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 function depends on both quantity and quality Quantity

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