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Polycythemia Vera

PV

Polycythemia vera is a rare chronic myeloproliferative disorder.

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Presentation

An increase in red cell mass is the primary feature of polycythemia vera (PV) [4] [8] [10]. Bone marrow analysis, however, shows a proliferation of all three myeloid lines: erythrocytes, granulocytes and platelets. The onset of polycythemia vera is often insidious. Early symptoms are related to blood hyperviscosity due to polycythemia. Decreased blood flow and thrombosis result in hypoxia [8] [10] [11]. Patients often present with either arterial or venous vascular occlusive events [10].

Presenting non-specific symptoms of polycythemia vera are related to hypoxia and include [10]:

The signs and symptoms found in individuals diagnosed with polycythemia vera include [9] [10]:

  • Elevated red blood cell mass >25%
  • Erythrocytosis, hematocrit >60 males, >56 females
  • Leukocytosis >10.9/ml
  • Thrombocytosis, platelet count >400,000/ml
  • Splenomegaly and splenic infract
  • Thrombotic and hemorrhagic complications
  • Vasomotor disturbances
  • Pruritus
  • Elevated Vitamin B12 level
  • Plethora, a ruddy complexion of face, palms, nail beds, mucosa, and conjunctiva, due to the increased total red blood cell count.

Thrombosis and bleeding are frequent in persons with polycythemia vera. These complications are the result of the increased red blood cell count and elevated platelet count [9] [10] [19]. Bleeding is seen in approximately 1% of patients, epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding [8] [10]. Peptic ulcer disease occurs with polycythemia vera due to increased histamine levels and resulting gastric acidity. This causes abdominal pain, abnormal feeling of fullness, and anorexia. Weight loss may result [9].

Erythromelalgia is a syndrome specific to polycythemia vera. It increases the risk of thrombosis. The symptoms are burning pain in the feet, hands, toes and fingers, sometimes associated with pallor, erythema, or cyanosis. Occasionally, it progresses to gangrene. This can be treated with aspirin (50-300 mg/d) and dipyridamole (75 mg orally 3 times a day) [11] [15].

Pruritus also results from increased histamine levels due to increased basophils and mast cells. This occurs in up to 40% of patients with polycythemia vera [9]. Splenomegaly is present in 75% of patients at the time of diagnosis, hepatomegaly in approximately 30% of patients [10] [16].

Easy Bruising
  • Individuals, who demonstrate signs and symptoms, have the following: Trouble breathing, feeling weak and tired Easy bruising and bleeding Severe, throbbing headache Skin appears red, or skin color changes due to lack of oxygen (blue) Visual problems,[dovemed.com]
  • Conditions where the body makes too many of these cells are known as myeloproliferative neoplasms . 0002027 Acute leukemia 0002488 Angina pectoris 0001681 Bruising susceptibility Bruise easily Easy bruisability Easy bruising Having too many red blood[rarediseases.info.nih.gov]
  • These symptoms are associated with a decrease in the red blood cells (anemia) Pain or fullness below the ribs on the left side, as a result of an enlarged spleen Poor appetite Enlarged liver Pale skin Easy bruising or bleeding Flat, red, pinpoint spots[cancersupportcommunity.org]
Splenomegaly
  • During multivariable analysis, leukocytosis 15 10 9 /l, palpable splenomegaly and grade 1 BM reticulin fibrosis remained significant.[ncbi.nlm.nih.gov]
  • I follow up patients monthly until normalization of their blood cell counts or splenomegaly, and afterwards every 2 months with visit, cell blood count and blood smear evaluation.[ncbi.nlm.nih.gov]
  • […] with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea.[ncbi.nlm.nih.gov]
  • In time myelofibrosis occurs Myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume; associated frequently with splenomegaly, leukocytosis[icd9data.com]
  • DISEASE OVERVIEW: Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding[ncbi.nlm.nih.gov]
Palpable Spleen
  • Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%).[ncbi.nlm.nih.gov]
  • A 50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients.[ncbi.nlm.nih.gov]
  • Polycythemia Vera Signs and symptoms Symptoms related to expanded blood volume and increased viscosity Headache, tinnitus, dizziness, blurred vision, TIAs, and fatigue Generalized pruritus (aquagenic) Engorged retinal veins Palpable spleen (75%) Thrombosis[slideshare.net]
  • spleen N (%) 16 (55) 14 (42) 0.316 Cardiovascular risk factors N (%) 16 (53) 20 (57) 0.758 Previous thrombosis N (%) 5 (17) 9 (26) 0.376 Globally, 87% of the patients treated with peg-INF responded (26/30), with a CR rate of 70% (21/30).[jhoonline.biomedcentral.com]
Fatigue
  • Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with[ncbi.nlm.nih.gov]
  • A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%).[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 68-year-old Caucasian woman, with a history of cigarette consumption and obstructive sleep apnoea syndrome (undergoing continuous positive airway pressure treatment) had presented to our institution with fatigue and a hemoglobin level[ncbi.nlm.nih.gov]
  • In 2009, 10 years after the diagnosis, while the patient was still being treated with hydroxyurea and phlebotomies, he noticed worsening of general conditions and fatigue, and the appearance of night sweats; he also reported that his spleen volume had[ncbi.nlm.nih.gov]
  • Low rates of constitutional symptoms were reported in this physician-based survey with concentration problems, fatigue and itching being the main PV-related symptoms.[ncbi.nlm.nih.gov]
Weakness
  • , tingling, burning or weakness in your hands, feet, arms or legs A feeling of fullness or bloating in your left upper abdomen due to an enlarged spleen Fevers Unexplained weight loss When to see a doctor Make an appointment with your doctor if you have[mayoclinic.com]
  • Headaches Double vision or seeing dark or blind spots that come and go Itching all over the body, especially after being in warm or hot water Reddened face that looks like a blush or sunburn Weakness Dizziness Weight loss for no known reason[seattlecca.org]
  • When left untreated, these headaches can intensify, leading to dizziness, lightheadedness, and overall feelings of weakness. If these feelings become a part of your daily routine, be sure to talk to your doctor. ADVERTISEMENT[activebeat.com]
  • Symptoms include lack of energy (fatigue) or weakness, headaches, dizziness, shortness of breath, visual disturbances, nose bleeds, bleeding gums, heavy menstrual periods, and bruising.[urmc.rochester.edu]
Weight Loss
  • Palpable splenomegaly is one of the worst offenders since it contributes to early satiety, bloating, pain, portal hypertension, weight loss, and exacerbation of cytopenia.[medpagetoday.com]
  • Headaches Double vision or seeing dark or blind spots that come and go Itching all over the body, especially after being in warm or hot water Reddened face that looks like a blush or sunburn Weakness Dizziness Weight loss for no known reason[seattlecca.org]
  • This is especially true for cytokine-driven items (night sweats, bone pain, weight loss) and abdominal-related complaints (abdominal discomfort, weight loss) in patients in the PV-HU subgroup.[jco.ascopubs.org]
  • loss When to see a doctor Make an appointment with your doctor if you have signs or symptoms of polycythemia vera.[mayoclinic.com]
Burning Pain
  • Doctors can also treat the itchy skin and burning pain that you may experience. Living with polycythemia vera PV is a serious illness that can cause death, especially if it is not treated. There is currently no cure for PV.[familydoctor.org]
  • Common signs and symptoms include itching (pruritus), and severe burning pain in the hands or feet that is usually accompanied by a reddish or bluish coloration of the skin. Patients with polycythemia vera are more likely to have gouty arthritis.[en.wikipedia.org]
  • Aspirin can help relieve symptoms related to the high platelet counts, such as migraines that affect vision and burning pain and redness of the hands and feet.[merckmanuals.com]
  • Low-dose aspirin may also help reduce burning pain in your feet or hands.[checkorphan.org]
  • The symptoms are burning pain in the feet, hands, toes and fingers, sometimes associated with pallor, erythema, or cyanosis. Occasionally, it progresses to gangrene.[symptoma.com]
Plethora
  • PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice. 2014 by The American Society of Hematology.[ncbi.nlm.nih.gov]
  • TABLE 1 Signs and Symptoms of Polycythemia Vera 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[aafp.org]
  • Plethora or a ruddy complexion is characteristic of PV and results from the marked increase in total red blood cell mass. This manifests in the face, palms, nailbeds, mucosa, and conjunctiva. Hypertension is common in patients with PV.[emedicine.medscape.com]
  • […] mass 25% Erythrocytosis, hematocrit 60 males, 56 females Leukocytosis 10.9/ml Thrombocytosis, platelet count 400,000/ml Splenomegaly and splenic infract Thrombotic and hemorrhagic complications Vasomotor disturbances Pruritus Elevated Vitamin B12 level Plethora[symptoma.com]
  • […] the tyrosine kinase ( JAK2 ) gene, which acts in signaling pathways of the EPO-receptor, making those cells proliferate independent from EPO. [12] Diagnosis [ edit ] Physical exam findings are non-specific, but may include enlarged liver or spleen, plethora[en.wikipedia.org]
Hepatomegaly
  • Less common symptoms associated with polycythemia vera include a tendency to bruise easily, frequent nosebleeds or bleeding from the gums, enlargement of the liver (hepatomegaly), and erythromelalgia, a condition characterized by a reddened or purplish[rarediseases.org]
  • […] 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[aafp.org]
  • […] liver is one of the organs that does it mostly when you're a little baby and a child but it's supposed to stop that when you get older, but the liver will be told to keep on producing these cells causing it to become big as well and causing you to have hepatomegaly[khanacademy.org]
  • Hepatomegaly is present in approximately 30% of patients. Plethora or a ruddy complexion is characteristic of PV and results from the marked increase in total red blood cell mass. This manifests in the face, palms, nailbeds, mucosa, and conjunctiva.[emedicine.medscape.com]
Headache
  • One visible symptom of polycythemia vera are headaches, according to this research from the National Institutes of Health . By reducing blood flow to the brain, painful headaches can become quite common.[activebeat.com]
  • Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with[ncbi.nlm.nih.gov]
  • A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%).[ncbi.nlm.nih.gov]
  • The presenting symptoms are frequently vague and consist of fatigue, headaches, dizziness, bleeding, pruritus, dyspepsia, and thrombosis.[medlink.com]
  • Headaches Double vision or seeing dark or blind spots that come and go Itching all over the body, especially after being in warm or hot water Reddened face that looks like a blush or sunburn Weakness Dizziness Weight loss for no known reason[seattlecca.org]
Stroke
  • Copyright 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. KEYWORDS: Stroke; intracranial stenosis; microembolic signals; polycythemia vera[ncbi.nlm.nih.gov]
  • PURPOSE: To report the case of a 49-year-old man who presented with profound visual loss in his right eye because of a central retinal artery occlusion, accompanied by a stroke in the ipsilateral middle cerebral artery with left upper extremity sequelae[ncbi.nlm.nih.gov]
  • The increased number of blood cells can cause bleeding problems and form clots causing serious health problems such as stroke or heart attack.[seattlecca.org]
  • They also cause complications, such as blood clots, which can lead to a heart attack or stroke. Polycythemia vera isn't common. It usually develops slowly, and you might have it for years without knowing.[mayoclinic.com]
Dizziness
  • Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with[ncbi.nlm.nih.gov]
  • A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%).[ncbi.nlm.nih.gov]
  • The presenting symptoms are frequently vague and consist of fatigue, headaches, dizziness, bleeding, pruritus, dyspepsia, and thrombosis.[medlink.com]
  • Do you sometimes feel dizzy or weak? Have you had shortness of breath? Do you sweat a lot at night? You may get some blood tests, too. These include: Complete blood count (CBC).[webmd.com]
Vertigo
  • Clinical description Symptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva.[orpha.net]
  • Many patients have neurologic symptoms such as headaches, dizziness or vertigo, visual problems, and paresthesias at the time of diagnosis.[medlink.com]
  • Common symptoms of PV include: Headache Sweating Ringing in the ears Blurred vision or blind spots Dizziness or vertigo Reddish or purplish skin Unexpected weight loss Bleeding or clotting Early feeling of fullness (satiety) Itching (pruritis), especially[mpnresearchfoundation.org]
  • Subsequent sludging of blood flow and thrombosis lead to poor oxygen delivery, with symptoms that include the following: Headache Dizziness Vertigo Tinnitus Visual disturbances Angina pectoris Intermittent claudication Bleeding complications, seen in[emedicine.medscape.com]
  • It may initially present with non-specific symptoms of decreased oxygen supply such as: headache, dizziness, vertigo, and angina. Other individuals will not be diagnosed until they experience a major blood clotting event.[symptoma.com]
Burning Sensation
  • As the disease progresses, symptoms include: Shortness of breath Dizziness Itchy or flushed skin Fatigue Headaches A tingling or burning sensation in the hands and feet What causes polycythemia vera? PV begins in the bone marrow.[familydoctor.org]
  • sensation in the hands and feet Polycythemia Vera Prevention Polycythemia vera cannot be prevented.[healthcommunities.com]
  • People may have redness and burning sensations in the hands and feet. More rarely, bone pain may be felt. A blood clot sometimes causes the first symptoms.[merckmanuals.com]
  • Your doctor may advise you to take aspirin to relieve bone pain and the burning sensation in hands or feet that you may experience as a result of PV. Aspirin also reduces the chance of blood clots.[daviddarling.info]
  • Erythromelalgia can also cause a painful, burning sensation or swelling of the affected areas.[rarediseases.org]
Abdominal Pain
  • Abdominal pain due to peptic ulcer disease may be present because PV is associated with increased histamine levels and gastric acidity or possible Budd-Chiari syndrome (hepatic portal vein thrombosis) or mesenteric vein thrombosis.[emedicine.medscape.com]
  • This causes abdominal pain, abnormal feeling of fullness, and anorexia. Weight loss may result. Erythromelalgia is a syndrome specific to polycythemia vera. It increases the risk of thrombosis.[symptoma.com]
  • The study also examined the symptoms associated with PV (ie, itching, night sweats, burning in the skin, headaches, abdominal pain from the spleen, fatigue, and weakness) and found that those also significantly improved with ruxolitinib treatment.[hematologyandoncology.net]
  • The most commonly reported side effects include headaches, fast or forceful heart beat (palpitations), diarrhoea, weakness, fluid retention, nausea, dizziness, abdominal pain and shortness of breath.[leukaemia.org.au]
Nausea
  • A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%).[ncbi.nlm.nih.gov]
  • Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients.[ncbi.nlm.nih.gov]
  • , autoimmunity, hyperlipidemia Psychiatric disease, cardiovascular disease Radioactive phosphorus ( 32 P) Radiopharmaceutical Anemia, thrombocytopenia, leukopenia, Leukemia may develop after treatment Diarrhea, fever, nausea, emesis — Busulfan (Myleran[aafp.org]
  • Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures.[ncbi.nlm.nih.gov]
  • The most commonly reported side effects include headaches, fast or forceful heart beat (palpitations), diarrhoea, weakness, fluid retention, nausea, dizziness, abdominal pain and shortness of breath.[leukaemia.org.au]
Early Satiety
  • Weight loss may result from early satiety or from the increased myeloproliferative activity of the abnormal clone.[emedicine.medscape.com]
  • Palpable splenomegaly is one of the worst offenders since it contributes to early satiety, bloating, pain, portal hypertension, weight loss, and exacerbation of cytopenia.[medpagetoday.com]
  • Patients in the PV-S subgroup were most likely to have abdominal-related complaints, including early satiety and weight loss, and were least likely to have fatigue.[jco.ascopubs.org]
  • Splenomegaly usually results in secondary symptoms, including abdominal pain, early satiety, weight loss, and nausea, and complications can lead to abdominal organ compression and portal hypertension [ 3 ].[link.springer.com]
Vomiting
  • Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures.[ncbi.nlm.nih.gov]
  • […] aphasia) Sudden blurred, double or decreased vision Sudden dizziness, loss of balance or loss of coordination A sudden, severe headache or an unusual headache, which may or may not be accompanied by a stiff neck, facial pain, pain between your eyes, vomiting[checkorphan.org]
  • The most frequently reported drug-related AEs across all grades were diarrhea (44 %); nausea (29 %); increased creatinine (21 %); and anemia, vomiting, and fatigue (9 % each); there were no grade 4 AEs.[link.springer.com]
Loss of Appetite
  • An enlarged spleen may also cause pressure on the stomach causing a feeling of fullness, indigestion and a loss of appetite. In some cases the liver may also be enlarged.This is called hepatomegaly.[leukaemia.org.au]
Bleeding Gums
  • Symptoms include lack of energy (fatigue) or weakness, headaches, dizziness, shortness of breath, visual disturbances, nose bleeds, bleeding gums, heavy menstrual periods, and bruising.[urmc.rochester.edu]
  • gums Excessive menstrual bleeding Hemoptysis (coughing up blood) Bruising Itchy skin, particularly after a hot bath Gout Numbness High blood pressure Blood clots also can occur, resulting in a heart attack, stroke, or pulmonary embolism.[hopkinsmedicine.org]
  • gums burning feeling in your hands or feet Most of these symptoms can be caused by other conditions as well, so getting a proper diagnosis from your doctor is critical.[healthline.com]
Hypertension
  • Abstract In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age 65 years[ncbi.nlm.nih.gov]
  • The major symptoms are related to hypertension or to vascular abnormalities caused by the increased red cell mass. The cause is unknown. With currently available treatment, the median survival exceeds 10 years.[icd9data.com]
  • 2018 - New Code 2019 Billable/Specific Code Applicable To Group 5 pulmonary hypertension Pulmonary hypertension with unclear multifactorial mechanisms Pulmonary hypertension due to hematologic disorders Pulmonary hypertension due to metabolic disorders[icd10data.com]
  • […] teardrops Platelets, often abnormal Marrow Myeloids Panmyelosis, erythroid hyperplasia, atypical megas Panmyelosis, atypical megas Megas Marrow fibrosis Varies In spent phase In fibrotic phase Minimal Splenomegaly Clinical Presentation /Other B symptoms Hypertension[surgpathcriteria.stanford.edu]
Chest Pain
  • Let’s See if this Goes Away In 2009, after almost two weeks of terrible radiating chest and neck pain (I am one of those “see if it goes away” people) I called my GP whom I had been seeing for my various complaints. chest pain He called me at home one[pvreporter.com]
  • pain Changes to these diagnostic criteria have been proposed.[aafp.org]
  • A blood clot can cause a stroke, chest pain (angina), a heart attack, deep vein thrombosis (DVT) or a pulmonary embolism. DVT occurs when a blood clot forms in the legs may cause the legs to become painful and swollen.[rarediseases.org]
  • You need to contact your doctor immediately if you experience the following symptoms: shortness of breath or difficulty breathing, swollen ankles, fast or irregular heartbeat, and/or chest pain.[leukaemia.org.au]
Cyanosis
  • Primary polycythemia; Polycythemia rubra vera; Myeloproliferative disorder; Erythremia; Splenomegalic polycythemia; Vaquez's disease; Osler's disease; Polycythemia with chronic cyanosis; Erythrocytosis megalosplenica; Cryptogenic polycythemia Kremyanskaya[medlineplus.gov]
  • Primary polycythemia; Polycythemia rubra vera; Myeloproliferative disorder; Erythremia; Splenomegalic polycythemia; Vaquez's disease; Osler's disease; Polycythemia with chronic cyanosis; Erythrocytosis megalosplenica; Cryptogenic polycythemia Polycythemia[mountsinai.org]
Bone Pain
  • Symptoms may include: Abnormal and heavy bleeding due to a cut or a nosebleed Intense and frequent bone pain and/or muscle pain Headaches, lightheadedness or gastrointestinal symptoms Vision problems Ringing in the ears Difficulty or labored breathing[uvahealth.com]
  • This 19 item instrument includes a previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment.[clinicaltrials.gov]
  • Despite advances in therapy, the PV symptom burden remains undermanaged , with symptoms such as fatigue, pruritus, night sweats, bone pain, fever, and undesired weight loss resulting in poor quality of life, noted the investigators.[medpagetoday.com]
  • pain, fevers, and weight loss.[jco.ascopubs.org]
Tinnitus
  • Polycythemia Vera Signs and symptoms Symptoms related to expanded blood volume and increased viscosity Headache, tinnitus, dizziness, blurred vision, TIAs, and fatigue Generalized pruritus (aquagenic) Engorged retinal veins Palpable spleen (75%) Thrombosis[slideshare.net]
  • Clinical description Symptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva.[orpha.net]
  • Symptoms of Polycythemia Vera Frequent headaches and a feeling of pressure in the head Dizziness and ringing in the ears (tinnitus) Fatigue Blurred or double vision Flushed or itching skin Night sweats Shortness of breath Itchy or flushed skin Frequent[healthcommunities.com]
  • Some people with polycythemia vera experience headaches, dizziness, ringing in the ears (tinnitus), impaired vision, or itchy skin. Affected individuals frequently have reddened skin because of the extra red blood cells.[ghr.nlm.nih.gov]
Blurred Vision
  • Polycythemia Vera Signs and symptoms Symptoms related to expanded blood volume and increased viscosity Headache, tinnitus, dizziness, blurred vision, TIAs, and fatigue Generalized pruritus (aquagenic) Engorged retinal veins Palpable spleen (75%) Thrombosis[slideshare.net]
  • Others might have: Itchiness, especially following a warm bath or shower Headache Dizziness Bleeding or bruising, usually minor Weakness Fatigue Blurred vision Excessive sweating Painful swelling of one joint, often the big toe Shortness of breath Numbness[mayoclinic.com]
  • Symptoms Symptoms of PV may include: Fatigue and/or weakness Headache Dizziness Shortness of breath and difficulty breathing while lying down Visual disturbance, such as double vision, blurred vision, and blind spots Inability to concentrate Night sweats[hopkinsmedicine.org]
Visual Impairment
  • Presenting non-specific symptoms of polycythemia vera are related to hypoxia and include: Headache Dizziness Visual impairment Tinnitus Angina pectoris The signs and symptoms found in individuals diagnosed with polycythemia vera include: Elevated red[symptoma.com]
Pruritus
  • Abstract Aquagenic pruritus is one of the main clinical features of polycythemia vera. The aim of this study was to analyse the clinical characteristics of aquagenic pruritus.[ncbi.nlm.nih.gov]
  • Christelle Le Gall-Ianotto and Laurent Misery , Pruritus in Hematological Diseases (Including Aquagenic Pruritus) , Pruritus , 10.1007/978-3-319-33142-3_36 , (271-281) , (2016) .[doi.org]
  • A detailed MEDLINE search for all English language articles related to PV, PV-associated pruritus and aquagenic pruritus that were published from 1965 till date was carried out.[ncbi.nlm.nih.gov]
  • The sudden onset and limited duration of the pruritus might suggest an activation or release of some humoral factor(s). In a controlled study we showed that aspirin alleviates this particular pruritus.[ncbi.nlm.nih.gov]
  • Management of pruritus Pruritus, sometimes aquagenic, is one of the most annoying, but not necessarily life-threatening complications of PV.[doi.org]
Erythema
  • The symptoms are burning pain in the feet, hands, toes and fingers, sometimes associated with pallor, erythema, or cyanosis. Occasionally, it progresses to gangrene.[symptoma.com]
  • […] present in 30% to 50% of PV patients. 14 Symptoms more specific to PV include: Pruritus, especially after warm baths or showers (aquagenic pruritus; reported by 70% of patients) 15 Erythromelalgia, or a burning pain in the feet or hands accompanied by erythema[mpncanada.com]
Urticaria
  • Soter , Acute and chronic urticaria and angioedema , Journal of the American Academy of Dermatology , 25 , 1 , (146) , (1991) . JULIA A. NEWTON, A.K. SINGH, M.W. GREAVES and C.J.F.[doi.org]
Chronic Urticaria
  • Soter , Acute and chronic urticaria and angioedema , Journal of the American Academy of Dermatology , 25 , 1 , (146) , (1991) . JULIA A. NEWTON, A.K. SINGH, M.W. GREAVES and C.J.F.[doi.org]
Epistaxis
  • Bleeding complications occur in 1% of patients with polycythemia vera and include epistaxis, gum bleeding, ecchymoses, and gastrointestinal bleeding.[symptoma.com]
  • […] 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[aafp.org]
  • […] thrombosis lead to poor oxygen delivery, with symptoms that include the following: Headache Dizziness Vertigo Tinnitus Visual disturbances Angina pectoris Intermittent claudication Bleeding complications, seen in approximately 1% of patients with PV, include epistaxis[emedicine.medscape.com]

Workup

The presence of the Janus kinase-2 (JAK2 V617F) mutation is diagnostic for polycythemia vera [4] [5] [12]. However, 2-3% of patients are negative for this genetic marker [12] [13]. The absence of the Janus kinase-2 mutation combined with a normal or increased serum erythropoietin level, excludes the diagnosis [9]. These patients have secondary erythrocytosis rather than polycythemia vera [5] [12].

Diagnostic criteria for polycythemia vera according to the World Health Organization guidelines require the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria [12] [14].

Major criteria [10] [12] [13]:

  • Elevated red cell mass >25% or Hemoglobin > 18.5 g/dL (Hematocrit >60) in men and > 16.5 g/dL (Hematocrit >56) in women
  • Presence of Janus kinase-2 mutation

Minor criteria [10] [12] [13]:

  • Palpable splenomegaly
  • Decreased serum erythropoietin level 
  • Bone marrow biopsy showing erythroid, granulocytic, and megakaryocytic proliferation 
  • Endogenous erythroid colony formation in vitro

Laboratory studies suggested for evaluation of polycythemia vera [2] [4] [12] [13]:

  • Janus kinase-2 mutation analysis
  • Direct measurement of the red blood cell mass is often not possible
  • Complete blood count: Red blood cell counts with hematocrit and hemoglobin levels, Red blood cells are generally normochromic and normocytic, White blood cell count (>12,000/µL) primarily neutrophils with a left shift, Platelet count is elevated to 400,000-800,000/µL
  • Serum erythropoietin level 
  • Erythroid progenitor cell assay
  • Leukocyte alkaline phosphatase (LAP) is elevated (>100 U/L)
  • Routine coagulation tests are usually normal
  • Vitamin B-12 levels elevated to > 900 /mL
  • Oxygen saturation (SaO2) and carboxyhemoglobin (COHb) levels
  • Iron studies

Imaging 

An enlarged spleen is often palpable and in such cases, imaging studies are not required [12] [13]. Ultrasonography or computed tomography scans may be able to detect splenic enlargement that was not evident on physical examination [12].

The diagnosis of Budd-Chiari syndrome is made using ultrasonography, computed tomography scan and magnetic resonance imaging [18].

Other tests

Bone marrow studies are not necessary to establish the diagnosis of polycythemia vera [2] [4]. They are important in identifying transformation to acute leukemia [4] [5]. Patients should be followed monthly until normalization of blood cell counts and splenomegaly, then every 2 months for complete blood count and blood smear evaluation [5].

Erythrocytosis
  • Unexpectedly, the symptom of erythrocytosis disappeared after the surgery. Further examination and analysis were performed, and we finally attributed his erythrocytosis to chromophobe renal cell carcinoma.[ncbi.nlm.nih.gov]
  • Abstract My diagnostic approach in case of isolated erythrocytosis is based on the visit and the interview of patients, and on checking the causes of secondary erythrocytosis.[ncbi.nlm.nih.gov]
  • Examination of her arterial blood gases found only a slight hypoxemia; erythropoietin and ferritin levels were very low and could not explain a secondary erythrocytosis.[ncbi.nlm.nih.gov]
  • The survey focused on 3 aspects of PV care: diagnosis, treatment of erythrocytosis, and treatment of thrombocytosis.[doi.org]
  • A significant minority of physicians undertreat erythrocytosis, and little consensus exists regarding the treatment of thrombocytosis.[ncbi.nlm.nih.gov]
Thrombocytosis
  • Hydroxyurea (62.8%) and anagrelide (35.4%) were the primary agents used to treat thrombocytosis.[ncbi.nlm.nih.gov]
  • Therapy for thrombocytosis in polycythemia vera Considerably less uniformity was noted among physicians regarding treatment of thrombocytosis.[doi.org]
  • CONCLUSIONS This case report illustrates that insufficient platelet inhibition with clopidogrel monotherapy in a patient with thrombocytosis may be associated with recurrent arterial thrombosis.[ncbi.nlm.nih.gov]
  • In addition, presence of extreme thrombocytosis (platelets 1000 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.[ncbi.nlm.nih.gov]
  • Abstract The occurrence of myocardial infarction in myeloproliferative disease is mostly attributed to coronary thrombosis due to hyperviscosity and thrombocytosis.[ncbi.nlm.nih.gov]
Vitamin B12 Increased
  • Polycythemia Vera Laboratory findings Elevated Hct – often 60% Increased WBCs and platelets Serum EPO levels are low Decreased iron stores (Ferritin) Increased Vitamin B12 Increased uric acid Presence of the JAK2 mutation Hypercellular bone marrow 5.[slideshare.net]
Hypercellular Bone Marrow
  • Polycythemia Vera Laboratory findings Elevated Hct – often 60% Increased WBCs and platelets Serum EPO levels are low Decreased iron stores (Ferritin) Increased Vitamin B12 Increased uric acid Presence of the JAK2 mutation Hypercellular bone marrow 5.[slideshare.net]

Treatment

The goal of treatment for polycythemia vera is to control myeloproliferation [10] [15] and decrease the risk of arterial and venous thrombotic events, which occur in approximately 20% of patients [2] [9]. The optimum management plan is unclear. Significant differences exist among physicians about the appropriate management of the disease [2]. Consultation with and management by a hematologist is recommended [5].

General guidelines for the management of polycythemia vera include [2] [5] [9] [15]:

  • Maintain a hematocrit of 44% or less is the target
  • Minimize the risk of transformation to acute leukemia and myelofibrosis
  • Manage complications such as thrombosis and hemorrhage

Medical management:

  • Phlebotomy alone is the first choice
  • A combination of phlebotomy and hydroxyurea
  • Hydroxyurea alone, (interferon, 32P or busulfan are used infrequently)
  • Low-dose aspirin
  • Treatment of thrombocytosis recommended for platelet counts above 400,000

All patients with polycythemia vera require phlebotomy to keep their hematocrit levels below 44% [5] [15]. This treatment removes excess red blood cells and lowers blood viscosity [10]. Patients can be phlebotomized once or twice a week [5] [10]. Elderly patients with cardiovascular or cerebral vascular conditions should have volume replaced with saline solution after each procedure to avoid postural hypotension [10]. Chemotherapy and phlebotomy can decrease the risk for thrombotic events [11].

Patients with this disorder should routinely take low-dose aspirin, 81 mg daily [5]. Low-dose aspirin suppresses thromboxane biosynthesis resulting from increased platelets and essential thrombocythemia [5] [11]. Treatment with aspirin may also reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes, pulmonary embolism, or major venous thrombosis [10] [11]. The incidence of major bleeding episodes was not significantly increased with aspirin [11].

Patient at high risk for thrombosis should have drug therapy to decrease blood cell production. Hydroxyurea at a starting dose of 500 mg twice daily is the most commonly used agent. It is an effective agent for myelosuppression [5]. It reduced the risk of thrombosis when compared with phlebotomy [5]. It should be the drug of choice for patients older than 40 years [6]. However, there are concerns that it may increase the long-term risks of leukemic transformation [6]. 

Interferon-alpha can be used as an alternative [9] [10]. Studies have shown that treatment with this drug was not as effective when compared with hydroxyurea. However, interferon alfa 2b had a lower transformation rate and no severe hematological adverse effects [8].

Busulfan is also an option for patients older than 65 years of age who do not respond to hydroxyurea [10].

Ruxolitinib (Jakafi), a Janus-associated kinase inhibitor, is the first US Food and Drug Administration drug approved specifically for polycythemia vera [1]. It is approved for use in patients with polycythemia vera who cannot tolerate or had an inadequate response to hydroxyurea [1]. Patients who received ruxolitinib had a significant reduction in splenomegaly [12] [13].

Once the patient's red blood cell values are reduced periodic phlebotomies or a myelosuppressive agent should be continued to maintain disease control [5] [10].

Splenectomy should be only considered in patients with painful splenomegaly or splenic infarction [10] [11]. Treatment of Budd-Chiari syndrome includes portal or mesenteric-systemic shunting, catheter-directed thrombolysis, and liver transplantation [18].

Prognosis

Untreated polycythemia has a very poor prognosis. The median survival in untreated patients is 1.5-3 years. Treated this may be extended to at least 10-20 years [1]. Thrombosis is the leading cause of death [10]. Thrombotic complications including stroke and other arterial thromboses occur in ~1% of patients. The risk of thrombosis depends on age of the patient and their past history of thrombosis. Patients older than 60 years or with a previous history of thrombosis are considered at high risk [1] [10].

Bleeding complications occur in ~ 1% of patients with polycythemia vera and include epistaxis, gum bleeding, ecchymoses, and gastrointestinal bleeding [8].

The long-term risks of polycythemia vera include leukemic and fibrotic transformation occurring in 5-10% of patients [8] [9] [15]. Studies have suggested an increased risk for all neoplasms with the use of chemotherapic agents in polycythemia vera.

Etiology

Vaquez is credited with the initial description of polycythemia vera in 1892. The clinical features were first described by Osler in 1903 [2]. In 1967, the Polycythemia Vera Study Group identified criteria for diagnosis and treatment of the disease [2] [5].

The etiology of all the myeloproliferative disorders is unknown [3]. The cause of the symptoms of polycythemia vera is an uncontrolled blood cell proliferation [4] [12] [13]. The abnormal cell production is a mutation in the Janus kinase-2 gene [13]. The cause if this mutation is unknown. Virtually all patients with polycythemia vera have the mutation. The discovery of the Janus kinase-2 gene mutation has improved the diagnosis of polycythemia vera [13].

The mean age of incidence of polycythemia vera is 50-70 years [8], but it can occur in all age groups, although rarely in childhood [7] [14]. Familial cases are very rare usually in elderly family members [7].

The severity of polycythemia vera and the rate of progression vary from patient to patient [8]. All myeloproliferative disorders, including polycythemia vera, are pre-leukemic as they can transform to acute leukemia over time. The rate of leukemic transformation in polycythemia vera is 5-10% of patients [8] [15].

Epidemiology

Polycythemia vera is relatively rare, affecting in 0.6-1.6/million population [10]. The disorder can occur at any age, but it has a median age at onset of 60 years [10]. Studies have shown that this condition concerns all ethnic groups [1]. Polycythemia vera occurs almost equally in both sexes [12], though a few studies have found that slightly more males than females are affected [2].

Sex distribution
Age distribution

Pathophysiology

Myeloproliferative disorders like polycythemia vera are hematopoietic stem cell malignancies [3] [8]. Abnormal stem cells present in the bone marrow of patients with polycythemia vera suppress normal stem cell maturation [12].

These abnormal blood stem cells respond aberrantly to growth factors [4]. A mutation on the Janus kinase-2 gene (JAK2) is the most likely gene involved in polycythemia vera [4] [6] [12]. It is thought that the defect alters the signal from growth enzymes to the stem cells [12]. Polycythemia vera stem cells are hypersensitive to erythropoietin and hematopoietic growth factors [8]. This mutation occurs in most (> 80%) polycythemia vera patients [6]. The mutation leads to tyrosine phosphorylation activation that causes cytokine hypersensitivity that induces erythrocytosis [6] [8].

Serum levels of erythropoietin are normal or subnormal in polycythemia vera patients, therefore the hyperproliferation is not stimulated extrinsically and the disease is classified as a primary polycythemia [8].

In polycythemia vera excessive red blood cells are produced in the bone marrow [1]. Patients may also experience an increase in white blood cells and platelets [1]. These blood cells show no cytogenetic abnormality, all blood cells produced are normal [8]. The overabundance of blood cells causes splenomegaly, bleeding problems, and thrombosis [1] [14]. Studies have shown that hematocrits above 44 are associated with an increased number of thromboembolic events [2].

Thrombotic events in polycythemia vera are the result of the increased viscosity of the blood due to the excessive numbers of blood cells. Increased thromboxane synthesis occurs as well due to thromboxane-dependent platelet activation [11]. This is a major cause of the increased risk of thrombosis. Low-dose aspirin suppresses the production of thromboxane by platelets in patients with high platelet counts and [11].

A paradoxical bleeding or hemorrhagic tendency occurs with high platelet counts that resembles acquired Von Willebrand disease in patients with polycythemia vera[16].

As in all the myleoproliferative disorders, polycythemia vera may progress to blood malignancies such as acute leukemia and myleofibrosis [9]. Transformation rates are estimated to be 10-20% [9] [10]. Leukemic transformation of polycythemia vera can be influenced by pharmacotherapy such as alkylating agents [10]. Acute leukemia is thought to be a part of the natural course of polycythemia vera [11].

Budd–Chiari syndrome, obstruction and occlusion of the suprahepatic veins, is a rare life-threatening complication in polycythemia vera [7]. It is the result of thrombosis within the vasculature of the liver[18].

Differential diagnoses for polycythemia vera include [7] [9]:

Prevention

A cause for the development of the Janus kinase-2 genetic mutation is unknown, therefore there is no way to prevent its occurrence.

Phlebotomy, myelosuppressive drugs, and anticoagulants can prevent thrombosis, stroke, liver and renal damage, and other cardiovascular events [10] [11]. Studies have shown that low dose aspirin (81 mg/d) is effective for preventing thrombosis without causing bleeding [11].

Summary

Polycythemia vera is a chronic myeloproliferative stem cell disorder [1] [2]. It is one of several acquired myeloproliferative diseases that are considered malignant bone marrow disorders [1] [3] [4]. Polycythemia vera and the other myeloproliferative diseases are relatively uncommon [5].

The primary characteristic of polycythemia vera is an elevated absolute red blood cell count due to uncontrolled red blood cell production [2]. Panmyelosis may also be seen as increased white blood cell and platelet production [1] [2]. Other characteristic features of polycythemia vera are splenomegaly, a predisposition to venous/arterial thrombosis, and bleeding [6]. It can eventually progress to myelofibrosis, and acute leukemia [2].

Polycythemia vera arises from acquired mutations in a hematopoietic stem cell [7] [8]. The mechanisms accounting for the development of these mutations are poorly understood [8]. The genetic mutations of polycythemia vera usually occurs sporadically, but occasional familial cases have been reported [7]. The median age at diagnosis of polycythemia vera is 60 years of age [11]. It is a progressive disease and approximately 5% of patients progress to acute leukemia [9] [10].

The rise in red blood cell load in polycythemia vera results in hyperviscosity of the blood and subsequent circulatory disturbances. The primary cause of death is acute cardiovascular or cerebrovascular events [11].

Patient Information

What is polycythemia vera ?

Polycythemia vera is a chronic disease of blood cell producing stem cells of the bone marrow. The overproduction of red blood cells, primarily, white blood cells and platelets occur because of a genetic mutation of these stem cells. The median age at diagnosis is 60 years of age. Although disease itself is not fatal, death will occur within 1 ½ to 3 years from cardiovascular complications of blood clot formation.

What are the symptoms?

Polycythemia vera is often asymptomatic at first. It may initially present with non-specific symptoms of decreased oxygen supply such as: headache, dizziness, vertigo, and angina. Other individuals will not be diagnosed until they experience a major blood clotting event.

The clinical signs of the disorder are:

  • Elevated red blood cell count; hematocrit over 60
  • Elevated white blood cell and platelet count
  • Enlarged spleen
  • Tendency for abnormal clotting

What causes polycythemia vera?

The cause is a mutation of the Janus Kinase-2 gene that is responsible for the regulation of blood cell production. Because of this mutation blood cell production is excessive. The extreme number of circulating blood cells causes the blood to be more viscous increasing the risk of blood clot formation.

Who gets polycythemia vera?

Polycythemia vera can occur at any age, however it is rare in individuals younger than 40 years of age. Mean age at onset is 60 years.

How is it diagnosed?

The definitive diagnosis of polycythemia vera is made when the Janus Kinase-2 gene mutation is detected. Routine blood tests will show an excessive increase in red blood cells, white blood cells, and platelets.

How is polycythemia vera treated?

Polycythemia vera is treated primarily with periodic phlebotomy, blood-letting, to remove excessive blood cells and reduce blood viscosity. Myelosupressive medications, such as Hydroxyurea, reduce blood cell production. All patients are also given low-dose aspirin to prevent clotting.

What are the complications?

The complications of polycythemia vera are due to abnormal clotting and include:

  • Stroke
  • Pulmonary emboli
  • Myocardial infarct
  • Circulatory compromise in the extremities
  • Obstructive liver disease
  • Obstructive renal damage

How can it be prevented?

Since a cause of the Janus kinase-2 genetic mutation is unknown, there is no way to prevent polycythemia vera. Phlebotomy, myelosuppressive drugs, and anticoagulants can prevent the complications of the disease and extend life expectancy.

References

Article

  1. Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol. 1975;12(4):339-51.
  2. 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;99(4):1144-9.
  3. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-8.
  4. Vannucchi AM, Guglielmelli P, Tefferi A. Advances in Understanding and Management of Myeloproliferative Neoplasms. Cancer J Clin. 2009;59:171-191.
  5. Passamonti F. How to manage polycythemia vera. Leukemia. 2012; 26(5):870-4.
  6. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol. 1994;52(3):134-9.
  7. Cario H, Pahl HL, Schwarz K, et al. Familial polycythemia vera with Budd–Chiari syndrome in childhood. British Journal of Haematology, 2003, 123, 346–352.
  8. Pahl HL. Towards a molecular understanding of polycythemia rubra vera. Eur. J. Biochem. 2000;267, 3395-3401.
  9. Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk-stratificati on. American Journal of Hematology. 2012; 87:285 293.
  10. McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/ erythrocytosis. British Journal of Haematology. 2005;, 130, 174–195.
  11. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350(2):114-24.
  12. Kralovics R, Teo SS, Buser AS, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood. 2005;106(10):3374-6.
  13. Guglielmelli P, Barosi G, Pieri L, Antonioli E, Bosi A, Vannucchi AM. JAK2V617F mutational status and allele burden have little influence on clinical phenotype and prognosis in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis. Haematologica. 2009;94(1):144-6.
  14. Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol. 1986;23(2):132-43.
  15. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. New Eng J Med. 2013;368(1):22-33.

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Last updated: 2018-06-22 06:21