 9].

Conducting retrospective studies on large samples of patients made it possible to identify the specific characteristics of latent PV. T. Barbui et al. [8] describe 140 patients with the JAK2V617 °F mutation and CM morphological features that meet the 2008 WHO criteria for PV, but with hemoglobin <15 g/l in men and <165 g/l in women. The control group consisted of 257 patients with PV, whose diagnosis met all the WHO classification criteria from 2008. At the time of diagnosis, there were statistically significant differences between latent and overt PV in the predominance of male patients, smokers, low hemoglobin and hematocrit, high thrombocytosis, low allelic load, high incidence of thrombotic complications (TO) in history in the study group. In patients with latent PV, compared with overt PV, a high incidence of arterial thrombosis was noted. There were no differences in age, leukocyte count, serum EPO, spleen size, frequency of venous thrombosis in the compared groups. The median follow-up was 3.8 years (0-29.8 years) with latent IP and 4.5 years (0-21.1 years) with overt IP. During the observation period, the frequency of TO development was the same in the compared groups. Latent I.P. was characterized by a rapid rate of progression with the development of postpolycythemic myelofibrosis, transformation into acute leukemia, and low overall survival. In multivariate analysis, the diagnosis of latent PV, age >65 years, and leukocytosis >10 10 ⁹ /l were independent factors for poor prognosis. The authors do not exclude the influence of epigenetic mechanisms that determine both the disease phenotype and the rapid progression of the disease [8].

F. Lussana et al. [10] conducted a retrospective analysis of a cohort of 538 MPN patients younger than 40 years of age with identified JAK2V617 °F mutation. After the revision of the diagnosis, taking into account the WHO classification of 2008, 97 (18%) patients met the criteria for PV, 66 (12%) were found to have latent PV, 375 (70%) were diagnosed with E.T. The median follow-up after diagnosis was 7.12 years (0–32.3 years) in the latent PV group, 7.89 years (0–39.8 years) in the overt PV group, 7. 25 years (0–26.8 years) in patients with E.T. During the observation period, in the entire cohort of patients, TOs were registered in 70 (13%) patients. Venous thromboses were observed more often than arterial thromboses — 47% and 34%, respectively ( p <0.001). The incidence of rhomboids in patients with latent PV was significantly higher than in patients with overt PV (3.01% of patients/year versus 1.99% of patients/year; p = 0.042) and ET (1.36% of patients/year). year). There were no differences in the incidence of thrombosis in groups of patients with overt PV and ET ( p = 0.278).

Patients received adequate treatment: 222 (41%) cytoreductive therapy, 175 (33%) phlebotomy and 430 (80%) antiplatelet agents. Cytoreductive therapy and phlebotomy in the group of patients with latent PV were used less frequently than in the group with overt PV ( p = 0.041), no differences were found in the use of antiplatelet agents. In order to determine the impact on the incidence of thrombosis of such factors as therapy, age and gender, a history of thrombosis, and the presence of risk factors for cardiovascular complications, a multivariate analysis was carried out. The only factor that increases the incidence of TO in patients with latent PV is less intensive therapy: the rare use of bloodletting and cytoreductive therapy in patients with latent PV. In this regard, the authors emphasize the need to isolate a latent IP in order to optimize treatment [10].

The purpose of this work was to identify latent PI as a separate nosological variant. In this regard, a comparative analysis of clinical characteristics in groups of patients was carried out: 1) extended PV; 2) with the JAK2V617 °F mutation, morphological signs of PV in the BM trephine biopsy, with a lower hemoglobin content than required according to WHO criteria.

Materials and methods

The study included 81 patients who applied to the outpatient department of the Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of the Russian Federation from 2014 to October 2015. The group consisted of 50 patients with overt PV and 31 patients with latent PV. The diagnosis was established in accordance with the WHO classification criteria of 2008. In the analyzed groups of patients, the distribution by sex was statistically comparable. Patients with overt PV are somewhat older than those with latent PV: the median age is 56 and 44 years, respectively.

Results

Between groups of patients with latent and overt PV, there are obvious differences in the number of erythrocytes – 5.37 10 ¹² / l (4.1-6.5 10 ¹² / l) versus 6.94 10 ¹² /l (5.4-8.8 10 ¹² /l), hemoglobin concentration — 148 g/l (100-167 g/l) versus 178 g/l (136-247 g/l) and hematocrit — 45% (30-52%) versus 53% (42-70%). The median platelet count is higher in the group of patients with latent PV compared with overt PV: median 644 10 ⁹ /l (179-1978 10 ⁹ /l) vs. 636 10 ⁹ /l (137-2437 10 ⁹ /l). There were no differences in the number of leukocytes in the compared groups. Molecular genetic study (qualitative analysis) was performed in all patients. All patients are carriers of the V617 °F mutation of the JAK2 gene. Determination of the allelic load JAK2V617 °F (quantitative analysis) was performed in 29 patients with latent PV and 37 with overt PV. The allelic load of JAK2 was significantly higher in the group of patients with overt PV compared with latent PV: a median of 14% (3-57%) and 55.5% (24-86%), respectively. The compared groups of patients differed in the incidence of thrombosis in history / at the time of diagnosis. In the case of latent PV, thrombosis was detected in 12 (38%) patients compared with 10 (16%) with extended PV. In the case of latent PV, predominantly venous thrombosis was detected, thrombosis of the abdominal vessels was often diagnosed. Arterial thrombosis was detected only in 4 cases. Clinical and laboratory characteristics of patients are presented in Table. 1

Table 1. Clinical and laboratory characteristics of patients with latent PV and extended PV MI – myocardial infarction; CVA is an acute cerebrovascular accident.

The morphological characteristics of the trephine biopsy of BM in patients with latent PV did not differ from that in patients with overt PV.

Talk

Differential diagnosis in the group of classical Ph-negative MPNs is carried out on the basis of anamnesis data, clinical and laboratory characteristics, and morphological examination of the BM trephine biopsy [11—16]. The large main diagnostic criterion for PI, indirectly reflecting the mass of circulating erythrocytes, according to the WHO classification from 2008, is the concentration of hemoglobin and hematocrit. In a number of cases, with morphological signs of PV, clinical or laboratory characteristics do not correspond to the diagnosis of PV [17]. The determination of EPO in blood serum can only serve as an additional diagnostic criterion, since EPO is below normal or subnormal in 60% of cases in patients with PV, and normal values ​​are found in undeniable cases of PV [18, 19].

The identified discrepancy between clinical laboratory and morphological characteristics was the reason for a number of clinical studies, which resulted in a revision of the diagnostic criteria for PV. In 2014, new diagnostic criteria for PV were proposed (Table 2) [20—22]. The first and most significant amendment is the reduction of the threshold diagnostic level of hemoglobin. Secondly, the hematocrit was introduced as an additional criterion for assessing the BCE. When comparing the WHO criteria based on hemoglobin concentration and the revised BCSH criteria, it was found that the BCSH criteria are more specific for the diagnosis of I.P. It is assumed that hematocrit is more specific than hemoglobin as an indicator of increased ECC [23]. Thirdly, the histological examination of the BM trephine biopsy has a leading diagnostic value, and can also play an important role in the differential diagnosis of PV with other MPN variants and reactive changes [24, 25].

Table 2. Diagnostic criteria for IP

Thus, in a number of patients with the JAK2V617 °F mutation, the histological picture of PV in the trephine biopsy of the BM (expansion of three hematopoietic lineages in different proportions – pancytosis), laboratory signs, in particular the hemoglobin content and hematocrit, do not meet the WHO diagnostic criteria of 2008 for I. P. This form of the disease (latent PV), as compared to overt PV, is characterized by a predominance among male patients, higher thrombocytosis, low white blood cell count, and a low allelic load of JAK2V617 °F. Our data correspond to the observations of foreign authors. The predominance of women in both the group with latent and overt PV in our study can be explained by the predominance of the number of women over men in the general population and the fact that women seek medical help more often, apparently due to a more attentive attitude to their health.

Statistical analysis of risk factors for the development of thrombohemorrhagic complications in latent PV and overt PV did not reveal any differences [26]. The results of our study showed that in patients with latent PV, the risk of developing TO is higher than with overt PV: 38% and 16% of cases, respectively. The same results confirm the data of F. Lussana et al. [10] on the predominance of venous thrombosis over arterial thrombosis in a group of young patients. It should be remembered that in the elderly, atherosclerosis is the most common cause of thrombosis. Young patients with MPN with borderline hemoglobin content without concomitant cardiovascular pathology are at low risk of developing thrombohemorrhagic complications. For this reason, observational treatment tactics are often chosen. According to the literature, the high incidence of thrombosis in patients with latent PV may be due to less intensive therapy. Due to the high risk of developing TO, recommendations for the treatment of patients with latent PV should not differ from recommendations for patients with overt PV, including those related to maintaining a hematocrit below 45% [27, 28].

According to the literature, latent PV is characterized by rapid progression and development of postpolycythemic myelofibrosis and transformation into acute leukemia [11-13]. However, it cannot be ruled out that latent IP may have a longer history before diagnosis compared to IP. This feature of the course of the disease can explain the low overall survival of patients with latent PV [8]. It is not possible to assess survival in our group of patients due to the short follow-up period.

Conclusion

The results of our study show that MPN with JAK2V617 °F mutation, borderline hemoglobin content, morphological features of BM trephine biopsy, characteristic of PV, represent a separate variant of PV — latent IP. Once again, it must be emphasized that the isolation of latent PV as a separate nosological variant is of great clinical importance, since, despite the non-compliance with all WHO criteria from 2008, patients have a high risk of developing thrombohemorrhagic complications, as well as patients with overt PV.

No conflict of interest.

Polycythemia vera: a new diagnostic concept and clinical forms

REVIEWS

diagnosis of polycythemia vera, polycythemia vera, myeloproliferative disease, forms of polycythemia vera

A.M. Kovrigina ¹ , V.V. Baikov ²

¹ Federal State Budgetary Institution “Hematological Research Center” of the Ministry of Health of Russia, Novy Zykovskiy pr-d, 4a, Moscow, Russian Federation, 125167

² Research Institute of Pediatric Oncology, Hematology and Transplantation named after R. M. Gorbacheva, SBEE HPE “First St. Petersburg State Medical University. acad. I.P. Pavlova” of the Ministry of Health of Russia, st. Rentgena, 12, St. Petersburg, Russian Federation, 197022

Correspondence : Alla Mikhailovna Kovrigina, Dr. Sciences, Professor, Novy Zykovsky pr-d., 4a, Moscow, Russian Federation, 125167; tel.: +7(495)612-61-12; e-mail: [email protected]

For citation: Kovrigina A.M., Baikov V.V. Polycythemia vera: a new concept of diagnosis and clinical forms. Clinical oncohematology. 2016;9(2):115–22.

DOI: 10.21320/2500-2139-2016-9-2-115-122

ABSTRACT

Polycythemia vera (PV) — clonal Ph-negative myeloprolifer active disease with excessive proliferation of 3 hematopoietic lineages and outcome in the stage of ineffective myelopoiesis. In the WHO classification (2008), hemoglobin and hematocrit are included in the main criteria for diagnosing the disease. However, in many patients with PV, the level of these indicators may be lower than the diagnostic level, which leads to underdiagnosis of this disease. Currently, three clinical forms of the disease have been identified: 1) masked (latent/prodromal), 2) classical (expanded), 3) PV with progression/transformation into myelofibrosis. Masked PV is the most difficult to diagnose. It is heterogeneous in terms of clinical and laboratory data, anamnesis, course of the disease; includes early stages , including those with high thrombocytosis, mimicking essential thrombocythemia, cases with abdominal thrombosis, as well as long-term latent PV. The most informative method for diagnosing the masked form of PV is the study of bone marrow trephine biopsy. Usually, the classic picture of PV is revealed: hypercellular bone marrow with a three-growth proliferation of myelopoiesis, proliferation of megakaryocytes with mild or moderate atypia and cell polymorphism. Determination of the degree of reticulin fibrosis has an important prognostic value and reflects the risk of progression/transformation to myelofibrosis. In the new edition of the WHO classification (2016), a morphological examination of bone marrow trephine biopsy will be included in the major criteria for diagnosing PV as mandatory for borderline values ​​of hemoglobin and hematocrit.

Key words: polycythemia vera, myeloproliferative disease, diagnosis of polycythemia vera, forms of polycythemia vera.

Received: Jan 19, 2016

Accepted: Feb 1, 2016

Read article in PDF

90 002 LITERATURE

1. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366. doi:10.1038/bcj.2015.95.
2. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90. doi 10.1056/nejmoa051113.
3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. cancer cell. 2005;7(4):387–97. doi: 10.1016/j.ccr. 2005.03.023.
4. Chloe J, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature. 2005;434(7037):1144–8. doi: 10.1038/nature03546.
5. Baxter EJ, Scott LM, Campbell PJ, et al. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The Lancet. 2005;365(9464):1054–61. doi: 10.1016/s0140-6736(05)71142-9.
6. Wang YL, Vandris K, Jones A, et al. JAK2 Mutations are present in all cases of polycythemia vera. Leukemia. 2008;22(6):1289. doi: 10.1038/sj.leu.2405047.
7. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90. doi: 10.1056/NEJMoa1311347.
8. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405. doi: 10.1056/NEJMoa1312542.
9. Broseus J, Park JH, Carillo S, et al. Presence of calreticulin mutations in JAK2-negative polycythemia vera. Blood. 2014;124(26):3964–6. doi: 10.1182/blood-2014-06-583161.
10. Fairbanks VF, Klee GG, Wiseman GA, et al. Measurement of Blood volume and Red Cell Mass: re-examination of 51Cr and 125I methods. Blood Cells Mol Dis. 1996;22(15):169–86. doi: 10.1006/bcmd.1996.0024.
11. Lorberboym M, Rahimi-Levene N, Lipszyc H, et al. Analysis of Red Cell Mass and Plasma Volume in Patients With Polycythemia. Arch Pathol Lab Med. 2005;129:89–91.
12. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol. 1999;36(1 Suppl 2):9–13.
13. Alvarez-Larran A, Ancochea A, Angona A, et al. Red cell mass measurement in patients with clinically suspected diagnosis of polycythemia vera or essential thrombocythemia. haematologica. 2012;97(11):1704–7. doi: 10.3324/haematol.2012.067348.
14. Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(3):285–93. doi: 10.1002/ajh.23135.
15. Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol. 2005;129(5):701–5. doi:-10.1111/j.1365-2141.2005.05517.x.
16. Thiele J, Kvasnicka HM, Orazi A, et al. Polycythaemia vera. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.pp. 40–43.
17. Silver RT, Chow W, Orazi A, et al. Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis. Blood. 2013;122(11):1881–6. doi: 10.1182/blood-2013-06-508416.
18. Berk PD, Wasserman LR, Fruchtman SM, et al. Treatment of polycythemia vera: a summary of clinical trials conducted by the polycythemia vera study group. In: Wasserman LR, Berk PD, Berlin NI, eds. Polycythemia Vera and the Myeloproliferative Disorders. Philadelphia: WB Saunders; 1995.pp. 166–94.
19. McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005;130(2):174–95. doi: 10.1111/j.1365-2141.2005.05535.x.
20. McMullin MF, Reilly JT, Campbell P, et al. Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis. Br J Haematol. 2007;138(6):821–2. doi: 10.1111/j.1365-2141.2007.06741.x.
21. McMullin MF. The classification and diagnosis of erythrocytosis. Int J Lab Hematol. 2008;30(6):447–59. doi: 10.1111/j.1751-553X.2008.01102.x.
22. Shih LY, Lee CT. Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay. Blood. 1994;83(3):744–8.
23. Thiele J, Kvasnicka HM, Diehl V. Initial (latent) polycythaemia vera with thrombocytosis mimicking essential thrombocythaemia. Acta Haematol. 2005;113(4):213–9. doi: 10.1159/000084673.
24. Thiele J, Kvasnicka HM. Diagnostic impact of bone marrow histopathology in polycythemia vera (PV). Histol Histopathol. 2005;20:317–28.
25. Kvasnicka HM, Thiele J. Prodromal myeloproliferative neoplasms: The 2008 WHO classification. Am J Hematol. 2010;85(1):62–9. doi: 10.1002/ajh.21543.
26. Barbui T, Thiele J, Gisslinger H, et al. Masked polycythemia vera (mPV): results of an international study. Am J Hematol. 2014;89(1):52–4. doi: 10.1002/ajh.23585.
27. Barbui T, Thiele J, Carobbio A, et al. Discriminating between essential thrombocythemia and masked polycythemia vera in JAK2 mutated patients. Am J Hematol. 2014;89(6):588–90. doi: 10.1002/ajh.23694.
28. Barbui T, Thiele J, Vannucchi AM, et al. Rethinking the diagnostic criteria of polycythemia vera. Leukemia. 2014;28(6):1191–5. doi: 10.1038/leu.2013.380.
29. Barbui T, Thiele J, Carobbio A, et al. Masked polycythemia vera was diagnosed according to WHO and BCSH classification. Am J Hematol. 2014;89(2):199–202. doi: 10.1002/ajh.23617.
30. Chu D, Cho Y-U, Jang S, et al. Straightforward Identification of Masked Polycythemia Vera Based on Proposed Revision of World Health Organization Diagnostic Criteria for BCR-ABL1-Negative Myeloproliferative Neoplasms. Ann Lab Med. 2015;35(6):651–3. doi: 10.3343/alm.2015.35.6.651.
31. Barbui T, Thiele J, Vannucchi AM, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015;5(8):e337. doi: 10.1038/bcj.2015.64.
32. Harrison CN, Campbell PJ, Buck G, et al. United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33–45.
33. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial.