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Polycythemia, Emergency Medicine

Basics

Description

- 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

- General: - Dyspnea - Weakness/fatigue - Excessive sweating - Epistaxis/gingival bleeding - Pruritus (40% of PV): - Generalized - Exacerbated by warm bath or shower - Excoriations common in PV

- 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

- Epigastric discomfort/early satiety - Peptic ulcer disease/GI bleed - Budd " “Chiari syndrome (hepatic vein thrombosis): Ascites and peripheral edema

- 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

- Complications of hyperviscosity: - Lethargy/confusion - Headaches, dizziness, vision changes - Crackles/findings of CHF

- 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

- 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

  • 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 volumeAcute: DehydrationChronic: 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 erythropoietinMedian age 60, 5% <40, peak in 70sHigher 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 diseaseSleep apnea (5 " “10% have high Hgb)Obesity hypoventilation syndrome (Pickwickian syndrome)Congenital heart disease (right-to-left shunt)High altitude (chronic)Smokers erythrocytosisCarbon monoxide poisoning (chronic)Chronic methemoglobinemiaRenal-mediated causes of increased erythropoietin production:Renal cell carcinomaRenal artery atherosclerotic narrowingFocal glomerulonephritisPostrenal transplant with or without rejectionChronic hydronephrosisPolycystic kidney disease and renal cystsInappropriate autonomous erythropoietin production:HepatomasCerebellar hemangioblastomaWilms tumorParathyroid carcinoma and adenomaOvarian tumorsAdrenal adenomas and carcinomas (pheochromocytoma, Cushing)Uterine leiomyomataBlood doping:Recombinant erythropoietin abuseAutologous transfusionsDrug abuse:Chronic cocaine abuseAndrogenic steroids
  • Genetic disorders with polycythemia:High-affinity Hgb variantsBisphosphoglycerate deficiencyvon Hippel " “Lindau syndromeChuvash polycythemiaErythropoietin-receptor mutationsCongenital methemoglobinemia
  • Infections:

Diagnostic Criteria for Polycythemia Vera

  • Major criteria:Hgb >18.5 g/dL in men, >16.5 g/dL in womenPresence of JAK2 mutation by polymerase chain reaction (PCR) " “ clinches the dxOxygen saturation >92% and no other cause for secondary erythrocytosis
  • Minor criteria:Low serum erythropoietin levelBone marrow aspirate and biopsy revealing panhyperplasia
  • Adjuncts to diagnosis:Platelets >400,000/mm3ANC >10,000 (WBC >12,000/mm3)Splenomegaly on exam or by CTLeukocyte alkaline phosphatase elevationB12 >900 pg/mL; unbound vitamin B12-binding capacity >2,200 pg/mL

Diagnosis

Signs and Symptoms

History

  • General:DyspneaWeakness/fatigueExcessive sweatingEpistaxis/gingival bleedingPruritus (40% of PV):GeneralizedExacerbated by warm bath or showerExcoriations common in PVGouty arthritis and tophi
  • Neurologic (hyperviscosity):HeadacheVertigo/dizziness/tinnitusLethargy/confusionParesthesiasCerebrovascular accident/TIAs
  • Visual (hyperviscosity):Amaurosis fugaxScotoma/blurred visionOphthalmic migraine
  • Cardiovascular:CHFAngina/myocardial infarctionDeep vein thrombosis (DVT)Hypertension
  • Extremities:Erythromelalgia:Secondary to capillary sludgingBurning pain in the feet or handsWarmth, erythema/cyanosis and puffiness of hand and feetAcral paresthesiasWorse at nightRelief with cooling and aspirinPulses intactPainful ulcers of fingers and toes (digital ischemia)
  • GI (unique to PV):Hepatomegaly/splenomegalySudden spleen enlargement in known PV suggests development of myelofibrosisEpigastric discomfort/early satietyPeptic ulcer disease/GI bleedBudd " “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 venousCumulative risk of 2 " “5% per yearTIAs, stroke, MI, digital infarctsUnusual venous thrombosis:Splenic or mesenteric veinsHepatic vein and IVC clot with subsequent cirrhosis/ascites (Budd " “Chiari syndrome)Cerebral sinus thrombosisDVT, PE
  • Complications of hyperviscosity:Lethargy/confusionHeadaches, dizziness, vision changesCrackles/findings of CHF
  • Hemorrhagic complications:EcchymosisEpistaxisGingival 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 levelErythropoietin level (normal or elevated if secondary)CXR, chest CT, pulmonary function testsSleep studyHgb electrophoresis
  • RBC mass:Cr-51 " “labeled RBCs by nuclear medicineConcomitant plasma volume with I-131 " “labeled albuminNot necessary if Hgb >18.5 in men, or >16.5 in womenRed 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 >10,000Platelet count >400,000Pulse oximetry >92%Low erythropoietin level " “ a major clueVitamin 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 splenomegalySuggested in symptomatic patients <60 yr
  • Anagrelide:Specific for thrombocytosisNo risk of leukemia, ideal for younger patients with postphlebotomy thrombocytosisEffective 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 elderlyHigh 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 neonatesUp to 50% of neonates with intrauterine growth retardation
  • Etiology:Maternal " “fetal hypoxemia secondary to maternal heart or lung disease, diabetes, preeclampsia, hypertension, or smokingDelayed clamping of the umbilical cord with increase cord transfusion
  • Symptoms and signs (most asymptomatic):Acrocyanosis/plethoricTachypnea/respiratory distressIrritable, lethargic, jittery, poor feeding
  • Hypoglycemia and hyperbilirubinemia common
  • Treatment:Observation and serial CBCs0.9 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)