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Polycythemia Rubra Vera
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Polycythemia Rubra Vera
, Polycythemia Vera
Definitions
Polycythemia Rubra Vera
Excessive
Red Blood Cell
production due to chronic myeloproliferative neoplasm
Epidemiology
Men affected more than women
Age
Median age of onset: 60-64 years old
Under age 40 years old represent 20-25% of cases
Incidence
: 2.3 per 100,000 persons per year
Prevelance: 44-57 per 100,000 persons (U.S.)
Pathophysiology
Chronic myeloproliferative neoplasm (primary Polycythemia Vera)
Other common myeloproliferative disorders include
Essential Thrombocythemia
and
Myelofibrosis
Associated with
Janus Kinase
2 gene (JAK2) resulting in unregulated hematopoiesis
JAK2 V617F mutation (96% of polycythemia cases)
JAK2 exon 12 mutations (3% of polycythemia patients)
Primarily causes erythrocytosis
Also causes
Leukocytosis
and
Thrombocytosis
Excessive
Red Blood Cell
production (erythrocytosis)
Results in increased blood viscosity and
Blood Volume
Ultimately results in thrombosis
Risk Factors
Non-modifiable
Older age
Male gender
Caucasian
European descent
Modifiable
Tobacco Abuse
Obesity
Hypertension
Hyperlipidemia
Diabetes Mellitus
Differential Diagnosis
Primary Polycythemia or Erythrocytosis
Polycythemia Rubra Vera
2,3 Bisphosphoglycerate Deficiency (2,3 BPG Deficiency)
Lindau-Von Hippel Disease
Primary Familial and Congenital Polycythemia (EPOR)
Other myeloproliferative neoplasm
Essential
Thrombocytosis
or
Thrombocythemia
Primary
Myelofibrosis
Chronic Myelogenous Leukemia
Myelodysplastic Syndrome
Secondary Polycythemia or Erythrocytosis
Decreased plasma volume or hemoconcentration (e.g..
Dehydration
)
Living at high altitude
See
High Altitude Related-Conditions
Chronic heart or lung disease
Chronic
Hypoxia
Left to Right Shunt
Obesity Hypoventilation Syndrome
Pickwickian syndrome
Sleep Apnea
Drug-Induced or Toxin-Induced Polycythemia
Tobacco Abuse
(Smoker's Polycythemia)
Anabolic Steroid
s
Testosterone Replacement
Erythropoietin
Blood Doping
Methemoglobinemia
Chronic
Carbon Monoxide Poisoning
Renal Disease
Renal Artery Stenosis
Hydronephrosis
Renal Transplant
Erythropoietin
Secretin
g tumor
Hepatocellular Carcinoma
Renal Cell Carcinoma
Hemangioblastoma
Pheochromocytoma
Uterine Leiomyomata
Symptoms
Thrombotic event on presentation: 20-39% of cases
Cerebrovascular Accident
(CVA) or
Transient Ischemic Attack
(TIA)
Myocardial Infarction
Peripheral arterial thrombosis
Deep Vein Thrombosis
Portal Vein Thrombosis
or hepatic vein thrombosis (budd-chiari syndrome)
Constitutional symptoms
Fatigue
(88%)
Weight loss (31%)
Night Sweats
(52%)
Insomnia
Difficult Concentration
Weakness
Fever
(18%)
Gene
ralized symptoms
Pruritus
(62%)
Gene
ralized burning, itching or
Paresthesia
s
Onset often within 10 minutes and lasting for up to 40 minutes after provocative exposure
Provoked by bathing, especially in warm water (
Aquagenic Pruritus
)
Also provoked by
Temperature
changes,
Alcohol
,
Exercise
Bone pain (50%)
Gout
history
Microvascular
Occlusion
symptoms
Headache
Tinnitus
Dizziness
Visual disturbance
Transient Ischemic Attack
symptoms
Distal
Paresthesia
s
Acrocyanosis
Erythromelalgia
(29% of cases)
Vasomotor findings with extremity congestion, redness, burning pain
Improves with
Aspirin
Splenomegaly
related symptoms
Abdominal Pain
Early satiety
Weight loss
Nausea
Signs
See complications below
Splenomegaly
(35-45% of patients, especially in advanced Polycythemia Vera)
Plethoric facies
Ruddy facial
Cyanosis
Eyes
Retina
l vein engorgement
Conjunctiva
l small vessel injection
Labs
Red Blood Cell
related increases
Elevated
Hemoglobin A
nd
Hematocrit
(often found incidentally)
White men:
Hemoglobin
>18.5 mg/dl (
Hematocrit
>52%)
Black men:
Hemoglobin
>16 mg/dl (
Hematocrit
>47%)
Women: >16.5 mg/dl (
Hematocrit
>48%)
Elevated Red Blood Bell count
RBC Count
>36 ml/kg in men (>33 ml/kg in women)
Proliferation of other cell lines (50% of patients)
Platelet Count
(median): 400k/mm3
Leukocyte
count (median) 10.4k/mm3
Liver Function Test
s
LDH increased in 50% of patients
Diagnostic Testing (indicated for diagnosis after erythrocytosis found)
Janus Kinase
2 Mutation (JAK2 V617F mutation
Erythropoetin Level
Bone Marrow Biopsy
Fluorescence in situ hybridization
Karyotype
Diagnosis
2016 Revised WHO Criteria
Major Criteria (both required)
Increased red cell mass (erythrocytosis)
Precaution: May miss masked Polycythemia Vera who are JAK2+, but normal RBC mass
Men
Hemoglobin
>18.5 g/dl (WHO) or
Hematocrit
>52% (BCSH PVSG) or
RBC Count
>25% mean normal per WHO (e.g. >36 ml/kg)
Women
Hemoglobin
>16.5 g/dl (WHO) or
Hematocrit
>48% (BCSH PVSG) or
RBC Count
>25% mean normal per WHO (e.g. >33 ml/kg)
Bone Marrow Biopsy
with hypercellularity for age
Trilineage growth (erythroid, granulocytic, megakaryocytic) AND
Pleomorphic mature
Megakaryocyte
s
Minor Criteria (at least one required)
Janus Kinase
2 Mutation (JAK2 V617F mutation, JAK2 exon 12 mutation or similar)
Present in 98% of patients with Polycthemia Vera
Serum erythropoetin level below normal reference range
Present in 81% of patients with Polycthemia Vera
Test Sensitivity
: 70%
Test Specificity
: 90%
No obvious secondary polycythemia cause
Normal arterial
Oxygen Saturation
(>92%)
Interpretation
Polycythemia Vera is unlikely if JAK2 V617F negative AND
Erythropoietin
normal or high
All other JAK2 V617F and
Erythropoietin
results (with erythrocytosis) prompt
Bone Marrow Biopsy
Complications
Accelerated atherosclerotic and thrombotic disease
Cerebrovascular Accident
Myocardial Infarction
Peripheral Vascular Disease
Other rarely affected vessels
Mesenteric thrombosis
Hepatic vein thrombosis or
Portal Vein Thrombosis
Hemorrhage
and
Bleeding Diathesis
with extreme
Thrombocytosis
>1.5M (acquired
Von Willebrand Syndrome
)
Epistaxis
Acute
GI Bleed
Myeloproliferative Disease Progression (typically after 10 years of PCV)
Myelofibrosis
(20% of patients)
Acute Myeloid Leukemia
(5% of patients)
Management
Gene
ral
Myelosuppression and other red cell reduction management is not currative
Goals are to improve survival and improve quality of life, reduce symptoms and complications
No treatment to date has been shown to reduce progression to
Leukemia
or
Myelofibrosis
Monitoring
Repeat exam and labs (
Complete Blood Count
) every 3 to 6 months
Risk Factor Reduction
Tobacco Cessation
Goal: Keep
Hematocrit
below threshold
White men:
Hematocrit
<45%
Black patients and all women:
Hematocrit
<42% (some guidelines recommend <45% in all patients)
Phlebotomy reduces risk of thrombosis and improves survival
Marchioli (2013) N Engl J Med 368(1): 22-33 [PubMed]
Podoltsev (2018) Blood Adv 2(20): 2681-90 [PubMed]
Low risk (age <60 years old without prior thrombosis)
Repeated phlebotomy
Low dose
Aspirin
(40 to 100 mg)
Decreased risk of thrombotic events (MI, CVA, VTE) as well as decreased symptoms (e.g.
Headache
,
Pruritus
)
Avoid in severe
Thrombocytosis
(>1000 x10^9) due to risk of acquired
Von Willebrand Deficiency
Landolfi (2004) N Engl J Med 350(2): 114-24 [PubMed]
High risk (age >60 years old OR prior thrombosis, possibly
Leukocytosis
>10k/mm3)
First-line
Hydroxyurea
Adverse effects include
Anemia
,
Neutropenia
,
Oral Ulcer
s and
Skin Ulcer
s,
Hyperpigmentation
Leukemogenicity risk (
Exercise
caution in age under 40 years old)
Leukemic transformation 0.4% persons per year
Myelofibrosis
5% at five years, 33.7% at 10 years
Ferrari (2019) Hematologica 104(12): 2391-9 [PubMed]
Anticoagulation
and antiplatelet agent indications
Arterial Thrombosis history
Increase
Aspirin
to twice daily
Venous thrombosis history
Add
Anticoagulation
Refractory Course or Intolerance to
Hydroxyurea
(24% of patients)
Younger patients
Pegylated
Interferon Alfa-2B
Adverse effects include severe skin toxicity,
Asthenia
Kiladjian (2008) Blood 112(8): 3065-72 [PubMed]
Older patients (>70-80 years old) or advanced disease
Busulfan
(leukemogenicity risk)
Adverse effects include cytopenia
Douglas (2017) Leuk Lymphoma 58(1): 89-95 [PubMed]
Symptomatic massive
Splenomegaly
or severe symptoms
JAK2 Inhibitor (e.g.
Ruxolitinib
)
Higher risk of
Herpes Zoster
infection (6% of patients)
Vannucchi (2015) N Engl J Med 372(5): 426-35 [PubMed]
Management
Pruritus
Occurs in 68% of patients (severe in 15%)
Symptomatic Therapy
Aspirin
Antihistamine
s
Paroxetine
Oatmeal Bath
Refractory cases
Interferon Alfa-2B
Ruxolitinib
Narrow Band
Ultraviolet B
Phototherapy
References
Diehn (2001) Br J Haematol 115:619-21 [PubMed]
Management
Pregnancy
Polycythemia Vera is rare in pregnancy (<0.03 per 100,000)
Stop
Teratogen
ic medications (e.g.
Hydroxyurea
) at least 3 months before conception
If Myelosuppression is needed,
Interferon
-alpha is the preferred cytoreductive agent in pregnancy
Continue low dose
Aspirin
Maintain
Hematocrit
at
Gestational age
appropriate levels
Avoid
Iron Supplementation
unless low
Enoxaparin
(
Lovenox
) for first 6 weeks postpartum to prevent
Venous Thromboembolism
Prognosis
Gene
ral
Median survival in symptomatic patients
Survival without treatment: 6-18 months (up to 2 years)
Death is typically due to thrombosis
Survival with treatment: >8-10 years
Median survival if diagnosed before age 60 years: 24 years
Median survival with
Aspirin
and
Hydroxyurea
: 13.5 to 14.1 years
Median survival in age over 60 years with thrombosis history: 8.3 years
Malignant transformation or
Myelofibrosis
risk
Acute Myeloid Leukemia
or
Myelodysplastic Syndrome
risk in 15 years: 5 to 18%
Myelofibrosis
risk in 15 years: 6 to 14%
Factors associated with poor prognosis
Age over 60 years
Thrombosis history
Leukocytosis
Abnormal karyotype
High JAK2 levels
Cardiovascular Risk Factor
s (e.g.
Tobacco Abuse
,
Hypertension
,
Hyperlipidemia
,
Diabetes Mellitus
)
References
Tefferi in Schrier (2015) Clinical Manifestations and Diagnosis of Polycythemia Vera, UpToDate, accessed 12/15/2015
Tefferi in Schrier (2015) Prognosis and Treatment of Polycythemia Vera, UpToDate, accessed 12/15/2015
Fox (2021) Am Fam Physician 103(11): 680-7 [PubMed]
Griesshammer (2015) Ann Hematol 94(6):901-10 +PMID:25832853 [PubMed]
Stuart (2004) Am Fam Physician 69(9):2139-46 [PubMed]
Tefferi (2001) Am J Med 109:146 [PubMed]
Tefferi (2003) Mayo Clin Proc 78:174-94 [PubMed]
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