Basics
Description
- Increase in hemoglobin (Hgb) above the normal range:
- Men: Hgb >17.5 g/dL, hematocrit (Hct) >52%
- Women: Hgb >16 g/dL, Hct >48%
- Symptoms are related to blood viscosity, which increases exponentially at Hct >60%.
Etiology
- Relative (apparent) polycythemia:
- Resulting from decrease in plasma volume
- Acute: Dehydration
- Chronic: Gaisbock syndrome (stress polycythemia): Obese, hypertensive, middle-aged smokers
- Primary erythrocytosis:
- Polycythemia vera (PV): A stem cell disorder characterized by panhyperplasia of all bone marrow elements leading to increased production of RBCs, WBCs, and platelets. Erythrocytosis is the most prominent feature:
- Mutation in the tyrosine kinase (JAK2), which acts in signaling pathways of the EPO-receptor, rendering those cells hypersensitive to erythropoietin
- Median age 60, 5% <40, peak in 70s
- Higher in Ashkenazi Jews and lower in Asians and African Americans.
- May progress to myelofibrosis or acute leukemia
- Secondary polycythemia:
- Central hypoxia increasing erythropoietin:
- Chronic pulmonary disease
- Sleep apnea (5 " “10% have high Hgb)
- Obesity hypoventilation syndrome (Pickwickian syndrome)
- Congenital heart disease (right-to-left shunt)
- High altitude (chronic)
- Smokers erythrocytosis
- Carbon monoxide poisoning (chronic)
- Chronic methemoglobinemia
- Renal-mediated causes of increased erythropoietin production:
- Renal cell carcinoma
- Renal artery atherosclerotic narrowing
- Focal glomerulonephritis
- Postrenal transplant with or without rejection
- Chronic hydronephrosis
- Polycystic kidney disease and renal cysts
- Inappropriate autonomous erythropoietin production:
- Hepatomas
- Cerebellar hemangioblastoma
- Wilms tumor
- Parathyroid carcinoma and adenoma
- Ovarian tumors
- Adrenal adenomas and carcinomas (pheochromocytoma, Cushing)
- Uterine leiomyomata
- Blood doping:
- Recombinant erythropoietin abuse
- Autologous transfusions
- Drug abuse:
- Chronic cocaine abuse
- Androgenic steroids
- Genetic disorders with polycythemia:
- High-affinity Hgb variants
- Bisphosphoglycerate deficiency
- von Hippel " “Lindau syndrome
- Chuvash polycythemia
- Erythropoietin-receptor mutations
- Congenital methemoglobinemia
- Infections:
Diagnostic Criteria for Polycythemia Vera
- Major criteria:
- Hgb >18.5 g/dL in men, >16.5 g/dL in women
- Presence of JAK2 mutation by polymerase chain reaction (PCR) " “ clinches the dx
- Oxygen saturation >92% and no other cause for secondary erythrocytosis
- Minor criteria:
- Low serum erythropoietin level
- Bone marrow aspirate and biopsy revealing panhyperplasia
- Adjuncts to diagnosis:
- Platelets >400,000/mm3
- ANC >10,000 (WBC >12,000/mm3)
- Splenomegaly on exam or by CT
- Leukocyte alkaline phosphatase elevation
- B12 >900 pg/mL; unbound vitamin B12-binding capacity >2,200 pg/mL
Diagnosis
Signs and Symptoms
History
- General:
- Dyspnea
- Weakness/fatigue
- Excessive sweating
- Epistaxis/gingival bleeding
- Pruritus (40% of PV):
- Generalized
- Exacerbated by warm bath or shower
- Excoriations common in PV
- Gouty arthritis and tophi
- Neurologic (hyperviscosity):
- Headache
- Vertigo/dizziness/tinnitus
- Lethargy/confusion
- Paresthesias
- Cerebrovascular accident/TIAs
- Visual (hyperviscosity):
- Amaurosis fugax
- Scotoma/blurred vision
- Ophthalmic migraine
- Cardiovascular:
- CHF
- Angina/myocardial infarction
- Deep vein thrombosis (DVT)
- Hypertension
- Extremities:
- Erythromelalgia:
- Secondary to capillary sludging
- Burning pain in the feet or hands
- Warmth, erythema/cyanosis and puffiness of hand and feet
- Acral paresthesias
- Worse at night
- Relief with cooling and aspirin
- Pulses intact
- Painful ulcers of fingers and toes (digital ischemia)
- GI (unique to PV):
- Hepatomegaly/splenomegaly
- Sudden spleen enlargement in known PV suggests development of myelofibrosis
- Epigastric discomfort/early satiety
- Peptic ulcer disease/GI bleed
- Budd " “Chiari syndrome (hepatic vein thrombosis): Ascites and peripheral edema
Physical Exam
- Hypertension
- Conjunctival suffusion
- Fundus: Venous engorgement
- Ruddy complexion/plethora
- Erythema/rubor of hands, feet, nail beds
- Skin excoriations from severe pruritus
- Splenomegaly (75% in PV)
- Hepatomegaly (30% in PV)
- Thrombotic complications:
- 2/3 arterial, 1/3 venous
- Cumulative risk of 2 " “5% per year
- TIAs, stroke, MI, digital infarcts
- Unusual venous thrombosis:
- Splenic or mesenteric veins
- Hepatic vein and IVC clot with subsequent cirrhosis/ascites (Budd " “Chiari syndrome)
- Cerebral sinus thrombosis
- DVT, PE
- Complications of hyperviscosity:
- Lethargy/confusion
- Headaches, dizziness, vision changes
- Crackles/findings of CHF
- Hemorrhagic complications:
- Ecchymosis
- Epistaxis
- Gingival bleeding
Essential Workup
CBC with platelets ‚
Diagnosis Tests & Interpretation
Lab
- 1st priority: Distinguish relative from true erythrocytosis:
- Volume repletion IV or PO, then repeat CBC
- 2nd priority: Evaluate for secondary causes:
- Pulse oximetry with pO2 <92%
- Carboxyhemoglobin level
- Erythropoietin level (normal or elevated if secondary)
- CXR, chest CT, pulmonary function tests
- Sleep study
- Hgb electrophoresis
- RBC mass:
- Cr-51 " “labeled RBCs by nuclear medicine
- Concomitant plasma volume with I-131 " “labeled albumin
- Not necessary if Hgb >18.5 in men, or >16.5 in women
- Red blood cell mass <35 mg/kg (males) or <31 mg/kg (females) is normal.
- Decreased plasma volume with normal RBC mass verifies relative erythrocytosis.
- Elevated RBC mass suggests PV or secondary polycythemia.
- Falsely low if iron deficient or obese
- PV suspected if:
- Hgb >18.5 g/dL (men), 16.5 g/dL (women)
- Absolute neutrophil count >10,000
- Platelet count >400,000
- Pulse oximetry >92%
- Low erythropoietin level " “ a major clue
- Vitamin B12 level elevated in 30% (unbound vitamin B12-binding capacity elevated in 75%)
- Uric acid elevated in 40%
- Leukocyte alkaline phosphatase elevated in 70%
- PCR for JAK2 gene mutation diagnostic of PV (seen in 97%)
Imaging
Abdominal US or CT can detect a splenomegaly ‚
Differential Diagnosis
See Etiology. ‚
Treatment
Initial Stabilization/Therapy
ABCs with emphasis on fluid resuscitation if no evidence of CHF ‚
Ed Treatment/Procedures
Emergency Management of Hyperviscosity Syndrome or Hct >60%
- Fluid resuscitation to achieve hemodilution:
- Withhold if evidence of CHF
- Emergency phlebotomy of 250 " “500 mL of blood over 1 " “2 hr replacing with an equal amount of 0.9% normal saline (NS)
- Removal of 1,000 " “1,500 mL of blood over 24 hr with a goal of Hct <60 or relief of symptoms:
- Keep Hct >45.
- Replace with an equal amount of 0.9% NS.
- Phlebotomize the elderly and those with cardiovascular disease more slowly:
- Every-other-day phlebotomy
- Emergent surgery with polycythemia:
- Phlebotomize to Hct of 45 to avoid thrombotic complications postoperatively.
- Thrombocytosis therapy:
- Administer aspirin if platelet count is 500,000 " “1,500,000/mm3 and there are no hemorrhagic complications.
- Treat pruritus with diphenhydramine.
Long Term Management
- Phlebotomy: Maintain Hct at 45% for men and 42% for women.
- Aspirin 81 mg daily if thrombocytosis
- Interferon-α (normalizes CBC in 80%):
- Especially helpful for refractory pruritus and painful splenomegaly
- Suggested in symptomatic patients <60 yr
- Anagrelide:
- Specific for thrombocytosis
- No risk of leukemia, ideal for younger patients with postphlebotomy thrombocytosis
- Effective alone and can decrease need for or frequency of chemotherapy
- Hydroxyurea:
- Mainstay of therapy, especially for patients >60 yr, with frequent phlebotomy requirements, thrombotic episodes, or refractory thrombocytosis
- Aldylating agents: Busulfan:
- Severe refractory disease in the elderly
- High risk of leukemic transformation
Temporary remission during pregnancy, no treatment usually needed ‚
- In the neonate, defined as a peripheral venous Hct >65%, Hgb >22 g/dL:
- Sample must be obtained >6 hr post delivery.
- Capillary Hgb and Hct are 10% higher than venous (always rely on venous)
- 1 " “5% of neonates
- Up to 50% of neonates with intrauterine growth retardation
- Etiology:
- Maternal " “fetal hypoxemia secondary to maternal heart or lung disease, diabetes, preeclampsia, hypertension, or smoking
- Delayed clamping of the umbilical cord with increase cord transfusion
- Symptoms and signs (most asymptomatic):
- Acrocyanosis/plethoric
- Tachypnea/respiratory distress
- Irritable, lethargic, jittery, poor feeding
- Hypoglycemia and hyperbilirubinemia common
- Treatment:
- Observation and serial CBCs
- 0.9 NS 100 mL/kg per day (symptomatic)
- Partial exchange transfusion: Remove 20 mL/kg blood and infuse equal amount of saline (persistent or severe symptoms)
- Dextrose solutions if hypoglycemia
Caution with speed of phlebotomy and fluid resuscitation as noted ‚
Follow-Up
Disposition
Admission Criteria
- New diagnosis of polycythemia
- Hct >60% without symptoms
- Symptoms of hyperviscosity
- Unstable vital signs/significant comorbidities
Discharge Criteria
- Previous diagnosis of polycythemia, Hct <60, and asymptomatic
- Stable vital signs
Issues for Referral
All patients should be referred to a hematologist or primary care physician. ‚
Pearls and Pitfalls
- Criteria for phlebotomy in polycythemia secondary to hypoxemia is not clear. While phlebotomy will decrease viscosity, it may decrease oxygen-carrying capacity.
- It is critical to distinguish PV from secondary causes of erythrocytosis since PV carries a high risk of thrombotic complications.
- Pruritus with water contact and erythromelalgia (pain, paresthesia and rubor in hands/feet) are unique features of PV.
Additional Reading
- Adams ‚ BD, Baker ‚ R, Lopez ‚ JA, et al. Myeloproliferative disorders and hyperviscosity syndrome. Emerg Med Clin North Am. 2009;27:459 " “476.
- Kremyanskaya ‚ M, Mascarenhas ‚ J, Hoffman ‚ R. Why does my patient have erythrocytosis? Hematol Oncol Clin North Am. 2012;26(2):267 " “283.
- Landolfi ‚ R, Nicolazzi ‚ MA, Porfidia ‚ A, et al. Polycythemia vera. Intern Emerg Med. 2010;5(5):375 " “384.
- McMullin ‚ MF. The classification and diagnosis of erythrocytosis. Int J Lab Hematol. 2008;30:447 " “459.
- Patnaik ‚ MM, Tefferi ‚ A. The complete evaluation of erythrocytosis: Congenital and acquired. Leukemia. 2009;23:834 " “844.
- Tefferi ‚ A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification and management. Am J Hematol. 2012;87(3):285 " “293.
Codes
ICD9
- 238.4 Polycythemia vera
- 289.0 Polycythemia, secondary
ICD10
- D45 Polycythemia vera
- D75.1 Secondary polycythemia
SNOMED
- 127062003 Erythrocytosis (disorder)
- 109992005 Polycythemia vera (disorder)
- 44865000 Secondary polycythemia (disorder)
- 389147003 Relative polycythemia (disorder)
- 36874002 Stress polycythemia (disorder)
- 48250002 Gaisbocks syndrome (disorder)