Introduction
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by the overproduction of red blood cells, often accompanied by increased white blood cell and platelet counts. This condition stems from the neoplastic proliferation of hematopoietic progenitor cells, frequently linked to a Janus kinase-2 (JAK2) mutation. The primary concern in polycythemia vera is the elevated blood viscosity, which heightens the risk of thrombotic events. Accurate Diagnosis Of Polycythemia is crucial for effective management and mitigating potential complications. This article provides a comprehensive overview of polycythemia vera, focusing on its diagnosis, and is tailored for expert automotive professionals who, while not medical practitioners, require a detailed understanding of various health conditions for context in related fields, such as understanding driver health and wellness.
Etiology of Polycythemia Vera
The fundamental cause of polycythemia vera is neoplastic proliferation within the bone marrow. This involves a signaling defect that leads to an abnormal cellular response to growth factors. The aberrant clonal cell line disrupts normal hematopoietic lineage proliferation. A key genetic factor in over 90% of polycythemia vera cases is the mutation of the Janus kinase-2 (JAK2) gene, which plays a vital role in intracellular signaling. Cytogenetic analyses reveal abnormal karyotypes in hematopoietic progenitor cells in approximately 34% of PV patients, with this percentage increasing over the duration of the disease.
Epidemiology of Polycythemia Vera
Polycythemia vera affects diverse ethnic groups and shows a slight predilection for men over women. Although it can manifest across all age ranges, the median age at diagnosis is around 60 years. The incidence of PV in the United States ranges from 0.6 to 1.6 cases per million people. Notably, Japan reports lower incidence rates compared to the United States and Europe. Understanding the epidemiology is important for recognizing the potential prevalence of this condition within broader populations.
Pathophysiology of Polycythemia Vera
In patients with polycythemia vera, the bone marrow contains both normal and abnormal clonal stem cells. The abnormal clonal stem cells dominate, suppressing the growth and maturation of normal stem cells. This unregulated neoplastic proliferation is the hallmark of panmyelosis in PV. The JAK2 kinase mutation, particularly the JAK2V617F mutation (a valine to phenylalanine substitution at position 617), leads to constitutively active cytokine receptors. This mutation is prevalent in over 90% of PV cases and is also found in a significant proportion of primary myelofibrosis and essential thrombocythemia cases. This pathological process results in excessive red blood cell and platelet production, leading to complications such as thrombosis and bleeding, which are critical aspects in the diagnosis of polycythemia.
Histopathological Findings in Polycythemia Vera
Peripheral blood smear findings in polycythemia vera vary depending on the disease stage. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are typically observed. Iron deficiency, if present, can lead to a hypochromic and microcytic pattern. Platelet and white blood cell counts may also be elevated. Leukocytosis, predominantly neutrophilic, can be present without blast activity. In the post-polycythemic stage, myelofibrosis may develop, characterized by teardrop red blood cells, poikilocytosis, and circulating nucleated red cells.
Bone marrow sampling generally reveals hypercellularity with panproliferation. Similar to peripheral blood findings, histopathology is stage-dependent. Erythrocytosis is seen in pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with fibrosis, ineffective production, and extramedullary hematopoiesis. These histopathological characteristics are vital in confirming the diagnosis of polycythemia.
Clinical Presentation and Symptoms
Symptoms of polycythemia vera are primarily related to hyperviscosity and thrombosis, which impair oxygen delivery throughout the body. Common physical complaints include fatigue, headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, itching triggered by water contact, particularly after a hot shower, is reported by about 40% of patients. This symptom is likely due to mast cell and basophil degranulation, causing a histamine release. Erythromelalgia, characterized by burning pain in the hands and feet with erythema or pallor, can also occur in PV and essential thrombocythemia, often responding well to low-dose aspirin. Bleeding events, such as epistaxis, gum bleeding, and gastrointestinal bleeding, and thrombotic events, including deep venous thrombosis (DVT), pulmonary embolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis, are significant complications. Early satiety is often due to splenomegaly, which impairs gastric filling. Gastrointestinal discomfort and peptic ulcer disease are also common, possibly due to increased histamine and increased blood viscosity in the gastrointestinal tract.
Physical examination may reveal plethora and flushing of the face and palms, conjunctival injection, and skin excoriations from pruritus. Splenomegaly and hepatomegaly are frequently observed. These clinical signs and symptoms are crucial indicators that prompt further investigation and are integral to the diagnosis of polycythemia.
Diagnostic Evaluation of Polycythemia Vera
Historical Diagnostic Criteria
In the 1970s, the Polycythemia Vera Study Group (PVSG) established the initial diagnostic criteria for polycythemia vera. According to these criteria, a diagnosis could be made if all three category A criteria were met, or if A1, A2, and two criteria from category B were present.
Category A (PVSG Criteria)
- Total red blood cell mass ≥ 36 mL/kg in males or ≥ 32 mL/kg in females
- Arterial oxygen saturation ≥ 92%
- Splenomegaly
Category B (PVSG Criteria)
- Platelet count > 400,000/microliter
- White blood cell count > 12,000/microliter
- Leukocyte alkaline phosphatase (ALP) score > 100 U/L
- Serum vitamin B12 > 900 pg/mL or unsaturated B12 binding capacity > 2200 pg/mL
However, the measurement of red blood cell mass, which required labeling with the 51Cr isotope, is no longer routinely available. Consequently, the PVSG guidelines have been largely replaced by more current diagnostic approaches.
Current WHO Diagnostic Criteria (2016 Revision)
The World Health Organization (WHO) published revised guidelines in 2016 for the diagnosis of polycythemia vera. These criteria consist of major and minor criteria. A diagnosis of PV can be established if either all three major criteria are met, or two major criteria and one minor criterion are fulfilled.
Major Criteria (WHO 2016)
- Hemoglobin level or Hematocrit:
- Hemoglobin > 16.5 g/dL or hematocrit > 49% in men, OR
- Hemoglobin > 16 g/dL or hematocrit > 48% in women, OR
- Red blood cell mass > 25% above mean normal predicted.
- Bone Marrow Biopsy: Demonstrating hypercellularity for age with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes.
- JAK2 Mutation: Presence of JAK2 V617F or JAK2 exon 12 mutation.
Minor Criteria (WHO 2016)
- Serum Erythropoietin Level: Subnormal serum erythropoietin level.
It is crucial to apply these criteria only after excluding secondary causes of polycythemia. The WHO criteria provide a more accessible and practical framework for the accurate diagnosis of polycythemia vera in contemporary clinical practice.
Treatment and Management Strategies
While there is no definitive cure for polycythemia vera, treatment aims to alleviate symptoms and reduce the risk of complications such as thrombosis, bleeding, and hematologic transformation. Currently, there are no methods to prevent progression to myelofibrosis or acute leukemia/myelodysplastic syndrome, but certain agents known to increase this risk should be avoided.
Medical Treatment Approaches
Treatment strategies are risk-stratified based on age and history of thrombotic events.
Low-Risk Patients: Patients under 60 years of age without a history of thrombosis are considered low risk. Treatment recommendations include:
- Phlebotomy: The primary treatment to reduce hematocrit levels to below 45%. Phlebotomy induces a mild iron deficiency, which limits erythropoiesis. Iron supplements should be avoided. Maintaining hematocrit below 45% significantly reduces cardiovascular and thrombotic events.
- Low-Dose Aspirin: Administered at 40 mg to 100 mg once or twice daily, if not contraindicated, to lower thrombotic risk. Aspirin is typically avoided in patients with platelet counts exceeding 1 million/microliter due to increased bleeding risk.
- Symptom Management: Addressing aspirin-refractory symptoms and optimizing cardiovascular health through weight loss, exercise, tobacco cessation, and blood pressure control.
High-Risk Patients: Patients 60 years or older or with a history of thrombosis are considered high risk. In addition to phlebotomy and aspirin, cytoreductive therapy is recommended.
- Hydroxyurea (HU): The first-line cytoreductive agent due to its safety, cost-effectiveness, and efficacy. Initial dosing is 15 mg/kg daily, aiming to reduce platelets to 100,000 to 400,000/microliter without causing excessive neutropenia or anemia. Dose adjustments should be made no more frequently than weekly.
- Second-line Agents: For patients intolerant or unresponsive to hydroxyurea, pegylated interferon, busulfan, ruxolitinib, anagrelide, pipobroman, and radioactive phosphorus are alternatives. Ruxolitinib, a JAK inhibitor, is FDA-approved for PV patients with inadequate response or intolerance to hydroxyurea, often achieving complete hematological remission.
Pruritus Management: Initial treatment includes antihistamines and selective serotonin reuptake inhibitors (SSRIs). For refractory cases, interferon-alpha (INF-α) or JAK2 inhibitors may be considered.
Surgical Treatment
- Splenectomy: May be considered for painful splenomegaly or recurrent splenic infarcts.
- Budd-Chiari Syndrome Management: Surgical interventions such as transjugular intrahepatic portosystemic shunt (TIPS) or other shunt procedures may be necessary for hepatic venous outflow thrombosis.
Differential Diagnosis of Polycythemia
The diagnosis of polycythemia vera requires distinguishing it from other conditions that cause erythrocytosis. Primary PV involves increased production in all three myeloid cell lines, not just red blood cells. Secondary polycythemia, often due to chronic hypoxia or erythropoietin-secreting tumors, is more common and must be ruled out. A rare erythropoietin (EPO) receptor mutation can mimic PV, but it involves EPO hypersensitivity rather than EPO independence. Isolated granulocytosis or thrombocytosis can arise from other causes like infections or iron deficiency, respectively.
Conditions in the differential diagnosis include:
- Essential thrombocythemia
- Chronic myelogenous leukemia
- Primary myelofibrosis
- Secondary polycythemia
- Agnogenic myeloid metaplasia
Toxicity and Adverse Effect Management
Managing adverse effects of treatments is crucial in polycythemia vera.
- Phlebotomy: In older patients and those with cardiovascular disease, smaller blood volumes should be removed per session to minimize orthostatic effects. Normal saline may be administered to replace volume. Patients should maintain hydration and avoid strenuous activity for 24 hours post-phlebotomy.
- Aspirin: High doses (>100 mg/day) increase bleeding risk, with very high doses (900 mg daily) associated with significant gastrointestinal bleeding.
- Hydroxyurea: Adverse effects include cytopenias, oral ulcers, GI upset, peripheral neuropathy, and rare pulmonary toxicity. Alternative cytoreductive agents should be considered if HU is not tolerated.
Prognosis of Polycythemia Vera
The prognosis of polycythemia vera has significantly improved with treatment. Untreated PV has an average survival of only 18 months, whereas treated patients have a median survival of 14 years overall, and up to 24 years if diagnosed before age 60. However, mortality in PV patients remains higher than in age- and sex-matched populations. Five-year survival rates are around 79.5%, but patients are at increased risk of second primary malignancies and leukemic transformation, which can affect long-term survival.
Complications of Polycythemia Vera
Complications from polycythemia vera, and consequently mortality, are primarily related to thrombosis, hemorrhage, peptic ulcer disease, myelofibrosis, acute leukemia, or myelodysplastic syndrome (MDS). Thrombosis is a major concern, and current treatments aim to minimize thrombotic risks. In the event of a thrombotic event, appropriate anticoagulation is necessary. Bleeding is also a common complication, although major bleeding is less frequent and is increased by severe thrombocytosis and high-dose aspirin or anticoagulation. Myelofibrosis can progress with the disease, and transformation to myelodysplasia or acute leukemia carries a poor prognosis.
Consultations and Specialist Involvement
Hematologist consultation is recommended for the management of polycythemia vera patients. Hematologists specialize in blood disorders and can provide expert guidance in diagnosis of polycythemia, treatment, and long-term management.
Deterrence and Patient Education
Patient education is crucial for managing polycythemia vera. Patients should understand that PV is a chronic condition requiring ongoing monitoring and treatment. Education should cover the importance of adherence to treatment plans, recognizing symptoms of complications, and the necessity of regular follow-up with a hematologist to mitigate risks of blood clots, bleeding, and blood cancers. Lifestyle modifications and awareness of symptoms are vital components of patient education.
Enhancing Healthcare Team Outcomes
Effective management of polycythemia vera relies on a collaborative interprofessional healthcare team, including general practitioners, hematologists, mid-level practitioners, nurses, and pharmacists. Initial symptoms are often vague, leading patients to first consult general practitioners. Recognizing the constellation of symptoms and abnormal hematologic labs is crucial for timely referral to a hematologist for further evaluation and diagnosis of polycythemia. Early and accurate diagnosis of polycythemia, followed by prompt treatment, significantly improves patient outcomes by reducing morbidity and mortality from disease complications. Open communication and collaboration within the interprofessional team are essential for optimal patient care in polycythemia vera.
References
1.Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kröger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A., European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011 Feb 20;29(6):761-70. [PMC free article: PMC4979120] [PubMed: 21205761]
2.Anía BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989. Am J Hematol. 1994 Oct;47(2):89-93. [PubMed: 8092146]
3.Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol. 1975 Oct;12(4):339-51. [PubMed: 1198126]
4.Johansson P. Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 2006 Apr;32(3):171-3. [PubMed: 16673273]
5.James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8. [PubMed: 15793561]
6.Spivak JL, Silver RT. The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal. Blood. 2008 Jul 15;112(2):231-9. [PubMed: 18401028]
7.Wasserman LR. The management of polycythaemia vera. Br J Haematol. 1971 Oct;21(4):371-6. [PubMed: 4941523]
8.Lelonek E, Matusiak Ł, Wróbel T, Szepietowski JC. Aquagenic Pruritus in Polycythemia Vera: Clinical Characteristics. Acta Derm Venereol. 2018 Apr 27;98(5):496-500. [PubMed: 29437189]
9.Saini KS, Patnaik MM, Tefferi A. Polycythemia vera-associated pruritus and its management. Eur J Clin Invest. 2010 Sep;40(9):828-34. [PubMed: 20597963]
10.Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, Randi ML, Vaidya R, Cazzola M, Rambaldi A, Gisslinger B, Pieri L, Ruggeri M, Bertozzi I, Sulai NH, Casetti I, Carobbio A, Jeryczynski G, Larson DR, Müllauer L, Pardanani A, Thiele J, Passamonti F, Barbui T. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013 Sep;27(9):1874-81. [PMC free article: PMC3768558] [PubMed: 23739289]
11.Michiels JJ. Erythromelalgia and vascular complications in polycythemia vera. Semin Thromb Hemost. 1997;23(5):441-54. [PubMed: 9387203]
12.Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol. 2013 Sep;162(6):730-47. [PubMed: 23855810]
13.Gilbert HS, Warner RR, Wasserman LR. A study of histamine in myeloproliferative disease. Blood. 1966 Dec;28(6):795-806. [PubMed: 5959473]
14.Accurso V, Santoro M, Raso S, Contrino AD, Casimiro P, Piazza FD, Perez A, Russo A, Siragusa S. Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study. Hematol Rep. 2019 Nov 29;11(4):8281. [PMC free article: PMC6902304] [PubMed: 31871612]
15.Streiff MB, Smith B, Spivak JL. The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members’ practice patterns. Blood. 2002 Feb 15;99(4):1144-9. [PubMed: 11830459]
16.Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. [PubMed: 27069254]
17.Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J. 2018 Jan 10;8(1):3. [PMC free article: PMC5802495] [PubMed: 29321547]
18.Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T., CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 03;368(1):22-33. [PubMed: 23216616]
19.van Genderen PJ, Mulder PG, Waleboer M, van de Moesdijk D, Michiels JJ. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol. 1997 Apr;97(1):179-84. [PubMed: 9136963]
20.Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015 Feb;90(2):162-73. [PubMed: 25611051]
21.Büyükaşık Y, Ali R, Turgut M, Saydam G, Yavuz AS, Ünal A, Ar MC, Ayyıldız O, Altuntaş F, Okay M, Çiftçiler R, Meletli Ö, Soyer N, Mastanzade M, Güven Z, Soysal T, Karakuş A, Yiğenoğlu TN, Uçar B, Gökçen E, Tuğlular T. Patterns of Hydroxyurea Prescription and Use in Routine Clinical Management of Polycythemia Vera: A Multicenter Chart Review Study. Turk J Haematol. 2020 Aug 28;37(3):177-185. [PMC free article: PMC7463219] [PubMed: 32075363]
22.Slakey DP, Klein AS, Venbrux AC, Cameron JL. Budd-Chiari syndrome: current management options. Ann Surg. 2001 Apr;233(4):522-7. [PMC free article: PMC1421281] [PubMed: 11303134]
23.Tefferi A, Spivak JL. Polycythemia vera: scientific advances and current practice. Semin Hematol. 2005 Oct;42(4):206-20. [PubMed: 16210034]
24.Arcasoy MO, Degar BA, Harris KW, Forget BG. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood. 1997 Jun 15;89(12):4628-35. [PubMed: 9192789]
25.Ruggeri M, Rodeghiero F, Tosetto A, Castaman G, Scognamiglio F, Finazzi G, Delaini F, Micò C, Vannucchi AM, Antonioli E, De Stefano V, Za T, Gugliotta L, Tieghi A, Mazzucconi MG, Santoro C, Barbui T., Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) Chronic Myeloproliferative Diseases Working Party. Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood. 2008 Jan 15;111(2):666-71. [PubMed: 17909074]
26.Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T., European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004 Jan 08;350(2):114-24. [PubMed: 14711910]
27.CHIEVITZ E, THIEDE T. Complications and causes of death in polycythaemia vera. Acta Med Scand. 1962 Nov;172:513-23. [PubMed: 14020816]
28.Khanal N, Giri S, Upadhyay S, Shostrom VK, Pathak R, Bhatt VR. Risk of second primary malignancies and survival of adult patients with polycythemia vera: A United States population-based retrospective study. Leuk Lymphoma. 2016;57(1):129-33. [PubMed: 26159045]
29.Ruggeri M, Gisslinger H, Tosetto A, Rintelen C, Mannhalter C, Pabinger I, Heis N, Castaman G, Missiaglia E, Lechner K, Rodeghiero F. Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol. 2002 Sep;71(1):1-6. [PubMed: 12221665]
