1. Differential Diagnosis of Polycythemia Vera

2. True / Absolute Polycythemia Either a clonal myeloproliferative disorder (polycythemia vera) or a nonclonal increase in red blood cell mass that is often mediated by erythropoietin (secondary polycythemia) Apparent / Relative Polycythemia Either a decrease in plasma volume (relative polycythemia) or a misperception of what constitutes the upper limit of normal values for either hemoglobin or hematocrit Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

3. APPARENT POLYCYTHEMIA A.Relative polycythemia  Conditions that cause acute depletion of plasma volume e.g. severe dehydration  The existence of chronic contraction of the plasma volume, such as postulated for:  Gaisböck's syndrome – relative polycythemia associated with hypertension and nephropathy  Stress / spurious polycythemia – relative polycythemia associated with emotional stress Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

4. ABSOLUTE / TRUE POLYCYTHEMIA A.Polycythemia vera B.Secondary polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level 2)Associated with low serum erythropoietin level ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

5. Secondary Polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level 2)Associated with low serum erythropoietin level ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

6. Secondary Polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level 2)Associated with low serum erythropoietin level ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

7. Secondary Polycythemia: Congenital Associated with high or normal serum erythropoietin level Chuvash and other polycythemias associated with von values Hippel-Lindau (VHL) gene mutation (autosomal) recessive) High–oxygen affinity hemoglobinop athy (autosomal dominant) 2,3- Diphosphogly cerate mutase deficiency (autosomal recessive) Pathogenetic ally undefined cases Associated with low serum erythropoietin level Activating mutation of the erythropoietin receptor (autosomal dominant) Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

8. Secondary Polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level 2)Associated with low serum erythropoietin level ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

9. Secondary Polycythemia: Acquired Erythropoietin mediated Hypoxia- driven Central hypoxic process Chronic lung disease Right-to- left cardiopu lmonary vascular shunts High- altitude habitat Carbon monoxide poisoning Smoker's polycythem ia (chronic carbon monoxide exposure) Hypoven tilation syndrom es includin g sleep apnea Peripheral hypoxic process Localized Renal artery stenosis Hypoxia-independent Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

10. Secondary Polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level 2)Associated with low serum erythropoietin level ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

11. Secondary Polycythemia: Acquired Erythropoietin mediated Hypoxia- driven Hypoxia-independent (pathologic erythropoietin production) Malignant tumors HCC Renal cell cancer Cerebellar hemangiobl astoma Parathyroid carcinoma Nonmalignant conditions Uterine leiomyo mas Renal cysts (polycyst ic kidney disease) Pheochr omocyto ma Meningi oma Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

12. Secondary Polycythemia i.Congenital ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated a)Erythropoietin doping b)Treatment with androgen preparations 3)Unknown mechanism Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

13. Secondary Polycythemia i.Congenital ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven b)Hypoxia-independent (pathologic erythropoietin production) 2)Drug associated 3)Unknown mechanism a)Post–renal transplant erythrocytosis Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

14. References Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

15. A.Polycythemia vera B.Secondary polycythemia i.Congenital 1)Associated with high or normal serum erythropoietin level a)Chuvash and other polycythemias associated with von values Hippel-Lindau (VHL) gene mutation (autosomal) recessive) b)High–oxygen affinity hemoglobinopathy (autosomal dominant) c)2,3-Diphosphoglycerate mutase deficiency (autosomal recessive) d)Pathogenetically undefined cases 2)Associated with low serum erythropoietin level a)Activating mutation of the erythropoietin receptor (autosomal dominant) ii.Acquired 1)Erythropoietin mediated a)Hypoxia-driven i.Central hypoxic process 1.Chronic lung disease 2.Right-to-left cardiopulmonary vascular shunts 3.High-altitude habitat 4.Carbon monoxide poisoning 5.Smoker's polycythemia (chronic carbon monoxide exposure) 6.Hypoventilation syndromes including sleep apnea ii.Peripheral hypoxic process 1.Localized 2.Renal artery stenosis b)Hypoxia-independent (pathologic erythropoietin production) i.Malignant tumors 1.Hepatocellular carcinoma 2.Renal cell cancer 3.Cerebellar hemangioblastoma 4.Parathyroid carcinoma ii.Nonmalignant conditions 1.Uterine leiomyomas 2.Renal cysts (polycystic kidney disease) 3.Pheochromocytoma 4.Meningioma 2)Drug associated a)Erythropoietin doping b)Treatment with androgen preparations 3)Unknown mechanism a)Post–renal transplant erythrocytosis