Polycythemia Vera and Cerebrovascular Events

Presentor: Christian Gallardo, MDResource: Dr. Nerissa Reyes (Neurologist) and Dr. Jesus Relos (Hematologist)Moderator: Dr. Ian Dennis FranciscoGuest Speaker: Dr. Rico Lodronio

POLYCYTHEMIA VERA AND CEREBROVASCULAR EVENTS

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

1 month

PTA

• Nape pain• (-) Headache, (-) Nausa and

Vomiting, (-) Loss of consciousness

• (-) Fever, (-) easy brusability, (-) no bleeding

• BP Taken = 160/100• ER consult.

Clonidine SL was given. Discharged

Known Hypertensive for 5 years maintained

Felodipine 5mg OD


1 weekPTA

• Nape pain• BP= 160/100

• Admitted at a local hospital in Imus, Cavite for control of BP

• Nurses noted to have concentrated blood flow when inserting IVF

• CBC revealed increase in Hgb and Hct

• Advised Hematology Consult as OPD

• Discharged

Home Medications:1. Telmisartan

(Micardis) 40 mg/ tab 1 tab OD

2. Cilostazol (Pletaal) 50mg/tab 1 tab BID

3. Bisoprolol 5mg/ tab 1 tab TID

4. Clonidine (Catapres) 75 ug/tab 1 tab SL for BP>160/100


2 daysPTA

•Nape pain•Eye redness•Flushed Face•Gum Bleeding•BP: 150/100•Had consult with AP and advised admission

Admitted

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

(-) Babinski reflex (-) Brudzinski sign (-) Kernig sign (-) Nuchal Rigidity (+) Mayers Reflex

++

5/5 ++5/5 100%

5/55/5

++

++100%

100% 100% ++ ++

++++

Pin prick test, Discrimination Test, Intact Pin prick test, Discrimination Test, Sense and Position

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

↑ in Hct and Hgb

Plethoric face,Fushed palms and

soles

Nape pain, eye redness,

gum bleeding

Problem #1: Hypercoagulable State

Primary

Causes

Secondary

Causes

Thrombocythemia

Erythrocytosis

Coagulation and

fibrinolysis

Myelofibrosis

Chronic Myeloproliferati

ve Disorder

Hypertension

Vascular

Hypercoagulable State

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 109L

15.8 x 109L

14.7 x 109L

12.6 x 109L

12.7 x 109L

12.1x 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 750Blood Chemistry

SGOT 36 U/L

SGPT 35 U/L

LDH 1180 U/L

Creatinine 107 umol/L

PTT

Control 29.0 sec

Test 31.3 sec

PT

Control 13.0sec

Test 14.6 sec

INR 1.16

% Act 80%

Course of Patient

Day 1 Day 2 Day 4 Day 5 Day 6 Day 70

50

100

150

200

250

61

4256 52 57 58

202191

168 169184

177

17.6 15.8 14.7 12.6 12.7 12.1

Hema-tocritHemo-globin

S/P Phlebotomy

S/P Phlebotomy

JAK 2 and LAP

Jak 2 Mutation Assay by Allele – Specific PCR

Positive

Leukocyte Alkaline Phosphatase

130 (10-100)

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

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 mutation2) 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 polycythemia vera, essential


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



4. 2006

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.



4. 2006

Three main clinical consequences during long-term follow-up (JAK2 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.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


4. 2006

Three main clinical consequences during long-term follow-up (JAK2 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.



4. 2006

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



4. 2006

Problem # 2: Neuro

Day 1 Day 2 Day 4 Day 5 Day 6 Day 70

50

100

150

200

250

61

4256 52 57 58

202191

168 169184

177

17.6 15.8 14.7 12.6 12.7 12.1

Hema-tocritHemo-globin

S> R Sided Paresthesia Mild Dysarthria (-) HA, (-) Dizziness

O> BP:140/90 CR: 89 Shallow Nasolabial fold L (-) Babinski

Plain Cranial Computed Tomography

Referred to Neurology Service

Transferred to ICU

Medications:1) ASA 300mg

POThe 160 mg OD

PO2) Pantoprazole 40mg/ tab 1 tab

OD PO

MAP: 110-120mmHG

S/P Phlebotomy

OtherDiagnostic Investigation

Diagnostics

ECG LAE and LVH by Voltage

Carotid Doppler Bilateral Normal Duplex ScanBilateral Tortous Common Carotid Artery Othewise Normal Forward FlowBilateral 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 eventsHuichun Zhan, MD, and Jerry L. Spivak, MD. The Diagnosis and Management of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis


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 hypertensionHuichun Zhan, MD, and Jerry L. Spivak, MD. The Diagnosis and Management of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis


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 Huichun Zhan, MD, and Jerry L. Spivak, MD. The Diagnosis and Management of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis


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 trialsSrdan Verstovsek. Therapeutic potential of JAK2 inhibitors.

American Society of Hematology. Hematology 2009

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!

Documents

Polycythemia Vera and Cerebrovascular Events