myeloproliferative disorders discribed in deatails for medical students

1. Myeloproliferative Disorders

2. Myeloproliferative disorders
● Uncontrolled clonal proliferation of one or more of the cell lines in bone
marrow – erythroid, myeloid and megakaryocyte lines
a. Polycythaemia vera
b. Essential thrombocythaemia
c. Myelofibrosis
d. CML
● Can undergo transition from one disease to another
● May also transform to AML

4. Polycythaemia
● ↑Hb, ↑ PCV, ↑ Red cell count
a. True increase in red cell volume
b. Relative erythrocytosis – red cell volume is normal but there is a
decrease in plasma volume

5. ● Primary polycythaemia vera
● Secondary polycythaemia - ↑ in RBC due to anoxia, tumours
○ High altitude
○ Lung disease
○ Cardiovascular disease
○ Heavy smoking
○ ↑ affinity of Hb
○ Relative – stress, spurious polycythaemia, dehydration, burns
○ Inappropriate increase in erythropoietin – RCC, hepatocellular CA,
adrenal tumour, cerebellar haemangioma
Polycythaemia - absolute erythropoiesis

6. Polycythaemia rubra vera
● Excessive proliferation of erythroid, myeloid and megakaryocyte progenitors
● JAK 2 mutation in 95%

7. ● Clinical features
○ Insidious onset
○ Usually > 60 years
○ Tiredness, vertigo, tinnitus- hyperviscosity
○ HT, angina, intermittent claudication
○ Severe itching after a hot bath
○ Gout – increased cell turn over
○ Plethoric, deep dusky cyanosis
○ Spleen – 70%, liver enlargement
Polycythaemia rubra vera

10. ● Diagnostic Criteria
According to 2016 revised World Health Organization (WHO) guidelines,
diagnosis of PV requires requires the presence of either all three major criteria or
the first two major criteria and the minor criterion.
Polycythaemia rubra vera

11. Major WHO criteria are as follows:
1. Hemoglobin >16.5 g/dL in men and >16 g/dL in women, or hematocrit >49%
in men and >48% in women, or red cell mass >25% above mean normal
predicted value
2. Bone marrow biopsy showing hypercellularity for age with trilineage growth
(panmyelosis) including prominent erythroid, granulocytic, and
megakaryocytic proliferation with pleomorphic, mature megakaryocytes
(differences in size)
3. Presence of JAK2V617F or JAK2 exon 12 mutation
Polycythaemia rubra vera

12. The minor WHO criterion is as follows:
● Serum erythropoietin level below the reference range for normal
Polycythaemia rubra vera

14. ● Course and management
○ Aim – keep PCV < 0.45, PLT < 400×109/L
○ Venesection
○ Chemotherapy – hydroxyl certamide
○ Low dose aspirin
○ General treatment – radioactive P
Polycythaemia rubra vera

15. Myelofibrosis
● Clonal proliferation of stem cells and myeloid metaplasia in liver, spleen and
other organs
● Increased fibrosis of bone marrow

18. ● Clinical features
○ Anaemic features
○ Splenomegaly→ splenic infarction
○ Bone pain and gout
○ Bruising and bleeding due to thrombocytopenia
○ Weight loss, night sweats
○ Signs-Anaemia, fever, massive splenomegaly
Myelofibrosis

19. ● Investigations
○ Anaemia- tear drop cells ,WBC ↑ - later leucopenia , Platelets ↑- later
thrombocytopenia
○ Bone marrow Trephine biopsy –Fibrosis with increased megakaryocytes
○ Philadelphia chromosome is absent- distinguishes it from CML
○ Leucocyte alkaline phosphatase – normal or high
○ Increased serum urate , Low serum folate, increased LDH
Myelofibrosis

22. ● Treatment
○ Supportive
○ Hydroxycarbamide (hydroxyurea)
○ Chemotherapy and radio therapy-↓spleen size
○ Splenectomy – if spleen is very large and painful
Myelofibrosis

23. Myelodysplasia
● Group of bone marrow disorders –defect in stem cells and increased bone
marrow failure- quantitative and qualitative abnormalities in all three myeloid
cell lines
● Can transform into AML

25. ● Clinical manifestations
○ Pancytopenia, Bone marrow usually shows increased cellularity despite
pancytopenia
○ Ring sideroblasts
Myelodysplasia

27. Blood
film

28. ● Management
○ Supportive care
○ Chemotherapy
○ Thalidomide analogue
○ BM transplantation
Myelodysplasia

30. ● Neoplastic proliferation of bone marrow plasma cells, characterized by lytic
bone lesions, plasma cell accumulation in bone marrow and presence of
monoclonal protein in serum and urine
● 98% >40 years of age, peak in 7th decade
● Malignant plasma cells have clonally rearranged Ig genes that secrete same
paraprotein that is present in serum
● Aetiology – unknown but cytokines have an important role
Multiple Myeloma

31. ● Il-6 potent growth factor for myeloma possibly by an autocrine mechanism
● Osteolytic lesions in this disease are probably the result of osteoclast
activating factor mainly TNF & IL-1 secreted by myeloma cells
● Gains, losses & structural alterations to different chromosomes are frequent
with clonal evolutions
● Most frequent monosomy is chromosome 13 – poor prognosis
Multiple Myeloma

33. ● Clinical features
○ Bone pain (specially backache) and pathological fractures
○ Features of anaemia – lethargy, weakness, dyspnoea, pallor, tachycardia
○ Recurrent infections – related to deficient antibody production, abnormal
cell mediated immunity and in advanced disease – neutropenia
○ Features of renal failure &/or hypercalcaemia – polydipsia, polyuria,
anorexia, vomiting, constipation, mental disturbance
Multiple Myeloma

34. ● Clinical features
○ Abnormal bleeding tendency – myeloma protein may interfere with
platelet function and coagulation factors, thrombocytopenia occurs in
advanced disease
○ Macroglossia, carpal tunnel syndrome, diarrhoea caused by amyloid
deposition.
○ 2% cases hyperviscosity syndrome with purpura, haemorrhage, visual
failure, CNS symptoms, neuropathies & heart failure.
Multiple Myeloma

35. ● Diagnosis
○ Diagnostic Criteria
○ Multiple myeloma is defined as smoldering (asymptomatic) or active
(symptomatic).
Multiple Myeloma

36. The diagnosis of Multiple myeloma requires the following: the Bone marrow
aspirate or biopsy showing atleast 10% of plasma cells or the presence of a
plasma cell tumour( plasmacytoma) plus atleast one of the following two features:
1. CRAB criteria (hyperCalcemia, Renal failure, Anemia, Bone lesions) for end-
organ damage, as follows [2] :
● Calcium >11.5 mg/dL (>2.65 mmol/L)
● Creatinine >2 mg/dL (177 μmol/L or more)
● Hemoglobin <10 g/dL or 2 g/dL <normal (<12.5 mmol/L<normal)
● Lytic or osteopenic bone disease
Multiple Myeloma

37. 2. Detection of one of the following
● Bone marrow plasma cells (BMPCs) ≥60%
● Involved/uninvolved serum free light chain ratio ≥100
● Abnormal MRI with more than one focal lesion, with each lesion >5 mm
Multiple Myeloma

42. X-ray spine of
myeloma patient

43. ● Other lab findings
1. Usually normochromic normocytic or macrocytic anaemia, WCC & PLT
count normal or low
2. Rouleaux formation are marked in most cases
3. Neutropenia and thrombocytopenia occurs in advanced disease
4. Abnormal plasma cells in blood film – some binucleate forms
5. High ESR, high CRP
6. Elevated serum Ca2+ in 45%, typically serum alkaline phosphatase
normal except in pathological fractures
Multiple Myeloma

45. 7. Serum urea and creatinine raised in 20% - proteinaceous deposits from
heavy Bence Jones proteinuria, hypercalcemia, uric acid, amyloid and
pyelonephritis contribute to CRF
8. Low serum albumin in advanced disease
9. Serum β2 microglobulin
10. Useful indicator of prognosis
11. Partly reflects renal function
12. Level <4 mg/L food prognosis
13. Uric acid – normal or elevated
Multiple Myeloma

46. ● Treatment
○ Specific
■ Chemotherapy – eg- Bortezomib
■ Stem cell transplantation
■ Using high dose melphalan& autologous stem cells
■ No cure of disease
■ IFN-α –
■ Radiotherapy
■ Thalidomide
Multiple Myeloma

47. ● Supportive
○ Renal failure – rehydrate and treat underlying cause (hypercalcaemia,
hyperuricaemia)
○ Bone disease &hypercalcaemia– bisphosphonate
○ Compression paraplegia – decompression laminectomy or irradiation,
corticosteroid therapy
○ Anaemia – transfusion or erythropoietin
○ Bleeding – repeated plasmapheresis
○ Infections – prophylactic infusions of Ig concentrates together with oral
broad spectrum antibiotics and antifungal agents
Multiple Myeloma

48. ● Prognosis
○ Median survival with chemotherapy – 3-4 years
○ 20% 5 year survival rate
○ Improved by autologous transplantation
Multiple Myeloma

50. Thrombophilias
Inherited or acquired defects of haemostasis leading to a predisposition to venous
or arterial thrombosis
1. Factor V Leiden – makes factor V less likely to be cleaved by activated
protein C- most common cause of thrombophilia
2. Prothrombin gene mutation
3. Antithrombin 3 deficiency – inherited as autosomal dominant
4. Protein C and protein S deficiency – AD, ↑ venous thrombosis
5. APLS
6. Homocysteine →arterial and venous thrombosis

51. Disseminated Intravascular coagulation (DIC)
● Widespread generation of fibrin within blood vessels owing to activation of
coagulation by release of procoagulant material and by diffuse endothelial
damage or generalised platelet aggregation
● ↑FDP
● Initial thrombosis followed by a bleeding tendency due to consumption of
coagulation factors and fibrinolytic activation

55. ● Causes
○ Malignant disease
○ Septicaemic (Gram –ve meningococci)
○ Haemolytic transfusion reaction
○ Obstetric causes (abruption placenta, amniotic fluid embolism)
○ Trauma, burns, surgery
○ Other infections (Falciparum malaria)
○ Liver disease
○ Snake bite
Disseminated Intravascular coagulation (DIC)

56. ● Clinical features
○ Often acutely ill and shocked
○ No bleeding at all to profound haemostatic failure
○ Bleeding from mouth, nose, venepuncture site
○ Thrombotic events – vessel occlusion by fibrin or platelet, skin, brain and
kidney mainly involved
Disseminated Intravascular coagulation (DIC)

57. ● Investigations
○ PT ↑, APTT ↑, TT ↑, Fibrinogen ↓
○ FDP ↑ including D-dimer
○ Thrombocytopenia
○ Blood film – fragmented RBC
Disseminated Intravascular coagulation (DIC)

59. ● Treatment
○ Treatment of underlying cause
○ Maintenance of blood volume and tissue perfusion
○ Transfusion of platelet concentrates, FFP, cryoprecipitate, RBC
concentrate
○ Avoid tranexamic acid (inhibition of fibrinolysis) leads to dangerous fibrin
deposition
Disseminated Intravascular coagulation (DIC)

60. Hematological malignancy
● Leukaemia
○ classified as acute and chronic leukaemia
○ in acute leukaemia there is proliferation of primitive stem cells causing
accumulation of blasts in the bone marrow
○ in chronic leukaemia the malignant cells retain the ability to differenciate
causing accumulation of cell of various levels of differentiation
○ Acute leukaemia occurs at all ages.
○ ALL has a peak incidence at1 to 5 years.
○ chronic leulaemia occurs in middle and old age individuals

61. Acute leukaemia
ALL
● clinical presentation-
○ features of bone marrow failure
○ organ infiltration (local expansion of bone marrow-pain & tenderness)
○ meningeal syndrome
● association with trisomy 21 translocation(9:22)
● ALL common in children

62. ALL
● investigations-
○ FBC- pancytopenia ,WBC can be increased ,decreased,or normal
○ Bloodpicture- blasts
○ bone marrow- >20% blast cells
○ Special stains and classification tests

63. Blood picture
showing blast
cells

64. ● Management-
○ general supportive therapy
○ Chemotherapy
○ induction of remission- prednisolone
○ Consolidation of remission- intensive multi agent chemotherapy, CNS
prophylaxis
○ Intensification
○ Maintenance chemotherapy
■ 2 years –Girls and adults.
■ 3 years- boys
ALL

65. ● Good prognosis-
○ Age > 1 yr to < 10 yrs
○ Female
○ WBC<50000
○ Philadelphia chromosome negative
○ No CNS disease at presentation
○ B-ALL
ALL

66. AML ( Acute Myeloid Leukaemia)
● More common form of acute leukaemia in adults
● Cinical presentation- features of bone marrow failure, organ infiltration
● Can have other features- DIC, gum hypertrophy ,skin involvement
● Acute promyelocytic leukaemia- Auer rods, DIC or thrombocytopemia often at
presentation, good prognosis

69. ● Investigations-
○ similar
○ Positive for myeloperoxidase stain
● Management-
○ general supportive therapy
○ Induction of remission
○ Consolidation
○ No maintenance treatment
AML ( Acute Myeloid Leukaemia)

70. Chronic leukaemia
CML ( Chronic Myeloid Leukaemia)
● Clinical presentation – middle age (40-50 years), anaemia, weight loss,
fever, sweats, headache, bruising, bleeding
● Signs-pallor, splenomegaly(often massive)
● Present usually with insidious features
● May undergo blast transformation (AML in 80%, ALL in 20%)

72. CML ( Chronic Myeloid Leukaemia)
● Associations- Philadelphia chromosome(95%) – translocation between long
arm of chromosome 9 and 22- the resulting BCR-ABL gene codes for a fusion
protein which has tyrosine kinase in excess of normal

74. ● Investigation
○ FBC- high leukocyte count
○ normocytic normochromic anaemia thrombocytosis
○ neutrophil alkaline phosphatase score-low
○ Blood picture- full range of granulocyte precursors and mature
neutrophils, spectrum of myeloid cells seen in peripheral blood
CML ( Chronic Myeloid Leukaemia)

75. Blood
picture of
CML

76. ● Management-
○ Imatinib- now considered first line- inhibitor of tyrosine kinase associated
with BCR-ABL defect, very high response in chronic phase of CML
○ Hydroxyurea
○ IFN- alpha
○ Allogenic bone marrow transplant
CML ( Chronic Myeloid Leukaemia)

77. CLL( Chronic Lymphocytic Leukaemia)
● CLL is caused by monoclonal proliferation of well differentiated lymphocytes
which are almost always B- Cells
● Presents with insidious features
● Clinical- anorexia, weight loss, Recurrent infection , bleeding Anaemia,
lymphadenopathy more marked than CML, LUQ discomfort

78. ● Complications:
○ Hypo gamma globulinaemia leading to recurrent infections
○ Warm auto immune haemolytic anaemia
○ Transformation to high grade lymphoma(Richter’s transformation)
CLL( Chronic Lymphocytic Leukaemia)

79. ● Investigation
○ FBC- lymphocytosis
○ Blood picture- lymphocyte precursors and mature lymphocytes, Smudge
cells
○ immunophenotyping
CLL( Chronic Lymphocytic Leukaemia)

81. ● Management
○ Has a better prognosis
○ Treatment is only required if the patient is progressively symptomatic , if
there is evidence of bone marrow failure, progressive lymphadenopathy,
progressive splenomegaly, progressive lymphocytosis, systemic
symptoms, autoimmune cytopenias eg –ITP
○ Fludarabine, cyclophosphamide and rituximab (FCR) is the first line
CLL( Chronic Lymphocytic Leukaemia)

82. Lymphoma
Hodgkin's lymphoma
● Malignant proliferation of lymphocytes characterised by the presence of Reed
Sternberg cells
● Bimodal age distribution- more common in 3 rd and 7 th decades

83. Hodgkin's lymphoma
● Clinical - lymphadenopathy usually begins from one group of peripheral
lymph nodes and spreads contiguously to others
● Can have mediastinal involment
● Extranodal spread rare
● Constitutional symptoms B symptoms- (weight loss, fever, night sweats)
common- imply poor prognosis

85. Histological types-
1. Nodular sclerosing- most common
2. Mixed cellularity
3. Lymphocyte predominant- best prognosis
4. Lymphocyte depleted
Hodgkin's lymphoma

86. ● Ix- lymph node biopsy shows Reed Sternberg cells
● Management
○ Early stage disease- radiotherapy
○ Advanced disease- chemotherapy+/- radiotherapy
Hodgkin's lymphoma

88. Non Hodgkin's lymphoma
● Clinical
● Has a more unpredictable and haphazard spread
● Involves oropharyngeal lymph nodes
● Extra nodal spread common
● Leukemic phase more common
● Constitutional symptoms rare
● Ix- no RS cells
● Mx- multi agent chemotherapy

90. Tumour Lysis Syndrome
● Potentially deadly combination related to the treatment of high grade
lymphomas and leukaemias
● Patients at high risk should be given IV allopurinol or IV rasburicase
immediately prior to and during the first days of chemotherapy

91. ● Features-
○ Increased uric acid
○ Increased S. potassium
○ Increased S.phosphate
○ Reduced S. calcium
● Can develop renal failure , cardiac arrhythmia, sudden death, seizure
Tumour Lysis Syndrome

93. Thank you