THE PARADOXICAL RBC
MEDICINE GRANDROUNDS
December 2, 2010
Presented by: Suzanne V. Santos, M.D.
Moderator: Jesus A. Relos, M.D., FPCP
Objectives
1. 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 Data
A.B.
 56 year old male
 Seaman

Chief Complaint
Headache
History of Present Illness
14 years PTC
(1995)
10 years PTC
(2005)
elevated BP 150-160/80
occasional headache
Consultation done:
Dx. Hypertension stage II
Dx: Dyslipidemia
Hyperuricemia
History of Present Illness
3 months PTC
(Oct. 2009)
occipital headache,
throbbing, grade 5-6/10
consultation:
CBC: elevated Hgb (19.3),
Hct (60)
Blood volume studies
Referral to hematologist
Review of Systems
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No fever
No weight loss
No loss of appetite
No dizziness
No nausea/vomiting
No easy bruisability
No bleeding tendencies
No mouth sores
No skin rashes
No hair loss
Past Medical History
Hypertensive for 14 years
Usual BP 120-130/80, Highest BP 160/90
Maintenance: 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 ODHS
 Hyperuricemia for 10 yrs, on Allopurinol
300mg/tab 1 tab OD
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Personal/Social History
 Non-smoker
 Occasional Alcoholic
Beverage
Drinker
 No history of Illicit Drug Use
Family History
Unremarkable
Physical Examination
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BP: 130/90, CR: 74 bpm regular, R: 20 cpm,
T:
36.8C
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
Physical Examination
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CHEST 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 Features
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56 year old male
Headache
Elevated blood
volume studies
14 yrs history of
elevated BP
10 yrs history of
hyperuricemia
Non smoker
Plethoric
 Hgb 19.3, Hct 60

Initial Clinical Impression
Myeloproliferative Disorder probably
Polycythemia Vera
 Hypertensive Cardiovascular Disease
 Dyslipidemia
 Hyperuricemia
 Chronic Kidney Disease probably
secondary to Hypertensive
Nephrosclerosis
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Definition of Terms
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Hemoglobin (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 mass
Polycythemia: hemoglobin, red blood cell
(RBC) count, and total RBC volume are all above
normal.
Definition of Terms
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Hemoglobin (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
cell Hct
mass
Men: Hgb > red
17 g/dL;
> 50%
Polycythemia: any
increase
redg/dL;
cells
Women:
Hgb in
> 15
Hct > 45%
Definition of Terms
MCV: volume of the average circulating RBC
MCH: hemoglobin content of the average circulating RBC
MCHC: hemoglobin concentration within circulating RBC
Microcytosis: MCV < 80
Macrocytosis MCV >100
Hypochromia: low values of MCH and MCHC
Problem: Erythrocytosis & Thrombocytosis
DATE
2/3/09 2/10/09 2/19/09
Hgb
19.3 H 17.60 H 14.5
Hct
60
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
H 55.90 H 46.8
1
monos 8
9
Plt
459K H 427K
334K
2
MCV
74.8 L
74.6 L
MCH
23.6 L
23.1 L
MCH
C
31.5 L
31
RDW
17.3 H
15.8 H
L
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Phlebotomy:
1st consult (2/3/09)
3rd consult (2/5/09)
10th consult (2/12/09)
Complete Blood Count
2/11/10
Problem: Erythrocytosis & Thrombocytosis
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: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic
Myeloproliferative Disorders
(Neoplasm)
 Chronic Myelogenous Leukemia
 Chronic Idiopathic Myelofibrosis
 Essential Thrombocytosis
 Polycythemia Vera
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic
Myeloproliferative Disorders
Chronic Myelogenous Leukemia
Chronic
Myelogenous
Leukemia
Patient
 Chronic
Idiopathic
Myelofibrosis
• translocation between chromosome • Detection of BCR-ABL
Vera
9 and 
22Polycythemia
resulting in fusion of
the
Gene Fusion by FISH
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BCR gene on chromosome 22q11
with the ABL gene on chromosome
9q34
• elevated WBC, plt count
• low LAP score
(4/12/10): 1% found positive
• normal WBC
• high LAP score at 189
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic
Myeloproliferative Disorders
Chronic Myelogenous Leukemia
 Chronic Idiopathic Myelofibrosis
 Polycythemia
Vera
Chronic
Idiopathic Myelofibrosis
Patient
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• marrow fibrosis, extramedullary
hematopoiesis, splenomegaly
• Blood smear: teardrop-shaped red
cells, nucleated red cells, myelocytes,
promyelocytes
• Bone Marrow Biopsy
done 3/31/10
A.B. 56/Male
10-2949 BM
Scanner 4x
Low Power
Objective, 10x
High Power Objective
40x
High Power Objective
40x
Problem: Erythrocytosis & Thrombocytosis
Bone Marrow, Core Biopsy and
Aspirate Smears (3/31/2010)
Normocellular bone marrow (40-50%) with
orderly trilineage hematopoiesis.
Problem: Erythrocytosis & Thrombocytosis
WHO Classification of Chronic
Myeloproliferative Disorders
(Neoplasm)
 Chronic Myelogenous Leukemia
 Chronic Idiopathic Myelofibrosis
 Essential
Thrombocytosis
Essential
Thrombocytosis
Patient
• Elevated platelet count
 Polycythemia Vera
• Platelet count not consistently
• 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
elevated
• elevated LAP score
• Normal bone marrow biopsy
Problem: Erythrocytosis & Thrombocytosis
Polycythemia Vera Study Group (PVSG)
 increased red blood cell mass (red cell volume >
36ml/kg) or increased hgb or hct
 Disorders 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/microL
 LAP score greater than 100
 Presence of a JAK2 gene mutation
 Bone marrow biopsy showing hypercellularity with
prominent erythroid, granulocytic, and megakaryocytic
proliferation
Problem: Erythrocytosis & Thrombocytosis
Polycythemia Vera Study Group (PVSG)
 increased red blood cell mass (red cell volume >
36ml/kg) or increased hgb or hct
 Disorders 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/microL
 LAP score greater than 100
 Presence of a JAK2 gene mutation
 Bone marrow biopsy showing hypercellularity with
prominent erythroid, granulocytic, and megakaryocytic
proliferation
Complete Blood Count
Problem: Microcytic and Hypochromic RBC
Hgb Electrophoresis
Problem: Microcytic and Hypochromic RBC
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Genetic Studies (May 6, 2010): No apparent
chromosomal abnormality
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Thalassemia Screening in the Philippines
using High Performance Liquid
Chromatography (HPLC) (July 9, 2010): HPLC
tracing is indicative of beta-thalassemia, intermedia
Polycythemia Vera
Most common of the myeloproliferative
disorders
 Incidence: 2 per 100,000 persons
Etiology: Unknown
 nonrandom chromosome abnormalities
such as 20q, trisomy 8, and 9p
 JAK2 V617F mutation causing constitutive
activation of the kinase
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Janus Kinase2-gene (JAK2)
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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: Clinical Features
Splenomegaly
 Elevated Hgb and Hct
 Neurologic symptoms: vertigo, tinnitus,
headache, visual disturbances, TIAs
 Systolic hypertension
 Venous or arterial thrombosis
 Intraabdominal venous thrombosis
 Digital ischemia, easy bruising, epistaxis, acid
peptic disease or GI hemorrhage
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Polycythemia Vera: Diagnosis
Erythrocytosis, leukocytosis, thrombocytosis
 Increased leukocyte alkaline phosphatase
(LAP) score
 Hyperuricemia
 Elevated Vit B12 or B12 binding capacity
 BMA: no specific diagnostic information
 No specific cytogenetic abnormality
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Polycythemia Vera: Complications
Increase in blood viscosity
 Increased turnover of red cells, leukocytes
and platelets with the attendant increases
in uric acid and cytokine production
 Spleenic infarction
 Increased incidence of acute
nonlymphocytic leukemia
 erythromelalgia
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Polycythemia Vera: Treatment
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.
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Polycythemia Vera: Treatment
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 Syndromes
Inherited disorders of α or β globin biosynthesis,
diminished production of Hgb tetramers
 Unbalanced chain accumulation
 Massive bone marrow expansion deranges
growth and development (“chipmunk” facies)
 Chronic transfusion leads to iron overload
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Thalassemia Syndromes
α Thalassemia
 β Thalassemia
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β Thalassemia
β 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.
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β Thalassemia Intermedia
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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
Polycythemia Rubra Vera in a 71- year old Woman
Jason Preston Thomas, M.D.
Hospital Physician April 2001
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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 Diagnosis
Myeloproliferative Disease probably
Polycythemia Vera
 Beta Thalassemia Intermedia
 Hypertensive Cardiovascular Disease
 Dyslipidemia
 Hyperuricemia
 Chronic Kidney Disease probably
secondary to Hypertensive
Nephrosclerosis

Complete Blood Count
10/2/10
Conclusion
Beta 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.
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On 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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THANK YOU AND
GOOD DAY!!!