1. Polycythemia

2. Introduction
• The three pathophysiologic categories of
polycythemia are:
Relative polycythemia (red blood cell mass
normal; plasma volume decreased)
Secondary polycythemia (red blood cell mass
increased)
Polycythemia vera (red blood cell mass
increased)

3. POLYCYTHEMIA VERA
• Alternative Names: Primary polycythemia
Polycythemia rubra vera Myeloproliferative
disorder Erythremia Splenomegalic
polycythemia Vaquez's disease Osler's disease
Polycythemia with chronic cyanosis
Myelopathic polycythemia Erythrocytosis
megalosplenica Cryptogenic polycythemia.

4. • Polycythemia
vera
is
a
chronic
myeloproliferative disorder characterized by
increased red blood cell mass (RCM), or
erythrocytosis The resultant hyperviscosity of
the blood predisposes such patients to
thrombosis.
• Increased RCM is accompanied by increased
white blood cell (myeloid) and platelet
(megakaryocytic) production, which is due to
an abnormal clone of the hematopoietic stem
cells with increased sensitivity to the different
growth factors for maturation.

5. • The mutation that causes polycythemia vera is
thought to affect a protein switch that tells
the cells to grow. Specifically, it's a mutation in
the protein JAK2 (the JAK2 V617F mutation).
Most people with polycythemia vera have this
mutation.

6. PATHOPHYSIOLOGY
• Normal stem cells are present in the bone
marrow of patients with PV. Also present are
abnormal clonal stem cells that interfere with
or suppress normal stem cell growth and
maturation.
• Evidence indicates that the etiology of
panmyelosis is unregulated neoplastic
proliferation. The origin of the stem cell
transformation remains unknown
Pathophysiology

8. • Polycythemia vera should be suspected in
patients with elevated hemoglobin or
hematocrit levels, splenomegaly, or portal
venous thrombosis.
• Polycythemia vera Bone marrow film at 100X
magnification demonstrating hypercellularity
and increased number of megakaryocytes
• Increase in blood hemoglobin level to 18g/dl.
An RBC count of 6 million/mm 3 or a
hematocrit of 55 percent or greater.

9. EPIDEMIOLOGY
• Polycythemia vera is a rare disease The peak
incidence of PV is age 50-70 years However, it
occurs in persons of all age groups, including
those in early adulthood and childhood. The
disease is slightly more common in males than
in females.

10. PROGNOSIS
• Generally, PV is associated with a shortened
life span. Median survival for all patients is
around 8 to 15 yr if especially treated,
although many patients live much longer.
Thrombosis is the most common cause of
death, followed by complications of
myelofibrosis and development of leukemia.
• PV is a malignant disease that progresses in
severity over time if left untreated.

11. SIGNS AND SYMPTOMS
3 MAJOR HALLMARK SIGNS
• Massive production of RBC
• Excessive leukocyte production
• Excessive production of platelets
Are related to :
• Hyperviscosity
• Extreme hyeprcellularity –cell excess

12. • Facial skin have a dark, flushed appearance
and can also be purplish or cyanotic
• Most patient have intense itching caused by
dilated blood vessels poor O2.
• Visisble superficial vein distention.
• thromboses that can lead to poor oxygen
delivery and symptoms that include:
headache, dizziness, vertigo, tinnitus, visual
disturbances, angina pectoris, or intermittent
claudications.

13. RISK FACTORS
• Increasing age. The risk of polycythemia vera
increases with age. It is more common in
adults older than 60, and it's rare in people
younger than 20.
• Being male. Polycythemia vera affects men
more often than women.
• Having a family history of polycythemia
vera. Having close relatives with polycythemia
vera may increase your risk of the disease

14. DIAGNOSIS
• The health care provider will perform a physical
exam. Tests that may be done include:
 Bone marrow biopsy
 Complete blood count with differential
 Comprehensive metabolic panel
 Erythropoietin level
 Genetic test for the JAK2V617F mutation
 Oxygen saturation of the blood
 Red blood cell mass
 Vitamin B12 level

15. • This disease may also affect the results of the
following tests:
ESR
Lactate dehydrogenase
Leukocyte alkaline phosphatase
Platelet aggregation test
Serum uric acid

16. WHO Criteria for Diagnosis of
Polycythemia Vera
Level Specifics
• Major criteria
1. Evidence of increased RBC volume, including ≥ 1 of the following:
– Hb > 18.5 g/dL in men or > 16.5 g/dL in women
– Hb or Hct > 99th percentile of method-specific reference range
for age, sex, and altitude of residence
– Hb > 17 g/dL in men or 15 g/dL in women if associated with a
documented and sustained increase of at least 2 g/dL from the
patient's baseline value not accounted for by correction of iron
deficiency
– Elevated RBC mass > 25% above mean normal predicted value
2. Presence of JAK2 617VF or other functionally similar mutation
(eg,JAK2 exon 12 mutation).

17. • Minor criteria
1. Bone marrow biopsy showing hypercellularity
for age with trilineage growth (panmyelosis)
and prominent erythroid, granulocytic, and
megakaryocytic proliferation
2. Serum erythropoietin level below the
reference range for normal
3. Endogenous erythroid colony formation in
vitro

18. • A diagnosis of polycythemia vera is made
when a patent fulfills all three of the major
criteria Or any two major and any two minor
criteria.
Major Criteria
total RBC vol Men > or = to 36 mL/kg Women
> or = to 32 mL/kg
arterial 02 saturation > or = to 92%
Splenomegaly

19. • Minor Criteria
Thrombocytosis with platelet count >
400,000/Ml
 Leukocytosis with WBC > 12,000/mL
Increased leukocyte alkaline phosphatase LAP
> 100U/L (no infection)
Serum B12 > 900 pg/mL

20. Laboratory findings
• Labs Peripheral blood findings Increased
hemoglobin & hematocrit ,Normal red blood
cell morphology, unless iron deficient or spent
phase, Normoblasts may be present, Mild to
moderate leukocytosis ,Mild neutrophilia
and/or basophilia, Thrombocytosis.

21. • Serum Epo assay Epo levels in patients with PV
are often below the lower limit of normal
compared with patients with secondary
erythrocytosis and pseudoerythrocytosis but
the levels for PV and secondary erythrocytosis
or pseudoerythrocytosis overlap and are
nonspecific for differentiating these
conditions.
• Fibrosis is increased and detected early by
silver stains for reticulin.

22. • Labs. The red blood cells in patients with PV
are usually normochromic normocytic unless
the patient has been bleeding from underlying
peptic ulcer disease or phlebotomy treatment
(wherein the cells may be hypochromic and
microcytic, reflecting low iron stores).
• An elevated white blood cell count
(>12,000/µL) occurs in approximately 60% of
patients. It is mainly composed of neutrophils
with a left shift and a few immature cells. Mild
basophilia occurs in 60% of patients. The
leukocyte alkaline phosphatase score is
elevated (>100 U/L) in 70% of patients.

23. • The platelet count is elevated to 400,000800,000/mL in approximately 50% of patients.
• Abnormal platelet function (as measured by
platelet aggregation tests with epinephrine,
adenosine diphosphate, or collagen) may be
demonstrated, but bleeding time may be
normal. Some patients' platelet-rich plasma
aggregates spontaneously without the
addition of any of the above substances. This
indicates a propensity for thromboses.

24. • Bone marrow studies are not necessary to
establish the diagnosis but the findings of:
hypercellularity hyperplasia of the erythroid,
granulocytic and megakaryocytic cell lines
myelofibrosis support the diagnosis of a
myeloproliferative process.
• Iron stores are decreased or absent because of
the increased red blood cell mass, and
macrophages may be masked in the myeloid
hyperplasia that is present.

25. • Hyperuricemia occurs in 40% of patients and
reflects the high turnover rate of bone
marrow cells releasing DNA metabolites.
• Imaging Studies An enlarged spleen is often
palpable and does not require any imaging
studies. In some patients with posteriorly
enlarged spleens or in those who are obese,
ultrasonography or CT scanning may be able
to detect an enlargement missed during the
physical examination.

26. COMPLICATIONS
• The disease usually develops slowly Symptoms
are often insidious in onset They are often
related to blood hyperviscosity secondary to a
marked increase in the cellular elements of
blood, which impairs microcirculation.
• Thromboses and bleeding are frequent in
persons with PV and myeloproliferative disease
(MPD), and they result from the disruption of
hemostatic mechanisms because of an
increased level of red blood cells an elevation
of the platelet count.

27. • Bleeding complications ,, include epistaxis,
gum bleeding, ecchymoses, and GI bleeding.
Thrombotic complications ,, include venous
thrombosis or thromboembolism and an
increased prevalence of stroke and other
arterial thromboses.
• Possible infarctions, necrosis
• Tissue hypoxia and anoxia
• Gout and hyperkalemia

28. • Abdominal pain due to peptic ulcer disease is
present because PV is associated with
increased histamine levels and gastric acidity
or possible Budd-Chiari syndrome (hepatic
portal vein thrombosis) or mesenteric vein
thrombosis.
• Hypertension is common in patients with PV.
The red blood cell mass should differentiate
PV from Gaisbock syndrome, which is
hypertension and pseudopolycythemia (ie,
high hemoglobin levels due to low plasma
volume).

29. • extramedullary hematopoiesis: Hepatomegaly
and Splenomegaly, when present, can cause
early satiety because of gastric filling being
impaired by the enlarged spleen or, rarely,
symptoms of splenic infarction. Weight loss
may result from early satiety or from the
increased myeloproliferative activity of the
abnormal clone.
• Pruritus results from increased histamine
levels released from increased basophils and
mast cells and can be exacerbated by a warm
bath or shower. This occurs in up to 40% of
patients.

30. TREATMENTS
• Treatment The objective of treatment is to
reduce the high blood viscosity (thickness of
the blood) due to the increased red blood cell
mass and to prevent hemorrhage and
thrombosis. No single treatment is available
for PV. The major goal of treatment is to
prevent thrombotic events.

31. Aspirin therapy
• (81 to 100 mg po once/day) reduces the
incidence of thrombotic complications. Thus,
patients undergoing phlebotomy alone or
phlebotomy and myelosuppression should be
given aspirin unless contraindicated. Higher
doses of aspirin are associated with an
unacceptably increased risk of bleeding.

32.  PHLEBOTOMY
• Is a simple procedure without many risks,
except for the eventual development of iron
deficiency.
• The mainstay of treatment for PV is
phlebotomy, which is aimed at reducing
hyperviscosity by decreasing the venous
hematocrit level.
• Common thresholds for phlebotomy are
Hct > 45% in men and > 42% in women.
• Initially, 300 to 500 mL of blood are removed
every other day

33. • Because phlebotomy is the most efficient
method of lowering the hemoglobin and
hematocrit levels to the reference range, all
new patients are initially phlebotomized to
decrease the risk of complications. The
presence of elevated platelet counts that may
be exacerbated by the phlebotomy is an
indication to use myelosuppressive agents to
avoid
thrombotic
or
hemorrhagic
complications.

34. Myelosuppressive Therapy
• The use of myelosuppressive agents such as
radioactive phosphorus (32P), chlorambucil
(Leukeran), busulfan (Myleran), pipobroman
(Vercyte), and hydroxyurea (Hydrea) in
conjunction with phlebotomy has been studied.
• Hydroxyurea has been the mainstay therapy for
PV after the PVSG results indicated it is an
effective agent for myelosuppression; however,
concerns have been raised regarding long-term
risks for leukemic transformation. In the PVSG
trial, HU therapy reduced the risk of thrombosis
compared with phlebotomy alone.

35. • Recombinant
interferon
alfa-2b
reduces
myeloproliferation and splenomegaly, and
alleviates the symptom of pruritus. It has no
established mutagenic potential, and thus may
prove a valuable option for younger patients and
those with significant splenomegaly. However,
many patients discontinue interferon because of
side effects, and high cost of treatment.
• Occasionally, chemotherapy may be given to
suppress the bone marrow. The use of antiplatelet therapy (such as aspirin) is controversial
because it may cause gastric bleeding. Allopurinol
is given for hyperuricemia (gout).

36. SECONDARY POLYCYTHEMIA

37. Introduction
• Secondary erythrocytosis is erythrocytosis
that develops secondary to circulating
erythropoiesis-stimulating substances.
• In secondary erythrocytosis, only the RBC line
is increased.
• Spurious erythrocytosis may occur with
hemoconcentration (eg, from burns, diarrhea,
diuretics).

38. CAUSES
•
•
•
•
Smoking
Chronic arterial hypoxemia
Tumors (tumor-associated erythrocytosis)
Secondary causes of increased red blood cell
mass (e.g., heavy smoking, chronic pulmonary
disease, renal disease) are more common than
polycythemia vera.

39.  Less common causes include certain
congenital disorders such as:
• High O2-affinity hemoglobinopathies
• Erythropoietin receptor mutations
• Chuvash polycythemia (in which a mutation in
the VHL gene affects the hypoxia-sensing
pathway)
• Proline hydroxylase 2 and hypoxia-inducible
factor 2 (HIF-2) α mutations

41. SIGNS AND SYMPTOMS
• Patients may present with complaints of
pruritus after bathing, burning pains in the
distal
extremities
(erythromelalgia),
gastrointestinal disturbances, or nonspecific
complaints such as weakness, headaches, or
dizziness.

42. DIAGNOSIS
Tests done when erythrocytosis is present
include:
• Arterial O2 saturation
• Serum erythropoietin levels
• P50

43. • A low or low-normal serum erythropoietin level
suggests
PV.
Patients
with
hypoxia-induced
erythrocytosis
have
an
elevated
level
or
inappropriately normal level for their elevated Hct.
Patients with tumor-associated erythrocytosis typically
have elevated erythropoietin levels. Patients with
elevated erythropoietin levels or microscopic
hematuria should undergo abdominal imaging, CNS
imaging, or both to seek a renal lesion or other tumor
sources of erythropoietin.
• P50 measures the affinity of Hb for O2; a normal result
excludes a high-affinity Hb (a familial abnormality) as
the cause of erythrocytosis.

44. Comparison of Polycythemia Vera and
Secondary Polycythemia
Polycythemia Vera
Secondary Polycythemia
Pathophysiology
Neoplastic hematopoietic
stem cell disorder
Due to tissue hypoxia
causing an appropriate
increase in Epo production,
or to renal or hepatic
disease causing an
inappropriate increase in
Epo production
CBC
Hct and often WBC and
platelets are increased
Only Hct is increased
Epo level
Decreased or low normal
Normal or increased
Treatment
Phlebotomy and/or
hydroxyurea to keep Hct
below 45%; most patients
should also take aspirin 81
mg daily to decrease the
risk of thrombosis
Treatment is usually not
required.

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