Polycythemia.

Polycythaemia (erythrocytosis) is defined as an increase in the haemoglobin concentration above the upper limit of normal for the patient's age and sex.

1. Polycythemia
DR RUHUL AMIN
REGISTRAR
Dept of GASTROENTEROLOGY

2. Polycythaemia (erythrocytosis)
is defined as an increase in the
haemoglobin concentration
above the upper limit of
normal for the patient's age
and sex.
Polycythaemia

3. ``

4. Relative vs. Absolute
Absolute erythrocytosis
Hct male > 60%, female > 55%
Classification of polycythaemia

5. I. Relative or spurious erythrocytosis
Relativepolycythemiaisanapparentriseoftheerythrocytelevelin
theblood;however,theunderlyingcauseisreducedblood
plasma.
Dehydration: Water deprivation, Vomiting
Plasma loss: Burns, Enteropathy
II. Absolute erythrocytosis
Primary marrow diseases: PV,PrimaryErythrocytosis
Secondary : increased EPO production
Erythrocytosis
(Polycythemia)

6. Reactive (Secondary ) : increased EPO production
Tissue hypoxia
Lung diseases : COPD
Heart disease: Rt to Lt shunt
High attitude
Abnormal Hb, smoking
Tumors produce EPO
Hypernephroma/Renal Cell Carcinoma
Hepatoma / Hepatocellular Carcinoma
Cerebellar hemangioblastoma
Uterine fibromyoma
Renal diseases
Polycystic kidney
Renal artery stenosis
Erythrocytosis

7. Malignantclonalproliferationofhematopoieticstem
cellsleadingtoexcessiveerythrocyteproduction
characterizedasapanhyperplastic,malignant,and
neoplasticmarrowdisorder.
TheincreaseinRBCmassoccursindependentof
erythropoietin.
Itisacomponentofmyeloproliferativedisorder
Polycythemia Vera (PV)

8. Myeloproliferative disorders
Polycythemia Vera (PCV)
Essential Thrombocytosis (ET)
Chronic myelogenous leukemia (CML)
Myelofibrosis with myeloid metaplasia

9. Incidence
Polycythemia vera (PV) is relatively rare, occurring in
0.6-1.6 persons per million population.
Median age of diagnosis is 60 but seen in wide age
range between 20 and 85
Slightly higher incidence in men than women (2.8 vs. 1.3
cases/100,000 per year, respectively)
Survival of untreated PCV estimated between 6 to 18
months but treated patient survival is >10years

10. Causes of Death in PCV
Thrombosis -29%
Hematologic malignancies ( AML or MD)-23%
Rate of hematologic transformation 1.3 episodes per 100
patient years
Non-hematologic malignancies -16%
Hemorrhage -7%
Myeloid metaplasia with myelofibrosis -3%

11. Increase RBC production independent of
normal mechanisms
Median age 60 years
Mutation of Janus 2 kinase gene (JAK2
V617F) on chromosome 9
Panmyelosis
Polycythemia vera

12. Disease
Thrombosis
Bleeding
Pathogenesis

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

14. Reported in 2005
Mutation: JAK2V617F
Valine to Phenylalanine
Codon 617
Myeloprolifertive disorders
PV 90-95%
ET50-70%
MF 40-50%
JAK2 mutation

15. JAK2 mutation
Single nucleotide JAK2 mutation (JAK2 V617F)
Valine to phenylalanine substition at codon 617
Mutation occurs in pseudokinase (normally negative
regulator of kinase activity) domain of JAK2 gene resulting in
constitutively activated tyrosine kinase
Exclusive to disorders of myeloid lineage and not observed in
lymphoid neoplasms or solid tumors
Mutation prevalence: PCV (60-90%), ET and Idiopathic
Myelofibrosis (30-50%)

16. Thrombosis
High Hct
Platelet
No correlation with platelet count
Platelet defect
Increase platelet thromboxane A
2production
Decrease response to prostaglandin D
2
Abnormal activation of leukocyte, endothelial cell
Decrease natural anticoagulant
Decrease fibrinolytic activity
Hyperhomocytinemia
Tissue factor synthesized by leukocytes
Pathogenesis

17. Contd
Thrombosis
1.Secondary to increases in blood viscosity and platelet
number
2.15% of PCV pts with a prior major thrombotic complication
(i.e. CVA, MI, thrombophlebitis, DVT, PE)
3.De novo presentation of thrombosis in pts with Budd-
Chiari syndrome and portal, splenic, or mesenteric vein
thrombosis
Suspect PCV in patients with these diagnosis under 45yrs.

18. Contd
Bleeding:
Results from disruption of hemostatic mechanisms due
to:-
1.Increased RBC.
2.Elevated platelet count.
3.Acquiredvon Willebrand syndrome (related to the
absorption of von Willebrand factor onto platelets)

19. Physical Findings Frequency (%)
Symptoms
Headache 48
Fatigue 47
Pruritus 43
Dizziness 43
Visual disturbances 31
Weight loss 29
Erythromelalgia 29
Dyspnea 26
Joint symptoms 26
Epigastric discomfort 24
Thrombosis 20
Signs
Splenomegaly 70
Skin plethora 67
Conjunctival plethora 59
Engorged vessels in the optic fluid46
Hepatomegaly 40
Systolic blood pressure > 140 mmHg 72
Diastolic blood pressure > 90 mmHg 32
Clinical features

20. Clinical Presentation
Pruritus
Especially following vigorous rubbing of skin after warm
bath or shower
Suggested that mast cell degranulation and release of
histamine play a role
Also release of adenosine diphosphate from red cells or
catecholamines from adrenergic vasoconstrictor nerves.
When skin is cooled may cause platelet aggregation and
local production of pruritogenic factors

21. Erythromelalgia
•Burning pain in the feet or hands accompanied by
erythema, pallor, or cyanosis in presence of palpable pulse.
•Microvascular thrombosis

22. •Category A / Major Criteria
1.Total red blood cell mass -In males, greater than or equal to 36 mL
/kg; in females, greater than or equal to 32 mL/kg
2.Arterial oxygen saturation greater than or equal to 92%
3.Splenomegaly
•Category B / Minor Criteria
1.Thrombocytosis with platelet count greater than 400,000/μL
2.Leukocytosis with a white blood cell count greater than 12,000/μL
3.Increased leukocyte alkaline phosphatase (LAP) greater than 100 U/L
4.Serum vitamin B-12 concentration greater than 900 pg /mL or binding
capacity greater than 2200 pg/mL
•The diagnosis is established with A1 plus A2 plus A3 or A1
plus A2 plus any 2 criteria from category B
BUT, there were significant limitations with these original criteria.
Diagnostic criteria set by the PVSG
are as follows:

23. Problems with PVSG criteria
Determination of red cell mass can be misleading if patient is
obese as body fat is relatively avascular
Many institutions do not have ability to calculate
Felt that females with Hb >16.5 and males with Hb >18.5
have increased RCM making measurement not necessary
Elevated LAP score is sensitive but not specific
B12 studies are neither sensitive nor specific

24. Revised WHO criteria for PCV
Major
Hb >18.5 in men, 16.5 g/dL in women
Presence of JAK2 V617F or other functionally similar mutation
Minor
Bone marrow biopsy showing hypercellularity for age with
trilineage growth with prominent erythroid, granulocytic, and
megakaryocytic proliferation
Serum erythropoietin level below normal reference range
Endogenous erythroid colony formation in vitro
Using vitro culture techniques, there is formation of erythroid
colonies in absence of added erythropoietin
Dx requires presence of both major criteria and 1 minor or first
major and 2 minor criteria

25. CBC
Peripheral blood film
Bone marrow examination
EPO level
JAK2mutation
Laboratory

26. Red cell
Increase Hct, Hb
Not increase in PV with iron deficiency
White cell
Leukocytosis
Band form, metamyelocyte, myelocyte (Lt shift)
Increase basophil, eosinophil
Platelet
Increase or normal
CBC

27. RBC:excess red cells, NC, NC
hypochromic microcytic red
cells (iron deficiency)
WBC:increase with band form,
myelocyte ,metamyelocyte
Platelet:increase
Blood Film

28. PBF of PV

29. Hypercellular marrow
Increase erythroid, myeloid, megakaryocyte
(panmyelosis)
Normal maturation of myeloid series
M:E = 2-3:1
Increase megakaryocytes with different size
Negative iron stain
Bone marrow smear

30. Bone Marrow Study of PV

31. Serum erythropoietin
Low Normal High
PV diagnosis
probable
PV diagnosis
possible
Evaluate for secondary
polycythemia
Bone marrow
examination
Characteristics for PV?
yes no
PV Specialized test
Consistent with PVNot consistent with PV Reevaluate in
3 mo
Specialized tests
-JAK2 mutation
-BM immunochemistry for c-mpl
-PCR for PRV-1 gene
-EEC formation
Mayo Clin Proc 2003;78:174-94.

32. Cause of death
Thrombosis
Malignancy : acute leukemia, non-RE malignancy
Myelofibrosis
Bleeding
Cause of death

33. Research markers
Thrombopoietin receptor MPLexpression:
Low in megakaryocytes and in CD34-positive bone
marrow cells.
Expression of PRV1mRNA in granulocytes: PRV1
transcription is increased.

34. Old age: age > 60 years
Previous thrombosis
Phlebotomy treated group
Other cardiovascular disease:
DM
Smoking
Risk of thrombosis

35. Treatment Polycythemia Vera
Phlebotomy to maintain
Hct < 45% male, <42% female
High risk of thrombosis
•Age>60 years
•Previous thrombosis
•Other cardiovascular risk
Platelet > 1,500,000 /um
Age < 50 yr
Age 50-70 yr Age > 70 yr
Interferon Hydroxyurea
Busulphan or
32
P
Low dose
ASA

36. Phlebotomy
Goal is to reduce viscosity, reduce HCT to <45.
Yielded best overall survival in initial PVSG trial from
1967-1987
But increased risk of thrombosis within 3 years leading
to addition of low-dose aspirin

37. Hydroxyurea
Acts by non-alkalating mechanism to inhibit the enzyme
ribonucleotide diphosphate reductase involved in DNA
synthesis
Reduced incidence of thrombosis compared to
phlebotomy
Effective in reducing blood counts although transient
cytopenia may occur
Some question of whether this drug has potential for
being leukemogenic, although not proven

38. Interferon alpha
Wide range of biological actions including anti-proliferative and
cellular differentiating effects
Shown to provide relief from intractable pruritus and reduce
spleen size
Associated with significant side effects including influenza-like
syndrome, pyrexia, myalgias, and athralgias
Not shown to be teratogenic or cross placenta thus could be
used in pregnancy

39. Potential Treatments
Imatinib (Gleevec)
Tyrosine kinase inhibitor which inhibits tyrosine kinase
activity of BCR-ABL (remember CML)
In vitro it inhibits autonomous growth of erythroid
colonies in PCV
Could this have similar effect on tyrosine kinase activity
of JAK2?

40. Surgery
Splenectomy:
1.Painful splenomegaly.
2.Repeated episodes of thrombosis causing splenic
infarction.
3.Budd-Chiari syndrome

41. High Hct, absent secondary erythrocytosis
Headache, plethora, thrombosis, pruritus
Mild to moderate splenomegaly
Hepatomegaly
Leukocytosis, thrombocytosis
Panmyelosis
Low erythropoietin level
JAK2mutation
Clue for diagnosis of PV