- Dec 5th, 2020
- Brian Sumner
Authors: Brian Sumner, MD (@briansumner93, EM Resident, Mount Sinai Morningside/West) and Elizabeth Brem, MD (@DrLizBrem, Attending Hematology and Oncology Physician, UC Irvine) // Reviewed by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)
Welcome to EM@3AM, an emDOCs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.
A 63-year-old male without any past medical history presents to the emergency department with several weeks of headaches, some blurry vision while walking at a quick pace, and shortness of breath. His last checkup with his primary doctor was about 3 years ago and everything was ‘normal’. He takes no medications, has no allergies, and has no previous surgeries. He admits to being a long-term smoker, about a half a pack a day for 20 years. Examination in the ED is normal. Basic lab work is drawn which reveals a hematocrit of 63%, elevated RBC mass, and thrombocytosis to 550K/ml. On further evaluation as an inpatient, it was found the patient had a low erythropoietin level.
What is the diagnosis?
Answer: Polycythemia Vera
Background: Polycythemia is a condition wherein there is an increased hemoglobin or hematocrit measured on complete blood count (CBC) tests. The increased levels may be relative or absolute.
Relative Polycythemia: In a state of reduced circulating plasma volume, such as in a dehydrated patient, there will be an artificial elevation in both HgB and Hct due to reduced plasma volume.(1)
– Polycythemia vera – A neoplastic proliferation of erythroid, megakaryocyte and granulocytic cells lines.(2) The aberrant proliferation is most commonly due to a tyrosine kinase (JAK2) activation mutation which results in an erythropoietin-independent proliferation of the hematopoietic stem cell lines.
- Side Note: Polycythemia vera is one disorder within a family called myeloproliferative neoplasms (MPNs). PV is joined by chronic myeloid leukemia (CML), essential thrombocytopenia (ET), primary myelofibrosis (PM). Upwards of 45% of patients with ET or PM have a mutation in JAK2. CML is more associated with a BCR-ABL (9:22) translocation, commonly referred to as the Philadelphia chromosome.
– Primary familial polycythemia – Autosomal dominant mutation of the EPOR (erythropoietin receptor) gene which leads to increased production of red blood cells.(3)
– Secondary polycythemia – There are many causes of secondary polycythemia. Chronic hypoxic states (heavy smokers/COPD/Emphysema, high altitude), renal hypoxia (PCOS, renal artery stenosis), high levels of testosterone + anabolic steroids.(1)
- A full review of systems is recommended for these patients.
- Assess for history of neurologic complaints such as vertigo, tinnitus, headaches, visual disturbances.(4)
- Assess for history of gastrointestinal complaints such as abdominal pain, melena, bright red blood per rectum, coffee ground emesis, early satiety.(4)
- Assess for history of ischemia.(4)
- Assess for history of cardiovascular/respiratory complaints such as chest pain, chest discomfort, shortness of breath, dyspnea on exertion, reduced exercise capacity.(4)
- Assess for history of integumentary changes such as ruddy skin or other rashes.(1)
- Assess vitals and ABCs.
- Comprehensive neurologic exam including extraocular movements, pupillary response and symmetry, peripheral field testing, visual acuity testing, present/absence of nystagmus, gait assessment, tests of coordination.
- Thorough abdominal exam evaluating for hepatosplenomegaly, abdominal distention, abdominal discomfort/peritoneal signs.
- Integumentary exam looking for a “ruddy” skin tone or other rash.
- Digit exam looking for clubbing, color change, pain on palpation, vascular status.
- Cardiopulmonary exam
- CBC, BMP, LFTs, coagulation assay, venous blood gas, erythropoietin levels (if possible, at your institution, urinalysis.
Routine lab work will identify polycythemia. In the setting that relative polycythemia is most likely, no further workup is usually needed. When clinical suspicion is concerned for primary/secondary, evaluation for renal abnormalities (urinalysis), blood gas to evaluate for carboxyhemoglobin/PaO2, and liver function tests are recommended.(4) Practice may differ by location, but on the inpatient service they may further workup polycythemia with erythropoietin levels. If low, this supports further workup for Polycythemia Vera or other MPN. If elevated, causes of secondary polycythemia are further investigated.(4)
It is also important to pursue typical workups for other possibly underlying causes of the broad range of symptoms that polycythemia can presents with. Always consider neurologic workups to exclude stroke, ACS workup to rule out cardiovascular compromise, and abdominal imaging in cases of abdominal pain.
- Polycythemia vera
- Essential thrombocytosis
- Primary myelofibrosis
- Chronic Myeloid Leukemia
- Relative Polycythemia
- Secondary Polycythemia (as described above)
- Primary Familial polycythemia (as described above)
- Barring other restrictive comorbidities, the answer is hydration with isotonic solutions.(1, 4) There is no consensus on which isotonic fluid is best.
- If the patient has known PV and they are on chronic aspirin therapy, they can receive their standard dose.
- However, there are certain cases where hematologist would prefer not to have patient on anti-platelets due to other underlying conditions increasing risk of bleeding – overall, it is important to contact hematology on these cases for treatment and disposition. If Hct is > 45%, consult hematology as phlebotomy may be indicated.(1)
ED Emergency – Hyperviscosity syndrome
In the most severe cases of polycythemia, patients can present with hyperviscosity syndrome.(1) Patients may present with the triad of visual disturbances, focal neurologic deficits and bleeding,(1) as well as shortness of breath and chest pain. In the setting where your patient has signs and symptoms concerning for hyperviscosity syndrome, emergency treatment is prudent. The slowed flow and impaired oxygenation of tissues secondary to the increased viscosity can result in neurologic and cardiovascular compromise. Aggressively hydrate with intravenous fluids and consult hematology.(1)
Take Home Points
- Consider relative vs absolute polycythemia.
- Consider hyperviscosity syndrome.
- Get hematology on board early for severe cases.
- Hydration and plasmapheresis are prudent in hyperviscosity syndrome.
A 62-year-old man presents to the emergency department with a chief complaint of prolonged generalized weakness, fatigue, and headache over the past month. Vital signs are within normal limits. Physical exam reveals plethoric facies and splenomegaly. His blood work shows WBC 18,000/μL, hemoglobin 19.8 g/dL, hematocrit 61%, platelets 517,000/μL, and LDH 370 U/L. Which of the following is the most likely diagnosis?
A) Chronic myelogenous leukemia
B) Essential thrombocythemia
D) Polycythemia vera
Polycythemia, also known as erythrocytosis, is defined as an increase in relative or absolute hemoglobin or hematocrit levels. Relative polycythemia is due to a decrease in plasma volume, commonly caused by dehydration or excessive diuresis. Absolute polycythemia is an increase in red blood cell (RBC) mass. Absolute polycythemia can be further classified as primary, due to mutations in erythroid cell lines or erythropoietin (EPO) receptors, or secondary, due to increased levels of circulating EPO, which directly stimulates RBC production. Polycythemia vera is an absolute primary polycythemia associated with a JAK2 gene mutation and is considered to be one of the chronic myeloproliferative disorders. The classic symptoms of polycythemia vera include pruritus, particularly when exposed to hot water, and early satiety due to splenomegaly from increased RBC production as a result of the JAK2 gene mutation. Other symptoms vary and are vague, including fatigue, generalized weakness, headache, chest pain, abdominal pain, or muscle pain. Some patients may be asymptomatic and are diagnosed incidentally after routine blood work. A rare but classic symptom of polycythemia vera is erythromelalgia, which occurs due to episodic occlusion of peripheral blood vessels that become hyperemic and inflamed when unoccluded. Patients with erythromelalgia present with intense, burning pain and a red-blue discoloration of the affected extremities. A feared and life-threatening complication of polycythemia vera is hyperviscosity syndrome that presents with the triad of vision changes, bleeding, and focal neurologic deficits due to microhemorrhage and thrombosis. On physical exam, patients with polycythemia vera may have splenomegaly, plethoric facies, flushed skin, nail clubbing, and distal cyanosis. Definitive diagnosis of polycythemia vera is made via biopsy or genetic testing for the JAK2 gene mutation. In the acute workup, patients will have hemoglobin levels greater than 18.5 g/dL in men and 16.5 g/dL in women, or hematocrit greater than 52% in men and 48% in women. Patients may also have a leukocytosis, thrombocytosis, and elevated lactate dehydrogenase. A useful blood test in distinguishing causes of polycythemia prior to availability of genetic testing or biopsy is an EPO level. Patients with polycythemia vera will have low EPO levels due to negative feedback repressing renal EPO production, whereas patients with absolute secondary polycythemia due to chronic lung disease or high altitude will have increased EPO levels. Treatment for polycythemia vera is low-dose aspirin and correction of decreased plasma volume with phlebotomy to a hematocrit of 45%. Other treatment options, after confirmation of diagnosis and discussion with a hematologist, include hydroxyurea, interferon-alpha, and ruxolitinib, a JAK1 and JAK2 inhibitor. Patients with hyperviscosity syndrome require intravenous fluid hydration and hematology consultation.
Chronic myelogenous leukemia (CML) (A), essential thrombocythemia (B), and myelofibrosis (C), in addition to polycythemia vera, are malignant hematopoietic neoplasms classified as chronic myeloproliferative disorders. CML is associated with the Philadelphia chromosome (t[9;22]) and BCR-ABL fusion gene. Patients typically have a decreased RBC count, a WBC count above 100,000 μL, and platelets between 600,000 and 700,000 μL. Patients with essential thrombocythemia have massive proliferation of megakaryocytes and platelets and predominantly present with thrombocytosis. Myelofibrosis is characterized by fibrotic bone marrow destruction due to increased fibroblast activity. Patients typically have decreased levels of uniquely formed RBCs referred to as “teardrop.”
1. Billet M, Hemphill RR. Anemia and Polycythemia. In: Tintinalli JE, Ma OJ, Yealy DM, Meckler GD, Stapczynski JS, Cline DM, et al., editors. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. New York, NY: McGraw-Hill Education; 2020.
2. Raedler LA. Diagnosis and management of polycythemia vera: proceedings from a multidisciplinary roundtable. American health & drug benefits. 2014;7(7 suppl3):S36.
3. Sokol L, Luhovy M, Guan Y, Prchal J, Semenza GL, Prchal J. Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin. 1995.
4. Adamson JW, Longo DL. Anemia and Polycythemia. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill Education; 2018.