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Myeloproliferative Disorders & PCV

Myeloproliferative Disorders
These are a group of disorders characterized by proliferation of each or all of the precursors for myeloid elements – RBC, WBC and platelets.
Table - WHO Classification of Chronic Myeloproliferative Disorders (Ref. Hari. 18th ed., Pg - 898, table 108.1)
Chronic myelogenous leukemia Chronic neutrophilic leukemia
Chronic eosinophilic leukemia Polycythemia vera
Chronic idiopathic myelofibrosis Essential thrombocythemia


Important Points:

They may undergo transformation into acute leukemia.


Blood count reflects two processes

  1. Proliferating cell line (may involve other myeloid elements also)
  2. Marrow infiltration (may cause a decrease in normal cells


Extra Edge:
  1. Flow cytometry is not used in diagnosis
  2. Flow cytometry is used in diagnosis of PNH.
  3. MPD are diagnosed by BM examination.

Polycythemia Vera

It is a myeloproliferati e disorder with an absolute increase in red blood cell mass. 
A mutation is JAK-2 plays an important role


Important Points

Clinical Features


Clinical symptoms are due to

  1. Blood iscosity
  2. ascular stasis
  3. Thrombotic tendency
  4. Hemorrhagic diathesis (uncommon).

Features are:


Patients are plethoric and cyanotic (owing to stagnation and deoxygenation of blood in periphery)

  1. Angina, CNS disturbance, gout (hyperuricemia), headache, dizziness, hypertension,
  2. GI symptoms, peptic ulcer disease, hematemesis, melena, abdominal pain, (splenic or renal infarction)
  3. Pruritus exaggerated by a warm bath (Aquagenic pruritus) due to release of histamine from basophils may also occur.
  4. Massi e Splenomegaly is present.


Aquagenic pruritus is a skin condition characterized by the de elopment of se ere, intense, prickling-like epidermal itching that is without obser able skin lesions and that is e oked by contact with water


Extra Edge (Ref. Hari. 18th ed., Pg- 899)
  1. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to ascular stasis or thrombocytosis. 
  2. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, is another complication of the thrombocytosis of P due to increased platelet stickiness. 
  3. Gien the large turno er of hematopoietic cells, hyperuricemia with secondary gout, uric acid stones, and symptoms due to hypermetabolism can also complicate the disorder.
Extra Edge Spontaenous bleeding is not a feature. (LQ 2012) 
Causes of Secondary Erythrocytosis
  1. Increased production of erythropoietin secondary to hypoxia
    1. High altitude
    2. Lung disorder
    3. Smoking
    4. Cyanotic congenital heart disease
  2. Inappropriate erythropoietin production: Tumours of kidney, lier, lung, uterus, and cerebellum.
    1. Renal cysts
    2. Hydronephrosis
    3. Hypernephroma
    4. Renal artery stenosis
    5. Renal transplantation
    6. Hepatoma
    7. Pheochromocytoma
    8. Uterine fibromyoma
    9. Cerebellar hemangioblastoma
  3. Spurious or Low Plasma olume Polycythemia
    Gaisböck's Syndrome: decrease in plasma olume with relati e increase in red cell count, hemoglobin, hematocrit,
Important Points
Deference between PCV and Secondary polycythemia
  PCV Secondary polycythemia
1. O2 saturation More than 90% Less than 90%
2. Serum erythropoietin Decrease or normal (LQ 2012) Increase
Criteria for Diagnosis of Polycythemia Vera
Category A
  1. Total red cell mass:
    Male ≥ 36 ml/kg
    Female ≥ 32 ml/kg
  2. Arterial oxygen saturation ≥ 92%
  3. Splenomegaly. 
Category B
  1. Thrombocytosis (platelets > 4 lacs/mL)
  2. Leukocytosis (white blood cells > 1200/mL)
  3. Increased leukocyte alkaline phosphatase (LAP) score (LQ 2012)
  4. Increased B12 level (LQ 2012)
    PV is diagnosed when A1 + A2 + A3 or A1 + A2 and any 2 from category B are present (LQ 2012)
  1. PCV is elevated > 60%
  2. Elevated RBC count 7 – 10 million/μL
  3. Hb level > 18 gm/dL in males and > 16 gm/dL in females (LQ 2012)
  4. Elevated white cell and platelet counts
  5. Hypercellular marrow with erythropoiesis or granulopoiesis and megakaryocytes
  6. Absent iron stores. 
  7. Elevated serum B12 levels > 900 pg/ml
  8. Elevated neutrophil alkaline phosphatase score.
  9. Hyperuricemia, pseudohyperkalemia (due to release of potassium from platelets during in vitro coagulation).
  10. O2 saturation > 92% at room temperature. 
  11. Serum iron may be reduced.
  12. S. erythropoietin ↓,
  13. Microcytic with erythrocytosis
  14. Thrombosis or bleeding both can happen.
Important Points
  1. Infection is not a feature.
  2. O2 saturation > 92% at room temperature
  3. ESR is not raised
  4. Pruritus and hypertension is the feature

Causes of Microcytosis with erythrocytosis

  1. Beta thalassemia
  2. Chronic Hypoxia
  3. PCV

Causes of decrease ESR = PCV, CHF, SSA, Afibroginemia


  1. Venesection
  2. Chemotherapy with hydroxyurea
  3. Symptomatic thrombocytosis or splenomegaly can be treated with interferon alfa.
  4. Anagrelide – a quinazoline derivative and platelet anti – aggregate that also lowers platelet count and can also control thrombocytosis.
  5. Radioactive phosphorous

Recent Advances


Clinical trials testing the effect of JAK2 inhibitors (Lestaurtinib) are currently being performed.


(Ref: Hari.18th ed., pg - 902)

  1. Primary thrombocytosis has very high platelet count. 
  2. These patients can have hemorrhagic and thrombotic tendencies expressed as easy bruising for the former and microvascular occlusions for the latter, such as erythromelalgia, ocular migraine, or TIAs. 
  3. Physical examination is generally unremarkable except occasionally for mild splenomegaly. Massive splenomegaly is more indicative of another myeloproliferative disorder, in particular PV, IMF, or CML.


Extra Edge
Other causes of Massive splenomegaly are:
  1. Chronic malaria
  2. Chronic kala azar
  3. Portal hypertension  
  4. Hairy Cell Leukemia
  5. Glycogen storage disease

Essential Thrombocythemia (ET) (Primary Thrombocytosis)

This is characterized by a very high platelet count of more than 6 Lacs/ml
Clinical Features
Thirty percent of patients are asymptomatic; others present with GI bleed, arterial clotting, paresthesias, erythromelalgia (burning feet), vascular headaches. Splenomegaly and hepatomegaly are there. 


Note: In ET splenomegaly is usually mild i.e. it is never massive splenomegaly which is seen in CML PCV & myelofibrosis (AIIMS Nov 10)
Treatment depends on urgency
  1. In an asymptomatic young patient < 40years, consider aspirin 60 mg/day and observe.
  2. Busulphan or hydroxyurea.
  3. Interferon alpha is given for extreme thrombocytosis.
  4. Radio active phosphorus is used in treatment
  5. Anagrelide is used to prevent thrombosis.
Thrombocytosis is almost always due either to (Ref. Hari. 18th ed., Pg- 970)
  1. Iron deficiency;
  2. Inflammation, cancer, or infection (reactive thrombocytosis);
  3. Underlying myeloproliferative process.
Causes of Thrombocytosis (Ref. Hari. 18th ed., Pg- 903, table 108.5)
  1. Malignancy
  2. Infection
  3. Myeloproliferative disorders:
  4. Myelodysplastic disorders
  5. Postsplenectomy
  6. Hemorrhage
  7. Iron deficiency anemia
  8. Surgery
  9. Rebound: Correction of vitamin B12 or folate deficiency
  10. Hemolysis

Chronic Myeloid Leukemia

Cytogenetic and Molecular Aspects
Ninety percent of patients with CML have Philadelphia chromosomes (Ph). Ph chromosomes occur as a result of reciprocal translocation of material between chromosomes 22 and 9. 
Ph' chromosome BCR-ABL fusion gene
  1. Ph chromosome is formed as a result of reciprocal translocation between long arm of chromosome 22 and chromosome 9 i.e. t (9; 22) (q 34: q11).
  2. ABL protooncogene from chromosome 9 is translocated to chromosome 22 where BCR is present and results in formation of BCR-ABL fusion chimeric gene. (Detected is peripheral blood) 


Important Points

Clinical Feature


CML affects adults between 25 and 60 years of age, and accounts for 15 to 20% of all cases of leukaemia. Peak incidence – fourth and fifth decades of life. It is a myeloproliferative disorder with a slight male preponderance.


The course has three phases

  1. Chronic phase blast cells <5%– responds to treatment (3 to 5 years)
  2. Accelerated phases (occasionally seen)
  3. Blast crisis phase – disease transforms into acute leukaemia, either myeloid or lymphatic. 
Accelerated phase
The WHO criteria to define the accelerated phase by any of the following:
  1. 10–19% myeloblasts in the blood or bone marrow
  2. >20% basophils in the blood or bone marrow
  3. Platelet count <100,000, unrelated to therapy
  4. Platelet count >1,000,000, unresponsive to therapy
  5. Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome
  6. Increasing splenomegaly or white blood cell count, unresponsive to therapy
The patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent. 
Blast crisis
Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed if any of the following are present in a patient with CML: 
  1. >20% myeloblasts or lymphoblasts in the blood or bone marrow
  2. Large clusters of blasts in the bone marrow on biopsy
  3. Development of a chloroma (solid focus of leukemia outside the bone marrow)
Sokal index (Prognosis in CML)
  1. % of circulating blast cells
  2. Spleen size
  3. Platelet count
  4. Age
  5. Cytogenetic clonal evaluation

Extra Edge Size of splenomegaly indicates prognosis.

  1. Normocytic normochromic anaemia
  2. Mean WBC count is (2–6 lakhs/mL) 
  3. Mean platelet count is 46 Lakh/mL
  4. Leucocyte alkaline phosphatase: absent in granulocytes in CML
  5. Plasma uric acid increased
  6. Serum B12 level is increased due to increase in transcobalamin III which is present in neutrophil granules. 
  1. Allogeneic or syngeneic bone marrow transplant: It is the best treatment & is a treatment of choice: It is useful for patients in early chronic phase. 
  2. Imatinib is the drug of choiceQ: If no major cytogenic remission, try dasatinib or INF-alpha
  3. Recent Advances Newer drugs for resistant cases – Nilotinib, Dasatinib
  4. Chemotherapy 
    1. Busulphan
    2. Hydroxyurea
    3. Treatment of accelerated phase and blast crisis: Hydroxyurea is very useful in this stage. When blast transformation occurs, treatment is according to the type of blasts, i.e. whether the type is lymphoblastic or myeloblastic as already described.
      Imatinib is also used in GIST (AIIMS May 2008)
  5. Leukapheresis and SplenectomyQ
  6. ArsenicQ
Recent Advances:
New Drugs:
Sunitinib - GIST, RCC
Sorafenib – RCC, Melanoma
Gefitinib - NSCC
Bortezomib – Multiple myeloma
Erlotinib - Non small cell ca lung (NSCC), Pancreatitis
Dasatinib - CML


Extra Edge (Ref. Hari. 18th ed., Pg- 917, table 109.6)
  1. Omacetaxine (also known as homoharringtonine) is a Protein translation inhibitor
  2. Finglolimod: It controls activation of protein phosphatase 2A that is essential for ABL1-mediated leukemogenesis
  3. Sorafenib: It is a Raf kinase inhibitor that down regulates down stream Bcr-Abl targets TK inhibitors.


Causes of raised HbF:
  1. Juvenile CML
  2. β thalassemia
  3. Sickle cell anemia
  4. Heriditary persistence of fetal hemoglobin (HPFF)
Note: In Juvenile CML Philadelphia chromosome is negative.

Difference between Juvenile and Adult CML


S.no.   Adult CML Juvenile CML
1. Age 10-12 yrs <2 yrs
2. Bleeding - ++
3. Platelet N, ↑ ↓↓
4. Rash - +
5. Spleen +++ +
6. Cell N M
7. HbF N
8. Immunoglobulin N
9. Muramidase N
10. Response to Busulphan Good Poor
The symptoms of CML
  1. Insidious onset.
  2. Tiredness, anorexia and abdominal discomforts are the common complaints.
  3. Weight loss and excessive sweating
  4. Visual disturbance and venous thrombosis.
  5. Pallor.
  6. Massive splenomegaly
  7. Hepatomegaly.
  8. Lymphadenopathy - Lymphadenopathy is not a feature of CML. (MCQ)
  9. Sternal Tenderness - Sternal tenderness is due to hypercellularity of marrow and irritation of periosteum.
  10. Priapism - A few male patients may present with painful, penile erection due to leukostasis.
Leukostatic manifestation due to severe leucocytosis or thrombocytosis
  1. Vaso occlusive disease
  2. CVA
  3. MI
  4. Venous thrombosis
  5. Priapism
  6. Visual disturbance
  7. Pulmonary insufficiency.


Diagnostic Criteria for Chronic Myelomonocytic Leukemia (CMML) according to WHO
  1. It is a chronic disorder (a variant of C.M.L) 
  2. Middle aged and elderly males are usually affected
  3. Persistent peripheral blood monocytosis is >1 x 109/L. 
  4. Absence of Philadelphia chromosome or BCR/ABL rearrangement
  5. Blasts are less than 20% in peripheral blood or bone marrow. 
  6. Dysplasia in one or more myeloid lineages, or in the absence of dysplasia, CMML can be diagnosed, if all other criteria are met together with either of the following
    1. Presence of clonal cytogenetic abnormality   
    2. Monocytosis has been persistent for at least 3 months and all other causes of monocytosis have been excluded
  CML CMML (Chronic myelomonocytic leukemia)
Basophil >2% <2%
Mono cyte <3% >3-10%
Immature granulocytic >20% <10%
Blast <2% <2%


  1. It is a chronic myeloproliferative disorder.
  2. It is characterized by splenomegaly, immature granulocytes and erythrocytes in the blood, distorted tear-drop-shaped RBC forms, and marrow fibrosis. 
  3. The disease is a monoclonal stem cell disease of primitive hematopoietic stem cells. 
  4. When fibrosis is due to a primary hematologic process, it is called myelofibrosis. When the fibrosis is secondary to a tumor or a granulomatous process, it is called myelophthisis.
Table - Disorders Causing Myelofibrosis (Ref. Hari. 18th ed., Pg - 901, table 108.3)
Malignant Nonmalignant
1. Acute leukemia (lymphocytic, myelogenous, megakaryocytic)
2. Chronic myelogenous leukemia
3. Hairy cell leukemia
4. Hodgkin disease
5. Idiopathic myelofibrosis
6. Lymphoma
7. Multiple myeloma
8. Myelodysplasia
9. Polycythemia vera
1. HIV infection
2. Hyperparathyroidism
3. Renal osteodystrophy
4. SLE
5. Tuberculosis
6. Vitamin D deficiency
The fibrosis is a secondary event.
  1. Anemia and signs and symptoms of massive splenomegaly are the hallmarks of the disease. 
  2. Most therapy is supportive. In selected case of true hypersplenism and symptoms from massive splenomegaly, splenectomy is beneficial. 
  3. ANA +ve, RA +ve, Coombs +ve Hemolytic anemia (Ref. Hari. 18th ed., Pg-901)
  4. ↑ CD34 + cell.
  1. Tear drop RBC
  2. Giant platelet
  3. Leukoerythroblastic picture
  1. Blood film shows macrocytic anemia, leukoerythroblastic picture, tear drop poikilocytes
  2. Neutrophil alkaline phosphatase scoreQ is high
  3. Raised urate levelsQ
  4. Bone marrow biopsy shows an excess of megakaryocytes and increased reticulin and fibrous tissue replacement. 
Diagnostic Criteria
  1. Splenomegaly (may be huge)
  2. Anemia (hemolytic and decreased production components)
  3. Leukocytosis or thrombocytosis may be seen in 60% of patients
  4. Leukoerythroblastic peripheral blood picture
  5. Tailed (dacryocytes) cells on blood smearQ (Tear drop)
  6. Bone marrow fibrosis (reticulin), which may be extensive
  7. Osteosclerosis seen on skeletal X – rays.
Tear drop cell also seen in:
  1. Myelo Dysplastic syndrome
  2. Sideroblastic anemia  
  3. BM infiltration
  4. Pernicious, IDA, thalassemia
  1. Blood transfusion
  2. Folic acid (50 mg/day)
  3. Androgen therapy (oxymetholone 50 mg/day)
  4. Corticosteroids (prednisolone 40 mg/day)
  5. Cytotoxic drugs (hydroxyurea upto 2 gm/day)
  6. Splenectomy (in mechanical embarrassment due to massive splenomegaly, severe hemolysis, hypermetabolism, painful splenomegaly, hypersplenism).
Newer Treatment:
  1. Thalidomide has produced definite responses.
  2. Allogeneic bone marrow transplantation.
Leukoerythroblastosis - (→ Nucleated RBC, immature WBC in P/S)
Seen in
  1. BM fibrosis
  2. Extramedullary hemopoiesis

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