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Myeloproliferative & 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
Chronic myelogenous leukemia, [Ph chromosome t(9;22)(q34;11), BCR/ABL-positive]
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
Polycythemia vera
Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
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 cells0
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 myeloproliferative disorder with an absolute increase in red blood cell mass.
A mutation is JAK-2 plays an important role
Important Points:
Clinical Features
  1. Clinical symptoms are due to
  2. Blood  Viscosity            
  3. Vascular stasis    
  4. Thrombotic tendency            
  5. 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. Massive Splenomegaly is present. 
Aquagenic pruritus is a skin condition characterized by the development of severe, intense, prickling-like epidermal itching that is without observable skin lesions and that is evoked by contact with water


Extra Edge:
  1. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. 
  2. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, is another complication of the thrombocytosis of PV due to increased platelet stickiness.
  3. Given the large turnover 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, liver, 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 Volume Polycythemia
    Gaisböck's Syndrome: decrease in plasma volume with relative 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
  1. Arterial oxygen saturation   92%
  2. 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
  5. LAP score is Increased
Important Points: 
Causes of Microcytosis with erythrocytosis
  1. Beta thalassemia         
  2. Chronic Hypoxia
  3. PCV
Important Points: 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.
  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
  1. Iron deficiency;                                          
  2. Inflammation, cancer, or infection (reactive thrombocytosis);
  3. Underlying myeloproliferative process.
Causes of Thrombocytosis
  1. Malignancy
  2. Infection
  3. Myeloproliferative disorders: polycythemia vera, idiopathic myelofibrosis, essential thrombocytosis, chronic myelogenous leukemia
  4. Myelodysplastic disorders: 5q-syndrome, idiopathic refractory sideroblastic anemia
  5. Postsplenectomy or hyposplenism
  6. Hemorrhage
  7. Iron deficiency anemia
  8. Surgery
  9. Rebound: Correction of vitamin B12 or folate deficiency, post-ethanol abuse
  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
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 4- 6 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. 
Imatinib is also used in GIST (AIIMS May 2008)

  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 choice Q : If no major cytogenic remission, try dasatinib or INF-alpha
  3. Recent Advances: Newer drugs for resistant cases – Nilotinib, Dasatinib
  4. Chemotherapy
i. Busulphan
ii. Hydroxyurea
iii. 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.
  1. Leukapheresis and Splenectomy Q
  2. Arsenic Q
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:
  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. b 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
  Adult CML Juvenile CML
Age 10-12 yrs <2 yrs
Bleeding - ++
Platelet N, ↑ ↓↓
Rash - +
Spleen +++ +
Cell N M
Immunoglobulin N
Muramidase N
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 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
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
  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 score Q is high
  3. Raised urate levels Q
  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 smear Q (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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