Polycythemia Vera and Cerebrovascular Events

POLYCYTHEMIA VERA AND
CEREBROVASCULAR EVENTS
Presentor: Christian Gallardo, MD
Resource: Dr. Nerissa Reyes (Neurologist) and Dr. Jesus Relos (Hematologist)
Moderator: Dr. Ian Dennis Francisco
Guest Speaker: Dr. Rico Lodronio
Objectives
 To present a case of Chronic

Myeloproliferative Disease such as
Polycythemia Vera.
 To discuss Janus Kinase 2 and its
significance in diagnosing Chronic
Myeloproliferative Disorder.
 To discuss the relationship of
Hypercoagulable State and Acute Cerebral
Events such as Ischemic Strokes
General Data
 D.C.
 56 year old
 Male
 Bacoor Cavite
 Roman Catholic
 Admitted Jan 12, 2010
Chief Complaint:
Nape Pain
History of Present Illness
●
Nape pain
●
(-) Headache, (-) Nausa and
1 month ●
Vomiting, (-) Loss of consciousness
(-) Fever, (-) easy brusability, (-) no
bleeding
PTA ●
●
BP Taken = 160/100
ER consult. Clonidine SL
was given. Discharged
Known Hypertensive for 5
years maintained
Felodipine 5mg OD
Home Medications:
●
Nape pain1. Telmisartan
●
BP= 160/100(Micardis) 40 mg/
tab 1 tab OD
●
Admitted at2.a local hospital in
Cilostazol (Pletaal)
Imus, Cavite for50mg/tab
control 1oftabBP
1 week
BID
●
Nurses noted3. toBisoprolol
have 5mg/
tab 1 tab
concentrated blood TIDwhen
flow
inserting IVF4. Clonidine
PTA ●
and Hct
(Catapres) 75 ug/tab
CBC revealed increase in Hgb
1 tab SL for
BP>160/100
●
Advised Hematology Consult as
OPD
●
Discharged
●
Nape pain
●
Eye redness
●
Flushed Face
2 days ●
Gum Bleeding
●
BP: 150/100
PTA ●
Had consult with
AP and advised
Admitted
admission
Past Medical History
 Hypertension – 5 years
 HBP:160/100
 UBP: 120 – 130/90
 Medications:
 Telmisartan (Micardis) 80mg/tab 1 tab OD
 Cilostazol 50mg/tab 1 tab TID
 Bisoprolol 5mg/tab 1 tab TID
 (-) Diabetes Mellitus
 (-) Bronchial Asthma
 (-) Allergy
 (-) Previous Surgeries
Family Medical History
 Hypertension – Paternal Side

 DM – Siblings
 (-) Cancer
 (-) Bronchial Asthma
 (-) Blood Dyscrasia
 (-) Kidney Disease
 (-) CVD
Past Medical History
 Non-smoker
 Occasional Alcoholic beverage
 No exposure to chemicals and toxic
substances
 Works as a Front Desk Manager
Review of Systems
 General: no weight loss, no easy fatigability
 EENT: no blurring of vision, no photophobia, no
ear discharge, no epistaxis
 Respiratory: no colds, no cough, no hemoptysis
 Cardiovascular: no chest pain, no orthopnea, no
palpitations
 Gastrointestinal: no abdominal pain, no
diarrhea, no constipation, no hematemesis
 Genitourinary: no flank pain, no frequency, no
urgency
 Musculoskeletal/Extremities: no joint pain
 Hematology: no abnormal bleeding, no easy
bruising
Physical Examination
 General: Conscious, Coherent, Conversant, Not in

distress
 Vital Signs: BP: 150/100 RR: 18 cpm
CR: 86 bpm T: 37C
 Skin: Warm to touch, No Rashes, No Lesions, No
Petecchiae
 HEENT: Anicteric Slerae, Slight Conjunctival
Effusion, Pink Palpebral Conjuctivae, (-)
Tonsillopharyngeal Congestion, (-) Nasoaural
Discharge, Plethoric face, (-) Neck Vein
Engorgement, (-) Carotid Bruit
Physical Examination
 Chest and Lung Findings: Symmetrical Chest Expansion,

No Lagging, No retractions, Clear Breath Sounds
 Heart: Adynamic precordium, normal rate, regular
rhythm, Normal S1 and S2, (-) S3, PMI at 5th ICS LMCL,
no murmur.
 Admomen: Flabby, Soft, tympanitic, non-tender, Liver
Edge non- palpable, Liver Span: 8 cm at the
midclavicular line, Intact Traube Space, No Abdominal
Bruit
 Extremities: Grossly Normal Pulses, No cyanosis, No
Clubbing, Flushed Skin and Palms, No Limitation of
motion
Neurological Examination
 Cerebral:
 Oriented to time, person and place
 Mini Mental status Exam: 30 points
 (-) dysarthria
 Cerebellar:
 (-) Dysmetria (-) Dysdiadochokenisia
 (-) Rhomberg Test, (-) apraxia, (-) ataxia
 Cranial Nerves:
 I: Can smell familiar odors in each nostrils
 II: 2-3mm PERTL, Visual Acuity :20/20, Fundoscopy: (+) ROR, Clear Media, Distinct Cup
borders, CDR: 1:3, AVR: 2:3, No exudates, No Hemorrhage
 III, IV, VI: Full EOM
 V: (+) bilateral corneal reflex, good masseter tone
 VII: (-) facial asymmetry
 VIII: Weber Test: no lateralization, Rinne‘s Test: AC>BC, (-) Nystagmus
 IX, X: (+) Gag Reflex
 XI: Can equally shrug shoulder
 XII: No tongue deviation
Neurological Examination
5/5 5/5 100% 100% ++ ++
++ ++
5/5 5/5 100% 100% ++ ++
++ ++
 Pin prick test, Discrimination Test, Intact Pin prick test,

Discrimination Test, Sense and Position
 (-) Babinski reflex (-) Brudzinski sign (-) Kernig sign
 (-) Nuchal Rigidity (+) Mayers Reflex
Salient Features
 55 year old
 Male
 Hypertensive for 5 years
 History of nape pains
 Flushed face, palms and hands
 Eye redness and gum bleeding
 Findings of Increased Hct and Hgb on
previous admission
 PE: BP: 150/90, Phletoric face, conjunctival
effusion, flushed palms and soles
Problem #1: Hypercoagulable State
Nape pain, Plethoric
eye redness, face,
gum Fushed
bleeding palms Vascular
and soles Thrombocythemia
↑ in Hct
Hypertension and Hgb
Chronic
Myeloproliferative
Erythrocytosis
Disorder
Hypercoagulable State
Myelofibrosis
Primary
Causes
Coagulation
Secondary and
Causes
fibrinolysis
Diagnostic Investigation:
CBC 1/12 1/13 1/15 1/16 1/17 1/18
Hemoglobin 202 g/L 191 g/L 168 g/L 169 g/L 184 g/L 177 g/L
Hematocrit 0.61 L 0.42 L 0.56 L 0.52 L 0.57 L 0.58 L
WBC 17.6 x 15.8 x 14.7 x 12.6 x 12.7 x 12.1x
109L 109L 109L 109L 109L 109L
Segmenters 0.61 0.62 0.77 0.84 0.82 0.80
Lymphocytes 0.30 0.28 0.15 0.09 0.09 0.10
Monocytes 0.05 0.08 0.06 0.04 0.03 0.06
Eosinophils 0.01 0.02 0.01 0.03 0.06 0.04
Platelets 758 740 648 651 702 750
Blood Chemistry PTT PT

SGOT 36 U/L Control 29.0 sec Control 13.0sec
SGPT 35 U/L Test 31.3 sec Test 14.6 sec
LDH 1180 U/L INR 1.16
Creatinine 107 % Act 80%
umol/L
Course of Patient
250
Hematocrit
S/P Hemoglobi
n
Phlebotomy WBC
200 202
191
184
177
168 169
150
JAK 2 and LAP
S/P
Phlebotomy Jak 2 Mutation Positive
Assay by Allele –
100 Specific PCR
Leukocyte 130 (10-100)
Alkaline
61 56 Phosphatase 57 58
50 52
42
17.6 15.8 14.7 12.6 12.7 12.1

0
Day 1 Day 2 Day 4 Day 5 Day 6 Day 7
Chronic Myeloproliferative
Disorders (MPD)
 Polycythemia vera (PV)
 Essential thrombocythemia (ET)
 Primary myelofibrosis (PMF)
 Characterized by clonal hematopoiesis involving a
multipotent hematopoietic progenitor cell,
 Unregulated production of red cells, white cells,
and platelets alone or in combination
 Tendency to extramedullary hematopoiesis, and
transformation to acute leukemia or myelofibrosis
at a variable but low rate.
Spivak J.and Silver R.The Revised World Health Organization diagnostic criteria for
polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an
alternative proposal. 2008 112: 231-239
Sylvia Bellucci, M.D and Jan J. Michiels, M.D. The Role of JAK2 V617F Mutation, Spontaneous
Erythropoiesis and Megakaryocytopoiesis, Hypersensitive Platelets, Activated Leukocytes, and
Endothelial Cells in the Etiology of Thrombotic Manifestations in Polycythemia Vera and Essential
Thrombocythemia. Seminars in Thrombosis and Hemostasis Volume 32, Number 4. 2006
Paradigm of Polycythemia Vera
Polycythemia Vera
 Malignant Disorder of the hematopoetic

stem cells which characterized by
 Clonal hyperproliferation
 Low rate of apoptosis
 Endogenous Erythroid Colonies
 Chracteristic biological feature of PV Erythroid
precursor
Major Criteria of PV
1) JAK2 mutation
2) Absolute erythrocytosis
 Hallmark of PV
 The diagnosis cannot be established, nor can PV
be distinguished
3) Plasma volume expansion, even in the
absence of splenomegaly
4) Presentation of PV is sufficiently
pleomorphic that all laboratory clues need
to be used
Spivak J.and Silver R.The revised World Health Organization diagnostic criteria for
Major Criteria of PV
5) Given practice situation to define pretest

probabilities with respect to the
frequency with which different forms of
erythrocytosis or apparent erythrocytosis
are encountered
Clinical Manifestation of
PV
 Hypercatabolism and hyperviscosity
 Resulting from excessive red cell production
 Concomitant thrombocytosis and
leukocytosis
 Lead to headache, fatigue, dizziness, pruritus
(particularly after bathing in hot water),
excessive sweating, and erythromelalgia.
Huichun Zhan, MD, and Jerry L. Spivak, MD. The Diagnosis and Management of Polycythemia Vera,
Essential Thrombocythemia, and Primary Myelofibrosis in the JAK2 V617F Era.
Clinical Advances in Hematology & Oncology Volume 7, Issue 5 May 2009
Janus Associated Kinase 2
 One member of a family of four

cytoplasmic tyrosine kinases that also
includes JAK1, JAK3 and Tyk2.
 Signaling by cytokine and growth factor
receptors that lack intrinsic kinase activity
 Utilizes some growth factors such as
erythropoietin and thrombopoietin
Srdan Verstovsek. Therapeutic potential of JAK2 inhibitors. American Society of

Hematology. Hematology 2009
Janus Kinase Pathophysiology
Jak 2 Mutations
JAK2 mutations (with highly sensitive allele-specific
polymerase chain reaction assays and blood
neutrophils)
 95% of Polycythemia vera
 50–60% of Essential Thrombocythemia and
Primary Myelofibrosis
 The mutation substitutes a valine for a
phenylalanine at position 617 within the
JAK2 kinase regulatory domain, releasing
the JAK2 kinase from regulatory control.
Possible Roles of the JAK2 V617F Mutation in Myeloproliferative Diseases. In model A, a mutation (V617F) of one allele of
JAK2 on chromosome 9p (red dot), alone or in combination with a hypothetical preexisting mutation in an unknown gene (“X”),
initiates the onset of the myeloproliferative disease (dashed arrow). In model B, the heterozygous V617F mutation on 9p
occurs after the initiation of the myeloproliferative disease (dashed arrow), which was provoked by one or more mutations in
an unknown gene or genes. Cells that are heterozygous for the V617F mutation have a proliferative advantage over cells
bearing only the wildtype allele. Mitotic recombination between homologous regions of the two chromosomes 9 in a cell
heterozygous for V617F results in loss of heterozygosity of 9p (9pLOH). One of the daughter cells is homozygous for V617F
and gains an additional proliferative advantage. This cell establishes a subclone that outcompetes both cells that are
heterozygous for V617F and cells that are homozygous for wild-type JAK2.
JAK2v617F
The Role of JAK 2 Tyrosine
Kinase
 The JAK2 V617F point mutation
 Makes the normal hematopoietic progenitor
cells hypersensitive
 Thrombopoietin
 Erythropoietin
 Myeloid progenitor cells
 leading to Trilinear hematopoietic
myeloproliferation
The Role of JAK 2 Tyrosine
Kinase
 Significant correlation between JAK2
V617F mutational status and hematocrit
(Ht), white blood cell and platelet counts in
PV patients, and Ht values in ET cases, was
observed by ASPCR.
Lucia E., Martino B., Mammi C. The incidence of JAK2 V617F mutation in bcr/abl-negative
chronic myeloproliferative disorders: assessment by two different detection methods.
Leukemia & Lymphoma, October 2008; 49(10): 1907–1915
Three main clinical consequences
during long-term follow-up (JAK2
V617F point mutation) -1st
 Spontaneous growth of enlarged mature
megakaryocytes in ET/PV with
overproduction of hypersensitive platelets
results
 Found in a broad spectrum of platelet-
mediated microvascular circulatory
disturbances
 Very sensitive to low-dose aspirin.
V617F point mutation) – 2nd
 Spontaneous growth of erythropoiesis
with the overproduction of erythrocytes
 Increased hemoglobin, hematocrit, and red
cell mass.
 Major arterial and venous thrombotic
complications
 Platelet-mediated microvascular circulatory
disturbances of thrombocythemia.
V617F point mutation) – 3rd
 Slowly progressive myeloid granulocytic
metaplasia in bone marrow and spleen
 1/4th to 1/3rd of JAK2 V617F-positive PV patients
after long-term follow-up
 No tendency of leukemic transformation as long as they
are not treated with myelosuppressive agents.
Leukocyte Alkaline
Phosphatase (LAP) Score
 In 1955, Kaplow described a cytochemical
technique for assessing LAP activity.
 Later, a score greater than 100 LAP in

granulocytes of peripheral blood was
included in the Polycythemia Vera Study
Group (PVSG) diagnostic criteria.
Basquiera A, Fassetta F, Soria E et al. Accuracy of leukocyte alkaline phosphatase

score to predict JAK2 V617F mutation. Haematologica 2007; 92:5:704-705
Leukocyte Alkaline
Phosphatase (LAP) Score
 A LAP score above 100
 Sensitivity: 88.2%
 Specificity: 87.5%
 The highest LAP score in patients with PV

may be due to a greater prevalence of
homozygosity for JAK2 V617F mutation in
PV
Basquiera A, Fassetta F, Soria E et al. Accuracy of leukocyte alkaline phosphatase

score to predict JAK2 V617F mutation. Haematologica 2007; 92:5:704-705
Why there is an increase
LAP Score in PV?
 Polymorphonuclear (PMN) leukocyte
hyperactivation
 Measured by the increased expression of
membrane CD11b
 Cellular elastase content or myeloperoxidase
levels
Problem # 2: Neuro
250
Hematocrit
Hemoglobi
n
WBC
200 S>
202R Sided Paresthesia
Mild Dysarthria
191
Medications: Transferred184
to ICU
(-) HA, (-) Dizziness 177
1) ASA 300mg PO 168 169
150 O> BP:140/90 The
CR:160
89 mg OD PO
Shallow 2) Pantoprazole
40mg/
Nasolabial foldtab
L 1 tab OD S/P
(-) Babinski PO
100 Phlebotomy
Plain Cranial Computed
MAP: 110- Tomography
61 120mmHG Referred to Neurology 58
56 52 57
50 Service
42
17.6 15.8 14.7 12.6 12.7 12.1

0
Day 1 Day 2 Day 4 Day 5 Day 6 Day 7
OtherDiagnostic
Investigation
Diagnostics
ECG LAE and LVH by Voltage
Carotid Doppler Bilateral Normal Duplex Scan
Bilateral Tortous Common Carotid Artery
Othewise Normal Forward Flow
Bilateral Forward Vertebral Artery Flow
Retrospective cohort study of patients
with polycythemia who had been followed
for 20 years.
 Arterial and venous thrombosis

 2/3rd and 1/3rd of thromboses either before or
when PV was diagnosed
 Ischemic stroke and transient ischemic
attacks
 70% of arterial thromboses at diagnosis and
 Prevalent as myocardial infarction (30%)
before diagnosis of PV
Polycythemia Vera: The Natural History of 1213 Patients Followed for 20 Years
Gruppo Italiano Studio Policitemia, Ann Intern Med. 1995;123:656-66
Thrombotic Events in PV
 Arterial or venous thrombosis can be the

presenting manifestation of PV
 PV must always be included in the
evaluation of a hypercoagulable state
 Age (>60 years) and a previous history of
thrombosis
 Major risk factors for recurrent thrombotic
events
Case Report
Final Diagnosis
 CVD, Multiple Ischemic Infarct Secondary

to Hypercoagulable State
 Polycythemia Vera
Management of Polycythemia Vera
Phlebotomy: Management of
PV
 Mainstay of therapy
 Target
 HCT below 45% in men
 HCT below42% in women
 Reduces the red cell mass
 Alleviates the symptoms of hyperviscosity
and the threat of thrombosis
Phlebotomy: Management of
PV
 Periodic phlebotomy
 To render the patient iron deficient to
prevent rapid elevation of the red cell mass
 Phlebotomy required only at 3-month
intervals.
 Once an iron-deficient state is achieved
Phlebotomy:Management of
PV
 Benefits
 Restoration of systemic and pulmonary pressures to
normal
 Increase in plasma volume and a reduction in blood
viscosity
 Reduction in spleen size
 Improved platelet function
 Improved cognition
 Decrease in nitric oxide scavenging by the elevated red
cell mass
 Contributes to vasoconstriction and pulmonary
hypertension
Management of PV
 Pruritus is a unique feature of PV

 Including phlebotomy
 H1 and H2 blockers
 Ataractics such as doxepin
 Antidepressants such as paroxetine
 Either UV B directly from sunlight or in a
tanning parlor, or UV A exposure with
psoralens (PUVA light therapy)
 Cytoreductive therapy with hydroxyurea or
alpha interferon
Management of PV
 Asymptomatic hyperuricemia (<10 mg%)

requires no therapy
 But allopurinol should be administered to
avoid further elevation of the uric acid when
chemotherapy is employed to reduce
splenomegaly or leukocytosis or to treat
pruritus
Fauci, Braunwald, Kasper et al. Harrison of Internal Medicine. Copyright The McGraw-Hill Companies
2008. Part 5 Sec 1 Chap 103.
Hydroxyurea: Management of
PV
 Widely used in PV
 Without any evidence
 Prolongs survival
 Prevents complications of PV, such as
thrombosis or myelofibrosis
 Should be used judiciously in PV
 It is only myelosuppressive
 Continued uncertainty about its leukemogenic
potential
Prognosis
 Each independent factors associated with

a shortened survival
 Progressive splenomegaly and myelofibrosis
 Anemia (hemoglobin <10g),
thrombocytopenia (<100,000/μL)
 Leukocytosis (>30,000/μL)
Aspirin: Management of PV
 Effective in relieving the microvascular

complications of erythromelalgia and
ocular migraine in PV
 Does not appear to be more effective than
anagrelide in preventing other forms of
thrombosis, either venous or arterial
 Caution: PC is in excess of 1,000,000/μL
because it can cause serious bleeding
Aspirin: Management of PV
 Whether low-dose aspirin (81 mg daily) is

effective in preventing thrombotic
complications without increasing the risk
of major bleeding has not been definitely
proven.
Drugs in Development
 There are several compounds targeting

the JAK2 mutation in development:
 INCB018424 (Incyte/Novartis)
 TG101348 (TargeGen)
 CEP-701 (Cephalon)
 AZD1480 (AstraZeneca)
 XL019 (Exelixis)
 WP1066 (Calistoga)
 CYT-387 (Cytopia)
Garber, K. JAK2 Inhibitors: Not the Next Imatinib But Researchers See Other
Possibilities. JNCI Journal of the National Cancer Institute. 2009. 101 (14), 980-982 DOI
JAK 2 Inhibitors
 INCB018424 (Incyte/Novartis)
 First to be evaluated in PMF and post-PV/ET
MF
 Entered clinical trials in mid-2007
 Inhibited hematopoietic progenitor cell
colony formation from CD34+ cells isolated
from PV patients
 Did so more potently than with cells from
normal donors
 Starting dose of 25 mg twice daily
INCB018424
JAK 2 Inhibitors
 CEP-701 (lestaurtinib) (Cephalon)

 Derivative of the indolocarbazole K252
(straurosporine analog)
 Potent inhibitory activity of JAK2, in
addition to a number of other kinases
including FLT-3, RET and Trk-A
 Dose of 80 mg BID PO
 Recommended for hematologic malignancy
trials

JAK 2 Inhibitors
 TG101348 (TargeGen)
 35- and 334-fold selectivity for JAK2 as
compared with JAK3 and JAK1, respectively
 Inhibited hematopoietic progenitor colony
formation and erythroid engraftment
 Twenty-eight patients were treated at 8
dose levels from 30 mg to 800 mg daily

JAK 2 Inhibitors

THANK YOU VERY MUCH!

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POLYCYTHEMIA VERA AND

 To present a case of Chronic

 Hypertension – Paternal Side

 General: Conscious, Coherent, Conversant, Not in

 Chest and Lung Findings: Symmetrical Chest Expansion,

5/5 5/5 100% 100% ++ ++

5/5 5/5 100% 100% ++ ++

 Pin prick test, Discrimination Test, Intact Pin prick test,

Blood Chemistry PTT PT

17.6 15.8 14.7 12.6 12.7 12.1

 Malignant Disorder of the hematopoetic

5) Given practice situation to define pretest

 One member of a family of four

Srdan Verstovsek. Therapeutic potential of JAK2 inhibitors. American Society of

 Later, a score greater than 100 LAP in

Basquiera A, Fassetta F, Soria E et al. Accuracy of leukocyte alkaline phosphatase

 The highest LAP score in patients with PV

Basquiera A, Fassetta F, Soria E et al. Accuracy of leukocyte alkaline phosphatase

17.6 15.8 14.7 12.6 12.7 12.1

 Arterial and venous thrombosis

 Arterial or venous thrombosis can be the

 CVD, Multiple Ischemic Infarct Secondary

 Pruritus is a unique feature of PV

 Asymptomatic hyperuricemia (<10 mg%)

 Each independent factors associated with

 Effective in relieving the microvascular

 Whether low-dose aspirin (81 mg daily) is

 There are several compounds targeting

 CEP-701 (lestaurtinib) (Cephalon)

Srdan Verstovsek. Therapeutic potential of JAK2 inhibitors. American Society of

Srdan Verstovsek. Therapeutic potential of JAK2 inhibitors. American Society of

Srdan Verstovsek. Therapeutic potential of JAK2 inhibitors. American Society of

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