Etiology

Polycythemia VeraGroup BRamos, RonaldRangel, ErikaRaymundo, NikkoRayos, KarenRecio, Maria KristinaReyes, CarmenReyes, JenileneReyes, LourdesRivera, LailaRivere, DjeauneRobosa,DeanRodas, FrancisRodriguez, ShereenRogelio, Ma.GracielaRoque, Marianne1Week 5Case 3RP, 62 y.o. maleCC: Left sided body weaknessHistory of Present IllnessReview of SystemsWeight loss of 25% in the past 3 mos.Have pruritus after showeringOccasional claudicationPast Medical HistoryKnown Hypertensive (2yrs)Maintained on amlodipine 5mg/tab od taken regularlyNon diabeticNo previous hospitalizationsPersonal Social HistoryNon smokerOccasional alcoholic drinkerFamily HistoryUnremarkable Physical ExamConscious, coherent, ambulates with assistance, not in cardiorespiratory distressBP 130/90CR 10bpmRR 21 cpmT 37.1CWarm moist skin, plethora notedPink palpebral conjunctivae, anicteric scleraSymmetrical chest expansion, no retrations, clear breath soundsAdynamic precordium, AB 5th LICS MCLFlabby abdomen, normoactive bowel sounds, no hepatomegaly, obliterated Traubes spaceExtremities: no cyanosis, no edema, full and equal pulses

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

LaboratoryPatients ResultsHgb190 g/LHct0.60WBC18.0 x 109 /LSeg0.58Lympho0.38Mono0.02Eos0.02Platelet850Normal ValuesHgb135-175 g/LHct0.40-0.52WBC4.0-11.0 x 109 /LSeg2.5-7.5Lympho1.5-3.5Mono0.02-0.8Eos0.04-0.44Platelet150-400Interpretation:Hemoconcentration, leukocytosis with thrombocytosisSalient FeaturesPertinent PositivesWeight loss of 25% in the past 3 mos.Have pruritus after showeringOccasional claudicationHypertensive (BP 130/90)Plethoraobliterated Traubes 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 extremititesHemoconcentration, leukocytosis with thrombocytosis

Pertinent NegativesExtremities: no cyanosis, no edema, full and equal pulsesno hepatomegaly

Polycythemia VeraEtiologyExact etiology is unknownAbnormalities in chromosome such as 20q, trisomy 8, and 9p, have been documented in up to 30% of untreated PV patientsA 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 kinaseClinical FeaturesClinical FeaturesSplenomegalyHigh Hgb and HctUncontrolled erythrocytosisHypervicosity leading to neurologic symptoms: vertigo, tinnitus, headache, visual disturbances, and TIAs.Systolic hypertensionIn some patients, venous or arterial thrombosisClinical FeaturesCerebral, cardiac, or mesenteric vessels are commonly involvedIntraabdominal venous thrombosisDigital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhageDue to vascular stasis or thrombocytosisErythromelalgiaErythema, burning and pain in extremitiesDiagnosisDiagnosisPresents with erythrocytosis in combination with leukocytosis, thrombocytosis or bothIf Px presents with with an elevated hemoglobin or hematocrit alone, or with thrombocytosis alone, evaluation becomes more complex because of the many diagnostic possibilitiesUnless hemoglobin is >20 gm% (hematocrit >60%), it is not possible to distinguish PV from disorders causing plasma volume contractionRed cell mass and plasma volume determination mandatory to establish presence of absolute erythrocytosisFauci et.al. Harrisons principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

DiagnosisOnce absolute erythrocytosis has been establisehd, its cause must be determinedAn elevated plasma erythropoeitin level suggests either a hypoxic cause or autonomous productionPulmonary function Abdominal CT scan to evaluate renal and hepatic anatomyOther labs:RBC countMean 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 disorderFauci et.al. Harrisons principles of Internal Medicine 2008 17th edition. McGraw-Hill USA

Differential Diagnosis of Polycythemia VeraTrue / 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: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.APPARENT POLYCYTHEMIARelative polycythemia Conditions that cause acute depletion of plasma volume e.g. severe dehydrationThe existence of chronic contraction of the plasma volume, such as postulated for:Gaisbck's syndrome relative polycythemia associated with hypertension and nephropathyStress / spurious polycythemia relative polycythemia associated with emotional stressFauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Conditions that cause acute depletion of plasma volume (i.e., relative polycythemia) are clinically obvious (e.g., severe dehydration, diarrhea, vomiting, use of diuretics, capillary leak syndrome, severe burns) and do not require diagnostic confirmation with the use of specialized tests.

X indicates not mentioned in the history21ABSOLUTE / TRUE POLYCYTHEMIA Polycythemia vera Secondary polycythemia Congenital Associated with high or normal serum erythropoietin level Associated with low serum erythropoietin level Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Secondary PolycythemiaCongenital Associated with high or normal serum erythropoietin level Associated with low serum erythropoietin level Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Secondary PolycythemiaCongenital Associated with high or normal serum erythropoietin level Associated with low serum erythropoietin level Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.X no noted congenital dse from the history; erythropoietin not yet measured in the patient24Secondary Polycythemia: CongenitalFauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Secondary PolycythemiaCongenital Associated with high or normal serum erythropoietin level Associated with low serum erythropoietin level Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Secondary Polycythemia: AcquiredFauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.X not in cardiorespiratory distress, nonsmoker, pulmo findings unremarkable27Secondary PolycythemiaCongenital Associated with high or normal serum erythropoietin level Associated with low serum erythropoietin level Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Secondary Polycythemia: AcquiredFauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.X no indication of liver and kidney pathology in the historyPossible tumor in the brain29Secondary PolycythemiaCongenital Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedErythropoietin dopingTreatment with androgen preparations Unknown mechanism

Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.X no drug intake of erythropoietin and androgen preparations30Secondary PolycythemiaCongenital Acquired Erythropoietin mediatedHypoxia-drivenHypoxia-independent (pathologic erythropoietin production)Drug associatedUnknown mechanism Postrenal transplant erythrocytosis

Fauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.X no medical history of renal transplantation31ComplicationsMajor 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

Harrisons Principle of Internal Medicine 17th ed.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 anemiaHarrisons Principle of Internal Medicine 17th ed.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 salicylatesHarrisons Principle of Internal Medicine 17th ed.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 Harrisons Principle of Internal Medicine 17th ed.ManagementPhlebotomyPhlebotomy or bloodletting has been the mainstay of therapyRemove excess cellular elements to improve the circulation of blood by lowering the blood viscosity mainly red blood cells

Harrisons Principle of Internal Medicine 17thedhttp://emedicine.medscape.com/article/205114-treatmentJan 23, 2009Phlebotomy or bloodletting has been the mainstay of therapy for the polycythemia vera (PV) disease process for a long time. The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity38PhlebotomyPatients 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 bloodHarrisons Principle of Internal Medicine 17thedhttp://emedicine.medscape.com/article/205114-treatmentJan 23, 2009Patients 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 (as seen in the patient) or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood

39Post-Phlebotomyvolume replacement with saline solution after each procedure to avoid postural hypotensionuse myelosuppressive agents (Hydroxyurea) to avoid thrombotic or hemorrhagiccomplications

http://emedicine.medscape.com/article/205114-treatmentJan 23, 2009Elderly patients with some cardiovascular compromise or cerebral vascular complications should have the volume replaced with saline solution after each procedure to avoid postural hypotension

The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications40Hydroxyureaeffective agent for myelosuppressionReduced 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 transformationHarrisons Principle of Internal Medicine 17thedhttp://emedicine.medscape.com/article/205114-treatmentJan 23, 2009The role of HU in leukemic transformation is not clear, but several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU41Anagrelide (Agrylin)A cyclic adenosine monophosphate phosphodiesterase inhibitor that prevents platelet aggregation and inhibits megakaryocyte maturation, thereby decreasing platelet countsTo date, this agent does not appear to increase the risk of acute leukemia in patients with PV and ET over timehttp://emedicine.medscape.com/article/205114-treatmentJan 23, 2009THANK YOU!

ReferencesFauci, et al: Harrisons Principles of Internal Medicine, 17th ed. Goldman: Cecil Medicine, 23rd ed.Polycythemia vera 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) Highoxygen affinity hemoglobinopathy (autosomal dominant) 2,3-Diphosphoglycerate mutase deficiency (autosomal recessive)Pathogenetically undefined cases Associated with low serum erythropoietin level Activating mutation of the erythropoietin receptor (autosomal dominant) Acquired Erythropoietin mediatedHypoxia-drivenCentral hypoxic processChronic lung diseaseRight-to-left cardiopulmonary vascular shuntsHigh-altitude habitatCarbon monoxide poisoningSmoker's polycythemia (chronic carbon monoxide exposure) Hypoventilation syndromes including sleep apneaPeripheral hypoxic process LocalizedRenal artery stenosis Hypoxia-independent (pathologic erythropoietin production)Malignant tumors Hepatocellular carcinomaRenal cell cancer Cerebellar hemangioblastoma Parathyroid carcinoma Nonmalignant conditionsUterine leiomyomas Renal cysts (polycystic kidney disease)PheochromocytomaMeningioma Drug associatedErythropoietin dopingTreatment with androgen preparations Unknown mechanism Postrenal transplant erythrocytosis