1. Polycytemia
Dr. Mamlook Elmagraby

2. Objectives of the lecture:
Upon completion of this lecture, students should be able to: Understand the physiological mechanisms that regulate erythropoiesis Recognize the secondary and primary causes of polycythemia Understand the clinicopathological features of polycythemia vera Recognize the importance of genetic studies in diagnosis and management of polycythemia vera Understand the general aspects of essential thrombocythemia and primary myelofibrosis

3. Major categories of neoplastic proliferation of white cells
Myeloid neoplasms
Acute myeloid leukemias
Myelodysplastic syndromes
Myeloproliferative neoplasms
Myelodysplastic/myeloproliferative neoplasms
Lymphoid neoplasms
Lymphocytic/lymphoid leukemias
Acute lymphoblastic leukemias
Chronic lymphocytic leukemias
Lymphoma: Non-Hodgkin and Hodgkin lymphoma
Histiocytic and dendritic cell neoplasms
Langerhans cell histiocytosis

4. WHO 2008 Myeloproliferative neoplasms
Chronic myelogenous leukemia, BCR-ABL-1 positive
Polycythemia vera – JAK2 mutation
Primary myelofibrosis – JAK2 or MPL mutation
Essential thrombocythemia
Platelet count > 450 × 109 /L
JAK2 mutation
Myeloproliferative neoplasm, unclassifiable
the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) 

5. Polycythemia

6. Absolute Relative Primary (low erythropoietin level) Polycythemia vera
Secondary (high erythropoietin level)
Lung disease
Living in high-altitude
Cyanotic heart disease (Tetralogy of Fallot)
Erythropoietin-secreting tumors (renal cell carcinoma)
Relative
Reduced plasma volume
Hemoconcentration (dehydration)
Classification of polycythemia
Polycythemia refers to an increase in the RBC mass, usually with a corresponding increase in hemoglobin level
Cyanosis bluish discoloration of the skin and mucous membranes, caused by a lack of oxygen in the blood
Tetralogy of Fallot pulmonary stenosis, a ventricular septal defect, right ventricular hypertrophy, an overriding aorta

7. Polycythemia Vera (PV)
PV is an acquired myeloproliferative neoplasm arising from malignant transformation of hematopoietic stem cell PV is strongly associated with activating mutations in the tyrosine kinase JAK2 PV is characterized by increased, uncontrolled marrow production of red cells, granulocytes and platelets This leads to erythrocytosis (polycythemia) and or granulocytosis and thrombocytosis in the peripheral blood Erythrocytosis is responsible for most of the clinical symptoms

8. Polycythemia Vera (PV)
Morphology
The major changes in polycythemia vera stem from increases in blood volume and viscosity caused by the polycythemia
Congestion of many tissues is characteristic
The spleen usually is slightly enlarged because of vascular congestion
The liver is enlarged and often contains small foci of extramedullary hematopoiesis
Congestion local increased volume of blood in a particular tissue

9. Polycythemia Vera (PV)
As a result of the increased viscosity and vascular stasis, thromboses and infarctions are common Hemorrhages also occur in a third of the patients Hemorrhages most often affect the GIT, oropharynx, brain Hemorrhages may occur spontaneously or following some minor trauma or surgical procedure Platelets produced from the neoplastic clone are often dysfunctional
Platelet dysfunction in PV typically is characterized by abnormal aggregation and reduced secretion products
platelets spontaneously activate, secrete their products, form aggregates then deaggregate, and recirculate as exhausted defective platelets
Thrombosis is intravascular coagulation of blood

10. Polycythemia Vera (PV)
Clinical Features.
Polycythemia vera appears insidiously, usually in late middle age.
Plethora and cyanosis due to stagnation and deoxygenation of blood in peripheral vessels are early findings
About 30% of patients develop thrombotic complications, usually affecting the brain or heart
Hepatic vein thrombosis is an uncommon complication
Plethora a red florid complexion
Insidious proceeding in a gradual, subtle way, but with harmful effects

11. Polycythemia Vera (PV)
Minor hemorrhages are common and fatal hemorrhages occurs in 5% to 10% of patients Headache, dizziness and visual problems result from vascular disturbances in the brain and retina Gastrointestinal symptoms (hematemesis, and melena) are common Extramedullary hematopoiesis in spleen leads to splenomegaly Because of the high rate of cell turnover, symptomatic gout is seen in 5% to 10% of cases
cell turnover The rate at which cells are removed and are replaced

12. Polycythemia Vera (PV)
In those receiving no treatment, death occurs from vascular complications within months The median survival is increased to about 10 years by lowering the red cell count to near normal through repeated phlebotomy About 10% of cases progress to myelofibrosis Acute myelogenous leukemia may develop in 2 to 5% of cases
Phlebotomy the act of removing blood from the circulatory system through a cut (incision)

13. Polycythemia Vera (PV)
Laboratory Findings.
Peripheral Blood
Hemoglobin: Increased. It is more than 18.5 gm/dL in men and gm/dL in women
Hematocrit: Increased to about 60%
Red cell count : Increased
Total leukocyte count is increased
There is mild to moderate leukocytosis
Basophils often increased
Platelet count: increased (often ˃400,000/μL)
Hematocrit the proportion of a column of centrifuged blood which is occupied by erythrocytes

14. Polycythemia Vera (PV)
Peripheral smear:
RBCs: Show normocytic normochromic picture
Platelets: The platelets are often abnormally large and functionally defective
Bone Marrow
Cellularity: Hypercellular
Hyperplasia of all elements, myeloid and megakaryocytic series with prominence of erythroid precursors

15. Primary Myelofibrosis

16. Primary Myelofibrosis
Primary myelofibrosis is a clonal MPN characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow
In the fully developed disease, the reactive marrow fibrosis replaces hematopoietic cells leading to:
Cytopenias
Extensive extramedullary hematopoiesis
JAK2 mutations are present in 50% to 60% of cases
Most of the remaining cases have other mutations, which also are hypothesized to stimulate increased JAK-STAT signaling

17. Primary Myelofibrosis
The marrow fibrosis may be caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes
Two factors synthesized by megakaryocytes have been implicated:
Platelet-derived growth factor
TGF-β
Red cell production at extramedullary sites is disordered
This factor and the concomitant suppression of marrow function result in moderate to severe anemia

18. Primary Myelofibrosis
Laboratory Findings
Peripheral Smears
RBCs: They show moderate to severe degree of normochromic normocytic anemia
Leukoerythroblastosis
WBCs: Total white cell count is usually normal or reduced, but can be markedly elevated in early stages of the disease
Platelets: They may be abnormally large
The platelet count is usually normal or elevated, but as the disease progresses the count decreases
normochromic normocytic anemia: anemia in which the average size and hemoglobin content of the red blood cells are within normal limits 

19. Primary Myelofibrosis
Bone Marrow
Cellularity:
In early stages, it is often hypercellular due to increase in maturing cells of all lineages
In later stags, it is replaced by fibrosis and becomes hypocellular
Erythroid and granulocytic precursors are morphologically normal
Megakaryocytes are large, dysplastic and abnormally clustered
The blood findings are not specific, and bone marrow biopsy is essential for diagnosis

20. Primary Myelofibrosis
Clinical Features.
Primary myelofibrosis usually occurs in individuals older than 60 years
The patients come to attention because of progressive anemia and splenomegaly
Nonspecific symptoms such as fatigue, weight loss, and night sweats are common
Hyperuricemia and secondary gout resulting from a high rate of cell turnover also are frequently seen

21. Primary Myelofibrosis
The median survival is in the range of 4 to 5 years
Risks to life include:
Infection
Thrombosis and bleeding related to platelet abnormalities
Transformation to AML 
Hematopoietic stem cell transplantation may be curative in those young and fit enough to withstand the procedure

22. Essential Thrombocythemia

23. Essential Thrombocythemia (ET)
ET is a chronic myeloproliferative neoplasm (MPN) which involves primarily megakaryocytic lineage ET is characterized by increased megakaryopoiesis Platelet function and length of survival remain normal ET is an uncommon disorder The median age at diagnosis is 60 to 65 years ET is an indolent disorder with asymptomatic periods interrupted by occasional thrombotic episodes or hemorrhage

24. Essential Thrombocythemia (ET)
Clinical Features. 
Symptoms include headache, dizziness, visual changes
Burning sensation of hands and feet due to blocking of small arterioles by platelet aggregates
Serious arterial thrombotic complications such as transient ischemic attacks, strokes, seizures, angina, and myocardial infarctions may occur
Patients may rarely have purpuric skin lesions or hematomas

25. Essential Thrombocythemia (ET)
Laboratory Findings.
Peripheral Smear
RBCs: Show normocytic normochromic picture
WBCs: Show mild leukocytosis
Platelets:
Increased number of platelets with variation in size and shape are seen
Abnormally large platelets are common
Platelets may form clusters

26. Essential Thrombocythemia (ET)
Bone Marrow
Cellularity: Mild to marked hypercellularity
Erythropoiesis: Normal or shows mild hyperplasia
Myelopoiesis: Normal or shows mild hyperplasia
Megakaryopoiesis: They are markedly increased in number, abnormally large