1. Polycythemia Vera Group B Ramos, Ronald Rangel, Erika Raymundo, Nikko Rayos, Karen Recio, Maria Kristina Reyes, Carmen Reyes, Jenilene Reyes, Lourdes Rivera, Laila Rivere, Djeaune Robosa,Dean Rodas, Francis Rodriguez, Shereen Rogelio, Ma.Graciela Roque, Marianne 1 Week 5Case 3

2. RP, 62 y.o. male CC: Left sided body weakness

3. History of Present Illness 3 wks PTA Headache with dizziness Consulted at a health center: BP 190/110 Rx sublingual clonidine Few hrs PTA Persistent headache Wife spotted him on the floor unable to stand by himself Admission

4. Review of Systems Weight loss of 25% in the past 3 mos. Have pruritus after showering Occasional claudication

5. Past Medical History Known Hypertensive (2yrs) Maintained on amlodipine 5mg/tab od taken regularly Non diabetic No previous hospitalizations

6. Personal Social History Non smoker Occasional alcoholic drinker Family History Unremarkable

7. Physical Exam Conscious, coherent, ambulates with assistance, not in cardiorespiratory distress BP 130/90CR 10bpmRR 21 cpmT 37.1C Warm moist skin, plethora noted Pink palpebral conjunctivae, anicteric sclera Symmetrical chest expansion, no retrations, clear breath sounds Adynamic precordium, AB 5 th LICS MCL Flabby abdomen, normoactive bowel sounds, no hepatomegaly, obliterated Traube’s space Extremities: no cyanosis, no edema, full and equal pulses

8. Physical Exam Neuro Exam: (+) slurring of speech (+) shallow Left nasolabial fold (+) tongue deviated to the right upon protrusion MMT grade 2/5 on both left upper and lower extremitites (-) Babinski

9. Laboratory Patient’s Results Hgb190 g/L Hct0.60 WBC18.0 x 10 9 /L Seg0.58 Lympho0.38 Mono0.02 Eos0.02 Platelet850 Normal Values Hgb135-175 g/L Hct0.40-0.52 WBC4.0-11.0 x 10 9 /L Seg2.5-7.5 Lympho1.5-3.5 Mono0.02-0.8 Eos0.04-0.44 Platelet150-400 Interpretation: Hemoconcentration, leukocytosis with thrombocytosis

10. Salient Features Pertinent Positives Weight loss of 25% in the past 3 mos. Have pruritus after showering Occasional claudication Hypertensive (BP 130/90) Plethora obliterated Traube’s space (splenomegaly) Neuro Exam:(+) slurring of speech; (+) shallow Left nasolabial fold; (+) tongue deviated to the right upon protrusion; MMT grade 2/5 on both left upper and lower extremitites Hemoconcentration, leukocytosis with thrombocytosis Pertinent Negatives Extremities: no cyanosis, no edema, full and equal pulses no hepatomegaly

12. Etiology Exact etiology is unknown Abnormalities in chromosome such as 20q, trisomy 8, and 9p, have been documented in up to 30% of untreated PV patients A mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2 appears to have a central role in the pathogenesis of PV. tyrosine kinase JAK2 replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase

14. Clinical Features Splenomegaly High Hgb and Hct Uncontrolled erythrocytosis Hypervicosity leading to neurologic symptoms: vertigo, tinnitus, headache, visual disturbances, and TIAs. Systolic hypertension In some patients, venous or arterial thrombosis

15. Clinical Features Cerebral, cardiac, or mesenteric vessels are commonly involved Intraabdominal venous thrombosis Digital ischemia, easy bruising, epistaxis, acid- peptic disease, or gastrointestinal hemorrhage Due to vascular stasis or thrombocytosis Erythromelalgia Erythema, burning and pain in extremities

17. Diagnosis Presents with erythrocytosis in combination with leukocytosis, thrombocytosis or both – If Px presents with with an elevated hemoglobin or hematocrit alone, or with thrombocytosis alone, evaluation becomes more complex because of the many diagnostic possibilities – Unless hemoglobin is >20 gm% (hematocrit >60%), it is not possible to distinguish PV from disorders causing plasma volume contraction Red cell mass and plasma volume determination mandatory to establish presence of absolute erythrocytosis Fauci et.al. Harrison’s principles of Internal Medicine 2008 17 th edition. McGraw-Hill USA

18. Diagnosis Once absolute erythrocytosis has been establisehd, its cause must be determined – An elevated plasma erythropoeitin level suggests either a hypoxic cause or autonomous production Pulmonary function Abdominal CT scan to evaluate renal and hepatic anatomy Other labs: – RBC count – Mean corpuscular volume – Red cell distribution width ** bone marrow aspirate and biopsy provide no specific diagnostic information unless there is need to establish a myelofibrosis or exclude some other disorder Fauci et.al. Harrison’s principles of Internal Medicine 2008 17 th edition. McGraw-Hill USA

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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 hemoglobin opathy (autosomal dominant) 2,3- Diphosphog lycerate mutase deficiency (autosomal recessive) Pathogenetically 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.

26. 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.

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

28. 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.

29. Secondary Polycythemia: Acquired Erythropoietin mediated Hypoxi a- driven Hypoxia-independent (pathologic erythropoietin production) Malignant tumors HCC Renal cell cancer Cerebellar hemangio blastoma Parathyroi d carcinoma Nonmalignant conditions Uterine leiomyo mas Renal cysts (polycys tic kidney disease) Pheochr omocyt oma Meningi oma Fauci, et al: Harrison’s Principles of Internal Medicine, 17 th ed. Goldman: Cecil Medicine, 23 rd ed.

30. 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.

31. 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.

33. Major clinical complications relate: directly to increase in blood viscosity with red cell mass elevation AND indirectly to increased turnover of red cells, leukocytes and and platelets with the attendant increase in uric acid and cytokine production Cytokines appears to be responsible for the increase in peptic ulcer disease and for the pruritus associated with this disorder Harrison’s Principle of Internal Medicine 17 th ed.

34. Sudden massive increase in spleen size can be associated with splenic infarction and progressive cachexia Myelofibrosis appears to be part of the natural history of the disease but is a reactive, reversible process that does not itself impede hematopoiesis; in some patients, however, it is accompanied by significant extramedullary hematopoiesis, hepatosplenomegaly, and transfusion dependent anemia Harrison’s Principle of Internal Medicine 17 th ed.

35. Organomegaly can cause significant mechanical discomfort, portal hypertension, and cachexia Erythromelalgia is a syndrome of unknown etiology associated with thrombocytosis, primarily involving the lower extremities and manifested usually by erythema, warmth, and pain of the affected appendage, and occasionally digital infarction - usually responsive to salicylates Harrison’s Principle of Internal Medicine 17 th ed.

36. If left uncontrolled, erythrocytosis can lead to thrombosis involving vital organs such as the liver, heart, brain, or lungs Patients with massive splenomegaly are particularly prone to thrombotic events because the associated increase in plasma volume masks the true extent of the red cell mass elevation as measured by the hematocrit of hemoglobin level Harrison’s Principle of Internal Medicine 17 th ed.

38. Phlebotomy Phlebotomy or bloodletting has been the mainstay of therapy Remove excess cellular elements to improve the circulation of blood by lowering the blood viscosity mainly red blood cells Harrison’s Principle of Internal Medicine 17 th ed http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009

39. Phlebotomy Patients with hematocrit values of less than 70% may be bled twice a week to reduce the hematocrit to the range of less than 45% Patients with severe plethora who have altered mentation or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood Harrison’s Principle of Internal Medicine 17 th ed http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009

40. Post-Phlebotomy volume replacement with saline solution after each procedure to avoid postural hypotension use myelosuppressive agents (Hydroxyurea) to avoid thrombotic or hemorrhagiccomplications http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009

41. Hydroxyurea effective agent for myelosuppression Reduced the risk of thrombosis compared with phlebotomy alone and should be the drug of choice for patients older than 40 years however, concerns have been raised regarding long- term risks for leukemic transformation Harrison’s Principle of Internal Medicine 17 th ed http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009

42. Anagrelide (Agrylin) A cyclic adenosine monophosphate phosphodiesterase inhibitor that prevents platelet aggregation and inhibits megakaryocyte maturation, thereby decreasing platelet counts To date, this agent does not appear to increase the risk of acute leukemia in patients with PV and ET over time http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009

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

45. 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