HEMAT-ONCOLOGY
DR.SRINATH.CHANDRAMANI
Asst. Prof & ICU in-charge
K.J. Somaiya Medical College,
Mumbai
Hematology Hematology is the study of Blood and its constituents.
Considering that blood is the vital fluid in the body which is delivering Oxygen, nutrition, antibodies, clotting factors and at the same time transporting back carbon dioxide and the metabolic waste products; hematology is a vital science.
Decoding Hematology
Hematological Disorders can be classified on the basis of the cell line they dominantly affect into :
A. RBC related disorders
B. WBC related disorders
C. Coagulation related disorders.
RBC Physiology
RBC Disorders
Iron deficiency Anaemia
Most common cause of microcytic, hypochromic anaemia.
Nutritional Deficiency along with menorrhagia make IDA Female-predominant disease
Clinical features
Iron deficiency Anaemia Lab investigations RBC indices Treatment Oral vs. Parenteral iron therapy
Differential diagnosis
Prognosis
Sideroblastic Anaemia What is a Sideroblast ?
Where are they present ?
ALA synthase + Pyridoxal phosphate
2 forms Genetic vs. Acquired
D/d of Sideroblasts.
Response to B6 supplementation.
Other Hypoproliferative states
CAUSE PATHOPHYSIOLOGY
APLASTIC ANAEMIA EXPLAINED NEXT
CHRONIC RENAL FAILURE DECREASED EPO, IRON DEFICIENCY
RA/SLE, ETC DECREASED EPO (IL-MEDIATED)
HYPOTHYROIDISM DECREASED EPO SYNTHESIS DUE TO LOW TISSUE OXYGEN DEMAND
FAMILIAL EPO RECEPTOR DEFICIENCY / RESISTANCE
PROTEIN ENERGY MALNUTRITION
GENERAL DEBILITY
Aplastic Anaemia Commonest cause is Idiopathic
Post-Viral
Drug induced
Chemotherapy/radiotherapy induced
Role of steriods
Role of ATG
Role of Bone Marrow transplant (BMT)
Megaloblastic Anaemia
B12 & Folate deficiency
Etiology Diet, Parasites, drugs, Malabsorption syndromes.
Clinical features
D/D of Macrocytic anaemia
Treatment
Myelodysplastic syndrome Pre-malignant condition Acute leukamia
Radiation only & main risk factor
Genetic cases recorded
Old age presentation
Types
Commonly Pancytopenia
Diagnosis
Treatment
Prognosis
Hemolytic Anaemia
Cytoskeletal defects
Spherocytosis / Elliptocytosis
Spectrin defect
Mild hemolytic anaemia
Auto-Hemolysis
Splenomegaly
Splenectomy curative
Enzyme deficiency RBC metabolism 80% by HMP shunt
Glutathione needs to be in reduced form
In G6PD, Glutathione in in oxidised state, leading to hemolysis.
Since reserve is sufficient, hemolysis only occurs when there is oxidative stress.
Following drugs are contra-indicated in G6PD states.
Hemoglobin defects
HBS Sickle cell disease Glu Val at 6.
Clinical features Auto-splenectomy
Emergencies
Diagnosis
Treatment
Prognosis
Thalassemia Normally Embryonic Hb at 6 weeks
Fetal HB from 11 weeks
Adult HB from 38 weeks
HbA 80-90%
HbA2 14-15%
HbF 0-5%
4 genes code alpha-chain
2 genes code beta-chain.
Alpha-Thalessemia
1 gene defect - asymptomatic
2 gene defect - HbH trait
3 gene defect - alpha-thal
4 gene defect - Hydrops fetalis
Beta-thalessemia
1 gene defect - B-Thal minor
2 gene defect - B-thal major
Gene mutation - Intermedia
Beta-thalessemia Clinical presentation
Diagnosis
Treatment
Role of chelating agents
Paroxysmal Nocturnal Hemoglobinuria
Acquired intra-corpuscular defect
Decay accelarating factor (DAF) defect
Lysis due to complement mediation.
Usually follows aplastic anaemia
Hemoglobinuria only in 1st urine sample
Precipitating factors
Diagnosis Acid HAM test, Sucrose lysis, CD59 & DAF detection by flow cytometry.
Treatment & Prognosis
Auto-immune Hemolytic anaemia
POLYCYTHEMIA Defined as increased RBC in circulation
RBC mass differentiates spurious cases
Hb > 17.5 or PCV > 50 is diagnostic.
Presents incidentally or as Hyperviscosity syndrome.
Approach to Polycythemia
Polycythemia rubra vera
Commonest of all myeloproliferative disorders.
Monoclonal proliferation of pleuripotent stem cells in absence of physiological stimuli is characteristic.
Polycythemia rubra vera Pathophysiology MpL mediated (Modified
thrombopoietic factor)
Etiology unknown
Clinical features : Massive splenomegaly, Erthromelalgia, Aquagenic pruritis, Gout, Gastritis, thrombotic events.
PRV
Diagnostic criteria of PRV Raised red cell mass
Massive splenomegaly
Normal Arterial Oxygen concentration
BM not essential.
JAK-2 mutation, Increased LAP score,
Uric acid, B12 levels are supportive.
PRV Aim of therapy
Treatment options
Hydroxyurea, Chemotherapy, Aspirin.
Radioactive phosphorus 32.
Anagrelide
Allogenic BMT
Prognosis
Test 1
Includes :
RBC disorders
WBC PHYSIOLOGY Totipotent stem cells
Myeloblast (recognisable precursor)
Promyelocyte
Myelocyte
Metamyelocyte
Band forms
Mature WBC
WBC DEFECTS Deficiency Quantitative vs. Qualitative
Quantitative : Neutropenia, Lymphopenia
Qualitative : Chediak Higashi syndrome
Leucocyte Adhesion defect
Oxidation defects
Immune deficiency states
Qualitative defects Chediak Higashi syndrome
Chemotactic defects.
Associated delayed lysosome release
Recurrent infections
Leucocyte Adhesion defect
Margination defect
Delayed falling of umbilical stump
Oxidation defects
Nitroblue Tetrazolium test
Dihydrorhodamine oxidation test
WBC excess states - Benign Leucocytosis
Lymphocytosis
Eosinophilia
Infectious Mononucleosis
Leukamoid reaction
Eosinophilia Normal eosinophil 150-350/mm3
Eosinophilia Mild 350-1500 Moderate 1501-5000 Severe - >5000 Classification: 1. Loefloes syndrome/ Simple pulmonary eosinophilia 2. ABPA 3. Drug induced 4. Tropical eosiniphilia 5. Churg Strauss syndrome 6. Hypereosinophilic syndromes 7. Chronic/ Prolonged pulmonary eosinophilia 8. Acute eosinophilic pneumonia
Infectious Mononucleosis Characterised by increase in Macrophage-
monocyte count mimicking leukamia.
Differentiated by Absence of Blast cells
Follows EBV infection
WBC > 20000.
Paul Bunnel reaction/ Heterophile antigen
D/D CMV / Cat scratch disease
Complete recovery in 2 months.
Parameter Leukamoid react Leukamia
Clinical features Underlying cause No apparent caus
WBC Usually 1,00,000
NAP score Elevated Reduced
Anaemia Rare, non toxic look
Common, toxic look
Platelets 6-7 lacs. > 10 lac
Splenomegaly Absent 25-50%
BM infiltration None Present
Blasts < 5% > 5%
Karyotyping Normal Abnormal
Leukamoid reaction
WBC excess states - Neoplastic
Leukamia
Myeloproliferative states
Lymphoma
Multiple Myeloma & Paraproteinemias
Leukamias Leukamias are malignant neoplasms of
hematopoietic system, arising in the bone marrow, that flood the circulating blood or other organs.
Classified on basis of cell type involved and state of maturity of leukamic cells :
- AML, ALL
- CLL, CML
Acute Myeloblastic leukemia Common in young and middle age
FAB classification
Auer rods & lower Nuclear : cytoplasm
Chemotherapy Duanorubicin, Cyotosine arabinoside, Etoposide, Thiogaunine.
80% remission but only 30% 5 yr survival. BMT improves remission to 50%.
ATRA (all trans retinoic acid) oral For M3.
ALL
Commonest in children.
Presents as hepatosplenomegaly & LNs.
Classification (Working classification)
CNS infiltration is almost certain. Hence intrathecal methotrexate/ Radiation is mandatory.
ALL Chemotherapy 3 phases : Adriamycin, Vincristine, Prednisolone and L-Asparaginase.
Oral Methotrexate/Mercaptopurine& prednisolone.
Poor prognosis Philadelphia chr. All translocations have worse prognosis. L2 & L3.
CML Myeloproliferative disease
90% have Philadelphia chromosome
50% of PH ve have ABL-BCR defect.
Alpha-interferon
Busulphan/Hydroxyurea
Leukapheresis
Splenectomy
CLL Most common variety of leukamia
Treatment only if symptomatic.
Coombs positive anaemia
Chlorambucil / cyclophoshamide
Fludarabine
Hairy cell Leukamia Lymphoproliferative B-cell disorder
CD25 & FM C7 hairy cells
Tatrate resistant acid phosphatase staining
High LAP score
Vasculitis
Interferons
Splenectomy
Lymphomas Lymphomas are malignant proliferation
of the lymphoid system.
Classified into :
Hodgkins (HL)
Non-Hodgkins (NHL)
Hodgkins disease
Progressive, painless lymphoid enlargement
Reed sternberg cell
4 types : Lymphocyte predominant Nodular sclerosis Mixed cellularity
Lymphocyte depleted
Hodgkins disease Lymphadenopathy cervical > mediastininal >
axillary >
Alcohol induced worsening
Pel Ebstein fever
LN biopsy diagnostic
Type A and B symptoms
Chemotherapy & Radiotherapy
Prognosis
Non-Hodgkins Lymphoma 70% of all lymphomas
Non contiguous LN spread
ENT and GIT commonly involved
Chr. Alterations common
BM involvement is stage 4 disease
CHOP regime / Rituximab CD 20
Poor curability
HIV
Plasma cell dyscrasias Monoclonal gammopathies :
Multiple myeloma
Waldenstorms macroglobulinemia
Heavy chain disease
MGUS
Multiple Myeloma M-Band in serum
Defective immunity
Long pre-clinical phase
Hypercalcemia/ Hyperviscosity syndrome
Renal insufficiency in 50%
Urine BJ/ Tom Harsfall protein
Conditions with BJ positive Primary Amyloidosis
Waldenstorms Macroglobulinemia
Malignant lymphoproliferative disorders
Idiopathic BJ proteinuria
MGUS only observation.
Waldenstorms alpha chain disease, jejunal biopsy is diagnsotic.
Transfusion Facts Whole blood and components
PCV
FFP
Platelets
Cryoprecipitate
Crystalloids/ Colloids/ Flourocarbons
Transfusion related disorders
Infections
Chelation
Iron overload
Test 2
Includes :
Wbc disorder
Transfusion medicine
Platelet & Coagulation Physiology
Hemostasis achieved by 2 pathways: A.Primary Primary adhesion
Platelet activation Platelet aggregation
B. Secondary - (coagulation cascade)
Intrinsic Pathway Minor Prolongs APTT Blocked by Heparin (Binds all except vii a)
Extrinsic Pathway Major Prolongs P.t. Blocked by Warfarin (ii, vii, ix, x)
White Thrombi Mainly in arteries (mi) Hence antiplatelets more
effective
Platelet disorders
Quantitative : Thrombocytopenia
Thrombocytosis
Qualitative : Described ahead
C. Increased destruction of circulating platelets Non immune
DIC Vascular prosthesis, cardiac bypass Sepsis Vasculitis
Immune mediated Autoantibodies to platelet antigen Drug associated Circulating immune complexes
-SLE -ITP -Bacterial sepsis -viral agents
HUS T.T.P
A. Decreased production of platelets Bone marrow aplasia Tumour infiltration/ fibrosis Drug induced
B. Increased sequestration Splenic enlargement due to
tumour invasion Splenic enlargement due to portal
hypertension
Causes of thrombocytopenia
ITP Auto-immune destruction
Post infectious
Variable presentation
IC bleed dreaded
Transfusion
IVIG, Plasmapheresis
Rituximab
TTP Platelet vessel wall disorder
Defect in metalloprotease ADAMS-13
Etiology - Pregnance, Malignancy,
High dose chemotherapy, - Milomycin C
HIV, Drugs Ticlopidine
- Rarely inherited deficiency recurrent TTP
autosomal recessive
TTP
DIC is widespread activation of the coagulation pathway by various factors. This leads to consumptive coagulopathy leading to hypofibrinogenimia, thrombocytopenia. Accompanied by secondary fibrinolysis, it can lead to subtle to life threatening bleeding, especially through skin and mucous membrane. ETIOLOGY OF DIC A. Increased tissue factors Obstetric causes :Abruption ,Amniotic fluid embolism Malignancy Mucinous adenocarcinoma Frost bite, Burns, Gunshot Wounds Hemolysis Fat embolism
Dissemminated Intravascular coagulation (DIC)
B. Endothelial damage Aortic aneurysm Acute glomerulonephritis Hemolytic uremic syndrome C. Infections Bacterial Streptococci, Pneumococci, Meningococci, Gram-
Negative Viral Arbovirus, HIV, Varicella, Rubella Mycosis Acute Histoplasmosis Parasitic Malaria, Kalaazar Ricketssiel Rocky Mountain spotted fever D. Misc Snake bite
HIT HIT is of two types: TYPE 1 1. Occurs because of initial platelet aggregation by heparin 2. It is transient, mild 3. Does not require treatment or discontinuation of Heparin TYPE 2 1. Occurs due to its activity of inactivating factor x a and other factors 2. It interacts with platelet factor 4 and forms antibody complexes 3. These platelets are rapidly cleared by the microphages and
Reticuloendothelial system 4. It is sever and may lead to fatal bleeding 5. It requires early recognition and Heparin disconitnuation
Qualitative platelet disorders
Congenital
Bernard-Soulier, Thromboasthenia
Disorders of ADP secretion
Acquired Drugs NSAIDS, Aspirin, etc Uremia
Summary Disorders of primary pathway (platelet-related) Platelet adhesion Von Willebrands factor deficiency Absence of Gp I/ix Platelet aggregation Glanzmanns thromboasthenia ( Gp ii b/ iii a deficiency/ dysfunction) Defects of platelet release Drug induces Aspirin Cox inhibition Congenital defects Uraemia Platelet coating (Penicillin/ paraproteins) Defects of platelet coagulant activity Scotts syndrome.
Von Willebrand Disease Autosomal inheritance
Interferes with platelet adhesion GpIb
Types
Clinical presentation
Treatment :
Desmopressin, Cryoprecipitate
Coagulation Cascade
Prolonged PTT No active bleeding XII, HMWK deficiency Mild bleeding IX Christmas factor Mod. To severe VIII Hemophilia B Prolonged PT Vit. K deficiency early Liver failure Factor vii deficiency Warfarin administration
Disorders of secondary hemostatic pathway
Disorders of secondary hemostatic pathway Both prolonged
Vit. K-Late (involves common pathway)
High/Prolonged Heparin administration
Warfarin, Dysfibrogenemia
Factor II, V, X deficiency
Not corrected by plasma
Coagulation inhibitors e.g. Anticoagulant Ab
(especially chronic factor replacements)
Clot solubility in 5M urea XIII deficiency
Rapid clot lysis 2 plasmin inhibitor
Hemophilia
A & B
X-linked recessive
Presentation
Treatment
Prognosis
Hyper coagulable states Inherited Defective Coagulation inhibition 1. Factor 5 mutation (Leiden 5) - Resistance to protein c 2. Protein S, Protein C deficiency - Thrombin with thrombomodulin
stimulates protein C, which inhibits 8a and 5a - Supported by Protein S
3. Antithrombin 3 deficiency - Neutralises all clotting factors except 7 a 4. Prothrombin gene mutation Impaired clot stability 1. Dysfibrogenemia 2. Plasminogen deficiency 3. TPA deficiency 4. Plasminogen activator inhibitor excess (PAI-1)
Unknown mechanism HyperHomocystinemia
Autosomal dominant More venous thromboembolism
Hyper coagulable states
Acquired Physiological states
Pregnancy
Obesity
Post operative Immobilizations
Old age
Pathological states
Malignancy
Nephrotic syndrome
Lupus Anticoagulant
T.T.P
Estrogen excess
Hyperlipidemia
Diabetes Mellitus
Congestive heart failure
Paroxysmal nocturnal hemoglobinuria (PNH)
Antiphospholipid syndrome
It is a characteristic syndrome presenting as thrombotic events, presence of aCL, 2-glycoprotein 1.
Has all types IgM, IgG, IgA
Automimmune is IgG3, Drug induced is IgG1
At least one clinical criterion and one laboratory criterion must be present for a patient to be classified as having APS.
The clinical criteria are as follows:
Vascular thrombosis
One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ
Thrombosis may involve the cerebral vascular system, coronary arteries, pulmonary system, arterial or venous system in the extremities, hepatic veins, renal veins, ocular arteries or veins, or adrenal glands.
Pregnancy morbidity
One or more late-term (>10 weeks' gestation) spontaneous abortions
One or more premature births of a morphologically healthy neonate at or before 34 weeks gestation because of severe preeclampsia or eclampsia or severe placental insufficiency
Three or more unexplained, consecutive, spontaneous abortions before 10 weeks gestation
Laboratory criteria: Patients must have (1) medium to high levels of immunoglobulin G (IgG) or immunoglobulin M (IgM) anticardiolipin (aCL), (2) antibeta-2 glycoprotein I, or (3) LA
on at least 2 occasions at least 12 weeks apart
BMT Autologous
Allogenic
Procedure
Role of CSFs
Peripheral Autologous stem cell transplant
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