THE PARADOXICAL RBCTHE PARADOXICAL RBC

MEDICINE GRANDROUNDSDecember 2, 2010

Presented by: Suzanne V. Santos, M.D.Moderator: Jesus A. Relos, M.D., FPCP

ObjectivesObjectives1. To discuss the diagnostic approach

in a patient presenting with erythrocytosis and thrombocytosis.

2. To present an unusual case of Beta Thalassemia intermedia with possible concurrent polycythemia vera.

3. To discuss the pathophysiology, diagnosis and treatment of polycythemia vera and beta thalassemia and their risk for thrombotic events.

General DataGeneral Data

A.B. 56 year old maleSeaman

Chief ComplaintChief Complaint

Headache

History of Present History of Present IllnessIllness14 years PTC elevated BP 150-160/80 (1995) occasional headache

Consultation done: Dx. Hypertension stage II

10 years PTC Dx: Dyslipidemia(2005) Hyperuricemia

History of Present History of Present IllnessIllness3 months PTC occipital headache, (Oct. 2009) throbbing, grade 5-

6/10 consultation: CBC: elevated Hgb (19.3), Hct (60) Blood volume studies Referral to hematologist

Review of SystemsReview of SystemsNo feverNo weight lossNo loss of appetiteNo dizzinessNo nausea/vomitingNo easy bruisabilityNo bleeding tendenciesNo mouth soresNo skin rashesNo hair loss

Past Medical HistoryPast Medical HistoryHypertensive for 14 years

Usual BP 120-130/80, Highest BP 160/90Maintenance: Losartan 100mg/tab, 1 tab OD Amlodipine 10mg/tab, 1 tab OD Imidapril 10mg/tab, 1 tab OD

Chronic Kidney Disease x 1 year, Rx: Sodium Bicarbonate 650mg/tab, 1 tab BID

Dyslipidemia for 10 years Simvastatin 80mg/tab, 1 tab ODHSHyperuricemia for 10 yrs, on Allopurinol

300mg/tab 1 tab OD

Non-smokerOccasional Alcoholic Beverage Drinker

No history of Illicit Drug Use

Personal/Social HistoryPersonal/Social History

Unremarkable

Family HistoryFamily History

Physical ExaminationPhysical ExaminationBP: 130/90, CR: 74 bpm regular, R: 20 cpm,

T: 36.8C Ht: 167.64 cm, Wt: 68 kg, BMI: 24 kg/m2

General appearance: conscious, coherent, not in cardiorespiratory distress, ambulatory, oriented to 3 spheres

Skin: flushed, moist skin, no rashes over face or body

HEENT: plethoric, pink palpebral conjunctivae, anicteric sclerae, no nasoaural discharge, no cervical lymphadenopathy, no palpable neck mass, thyroid not enlarged

Physical ExaminationPhysical ExaminationCHEST and LUNGS: symmetrical chest

expansion, no retractions, clear breath sounds, no crackles or rhonchi, no wheeze

HEART: quiet precordium, apex beat at 5th ICS left mid clavicular line, regular rate and rhythm, no murmurs. No S3, No S4 gallop, S1>S2 apex, S2>S1 base, JVP at 9 cm, distinct heart sounds

ABDOMEN: Flabby abdomen, soft, nontender, normoactive bowel sounds, no hepatosplenomegaly

EXTREMITIES: no cyanosis, no edema, full and equal pulses, no nail changes, no tender or swollen joints

Neurological Examination: essentially normal

Salient FeaturesSalient Features56 year old maleHeadacheElevated blood

volume studies14 yrs history of

elevated BP10 yrs history of

hyperuricemiaNon smoker

PlethoricHgb 19.3, Hct 60

Initial Clinical Initial Clinical ImpressionImpressionMyeloproliferative Disorder

probably Polycythemia VeraHypertensive Cardiovascular

DiseaseDyslipidemiaHyperuricemiaChronic Kidney Disease probably

secondary to Hypertensive Nephrosclerosis

Definition of TermsDefinition of TermsHemoglobin (Hgb): concentration of the

major oxygen-carrying pigment in whole blood; tetramer consisting of a pair of α-like chains andβ-like chains

Hematocrit (HCT): percentage of a sample of whole blood occupied by intact red blood cells.

RBC count: number of red blood cells contained in a specified volume of whole blood.

Erythrocytosis: increased red cell massPolycythemia: hemoglobin, red blood cell

(RBC) count, and total RBC volume are all above normal.

Definition of TermsDefinition of TermsHemoglobin (Hgb): concentration of

the major oxygen-carrying pigment in whole blood; tetramer consisting of a pair of α-like chains andβ-like chains

Hematocrit (HCT): percent of a sample of whole blood occupied by intact red blood cells.

RBC count: number of red blood cells contained in a specified volume of whole blood.

Erythrocytosis: increased red cell massPolycythemia: any increase in red cells

Men: Hgb > 17 g/dL; Hct > 50%Women: Hgb > 15 g/dL; Hct > 45%

Definition of TermsDefinition of Terms

Microcytosis: MCV < 80Macrocytosis MCV >100Hypochromia: low values of MCH and MCHC

MCV: volume of the average circulating RBCMCH: hemoglobin content of the average circulating RBCMCHC: hemoglobin concentration within circulating RBC

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosisDATE 2/3/0

92/10/09

2/19/09

Hgb 19.3 H

17.60 H

14.5

Hct 60 H

55.90 H

46.8

RBC 7.92 7.47 H

6.27

WBC 9.86 10.54 9.55

Segs 76 65 65

lymph

20 25 30

eos 1 1

monos

8 9 2

Plt 334K 459K H

427K

MCV 74.8 L

74.6 L

MCH 23.6 L

23.1 L

MCHC

31.5 L

31 L

RDW 17.3 H

15.8 H

Phlebotomy: 1st consult

(2/3/09) 3rd consult (2/5/09)

10th consult (2/12/09)

Complete Blood CountComplete Blood Count2/11/10

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

Cranial CT scan without contrast: (Feb. 16, 2010)Suspicious small infarct, anterior limb of the right internal capsule. Microvascular disease.Atherosclerotic disease of the vertebro-basilar and internal carotid arteries.

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

WHO Classification of Chronic Myeloproliferative Disorders (Neoplasm)

Chronic Myelogenous LeukemiaChronic Idiopathic MyelofibrosisEssential ThrombocytosisPolycythemia Vera

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

WHO Classification of Chronic Myeloproliferative Disorders

Chronic Myelogenous LeukemiaChronic Idiopathic MyelofibrosisPolycythemia Vera

Chronic Myelogenous Leukemia

• translocation between chromosome 9 and 22 resulting in fusion of the BCR gene on chromosome 22q11 with the ABL gene on chromosome 9q34• elevated WBC, plt count • low LAP score

Patient• Detection of BCR-ABL Gene Fusion by FISH (4/12/10): 1% found positive• normal WBC• high LAP score at 189

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

WHO Classification of Chronic Myeloproliferative Disorders

Chronic Myelogenous LeukemiaChronic Idiopathic MyelofibrosisPolycythemia VeraChronic Idiopathic

Myelofibrosis• marrow fibrosis, extramedullary hematopoiesis, splenomegaly• Blood smear: teardrop-shaped red cells, nucleated red cells, myelocytes, promyelocytes

Patient• Bone Marrow Biopsy done 3/31/10

10-2949 BM10-2949 BMA.B. 56/Male

Scanner 4x

Low Power Objective, 10x

High Power Objective 40x

High Power Objective 40x

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

Bone Marrow, Core Biopsy and Aspirate Smears (3/31/2010)

Normocellular bone marrow (40-50%) with orderly trilineage hematopoiesis.

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

WHO Classification of Chronic Myeloproliferative Disorders (Neoplasm)

Chronic Myelogenous LeukemiaChronic Idiopathic MyelofibrosisEssential ThrombocytosisPolycythemia Vera

Essential Thrombocytosis• Elevated platelet count• hemorrhagic and thrombotic tendencies• mild neutrophilic leukocytosis• normal or elevated LAP score• Bone marrow biopsy reveals megakaryocyte hyperplasia and hypertrophy with increase in marrow cellularity

Patient• Platelet count not consistently elevated• elevated LAP score• Normal bone marrow biopsy

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

Polycythemia Vera Study Group (PVSG)increased red blood cell mass (red cell volume >

36ml/kg) or increased hgb or hctDisorders causing secondary erythrocytosis are

absent.PVSG criteria: two basic criteria plus 2 of the ff.:Platelet count >400,000/microL White blood cell count >12,000/microLLAP score greater than 100Presence of a JAK2 gene mutation Bone marrow biopsy showing hypercellularity with

prominent erythroid, granulocytic, and megakaryocytic proliferation

  

Problem: Problem: Erythrocytosis & Erythrocytosis & ThrombocytosisThrombocytosis

Polycythemia Vera Study Group (PVSG)increased red blood cell mass (red cell volume >

36ml/kg) or increased hgb or hctDisorders causing secondary erythrocytosis are

absent.PVSG criteria: two basic criteria plus 2 of the ff.:Platelet count >400,000/microL White blood cell count >12,000/microLLAP score greater than 100Presence of a JAK2 gene mutation Bone marrow biopsy showing hypercellularity with

prominent erythroid, granulocytic, and megakaryocytic proliferation

  

Complete Blood CountComplete Blood Count

Problem: Problem: Microcytic and Microcytic and Hypochromic RBCHypochromic RBC

Hgb ElectrophoresisHgb Electrophoresis

Problem: Problem: Microcytic and Microcytic and Hypochromic RBC Hypochromic RBC

Genetic Studies (May 6, 2010): No apparent chromosomal abnormality

Thalassemia Screening in the Philippines using High Performance Liquid Chromatography (HPLC) (July 9, 2010): HPLC tracing is indicative of beta-thalassemia, intermedia

Polycythemia VeraPolycythemia Vera

Most common of the myeloproliferative disorders

Incidence: 2 per 100,000 personsEtiology: Unknown nonrandom chromosome

abnormalities such as 20q, trisomy 8, and 9p

JAK2 V617F mutation causing constitutive activation of the kinase

Janus Kinase2-gene Janus Kinase2-gene (JAK2)(JAK2)

Janus Kinase 2 (JAK2) has tyrosine kinase activity and is involved in signal transduction from EPOR (erythropoietin receptor) to nucleus for gene expression

Polycythemia Vera: Polycythemia Vera: Clinical Clinical FeaturesFeaturesSplenomegalyElevated Hgb and HctNeurologic symptoms: vertigo, tinnitus, headache, visual disturbances, TIAs

Systolic hypertensionVenous or arterial thrombosisIntraabdominal venous thrombosisDigital ischemia, easy bruising,

epistaxis, acid peptic disease or GI hemorrhage

Polycythemia VeraPolycythemia Vera: : DiagnosisDiagnosis

Erythrocytosis, leukocytosis, thrombocytosis

Increased leukocyte alkaline phosphatase (LAP) score

HyperuricemiaElevated Vit B12 or B12 binding

capacityBMA: no specific diagnostic

informationNo specific cytogenetic abnormality

Polycythemia VeraPolycythemia Vera: : ComplicationsComplications

Increase in blood viscosityIncreased turnover of red cells,

leukocytes and platelets with the attendant increases in uric acid and cytokine production

Spleenic infarctionIncreased incidence of acute

nonlymphocytic leukemiaerythromelalgia

Polycythemia Vera: Polycythemia Vera: TreatmentTreatment

Phlebotomy or bloodletting has been the mainstay of therapy.

Elevated platelet counts may be exacerbated by phlebotomy, thus is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.

Polycythemia Vera: Polycythemia Vera: TreatmentTreatment

Hydroxyurea has been the mainstay therapy after the PVSG results indicated it as an effective agent for myelosuppression. The role of HU in leukemic transformation is not clear, but several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with long term use of HU in persons with polycythemia vera (from 2.1% to 10%).

Besa, Emmanuel, M.D., and Woermann, Ulrich, M.D. Polycythemia Vera: Treatment and Medication. January 23, 2009.

Thalassemia SyndromesThalassemia Syndromes

Inherited disorders of α or β globin biosynthesis, diminished production of Hgb tetramers

Unbalanced chain accumulationMassive bone marrow expansion

deranges growth and development (“chipmunk” facies)

Chronic transfusion leads to iron overload

Thalassemia SyndromesThalassemia Syndromes

α Thalassemiaβ Thalassemia

β Thalassemiaβ Thalassemiaβ Thalassemia Major: either no

effective production or severely limited production of beta globin.

β Thalassemia Minor: heterozygotes who have inherited a single gene leading to reduced beta globin production.

β Thalassemia Intermedia: disease of intermediate severity, such as those who are compound heterozygotes of two thalassemic variants.

β Thalassemia Intermediaβ Thalassemia Intermedia

Malaise, pallor, easy fatigability, splenomegaly

CBC reveal anemia with marked hypochromasia and microcytosis

Accepted Hgb: 6-7 g/dL without blood transfusions.

Treatment: close monitoring and observation.

Indications for blood transfusions: intercurrent infections, hypersplenism, or other illnesses.

β Thalassemia Minor and Newly Diagnosed β Thalassemia Minor and Newly Diagnosed Polycythemia Rubra Vera in a 71- year old Polycythemia Rubra Vera in a 71- year old

WomanWomanJason Preston Thomas, M.D.Jason Preston Thomas, M.D.Hospital Physician April 2001Hospital Physician April 2001

β Thalassemia Minor and polycythemia rubra vera (PRV) are hematologic disorders that give opposite results and the 2 disease entities occurring simultaneously has only been reported ONCE.

Due to the low-grade hemolysis resulting from precipitation of impaired alpha globin chains in association with β Thalassemia Minor, the often substantial elevations in Hgb and Hct seen in PRV were probably blunted.

The low grade anemia of β Thalassemia Minor is not evident because of the overproduction of erythrocytes.

Final DiagnosisFinal DiagnosisMyeloproliferative Disease probably

Polycythemia Vera Beta Thalassemia IntermediaHypertensive Cardiovascular

DiseaseDyslipidemiaHyperuricemiaChronic Kidney Disease probably

secondary to Hypertensive Nephrosclerosis

Complete Blood CountComplete Blood Count10/2/10

ConclusionConclusionBeta Thalassemia and PRV are 2 indirectly

opposing processes and its occurrence in a patient is rare.

For the long term, chemotherapy could be considered if the patient develops a blood clot or requires phlebotomies too frequently.

Median survival of PRV in the absence of therapy extended to at least 10-20 years.

Thrombotic complications are the main cause of morbidity and mortality, hence close monitoring and observation with repeat CBC should be done every 2 months.

On Follow upOn Follow up

Patient is doing well, asymptomatic.

Has been having regular follow up every 2 months with repeat CBC, and undergoes phlebotomy depending on CBC results.

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