The document provides a comprehensive overview of chronic myeloproliferative disorders, particularly focusing on polycythemia vera (PV), which is characterized by excessive blood cell production due to mutations in hematopoietic stem cells. It details diagnostic criteria, incidence, clinical features, pathophysiology, genetics, differential diagnosis, and available treatment options for PV, emphasizing the role of the JAK2 mutation in disease progression. While there is no cure for PV, treatment strategies aim to manage symptoms and prolong survival, with myelosuppressive therapies being particularly highlighted.

1. Chronic Myeloproliferative
Disorders II
Polycythemia Vera, Essential
Thrombocythemia, and Idiopathic
Myelofibrosis
By : Maisoon Amarni & Lana Abu Ghali
Dr Fekri Samarah

2. Myeloproliferative Disorders (MPDs)
Definition :
Chronic myeloproliferative disorders (CMPDs) are a diverse group of diseases
originating from the clonal expansion of hematopoietic pluripotent stem cells, leading
to excessive production of one or more blood cell types :
• Erythrocytes
• Leukocytes
• or platelets

3. Myeloproliferative Disorders (MPDs)
Classical Classification :
 Chronic Myelogenous Leukemia (CML): Characterized by excessive granulocyte
production.
 Polycythemia Vera (PV): Marked by overproduction of erythrocytes.
 Essential Thrombocythemia (ET): Involves excessive platelet production.
 Idiopathic Myelofibrosis (IMF): Characterized by marrow fibrosis and extramedullary
hematopoiesis.
 Hallmark physical finding: Splenomegaly (40% to 99% occurrence).

4.  In 1999 WHO expand the classification and introduce :
• chronic neutrophilic leukemia,
• chronic eosinophilic leukemia
• hypereosinophilic syndrome,
• and unclassifiable myeloproliferative disease.
 2008 WHO Classification Changes:
• Replaced term CMPD with “myeloproliferative neoplasms (MPN)”
• Revised diagnostic criteria were implemented for BCR-ABL negative MPNs,
including.(PV, ET, IMF)
• diagnostic criteria for (CEL/HES) MPNs were updated .

5. Polycythemia :
 Absolute polycythemia :
• True polycythemia
• increase in total body red cell volume,
• leading to elevated levels of Hb
• and/ hematocrit/packed cell volume.
 Relative polycythemia:
• Or pseudo polycythemia
• Elevated Hb or hematocrit
• occur due to a decrease in plasma volume,
• without a proportional increase in total red cell volume;
Polycythemia vera

6. Polycythemia :
Absoute Polycythemia:
Classified into two main types:
 Primary Polycythemia:
• Involves an intrinsic abnormality in hematopoiesis
• e.g., polycythemia vera ( PV ).
 Secondary Polycythemia:
• Arises from increased erythropoietin stimulation,
• either with or without hypoxia.
Polycythemia vera

7. Diffinision:
 PV, also known as polycythemia rubra vera, is a chronic disorder affecting the
hematopoietic stem cells.
 It is characterized by the uncontrolled proliferation of:
• erythroid (RBC),
• granulocytic (WBC),
• and megakaryocytic (PLT-producing cells).
 PV results in :
• an increase in the total volume of circulating blood cells,
• this leads to :
 increased blood viscosity,
 thrombosis,
 and hemorrhage.

8. Polycythemia Vera
Diffinision:
Differentiation from Secondary Polycythemia:
 Secondary polycythemia :only erythrocytes (red blood cells) are increased
in number.
 PV : involves proliferation of multiple blood cell types, not just
erythrocytes.
 Differentiation from Relative Erythrocytosis:
 Relative erythrocytosis : increase in hematocrit secondary to a decrease in
plasma volume.
 PV : actual increase in the total number of blood cells, not just a shift in
blood volume.

9. Polycythemia Vera

10. Polycythemia Vera
Diagnostic Criteria:
 established by the Polycythemia Vera Study Group (PVSG)
 help differentiate PV from other conditions and ensure an accurate diagnosis
Major criteria
 Red Cell Mass Increase:
• One of the primary criteria
• indicating elevated production of (RBC)
• This is often a hallmark of PV.
 Absence of Secondary Causes:
• such as chronic hypoxia or
• tumors producing erythropoietin.
• Arterial oxygen saturation ≥ 92%

11. Polycythemia Vera
Diagnostic Criteria:
 Splenomegaly:
• Enlargement of the spleen
• is commonly observed in PV patients.
• It's a significant clinical indicator aiding in diagnosis.
 Minor criteria:
 Thrombocytosis:
• is an increased platelet count.
• This is another characteristic feature

12. Polycythemia Vera
Diagnostic Criteria:
 Leukocytosis:
• characterized by an increased WBC count.
• This, along with other criteria, contributes to the diagnostic process.
 Erythropoietin Levels:
• erythropoietin levels are typically normal or decreased.
• contrasts with conditions like secondary polycythemia
 where erythropoietin levels are elevated
 due to compensatory mechanisms.

13. Polycythemia Vera
Diagnostic Criteria:
 elevated Leukocyte alkaline phosphatase score (>100)
 Increased Vitamin B12 (>900 pg/ml)
 To establish a diagnosis of polycythemia vera:
 3 major criteria are needed,
 or an elevated red cell mass and normal arterial
oxygen saturation and two minor criteria.

14. Polycythemia Vera
 Revisions by WHO
• in 1999 (WHO) updated the diagnostic criteria for Polycythemia Vera (PV) refining
the parameters used for diagnosis.
• introduced additional parameters to enhance diagnostic accuracy include:
 Bone Marrow Panmyelosis:
o PV diagnosis now considers bone marrow examination
o showing panmyelosis, characterized by increased proliferation of erythroid and
megakaryocytic lineages, and granulocytic .
 Erythropoietin Independent Endogenous Erythroid Colony Growth:
o This refers to the ability of erythroid colonies to grow independently of
erythropoietin stimulation.
o Hallmark of PV
o helping differentiate it from other conditions with similar symptoms.

15. Polycythemia Vera
 2008 Criteria Revision:
• Discovery of Genetic Abnormality:
 of JAK2 exon 12 mutations
 the JAK2 V617F mutation.
• JAK2 mutations as part of the diagnostic process
 Major criteria :
 Hemoglobin > 18.5 g/dL in males and > 16.5 g/dL in females
 Presence of JAK2 V617F or other
o functionally similar mutation, such as JAK2 exon 12 mutation

16. Polycythemia Vera
 Minor criteria :
 Bone marrow biopsy
• indicates an increased cellularity for the patient's age
• shows growth in all three major blood cell lineages:
o erythroid (RBC),
o granulocytic (WBC),
o and megakaryocytic (PLT)
o This condition is termed panmyelosis
 Serum erythropoietin subnormal
 Endogenous erythroid colony formation in vitro (EEC)
 To establish a diagnosis of polycythemia vera :
1. requires meeting either both major criteria and
one minor criterion
2. or the first major criterion and 2 minor criteria

17. Incidence :
 Incidence Rate: ranging from 0.5 to 2.3 case per 100,000 population.
 Median Age: around 60 to 65 years old.
 Gender Predominance: PV shows a slight predominance in males.
 Age Range Affected:
 occur in all age groups,
 including young adults
 and occasionally children.
Polycythemia Vera

18. Incidence :
 Familial Incidence:
 Rare
 Reports of familial incidence of PV,
 Suggesting a genetic component.
 Ethnicity:
 more common in Jewish individuals of Eastern European descent
 indicating a potential ethnic predisposition.
Polycythemia Vera

19. The pathophysiology of PV :
• dysregulated production of blood cells
• particularly red blood cells
• due to genetic mutations
• lead to abnormal signaling pathways in HPCS
Mutations:
• mutations in the JAK2 gene
• particularly the JAK2 V617F mutation.
• This mutation leads to constitutive activation of the JAK-STAT signaling pathway,
• in the absence of normal signaling cues such as erythropoietin
Pathogenesis

20. JAK-STAT Signaling Pathway:
 Point Mutation: JAK2 V617F is characterized by a single point mutation where valine (V) is
replaced by phenylalanine (F) at position 617 of the JAK2 protein.
 This mutation leads to the constitutive activation of the JAK-STAT signaling pathway,
promoting uncontrolled cell proliferation.
Pathogenesis
Phenylalanine to valine
substitution at position
617(V617F)

21. JAK-STAT Signaling Pathway:
 The JAK2 V617F mutation in polycythemia vera (PV).
 dysregulated activation of the JAK-STAT pathway
 bypassing the need for normal signaling stimuli like erythropoietin.
 Erythropoiesis, becomes dysregulated in PV.
 The mutated JAK2 protein promotes :
• the survival
• proliferation
• and differentiation of erythroid progenitor cells
• leading to excessive production of red blood cells.
Pathogenesis

22. Pathogenesis
Genetic cause of polycythemia vera

23. autonomous Erythropoiesis
• In PV, erythropoiesis becomes autonomous
• and independent of erythropoietin stimulation.
• PV progenitor cells demonstrate increased sensitivity to erythropoietin and other growth
factors,
• Clonal Stem Cell Disorder:
• PV is characterized by clonal expansion of HPCS
• carrying the JAK2 mutation.
• major myeloid cell lineages (neutrophils, erythrocytes, and platelets) originate from the same
mutated clone, indicating a stem cell origin for PV.
Pathogenesis

24. Bone Marrow Changes:
• In addition to erythroid hyperplasia,
• bone marrow biopsy in PV typically shows hypercellularity
• increased numbers of myeloid, erythroid, and megakaryocytic precursors.
• Fibrosis may develop in advanced stages,
• particularly in primary myelofibrosis transformation.
Pathogenesis

25. Clinical feature
Chronic Nature:
• PV typically has a gradual onset
• and may remain asymptomatic for a long time,
• diagnosed incidentally during routine blood work for other reasons.
Thrombotic and Bleeding Complications:
• Thrombotic and bleeding events are common due to:
 increased erythroid expansion,
 elevated platelets,
 and hyperviscosity of the blood.
Symptoms of thrombosis or bleeding :
o headache, epistaxis, stroke, angina, myocardial infarction

26. Clinical feature
complications of Untreated PV:
• Thrombosis : especially in unusual sites
o like the hepatic vein,
o mesenteric vein,
o and portal vein, is a common complication.
• Up to 10% of PV patients may develop hepatic vein thrombosis,
o leading to Budd–Chiari syndrome.
Other Complications:
• PV patients may also experience gout
• acute gouty arthritis,
• increased risk of peptic ulcer disease,
• early satiety due to splenomegaly,
• and abdominal pain from splenic infarction

27. Clinical feature
Physical Findings:
• Splenomegaly is the most common
• often accompanied by mild hepatomegaly
• and facial plethora due to increased vascular congestion.
• Hypertension may occur in about half of patients.
Transformation and Spent Phase:
• Approximately 15-20% of patients may progress to a "spent phase“
• characterized by increasing anemia,
• worsening hepatosplenomegaly,
• and constitutional symptoms like fever, night sweats, and weight loss.
Leukemic Transformation:
The risk of leukemic transformation in PV over 20 years is around 15%.

28. Clinical finding
Peripheral Blood :
 Erythrocytosis:
• absolute increase in red blood cell count,
• with hemoglobin concentrations typically elevated in males and females.
 Hematocrit Levels:
• Hematocrit levels are usually elevated,
• around 48% in females and 52% in males.
 Total Red Cell Mass (RCM):
• RCM is increased,
• contributing to the erythrocytosis

29. Clinical finding
 Plasma Volume Variability:
• normal, elevated, or decreased,
• influencing the concentration of red blood cells in the blood.
 Peripheral Blood Morphology:
• Initially, erythrocytes are typically normocytic and normochromic
• After therapeutic phlebotomy,
 iron-deficient erythropoiesis
 may result in microcytic hypochromic cells
• Occasionally, patients present with iron deficiency
 secondary to occult blood loss,
 peripheral blood picture resembling thalassemia.
Peripheral Blood :

30. Clinical finding
• Peripheral Blood :
• Nucleated erythrocytes may be present.
• On blood smear,
 erythrocytes often appear crowded,
 even at the feathered edge.
• Reticulocyte count is usually normal or slightly elevated.
 Erythrocyte sedimentation rate (ESR) remains within normal limits
 Leukocytosis:
• ranging from 12-20 * 10^9 /L,
• occurs in about two-thirds of cases
• due to increased granulocyte production.

31. Clinical finding
• Relative granulocytosis
• and relative lymphopenia may be present initially
• Relative and absolute basophilia are common.
• Shift to the left may occur,
 with the presence of myelocytes and metamyelocytes,
 Platelet Abnormalities:
 Megakaryocytic hyperplasia
 leads to increased platelet production.
 Platelet count may be elevated,
 Qualitative platelet abnormalities
 such as abnormal aggregation

32. Clinical finding
 Coagulation Profile:
• Prothrombin time (PT) normal
• activated partial thromboplastin time (APTT) usually normal.
• thrombin time (TT), and fibrinogen level normal
 Advanced Disease Morphology:
• In advanced disease stages,
• morphologic changes in erythrocytes
• resembling myelofibrosis, leukoerythroblastic anemia, and
thrombocytopenia may be observed.

33. Clinical finding
Bone marrow :
 increased Bone Marrow Cellularity:
• Most PV patients exhibit
• a moderate to marked increase in bone marrow cellularity.
• The hypercellularity exceeds that seen in secondary polycythemia.
 Expansion into Long Bones:
• Hematopoietic marrow can extend into the long bones
• due to the increased cellularity.
 Balanced Myeloid to Erythroid Ratio:
• Granulopoiesis and erythropoiesis are often increased.
• the myeloid:erythroid ratio in the bone marrow is usually normal.

34. Clinical finding
Bone marrow :
 Normal Myeloblast Count
 Increased Megakaryocytes:
• One of the significant findings
• increase in megakaryocytes,
• precursor cells of platelets.
 Fibrotic Material :
• Bone marrow biopsies
 reveal a slight to marked increase in fibrotic material
 generally directly proportional to the degree of cellularity.

35. Clinical finding
Bone marrow :
 Eosinophil Increase:
 Iron stores in the bone marrow
• are usually absent
• due to diversion of iron to developing erythroblasts.
 Post polycythemic Stage Changes:
• the bone marrow may show reticulin and collagen fibrosis.
• Cellularity varies but is often hypocellular
• with prominent clusters of megakaryocytes
• Erythropoiesis and granulopoiesis decrease

36. Clinical finding
Genetics :
 JAK2(V617F) Mutation:
• in approximately 95% of patients with Polycythemia Vera (PV),
• 50% of patients (CIMF) and (ET).
 Cytogenetic Abnormalities:
• may exhibit chromosomal abnormalities
• Including aneuploidy and deletions
 Common Abnormalities:
• trisomy 8 or 9.
• abnormally long chromosome 1
• partial deletions of chromosomes 13 and 20 are observed.

37. Clinical finding
Genetics :
 Progression Indicators:
• the frequency of multiple karyotypic abnormalities increases,
• progression from a normal to an abnormal
• considered an adverse prognostic indicator,
• suggesting disease progression and poorer outcomes.

38. Differential Diagnosis
Differential Diagnosis between PV and Secondary Polycythemia:
 According to PVSG criteria, arterial oxygen saturation should be ≥92%.
 If saturation is below 92%, secondary polycythemia related to hypoxia is
suspected.
 PV is described as a pan-myelopathy, affecting various blood cell lines.
 Typically associated with thrombocytosis and leukocytosis

39. PROGNOSIS AND THERAPY
 No Cure, but Prolongs Survival:
• There's currently no known cure for PV
• treatment typically helps in prolonging survival and managing symptoms.
 Therapiotic Phlebotomy:
• is a common treatment approach.
• removing blood from the body
• to lower the hematocrit
• below a certain threshold
• typically below 0.45 L/L or 45%.
• This helps reduce the number of red blood cells
• decreases iron levels in the body.

40. PROGNOSIS AND THERAPY
 Myelosuppressive Therapy:
• aims to reduce the overproduction of blood cells.
• This therapy may involve chemotherapy and/or radiotherapy.
• Hydroxyurea is a commonly used medication in this category,
 as it inhibits ribonucleotide reductase
 a key enzyme involved in DNA synthesis.
 Compared to other agents like busulphan,
 hydroxyurea carries a lower risk of causing secondary leukemia.

41. PROGNOSIS AND THERAPY
 Survival Rates with Treatment:
• Without any treatment,
• approximately 50% of PV patients survive for about 18 months.
• With only phlebotomy survival can extend to around 14 years.
• thrombosis, or abnormal blood clotting, is a common complication in PV,
• patients may require antiplatelet therapy

42. PROGNOSIS AND THERAPY
 Survival with Myelosuppressive Therapy:
• myelosuppressive therapy, with or without phlebotomy,
• typically have a mean survival of 9 years with chlorambucil therapy
• and 12 years with hydroxyurea therapy.
• these patients may also experience a progressive increase in malignant complications over time.
 Ongoing Research:
• Research efforts are ongoing to develop molecularly targeted therapies
• specifically target the abnormal JAK2 kinase
• targeted therapies aim to provide more effective and less toxic treatment options

43. Essential Thrombocythemia
Definition :
ET is a chronic myeloproliferative disorder characterized by:
 Chronic myeloproliferative disorder
 Characterized by marked thrombocytosis
 Associated with abnormal platelet function
 Increased risk of thrombosis and hemorrhage
 Last of the (MPDs) to be recognized as a distinct entity.
 Thrombocytosis is also seen in other MPDs like (CML), (PV), and (IMF).

44. Essential Thrombocythemia
Definition :
 Diagnosis of Exclusion:
• meaning that other conditions with similar symptoms and features
• must be ruled out before diagnosing ET.
 Lack of Defining Cytogenetic Abnormalities:
 Unlike some other myeloproliferative disorders,
 ET typically does not have any defining cytogenetic abnormalities.
 Diagnostic Criteria:
• proposed by the PVSG in the mid-1970s.
• help define the clinical and laboratory parameters necessary for diagnosing
ET accurately.

45. Essential Thrombocythemia
Incidence :
 The incidence of ET is reported to be 2.5 per 100,000 individuals.
 ET is one of the most common MPDs, with around 6000 new cases identified each year in the US.
 The median age at diagnosis for ET is 60 years.
• up to 20% of patients may be diagnosed at a younger age,
• some being younger than 40 years old.
• Rare in children .
 ET exhibits a gender discrepancy, being more common in women.
• The female to male ratio is reported to be 1.6.

46. Essential Thrombocythemia
Pathogenesis:
ET is a neoplastic disorder primarily affecting the HSCs.
 Clonal Nature of ET:
• ET is identified as a clonal stem cell disorder through sex-linked G6PD studies
• indicating that it originates from a single abnormal hematopoietic stem cell.
• Research using RT-PCR and DNA methylation of X-linked genes
 revealed that 74% of ET patients exhibit monoclonal hematopoiesis.
• Monoclonal hematopoiesis
 refers to the presence of a single clone of cells
 giving rise to various blood cell types.
• In ET:
 monoclonal hematopoiesis is primarily detectable in platelets,
 indicating clonal expansion within the megakaryocytic lineage.

47. Essential Thrombocythemia
Pathogenesis:
 Rare Cytogenetic Abnormalities:
 Frequency of cytogenetic abnormalities in ET is rare,
 suggesting genetic stability in the majority of ET cases.
 Serum Thrombopoietin (TPO):
 TPO levels reported to be inappropriately normal or elevated in ET.
 studies on TPO and its receptor (c-Mpl) haven't confirmed their role in ET pathogenesis.

48. Essential Thrombocythemia
Pathogenesis:
 JAK2 Gene Mutation:
 Detected in 30% to 50% of ET patients,
 constitutive activation of the JAK-STAT signaling pathway.
 ET classification into two groups
• based on the presence of endogenous erythroid colony (EEC) growth and the JAK2 mutation.
• Those with EEC and the JAK2 mutation may have a higher risk of symptomatic hemorrhage and
thrombosis.

49. • Incidental Discovery and Symptomatic Presentation: Automated instruments for platelet counts
lead to more frequent discovery of asymptomatic patients, especially among younger individuals.
Approximately two-thirds of Essential Thrombocythemia (ET) patients are asymptomatic at
diagnosis, while one-third present with hemorrhagic or vaso-occlusive symptoms.
• Clinical Complications: Common complications in ET include thrombosis (11% to 25%) and
hemorrhage (3.6% to 37%). Bleeding is primarily mucocutaneous, with manifestations such as
epistaxis and ecchymoses. Severe bleeding may occur after trauma or surgery. Gastrointestinal
bleeding and esophageal varices bleeding are reported.
• Thrombotic Events: Thrombosis results from intravascular clumping of hyperaggregable platelets
and can occur in arterial, venous, or microcirculatory sites. Common thrombotic events include
stroke, transient ischemic attacks, myocardial infarction, peripheral arterial occlusion, deep
venous thrombosis, pulmonary embolism, and intra-abdominal venous thrombosis.
Clinical Features

50. • Vaso-occlusive Symptoms: Microcirculatory occlusions lead to headache, paresthesia,
erythromelalgia, and acral cyanosis. Erythromelalgia, characterized by painful redness and tingling
sensations in extremities, can progress to necrosis and is alleviated by decreasing platelet count or
anti-inflammatory agents like aspirin.
• Platelet Count and Complications: Thrombotic and bleeding complications are more common when
platelet count exceeds 2000 x 10^9/L. Bleeding manifestations usually involve skin and mucous
membranes, while neurologic manifestations include transient ischemic attacks, visual disturbances,
and headaches. Other symptoms may include recurrent abortions, fetal growth retardation, pruritus,
gout, and priapism. Splenomegaly is present in about 40% of ET patients, with splenic atrophy
occurring in up to 20%.
Clinical Features

51. • Peripheral Blood Smear Findings:
 Characteristic features include marked thrombocytosis (>600,000/µL) with platelet anisocytosis and a
range of platelet sizes from tiny to large giant platelets.
 Platelet anisocytosis correlates with elevated platelet distribution width (PDW), complicating platelet
enumeration on whole blood counters.
 Other abnormalities may include microthrombocytes, platelet aggregates, abnormally granulated
platelets, and megakaryocytic cytoplasmic fragments.
 Review of peripheral smears for platelet aggregates is crucial to avoid counting errors.
• Anemia:
 Up to 50% of patients may have mild normocytic, normochromic anemia, often due to recurrent mucosal
or gastrointestinal bleeding leading to iron-deficiency anemia.
 Peripheral smear examination reveals decreased mean corpuscular volume (MCV) and mean corpuscular
hemoglobin concentration (MCHC), indicative of a microcytic, hypochromic blood picture.
 Erythrocyte morphological findings reflective of hyposplenism may include Howell–Jolly bodies, target
cells, and acanthocytes.
Laboratory Findings

52.  Leukocytosis:
• Present in about one-third of patients, with rare counts exceeding 50 x 10^9/L.
• Neutrophilia is common, but mild eosinophilia or basophilia may occasionally occur. Nucleated red
cells and immature granulocytes may also be evident.
• Variable leukocyte alkaline phosphatase (LAP) score, often normal.
 Bone Marrow Findings:
• Demonstrates a marked increase in the megakaryocytic component, typically larger than normal
and may be dysplastic in appearance.
• Increased erythroid and granulocytic proliferation may be observed without dysplasia or
increased myeloblasts.
Laboratory Findings

53. Platelet Function Studies:
• Abnormalities in platelet aggregation to various agents like epinephrine, collagen, and ristocetin
are frequent.
• Studies may reveal normal bleeding times despite hemorrhagic tendencies.
• The severity of thrombocytosis does not necessarily correlate with symptom presence or
severity.
JAK2 Gene Mutation:
• Found in 23% to 57% of ET patients, supporting multiple etiologies for the disease.
• Red cell mass determinations and erythropoietin levels may be necessary to differentiate from
polycythemia vera.
Laboratory Findings

54. Differential Diagnosis
Diagnosis of Exclusion: ET is often a diagnosis of exclusion, meaning it’s considered only after other
causes of thrombocytosis are ruled out.
Platelet Count: In reactive thrombocytosis, the platelet count seldom exceeds 1000 x 10^9/L and
usually falls in the range of 500 to 750 x 10^9/L. In ET, counts persistently greater than 600 x 10^9/L
warrant investigation.
Bone Marrow Examination: May not distinguish between ET and reactive thrombocytosis. Avoided if
other causes are apparent.
Platelet Morphology and Function: Generally normal in chronic reactive states, whereas ET shows a
variety of abnormalities.
Associated Conditions: ET must be differentiated from other chronic myeloproliferative disorders
(MPDs) and myelodysplastic syndromes with thrombocytosis

55. Differential Diagnosis
Red Cell Mass Determination: May be necessary to rule out polycythemia vera (PV) in ET patients with increased platelets.
Hemoglobin Level: Usually normal or mildly decreased at presentation in ET.
Iron Therapy Trial: If bone marrow aspirate is refused, a trial of iron therapy can be administered to monitor for masked PV.
Chromosomal Analysis: To ensure the absence of the Philadelphia (Ph) chromosome, which is associated with chronic myeloid
leukemia (CML).
Markers of Acute Phase Response: Elevated levels of interleukin-6 (IL-6), plasma fibrinogen, and C-reactive protein may
help differentiate reactive thrombocytosis from ET.
Myelodysplastic Syndromes: These syndromes present with more severe anemia and specific cytogenetic abnormalities or
ringed sideroblasts, differentiating them from ET.
Endogenous Erythroid Colony Formation (EEC): Presence of EEC supports the diagnosis of an MPD like ET and is not found in
reactive thrombocytosis

57. Treatment
Treatment Criteria: Reserved for high-risk patients (age 60+, history of thrombosis, cardiovascular risk factors) or
symptomatic younger patients.
Risk Stratification: Patients are categorized as low-risk (younger than 60, no thrombosis history, platelet count <
1,500,000/µL, no cardiovascular risks), intermediate-risk, or high-risk.
Monitoring: Asymptomatic low-risk patients with extreme thrombocytosis are generally monitored without specific
therapy to lower platelet count.
Plateletpheresis: Used for immediate control of elevated platelet count in urgent situations like surgery or childbirth.
Aspirin: Beneficial for asymptomatic young patients, as shown in trials.
Chemotherapy: Initiated for high-risk patients or those with thrombohemorrhagic complications; includes
myelosuppressive agents like hydroxyurea and anagrelide.
Hydroxyurea: Preferred for its efficacy in reducing thrombosis risk; dosage adjusted to patient response, aiming to reduce
platelet count to < 600 x 109/L

58. Treatment
Anagrelide: Considered for long-term use due to lack of mutagenic potential; side effects include headaches,
palpitations, fluid retention, and diarrhea.
Alpha Interferon: Inhibits megakaryocyte progenitor growth, reducing platelet count; effective in ET treatment
with notable side effects.
Pipobroman: Used in Europe for PV and ET treatment; as effective as hydroxyurea but with a risk of leukemic
transformation.
Low-Dose Aspirin: Effective in preventing thrombosis in ET patients with platelet count < 1000 x 109/L and no
bleeding history; avoided in very high platelet counts until reduced by therapy.
Urgent Treatment: Required for life-threatening symptoms; plateletpheresis can provide temporary relief, but
myelosuppression is necessary for sustained control

59. Idiopathic Myelofibrosis

60. Definition
• Classic Triad of Findings: Chronic idiopathic myelofibrosis (CIMF) is characterized by
fibrosis of the marrow, extramedullary hematopoiesis in spleen and liver leading to
splenomegaly and hepatomegaly, and leukoerythroblastosis and teardrop poikilocytosis in
peripheral blood.
• Clonal Myeloproliferative Disease: CIMF, like other myeloproliferative disorders, is a clonal
disorder characterized by the proliferation of mainly granulocytes and megakaryocytes,
resulting in bone marrow fibrosis.
• Synonyms and Nomenclature: CIMF is known by various synonyms including agnogenic
myeloid metaplasia, myelosclerosis, osteosclerosis, chronic erythroblastosis, aleukemic
myelosis, and chronic or primary myelofibrosis.

61. Definition
• Stages of CIMF: According to WHO criteria, CIMF can be divided into . a prefibrotic
stage (p-CIMF) and a fibrotic stage (f-CIMF). The p-CIMF stage is characterized by
granulocytic and megakaryocytic myeloproliferation without fibrosis.
• Clinical Presentation: Clinically, the prefibrotic stage of CIMF mimics early stages
of Essential Thrombocythemia (ET) and Polycythemia Vera (PV), while the fibrotic
stage is characterized by marrow fibrosis, splenomegaly, and leukoerythroblastosis.
• Diagnosis and Staging: The Updated Cologne criteria are utilized for both diagnosis
and staging of IMF, incorporating specific clinical and laboratory parameters.

62. Incidence and Etiology
 Incidence in the United States: Chronic idiopathic myelofibrosis (CIMF) has an incidence of 1.5 per 100,000 per
year.
 Age and Demographics: Occurs mainly in middle-aged and elderly patients, with a median age of 67 years at
presentation. Rare in childhood, but familial occurrences have been reported across generations.
 Ethnicity and Environmental Factors: CIMF is less common in individuals of African or Spanish descent. Linked
to exposure to thorium dioxide, toluene, benzene, ionizing radiation, and reported with high incidence in
Hiroshima survivors.
 Secondary Causes: Myelofibrosis can occur secondary to chronic infections, particularly tuberculosis and
histoplasmosis, and following myocardial infarction, although the fibrosis in these cases is reactive or
secondary.

63. Pathogenesis
• Origin and Clonal Abnormalities: Recent evidence suggests that Chronic Idiopathic
Myelofibrosis (CIMF) originates at the level of the CD34 hematopoietic stem cell. Clonal
chromosomal abnormalities are found in up to 57% of patients with CIMF, including common
ones such as 13q, 20q, and abnormalities of chromosomes 1 and 7.
• JAK2 Mutation and Granulocyte Activation: The JAK2 (V617F) mutation is reported in 56% of
CIMF patients and correlates with granulocyte activation and increased CD34 counts in
peripheral blood. Higher JAK2 (V617F) mutation burden correlates with increased CD34 cell
counts and progression to marrow fibrosis.

64. • Pathogenesis and Genetic Abnormalities: Unlike Polycythemia Vera (PV) and Essential
Thrombocythemia (ET) characterized by hyperproliferation, CIMF is characterized by ineffective
erythropoiesis and megakaryopoiesis, suggesting additional genetic abnormalities. Fibroblasts do
not share clonal chromosomal abnormalities, suggesting bone marrow fibrosis is a secondary
reaction.
• Role of Cytokines: Various cytokines secreted from platelets and megakaryocytes, including
Transforming Growth Factor Beta (TGF-B), Platelet-Derived Growth Factor (PDGF), and basic
Fibroblast Growth Factor (bFGF), are involved in fibrosis pathogenesis. TGF-B is considered crucial,
promoting collagen secretion. PDGF stimulates fibroblast proliferation, while bFGF moderates
megakaryocyte-stromal cell interactions.
• Thrombopoietin: Thrombopoietin promotes megakaryocyte growth, but mutations in its receptor or
autocrine stimulation haven't been implicated in CIMF pathogenesis
Pathogenesis

65. Clinical Features
• Chronic Progressive Disorder: Myelofibrosis (MF) typically progresses gradually with an
insidious onset, often remaining symptom-free for many years.
• Asymptomatic Presentation: About a third of patients over 60 years old are asymptomatic
initially, with diagnosis often incidental during routine physical exams or through the
discovery of unexplained splenomegaly or abnormal peripheral blood results.
• Symptoms and Complications: Symptoms may include weakness, pallor,dyspnea on exertion,
and bleeding tendencies. Thrombocytopenia or thrombocytosis, platelet defects, or
coagulation abnormalities can lead to bleeding manifestations ranging from minor petechiae
to severe esophageal variceal bleeding.
• Extramedullary Hematopoiesis: Can lead to various complications such as
hepatosplenomegaly, pulmonary hypertension, and epidural space involvement

66. • Infection Risk: Immune deficiency can lead to increased
susceptibility to infections even in the absence of
neutropenia.
• Hyperuricemia and Gout: Increased cellular turnover can
result in hyperuricemia and secondary gout.
• Osteosclerosis: Characterized by increased bone density and
prominence of bony trabeculae on radiologic studies, often
associated with severe bone pain.
• Prognostic Scoring Systems: Various scoring systems, such
as the Lille System, incorporating parameters like
hemoglobin level, white count, constitutional symptoms, and
circulating blasts, are used for prognostication in MF.
Clinical Features

67. Laboratory Findings
• Normocytic Normochromic Anemia: Present in 50% to 90% of patients at diagnosis, with 25%
having severe anemia (Hb < 8 g/dL). The multifactorial cause includes bone marrow failure,
autoimmune hemolysis, ineffective erythropoiesis, and hypersplenism.
• Morphological Changes: Progressively abnormal with leukoerythroblastic blood picture
including abundant nucleated red cells, immature granulocytes, and teardrop-shaped red cells.
• Hemolytic Anemia: Occurs in 15% of cases, usually direct antiglobulin test (DAT) negative but
may be autoimmune, evidenced by marked reticulocytosis and positive DAT.
• Other Anemias: Hypochromic, microcytic anemia from gastrointestinal bleeding, and
megaloblastic anemia from relative folate deficiency are occasional occurrences.
• Leukocyte Count: Variable, with leukocytosis (>10.0 x 10^9/L) initially in 11-13% of patients,
but declines as disease progresses. LAP score typically normal or moderately increased.

68. • Platelet Count: Normal, elevated, or decreased, with approximately 50% of patients having
counts ranging from 450 to 1000 x 10^9/L at diagnosis. Thrombocytopenia becomes more
prevalent as the disease progresses.
• Platelet Morphology and Function: Dysplastic platelets and abnormal platelet functions present
in 50% of patients. Spontaneous platelet aggregation may occur, contributing to bleeding
tendency.
• Bone Marrow Findings: Often “dry tap” due to myelofibrosis, requiring needle biopsy.
Hypercellular with atypical megakaryocytes in prefibrotic phase; reticulin fibrosis minimal in
this phase.
• Prefibrotic Stage: Approximately 25% of patients present in this stage, characterized by a
left-shift in bone marrow, decreased overall erythropoiesis, and abnormal megakaryocytes
without significant reticulin fibrosis.
• Fibrotic Phase: Bone marrow cellularity normal or decreased, with regions of hematopoiesis
separated by loose connective tissue or fat.
Laboratory Findings

69. Differential Diagnosis
• Distinguishing from Other Disorders: Myelofibrosis (MF) needs to be distinguished from other
chronic myeloproliferative disorders (CMPDs) and secondary fibrosis from infiltrative disorders.
• Clinical Mimicry: The prefibrotic stage of chronic idiopathic myelofibrosis (CIMF) may mimic
Essential Thrombocythemia (ET).
• Differentiation from CML: Chronic Myeloid Leukemia (CML) is commonly considered in the
differential diagnosis. Key differentiators include leukocytosis in CML versus usually lower WBC
count in MF, normal to slightly abnormal red cell morphology in CML compared to teardrop
poikilocytosis in MF, and the presence of Ph chromosome and low LAP score in CML.
• Transition from PV: Around 15% to 20% of PV patients may progress to terminal myelofibrosis
characterized by severe anemia, bone marrow fibrosis, and progressive splenomegaly.

70. Differential Diagnosis
• Secondary Causes: MF must be differentiated from secondary causes like metastatic carcinoma,
lymphoma, granulomatous disorders (e.g., tuberculosis), and other hematologic diseases such as
acute megakaryocytic leukemia, hairy-cell leukemia, and myelodysplastic syndromes.
• Autoimmune Disorders: Autoimmune disorders like systemic lupus erythematosus and
scleroderma can also lead to marrow fibrosis, differentiated by specific examination and staining
techniques.
• Multiple Myeloma: Easily differentiated from MF by diffuse marrow plasmacytosis and presence
of monoclonal protein in serum and urine.
• Myelodysplasia (MDS): Difficult to differentiate from MF, but marked splenomegaly,
extramedullary hematopoiesis, and osteosclerosis are indicative of MF.
.

71. Treatment
• Symptomatic Treatment: Similar to Polycythemia Vera (PV) and Essential
Thrombocythemia (ET), management of symptoms in Myelofibrosis (MF) involves cytotoxic
agents to control thrombocytosis, leukocytosis, and splenomegaly.
• Hydroxyurea: Typically administered at doses of 500 mg twice daily, helps reduce spleen
size and control thrombocytosis and leukocytosis, although benefits are often temporary. It
may worsen anemia, potentially mitigated by erythropoietin use..
• Interferon Alpha: Offers hematologic response in hyperproliferative patients.
• Etanercept: A TNF-alpha blocker, palliates constitutional symptoms in MF, which can be
severe.
• Androgens: About one-third of patients respond, although chronic use may lead to
complications such as fluid retention and thromboembolic events.
• Erythropoietin: Generally unsuccessful, but some regressions noted in patients with low
erythropoietin levels.

72. • Thalidomide and Lenalidomide: Thalidomide has mixed effects, while lenalidomide shows promise
with improved side effect profiles and potent immunomodulatory properties.
• SU5416 (Sugen): Limited efficacy in MPD including MF.
• Imatinib Mesylate (Gleevec): Minimal to moderate activity in reducing splenomegaly, with
platelet count increase noted in some trials.
• Zarnestra: Trials in progress; efficacy to be determined.
• Splenectomy: Considered for symptomatic splenomegaly, but carries significant operative
mortality and risk of postoperative thrombosis. Blast transformation post-splenectomy
reported.
• Splenectomy Alternatives: Splenic irradiation provides transient benefit, but requires caution
due to potential severe pancytopenia. Allogeneic stem cell transplantation is the only curative
option, but often hindered by patient factors and donor availability.
Treatment

73. Characteristics of the Chronic Myeloproliferative Disorder