Approach to patients with

thrombocytosis and polycythemia

Dr. Işık Atagündüz

 Polycythemia

• Increase in the hemoglobin concentration

above the upper limit of normal for the
patient's age and sex.

• Increase in hemoglobin above 16.5 g/dl in

males, above 16.0 g/dl in females

• Increase in hematocrit above 49 percent in

males, above 48 percent in females
 Classification of polycythemia

• Polycythemia is classified according to its

pathophysiology

• But major subdivision is into

- Absolute polycythemia: The red cell mass (volume) is

raised

- Relative or pseudopolycythemia: The red cell volume

is normal but the plasma volume is reduced.
 Classification of polycythemia

• Absolute polycythemia:

- Primary polycythemia (PV)

- Secondary polycythemia
 Classification of polycythemia

Relative polycythemia:
The total number of red cells in the body is not
increased.

The red cell volume is normal but the plasma

volume is reduced

- Dehydration: Water deprivation, vomiting

- Plasma loss; burns, enteropathy
Stress polycythemia or Gaisböck syndrome

• The result of plasma volume contraction.

• The TRCV is normal.

• The cause is uncertain

• It occurs particularly in young or middle-aged

men
 Stress polycythemia or Gaisböck syndrome

• May be associated with cardiovascular

problems; e.g. Hypertension, myocardial
ischaemia or cerebral transient ischaemic
attacks

• Diuretic therapy, heavy smoking, obesity and

alcohol consumption are frequently
associated.
 Causes of Secondary Erythrocytosis

as a result of an underlying non-hematologic condition

Associated with Hypoxia:

Chronic hypoxemia, which triggers increased production of

erythropoietin (EPO)

a. Obstructive sleep apnea, obesity hypoventilation syndrome,

and chronic obstructive pulmonary disease (COPD)

b. Cardiovascular disease, usually congenital resulting in

significant venous admixture
 Causes of Secondary Erythrocytosis

c. High altitude residence

d. Hemoglobin variant with increased affinity for

oxygen

e. Heavy smoking

f. Carbon monoxide poisoning

 Causes of Secondary Erythrocytosis

Due to Inappropriate Erythropoietin Increase

a. Benign and malignant tumours of
- kidney (renal cell cancer)
- liver (hepatocellular carcinoma)
- CNS (cerebellar haemangioblastoma,
meningioma)
- uterus (uterine leiomyoma)
- ovary
- phaeochromocytoma
 Causes of Secondary Erythrocytosis
Due to Inappropriate Erythropoietin Increase

b. Non- malignant Renal disease

- hydronephrosis
- vascular impairment (renal artery stenosis)
- cysts (polycystic kidney disease)
 Causes of Secondary Erythrocytosis

Associated with Adrenocortical Steroids or

Androgens
a. Adrenal- hypercorticism (all types)
b. Virilizing tumours
c. Androgens used therapeutically (rarely
corticoids)
 Differential diagnosis of polycythemia

• Look for lung or cardiac disease

• Check arterial PO2

• The serum erythropoietin level is useful in

screening for tumours.

• Look for erythropoietin secreting tumours by

ultrasound, computed tomography (CT) or
magnetic resonance imaging (MRI).
 Differential diagnosis of polycythemia

• Ultrasound of the abdomen to assess spleen size

and to detect renal abnormalities are the most
useful additional tests.

• The full blood count, bone marrow aspirate and

biopsy

• If PV is suspected, polymerase chain reaction (PCR)

test for the JAK2 mutation will confirm this in almost
all cases.
 Polycythemia Vera (PV)
• Excess production of the formed elements of
the blood by a hyperplastic bone marrow.

• The marrow hyperplasia is not secondary to

any recognized bone marrow stimulus.

• The affected cells are members of a clone that

has arisen from a single progenitor
 Polycythemia Vera
• Somatic mutation of a single hematopoietic stem
cell

• Gives its progeny a proliferative advantage.

• The JAK2 mutation is present in hematopoietic

cells in almost 100 % of patients.

• Over-production of granulocytes and platelets.

 Polycythemia Vera

• JAK2 plays a major role in normal myeloid

development

• The V617F JAK2 mutation allows the JAK

protein to become activated even when no
growth factor is bound.

• Increased cell survival and proliferation.

 Polycythemia Vera
• Progenitors of red cells in polycythemia vera are
unusually responsive to erythropoietin

• Relatively benign type of neoplasm of

hematopoietic tissue

• Dominant clinical manifestations are due to the

abnormal increase in red cell precursor activity
 Pathophysiology
• There is a hyperplasia of the precursors of the red
cells, granulocytes, and platelets in the bone
marrow.

• Over production of red cells results in an increase

in the total red cell volume

• Increse in the number of red cells per litre of blood

• absolute increase in the total blood volume of the

body.
 Pathophysiology
• The increased blood volume is due
predominantly to the increase in total red cell
volume

• The plasma volume generally being within the

normal range
 Pathophysiology

• Excessive production of red cells and platelets cause

vascular insufficiency

• Increased blood volume and viscosity slow the blood flow.

• Decreased blood flow rates predispose to thrombosis

• Increased platelet adhesiveness may contribute.

 Pathophysiology

• A hemorrhagic tendency also occurs.

• The cause is incompletely understood

• Vascular swelling and defects of platelet

function may contribute
 Clinical Presentation

• This is a disease of older subjects with an

equal gender distribution.

• The majority of cases occurring between 40

and 80 years

• Most frequently at about 60 years.

 Clinical Features
• Result of hyperviscosity, hypervolaemia or
hypermetabolism.

• The increased blood volume causes swelling and

slowing of the circulation in many organs.

• Therefore, symptoms may be referred to a

number of systems.
 Clinical Features

1. Cerebral symptoms; Headache, fullness in the

head, and dizziness, visual symptoms, tinnitus,
syncope, loss of memory, inability to concentrate,
irritability, cerebrovascular accidents

2. Weakness, fatigue, and weight loss

3. Dyspnoea, blurred vision and night sweats,

pruritus, characteristically after a hot bath
 Clinical Features

4. Plethoric appearance: ruddy cyanosis,

conjunctival redness and retinal venous swelling

5. Splenomegaly occurs in 75% of patients.

6. Haemorrhage

7. Thrombosis (either arterial or venous)

 Laboratory Findings

1. The red cell counts is raised, usual values being 8-

10x1012/L, the hemoglobin level is usually in the range of
18-24 g/dl. The HCT is raised, usually 0,60-0,70

2. A neutrophil leucocytosis is seen in over half of patients

3. A raised platelet count is present in about half of patients

4. The JAK2 mutation is present in nearly 100 % of patients

 Laboratory Findings

5. The bone marrow is hypercellular with

trilineage growth (panmyelosis)

6. Serum erythropoietin usually low.

7. Plasma iron and ferritin levels may be decreased

 Laboratory Findings

9. Blood viscosity is increased.

10. Plasma urate is often increased

 The Diagnostic Criteria- WHO 2016
Major Criteria:

1- Haemoglobin>16.5 g/dl in men, 16.0 g/dl in women or

Hematocrit >49% in men, Hematocrit >48% in women

2- Bone marrow biopsy showing hypercellularity for age with

trilineage growth (panmyelosis) with prominent erythroid,
granulocytic, and megakaryocytic proliferation

3- Presence of JAK2V617F or JAK2 exon 12 mutation

Minör Criterion:
Serum erythropoietin level below the reference range for normal
 Differential Diagnosis
• Other causes of a raised hemoglobin levels
must be considered.

• Which are;
- Pseudopolycythemia
- Secondary hypoxic erythrocytosis
- Renal erythrocytosis
 Course and prognosis

• Median survival is about 10 to 16 years.

• Thrombosis and haemorrhage are major problems.

• Transition from PV to myelofibrosis occurs in

approximately 20 % of patients

• Approximately 5 % of patients progress to acute

leukaemia.
 Treatment

• The principle of treatment is reduction in the red cell

mass by venesection, followed by suppression of
bone marrow cell production

• Asymptomatic patients may not be treated

• Symptomatic patients and those at high risk of

thrombosis require therapy

• The primary risk factors for thrombosis are older age

(≥ 60 years) and a previous history of thrombosis
 Treatment
• ASA of 100 mg per day per orally is given.

• Phlebotomy: Removal of 500 cc blood once a week or biweekly

target Hct is <45%, then maintain this level

• Myelosuppressive agents used in treatment are;

– Hydroxyurea
– Alkylating agents such as busulfan

• Interferon alpha
 Thrombocytosis

• Thrombocytosis is defined as a platelet count

exceeding the upper limit of the reference
range.

• A value of > 450,000 platelets/micL (>450 x

109/L)
Causes of Thrombocytosis
 Evaluation of Thrombocytosis

• The most important distinction is between

reactive thrombocytosis and primary
thrombocythemia.

• Some features may be helpful in the distinction

• Sometimes the only way to be certain is to

follow the patient for several months
 Approach to Reactive Thrombocytosis

• Reactive thrombocytosis is far more common than

primary thrombocythemia

• It is not associated with increased risk of either

thrombosis or hemorrhage

• Treatment is unnecessary.

• The underlying cause of thrombocytosis should be

identified and treated appropriately.
Essential thrombocythaemia- Definition

• Primary thrombocythemia (essential

thrombocythemia) is a clonal hematopoietic
stem cell disorder.

• There is a sustained increase in platelet count,

because of megakaryocyte proliferation.

• Half of the patients have JAK2 (Va1617Phe)

mutation.
 Essential thrombocythaemia

• The major clinical consequences of primary

thrombocythemia are thrombosis and
hemorrhage

• The occurrence of thrombosis or hemorrhage

appears to be related to qualitative platelet
abnormalities

• Transformation to AML occurs but is rare

 Epidemiology

• The estimated incidence of primary

thrombocythemia is low
(~1 to 2 per 100,000 per year)

• It occurs predominantly in older people, with

an average age at diagnosis of ~50 to 60 years
 Clinical Features

• Most patients are asymptomatic,

• Thrombocytosis is discovered as an incidental

finding on a routine CBC.
 Common clinical features

Microvascular occlusions:
Usually involve the digits and can cause pain,
acrocyanosis, necrosis, and gangrene of the
fingertips or toes.

Erythromelalgia (redness and burning pain in the

digits which is relieved by aspirin) is a
common symptom.
 Common Clinical Features
Large vessel thromboses: The arteries to the lower
extremities but can involve the coronary, renal,
mesenteric, subclavian, or carotid arteries.

Thrombosis of the hepatic veins (Budd-Chiari

syndrome), splenic veins, and veins of the lower
extremities may occur.

Bleeding: Gastrointestinal, the urinary tract, skin,

eyes, gums, joints, and brain is commonly seen.
 Common Clinical Features

• Neurologic events: Headaches, paresthesias,

transient ischemic attacks, visual disturbances,
and seizures can occur.
 Physical Examination

• Generally unremarkable.

• Discoloration or gangrene of the toes or

fingertips.

• Mild splenomegaly

• Marked splenomegaly suggests another disease.

 Laboratory Findings

• The platelet count is over 600x109/L

• Hemoglobin level is usually normal

• Mild leukocytosis (<20,000/L) is often present

• The bone marrow is hypercellular, with a

marked increase in megakaryocytes.
 Laboratory Findings

• Mild increase in LDH and uric acid.

• The bone marrow is hypercellular, with a

marked increase in megakaryocytes.

• Clustering of megakaryocytes is characteristic

 The Diagnostic Criteria WHO 2016

Major criteria:

1- Sustained platelet count ≥ 450x10 9/L

2- Bone marrow biopsy specimen showing proliferation mainly of the

megakaryocytic lineage with increased numbers of enlarged, mature
megakaryocytes. No significant increase or left-shift of neutrophil
granulopoiesis or erythropoiesis

3- Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-
ABL1 positive chronic myelogenous leukemia or myelodysplastic syndrome or
other myeloid neoplasm

4- Presence of JAK2, CALR or MPL mutation

Minor criterion:

Presence of a clonal marker or absence of evidence for reactive thrombocytosis

 Disease Course

• Survival is good

• Progression to end-stage myelofibrosis or

transformation to acute leukemia occur in
less than 5% of patients
 Treatment

• Asymptomatic patients may not be treated

• Symptomatic patients and those at high risk of

thrombosis require therapy

• The primary risk factors for thrombosis and

hemorrhage are older age (> 60 years) and a
previous history of thrombosis
 Treatment

• Low-dose aspirin: In all the patients

• Hydroxyurea or Interferon: For bone marrow

supression

• Anagrelide (Agrylin): supresses megakaryocyte

maturation.