Polycythaemia (erythrocytosis) is defined as an increase in the haemoglobin concentration above the upper limit of normal for the patient's age and sex.
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
4. Relative vs. Absolute
Absolute erythrocytosis
Hct male > 60%, female > 55%
Classification of polycythaemia
5. I. Relative or spurious erythrocytosis
Relative polycythemia is an apparent rise of the erythrocyte level in
the blood; however, the underlying cause is reduced blood
plasma.
Dehydration: Water deprivation, Vomiting
Plasma loss: Burns, Enteropathy
II. Absolute erythrocytosis
Primary marrow diseases: PV, PrimaryErythrocytosis
Secondary : increased EPO production
Erythrocytosis
(Polycythemia)
7. Malignant clonal proliferation of hematopoietic stem
cells leading to excessive erythrocyte production
characterized as a panhyperplastic, malignant, and
neoplastic marrow disorder.
The increase in RBC mass occurs independent of
erythropoietin.
It is a component of myeloproliferative disorder
Polycythemia Vera (PV)
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
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
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 A2 production
Decrease response to prostaglandin D2
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. Acquired von Willebrand syndrome (related to the
absorption of von Willebrand factor onto platelets)
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
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
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
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 PV Not 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 MPL expression:
Low in megakaryocytes and in CD34-positive bone
marrow cells.
Expression of PRV1 mRNA 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
32P
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
JAK2 mutation
Clue for diagnosis of PV