Haematologic and Lymphoreticular Diseases

HAEMATOLOGIC AND
LYMPHORETICULAR DISEASES
DR. G.D WAZIRI
MBBS, FMCPath, FICS, LMIH (Cert)
DEPT OF PATHOLOGY, FACULTY OF BASIC

1 CLINICAL SCIENCE, COLLEGE OF MEDICAL 1/23/2023
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SYNOPSIS
 Cellular Components
 Components of Blood
 Red Blood Cells
 White Blood Cells
 Inflammatory process
 Coagulation
 Clotting disorders
 Sickle cell diseases
 Leukaemias
 Lymphomas
Hematology
Spleen
Blood Kidneys
Hematopoietic
System
Bone
Liver
Marrow
Hematopoeisis
 Three developmental periods
 Mesoblastic
 Blood islands of yolk sac
 Primarily RBC production
 Embryonic hemoglobin produced
 Hepatic
 At 6 weeks cell production in liver
 Fetal hemoglobin produced
 Spleen, thymus, lymph nodes also active prod.
 Myeloid
 At 5th month Bone Marrow becomes site of prod.
 Liver & spleen now Extramedullary
 Hemoglobin A (22)
Requirements For Hematopoiesis
 Stem Cells
 Growth Factors
 Microenviroment
Stem Cell theory
 Pluripotent stem cell originator of all cells
 Gives rise to cells committed to specific development
 Research supporting the theory
 PHSC has self-maintaining ability
 Committed cells differentiate continuously/ No Reverse
Flow
Stem cells in Research
 Pluripotent cells derived from:
 Cell mass of embryos at blastocyst stage (IVF)
 Fetal tissue from terminated pregnancy
 Application
 Identification of factors of cellular decision-making
 Development and testing of drugs
 Generation of cells and tissue for therapy
Cytokines & Growth Factors
 Cytokines stimulate or inhibit
 Prevent apoptosis
 Colony-Stimulating Factors produced by many different
cells
 Interleukins numbered according to discovery
Components of Blood
Plasma Components
 Plasma
 Transport mechanism Water
 90-92% water.
90%
 6-7% proteins
 2-3%
 Fats
 Carbohydrates (glucose)
 Electrolytes
 Gases (O2, CO2)
 Chemical messengers
Other Protein
3% 7%
Cellular Components
Pluripotent Stem Cell
Myeloid Multipotent Common Lymphoid

Stem Cells Stem Cells
Unipotent Lymphocytes
Progenitors
WBC’s
Basophils RBC’s
Eosinophils
Thrombocytes Erythrocytes
Neutrophils
Monocytes Platelets Erythropoietin
Components of Blood
 Red Blood Cells

 Erythrocyte
 Hemoglobin – O2 bearing
molecule
 Comprised of 4 subunits:
o Globin (binds to 1 O2
molecule)
o Heme (iron)
 100% saturation = 4 globin
subunits carrying O2
o Each gram of hemoglobin =
1.34 ml O2
Cellsalive.com
Blood Products and Blood Typing
 Blood Types
 Antigens
 A, B, AB, O
 Rh factor
 Rh+ = ~85%
 Rh- = ~15%
Blood transfusion
Components of Blood
 Leukocytes (cont.)
 White Blood Cell Count
 Leukopoiesis
 Granulocytes
 Neutrophil
 Basophil
 Eosinophil
 Monocytes
 Lymphocytes
Human Neutrophil:
Phagocytosis of Strep pyogenes
Components of Blood
 Immunity
 Subpopulation of lymphocytes known as T cells and B cells
 T cells develop cellular immunity.
 B cells produce humoral immunity
Components of Blood
 Inflammatory Process
 MAST CELLS.
 Immunoglobulin E antibody IgE,
 Antigens
 Antigens stick to the mast cell IgE
antibodies, causing granules in the
mast cell to fire their contents into the
surrounding tissue.
 This releases a host of inflammatory
materials - leukotrienes, tumor
necrosis factor, interleukin-4 and other
cytokines that turn on other
inflammatory cells.
 These materials cause fluid to leak from
the capillaries and white cells including
neutrophils, T cells and eosinophils to
leave the circulation. The end result is a
"local inflammatory response", a red,
Cellsalive.com
itchy welt.
Components of Blood
 Hemostasis-
 3 mechanisms
 Vascular spasm
 Contraction of tunica media
 Platelet plug
 Platelet aggregation
 Coagulation
 Formation of fibrin clot
Components of Blood
 Hemostasis (cont.)
 Fibrinolysis
 Lysis of clot (plasmin)
 Thrombosis
 Thrombolytics
 Medications affecting clot formation
 Alter the enzyme
on the platelet.
 Affect the coagulation cascade.
 Enhance clotting.
Coagulation Cascade - Synopsis
This scanning electron micrograph shows the fine structure of
a blood clot. Platelets released from the circulation and exposed
to the air use fibrinogen from the blood plasma to spin a mesh
of fibrin.
Blood Products and Blood Typing
Brady; Paramedic Care Principles and Practice

Diseases of Erythrocytes
 Anemias
 Anemia is a sign, not a separate disease process.
 Signs and symptoms may not be present until the body is stressed.
 Differentiate chronic anemia from acute episode.
 Treat signs and symptoms.
 Maximize oxygenation and limit blood loss.
 Establish IV therapy if indicated.
Brady; Paramedic Care Principles and Practice

 Polycythemia
 Overproduction of erythrocytes.
 Occurs in patients > 50 years old or with secondary dehydration.
 Most deaths due to thrombosis
 Results in bleeding abnormalities:
 Epistaxis, spontaneous bruising, GI bleeding.
 Management:
 Follow general treatment guidelines.
Diseases of Leukocytes
 Leukopenia/Neutropenia
 Too few white blood cells or neutrophils.
 Follow general treatment guidelines and provide supportive
care.
 Leukocytosis
 An increase in the number of circulating white blood cells,
often due to infection.
 Leukemoid reaction
Clotting Disorders
 Thrombocytosis and Thrombocytopenia
 Thrombocytosis
 An abnormal increase in the number of platelets
 Thrombocytopenia
 An abnormal decrease in the number of platelets
 Sequestration
 Destruction (ITP)
 Decreased production
 Management
 Provide supportive care and follow general treatment guidelines.
Clotting Disorders
 Hemophilia
 Deficiency or absence of a blood clotting factor
 Deficiency of factor VIII causes hemophilia A.
 Deficiency of factor IX causes hemophilia B.
 Deficiency is a sex-linked, inherited disorder.
 Defective gene is carried on the X chromosome.
 Signs & Symptoms
 Numerous bruises, deep muscle bleeding, and joint bleeding.
Clotting Disorders
 Hemophilia (cont.)
 Management
 Treat the patient similarly to others.
 Administer supplemental oxygen.
 Establish IV access.
 Be alert for recurrent or prolonged bleeding, and prevent additional
trauma.
 Von Willebrand’s Disease
 Deficient component of factor VIII
 Generally results in excessive bleeding.
 Generally is not serious; provide supportive care.
Components of Blood
 Autoimmune disease
 May be specific or general
 Alterations in the immune process
 Immunosuppression
 HIV
 Anti-rejection medication
 Chemotherapy/Cancer
 System activation of coagulation cascade.
 Results from sepsis, hypotension, OB complications, severe tissue
or brain injury, cancer, and major hemolytic reactions.
 Multiple Myeloma
 Cancerous disorder of plasma cells.
 Pathologic fractures are common.
Anticoagulants/Antiplatelets
 Classifying agents
 Anticoagulants
 Block synthesis and activation of clotting factors
 Antiplatelets
 Interfere with platelet aggregation or activation
 Fibrinolytics
 Dissolve fibrin component of thrombi
 Anticoagulants
 Warfarin
 Blocks activation of Vit K
 Interferes w/ coagulation factors II, VII, IX, and X
 Unfractionated Heparin
 Binds antithrombin III (AT-III)
 Inhibits coagulation factors IX and X and thrombin
 Hirudin (medicinal leech)
 Prevents thrombin binding
 Antiplatelets
 Aspirin
 Prevents platelet activation through cyclooxygenase blockade.
 Prevents production of thromboxane A2
 Allows prostacyclin synthesis
 Ticlodipine
 Deforms platelet membrane fibrinogen receptor
 Antiplatelets (cont.)
 Glycoprotein IIb-IIIa Receptor Inhibitors
 G IIb-IIIa = platelet membrane receptor of fibrinogen
 Abciximab
 Eptifibatide
 Tirofiban
 Fibrinolytics
 Activate plasminogen to plasmin = fibrinolysis
 Streptokinase
 Anistreplase
 Tissue Plasminogen Activator
 Reteplase
 Urokinase
Hemorrhage
Class I Class II Class III Class IV
Blood Loss (ml) Up to 750 750-1500 1500-2000 >2000
Blood Loss (% Up to 15% 15%-30% 30%-40% >40%
volume)
Pulse <100 >100 >120 >140
BP Normal Normal Decreased Decreased
Pulse Pressure Normal or Decreased Decreased Decreased
increased
Resp. Rate 14-20 20-30 30-40 >35
Urine Output (ml/hr) >30 20-30 5-15 Negligible
Mental Status Slightly Mildly Anxious, Confused,
anxious anxious confused lethargic
Fluid Replacement Crystalloid Crystalloid Crystalloid and Crystalloid and
(3:1) rule blood blood
Transfusion Reactions
 Hemolytic Reaction
 Facial flushing, hyperventilation, tachycardia, hives, chest pain, wheezing,
fever, chills, and cyanosis
 Treatment
 Stop transfusion, change all IV tubing, and initiate IV therapy with normal
saline or lactated Ringer’s.
 Consider furosemide, dopamine, and diphenhydramine.
Transfusion Reactions
 Febrile Non-hemolytic Reactions
 Headache, fever, and chills
 Treatment
 Stop transfusion, change all IV tubing, and initiate IV therapy with normal
saline or lactated Ringer’s.
 Consider Diphenhydramine and an antipyretic.
 Observe closely to ensure reaction is non-hemolytic.
SICKLE CELL ANAEMIA
DR. G.D WAZIRI

MBBS, FMCPath, FICS, LMIH (Cert)
OBJECTIVES
 AT THE END OF THIS LECTURE STUDENTS SHOULD
BE ABLE TO
1. Clearly state the genetic mutation in sickle cell anaemia
2. Define sickle cell anaemia, sickle cell disease and sickle cell
disorder
3. Enumerate factors that determine the severity of sickle cell
anaemia
4. Classify types of crises
5. List factors that precipitate crises
6. List four steps in treating crises
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OUTLINE
 Introduction
 Epidemiology
 Aetiology and pathogenesis
 Clinical features
 Factors that determine disease severity
 Investigations
 Treatment
 Sickle cell genetic counselling
 Summary
 Conclusion

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INTRODUCTION
 SICKLE CELL TRAIT (HbAS): Inheritance of the genes that
code for Haemoglobin A (HbA) and Haemoglobin s (hbs). This is a
heterozygous condition
 SICKLE CELL ANAEMIA (HbSS) INHERITANCE OF TWO
GENES THAT CODE FOR HbS. THIS IS A HOMOZYGOUS
CONDITION
 SICKLE CELL DISORDER: INHERITANCE OF THE GENE
THAT CODES FOR HbS AND ANY OTHER ABNORMAL
HAEMOGLOBIN EG HbC, HbD , HbE ETC
 SICKLE CELL DISEASE: THIS IS SYMPTOMATIC SICKLE
CELL ANAEMIA OR SICKLE CELL DISORDER
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 VARIOUS ACCOUNTS HIGHLY SUGGESTIVE OF
HAEMOGLOBINOPATHIES HAVE EXISTED IN
DIFFERENT AFRICAN TRADITIONS
 FIRST DESCRIPTION OF CLINICAL FEATURES WERE
BY JAMES B AFRICANUS HORTON - 1874
 IN 1904 DR. JAMES HERRICK,AND HIS
INTERN DR. ERNEST IRONS STARTED
TREATING WALTER CLEMENT NOEL IN
CHICAGO.
 PUBLISHED IN 1910

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 THE HUMAN α AND β GLOBIN GENES ARE CODED
FOR BY CHROMOSOMES 16 AND 11 RESPECTIVELY.
 HAEMOGLOBIN CONSISTS OF HAEM AND GLOBIN
COMPONENTS
 HAEMOGLOBINOPATHIES ARE INHERITED
DISORDERS OF HAEMOGLOBIN DUE TO
STRUCTURAL ALTERATIONS OF THE GLOBIN
POLYPEPTIDE CHAIN

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EPIDEMIOLOGY
 MUTATIONS OF THE GLOBIN GENE AFFECT
APPROXIMATELY 7% OF THE WORLD’S POPULATION
 SCA HAS FIVE EPICENTERS : BENIN,
SENEGAL,CAR(BANTU), CAMEROON AND SAUDI
ARABIA/INDIA
 300 000 CHILDREN ARE BORN WITH SICKLE CELL
DISEASE WORLD WIDE
 FREQUENCY OF SICKLE CELL GENE (HbAS) IS 24% IN
NIGERIA WITH 2% OF THE NIGERIAN POPULATION
HAVING HbSS
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 SICKLE CELL GENE EXHIBITS BALANCED
POLYMORPHISM
 THIS IS A PHENOMENON WHEREBY THE
DELETERIOUS EFFECTS OF A GENE ARE
COMPENSATED FOR BY A CERTAIN SURVIVAL
ADVANTAGE IT CONFERS ESPECIALLY IN THE
HETEROZYGOTE STATE
 HENCE HbAS CONFERS MORE RESISTANCE TO
SEVERE MALARIA THAN HbSS OR HbAA

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GEOGRAPHICAL DISTRIBUTION IS
IDENTICAL TO THAT OF MALARIA

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AETIOLOGY
 THE β GLOBIN GENE IS LOCATED ON CHROMOSOME 11
AND CODES FOR THE PRODUCTION OF A 146 AMINO
ACID POLYPEPTIDE
 INHERITED IN AN AUTOSOMAL RECESSIVE MANNER
 A RESULT OF A SINGLE POINT MUTATION IN WHICH
ADENINE IS REPLACED BY THE NUCLEOTIDE
THYMINE AT THE 6TH CODON OF THE GLOBIN GENE IN
THE DNA (GAG → GTG)
 THIS LEADS TO THE SYNTHESIS OF THE AMINO ACID
VALINE INSTEAD OF GLUTAMIC ACID
 VALINE IS A NEUTRAL AMINO ACID AND IMPARTS A
HYDROPHOBIC INTERACTION
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 HAPLOTYPES REFER TO GENES THAT ARE CLOSELY
LINKED TO A PARTICULAR GENE OF INTEREST (
THE β-GLOBIN GENE IN THIS CASE) WHICH ARE
INHERITED TOGETHER FROM A SINGLE
INDIVIDUAL.
 THE BENIN AND BANTU HAPLOTYPES ARE MORE
SEVERE COMPARED TO THE SENEGAL AND ARABIAN
HAPLOTYPES

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PATHOPHYSIOLOGY
THE PATHOGENESIS OF SICKLE CELL REVOLVES
AROUND THE FOLLOWING
 HbS POLYMERISATION
 INTERCELLULAR ADHESION
 ACTIVATION OF COAGULATION
 ERYTHROCYTE MEMBRANE ABNORMALITIES
 PERTUBATION OF VASODILATATION

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CLINICAL FEATURES
 COULD BE ASYMPTOMATIC,MILD,MODERATE OR SEVERE
 GENERALLY MULTI-ORGAN AFFECTATION
 FACTORS THAT AFFECT SEVERITY ARE:
1. GENETIC:
 PERSISTENCE OF HbF,
 BETA GLOBIN GENE HAPLOTYPE,
 THALASSAEMIA,
 TYPE OF HbS VARIANT,
 CONCOMITANT G6PD DEFICIENCY

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2. ENVIRONMENTAL:
 NUTRITION,
 INFECTIONS,
 COMPLIANCE WITH ROUTINE MEDICATIONS AND
HOSPITAL VISITS

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 PRESENTATION IS RARE BEFORE 3 MONTHS OF LIFE.
THIS IS WHEN THE GLOBIN SWITCH STARTS
FROM THE FETAL HAEMOGLOBIN TO THE ADULT
FORM
 PAINFUL DACTYLITIS (HAND-FOOT SYNDROME) IS
USUALLY THE FIRST PRESENTATION OF THE
DISEASE
 ANAEMIA AND JAUNDICE OF VARYING DEGREES ARE
PRESENT IN MOST PATIENTS

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SUMMARY OF MANIFESTATIONS
TISSUE/ORGAN MANIFESTATION(S)
BRAIN STROKE
EYES RETINOPATHY (IMPAIRED VISION)
LUNGS ACUTE CHEST SYNDROME, PULMONARY
HYPERTENSION
HEART CARDIOMEGALY
KIDNEYS HYPOSTENURIA,PAPILLARY NECROSIS,SICKLE CELL
NEPHROPATHY
MUSCULOSKELETAL BONE PAINS, OSTEOMYELITIS,AVASCULAR NECROSIS
SYSTEM
SKIN LEG ULCERS
ENDOCRINE SYSTEM DELAYED PUBERTY
PLACENTA MISCARRIAGES
SPLEEN FUNCTIONAL ASPLENIA,AUTOSPLENECTOMY
OTHERS PRIAPISM, INFECTIONS
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TISSUE/ORGAN MANIFESTATION(S)
HEPATOBILLIARY PIGMENT (BILIRUBIN) GALLSTONES

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COMPLICATIONS
 STROKE
 PULMONARY HYPERTENSION
 RETINAL DETACHMENT
 PRIAPISM (IMPOTENCE)
 LEG ULCERS
 SICKLE CELL NEPHROPATHY
 HEPATOPATHY
 PIGMENT GALLSTONES
 INFERTILITY OR SUBFERTILITY (MISCARRIAGES)
 INFECTIONS

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Treatment
1. STEADY STATE
 COUNSELING
 FOLIC ACID
 PROGUANIL
 HYDROXYUREA
 PNEUMOCOCCAL VACCINE
 PENICILLIN V PROPHYLAXIS
 LIBERAL ORAL FLUIDS

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EMERGING THERAPIES
 Novel targeted therapies exploiting the roles E- and P-
Selectins play in vaso-occlusion have shown great promise.
These are:
 Crizanlizumab: an anti-P Selectin which reduces pain even
among patients on Hydroxyurea
 Rivipansel (GMI 1070): A pan-Selectin inhibitor with
enhanced anti-E Selectin activity.

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MANAGEMENT OF CRISES
 ADEQUATE HYDRATION
 ANTIBIOTICS
 ANTIMALARIALS
 ANALGESICS ORAL AND PARENTERAL
 BLOOD TRANSFUSION
 EXCHANGE TRANSFUSION IN PRIAPISM,
INTRACTABLE PAINS, ACUTE CHEST SYNDROME
 BED REST

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OTHER FORMS OF TREATMENT
 L-GLUTAMINE POWDER
 HYDROXYUREA (MOST COMMON AFTER FOLIC
ACID AND PALUDRIN)
 STEM CELL TRANSPLANTATION
 GENE THERAPY

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WHAT IS STEADY STATE?
 Crises- and blood transfusion-free for at least 3 weeks and 3
months respectively in addition to remaining crises free for
up to one week. (NO Akinola, SM Stevens, IM Franklin, GB Nash, J Stuart. Subclinical ischaemic episodes
during the steady state of sickle cell anaemia. J Clin Pathol. 1992;45(10):902-06
 Phases of VOCs
Prodromal, Initial, Established and Resolving

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CRISES
 THESE ARE ACUTE CLINICAL EPISODES REQUIRING
URGENT INTERVENTION OR HOSPITAL ADMISSION
 BEING REPLACED BY THE WORD ‘EPISODES’
 PRECIPITATED BY :
 INFECTIONS,
 EXTREMES OF WEATHER
 DEHYDRATION
 EXCESSIVE PHYSICAL EXERTION
 TRAUMA
 DEHYDRATION
 PSYCHOLOGICAL STRESS
 UNKNOWN

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TYPES OF CRISES
1. VASO-OCCLUSIVE
2. VISCERAL SEQUESTRATION
3. APLASTIC
4. HYPERHAEMOLYTIC

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CRISES
 VASO-OCCLUSIVE CRISES - THE MOST FREQUENT
FORM OF CRISES. THEY ARE CHARACTERIZED BY
PAIN
 MAY AFFECT THE
 BONES
 SPLEEN
 LUNGS
 BRAIN

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 VISCERAL SEQUESTRATION: ORGANS AFFECTED
ARE THE SPLEEN,LIVER,PELVIC GIRDLE AND LUNGS
 APLASTIC CRISES: THIS IS CAUSED BY INFECTION

WITH PARVOVIRUS B19 WHICH INFECTS
DEVELOPING ERYTHROBLASTS IN THE BONE
MARROW.

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 HYPERHAEMOLYTIC CRISES WHEN THERE IS AN
INCREASED RATE OF HAEMOLYSIS. PATIENTS
USUALLY PRESENT WITH WORSENNING ANAEMIA
AND JAUNDICE

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INVESTIGATIONS
 CAN BE BROADLY CLASSIFIED AS THOSE THAT
1. AID IN DIAGNOSIS
2. MONITORING OF DISEASE
3. AID IN INVESTIGATION OF CRISES

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INVESTIGATIONS THAT AID IN
DIAGNOSIS
1. SICKLING TEST USING 2% SODIUM
METABISULFITE OR SODIUM DITHIONITE. THIS
HOWEVER SIMPLY DETECTS THE PRESENCE OF HbS
AND CANNOT DIFFERENTIATE HbSS FROM HbAS
OR EVEN HbSC ETC.
2. SOLUBILITY TEST USING A SOLUTION THAT
CONTAINS A HIGH PHOSPHATE BUFFER,A
REDUCING AGENT AND SAPONIN. THIS HAS
SEVERAL FALSE POSITIVE AND FALSE NEGATIVE
FACTORS

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 HAEMOGLOBIN ELECTROPHORESIS: THIS UTILISES
THE DIFFERENTIAL RATES OF MIGRATION OF
CHARGED PARTICLES (HAEMOGLOBIN IN THIS
INSTANCE) ACROSS AN ELECTRIC FIELD. ALKALINE
AND ACIDIC MEDIA MAY BE USED.
 HPLC
 IEF
 PCR AND RFLP:THESE MAY BE UTILISED IN
PRENATAL DIAGNOSIS USING CHORIONIC VILLUS
BIOPSY,AMNIOTIC FLUID OR FOETAL BLOOD
SAMPLES

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INVESTIGATIONS THAT AID IN
MONITORING SCA
 COMPLETE BLOOD COUNT
 URINALYSIS
 UREA,ELECTROLYTES AND CREATININE
 TRANSCRANIAL DOPPLER ULTRASONOGRAPHY
 FUNDOSCOPY
 HbF QUANTIFICATION

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OTHER INVESTIGATIONS AS MAY ARISE
 BLOOD CULTURE
 STOOL MCS
 URINE MCS
 WOUND SWAB MCS
 CXR
 ABDOMINAL USS

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GENETIC COUNSELLING
 THE PROCESS BY WHICH PATIENTS OR RELATIVES
AT RISK OF A DISORDER THAT MAY BE
HEREDITARY ARE ADVISED OF THE PROBABILITY
OF DEVELOPING AND TRANSMITTING IT AND OF
THE WAYS IN WHICH THIS MAY BE PREVENTED
OR AMELIORATED

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PRINCIPLES OF GENETIC
COUNSELLING
 INFORMATIVE
 CONFIDENTIAL
 NON-DIRECTIVE
 SUPPORTIVE

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CONCLUSION
 SICKLE CELL ANAEMIA IS A VERY IMPORTANT
CONDITION WITH PROTEAN
MANIFESTATIONS.HENCE A GOOD GRASP OF THIS
CONDITION IS VERY IMPORTANT FOR EVERY
PHYSICIAN.

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Acute Lymphoblastic Leukaemia
(ALL)
Learning Objectives
 By the end of this lecture you should be able to:
1. Define Acute Lymphoblastic Leukaemia (ALL)
2. List 5 risk factors
3. Discuss the pathogenesis of ALL
4. List 3 translocations in ALL
5. Enumerate 3 diagnostic investigations
6. Enumerate the FAB Classification
7. List 4 Supportive and 2 Specific treatments for ALL
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Definition of Acute Lymphoblastic
Leukaemia
 Clonal disorder of the haematopoietic stem cells
characterized by proliferation of lymphoblasts in the
bone marrow/peripheral blood and associated with a
short rapidly progressive and fatal outcome if untreated
 ≥ 20% lymphoblasts or characteristic mutation
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Risk Factors
 Aetiology is unknown
1. Hereditary
- Down Syndrome, Fanconi Anaemia, Bloom Syndrome
2. Acquired
- Ionizing radiation, chemical agents, viruses
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Mechanisms of ALL
Leukemogenesis
 Proto-oncogene + Transcriptionally active site =
oncogene
 chromosomes 8 (C-MYC) and 14 (Ig Heavy chain gene)
 Fusion protein with enhanced tyrosine kinase
activity
 chromosomes 9 and 22 – BCR/ABL-1 (de novo ALL vs
CML transformation)
 Activation of FLT3 – Receptor Tyrosine Kinase,
signal transduction – neoplastic transformation
 Inactivation of tumour suppressor gene pathway:
RB1 or P53
 Foetal origin – In Utero first hit (t12;21)
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Most common among 3-7 year old
75% of cases occur among <10 year old
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Some Definitions
 REMISSION
- Normal Clinical Status
- Normal Blood Counts
- Less than 5% blasts in the bone marrow
 RELAPSE
- Recurrence of symptoms, signs and laboratory features of
ALL in a patient who was in remission
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Classification
 French American British
(FAB) Co-operative Group
 ALL-L1
 ALL-L2
 ALL-L3 (later expunged by
WHO)
 World Health Organization
(WHO)
 Morphology,
immunophenotype, genetic
features
 Clinical, therapeutic and
prognostic importance
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Clinical Features
 Bone marrow failure:
- Anaemia, neutropenia and thrombocytopenia
 Organ infiltration:
- Lymphadenopathy, hepatomegaly, splenomegaly, tender
bones, testes, meninges. Compression syndrome (mediastinal
mass in T-ALL)
 Hyperleucocytosis:
- headaches, visual symptoms etc
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Investigations
 Diagnostic  Ancillary
- Morphology (Peripheral - FBC
film and bone marrow) - Blood culture
- Cytochemistry - Urea, Electrolytes, Uric
- Immunophenotyping acid, LFTs, Calcium
- Cytogenetic studies phosphates
- Molecular genetic analyses - Lumbar puncture
- Stool microscopy
- X-rays, USS
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 Importance of Molecular Genetics in ALL
- Determine lineage: Heavy and light chain re-arrangements,
T-Cell receptor genes
- Establish clonality
- Prognostication
- Minimal residual disease
- Early detection of relapse
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Differential Diagnoses
 Reactive lymphocytosis: CMV,EBV, Brucellosis
 Acute Myeloblastic Leukaemia (AML)
 Leukaemic phase of a lymphoblastic lymphoma
 Metastasis: Neuroblastoma, Ewing’s Sarcoma, lung cancer
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PROGNOSTIC FACTORS
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Treatment
 Supportive
 Antivirals, antifungals,
antibiotics
 Hydration, rasburicase
 Blood products
 G-CSF
 etc
 Specific
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Stages of Chemotherapy
 Remission Induction
- Reduce the leukemic cell burden to undetectable levels thus
restoring/normalizing haemopoiesis and health
 Consolidation (very high dose)
- Eradicate residual blast cells and prevent resistance and
relapse
 Maintenance
- To sustain remission and prevent relapse
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Prognosis
 Variable
 Depends on factors already discussed
 Additional limitations in our setting

- Funds, equipment/facilities, availability of supportive
interventions, awareness, quackery.You can list more ……..
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Conclusion
 This is a very brief overview. There is more to ALL than
discussed. However what is presented is sufficient for
you. No hyper stuff please
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Some References
 Hoffbrand AV, Moss PAH. Acute Lymphoblastic Leukaemia.
In:Hoffbrand’s Essential Haematology 7th Edition Blackwell
Publishers Ltd Massachusetts, 2016.187-196
 Kawthalkar SM. Acute Lymphoblastic Leukaemia. In:
Essentials of Haematology 1st Edition JAYPEE Brothers
Medical Publishers (P) LTD New Delhi, 2006.250-260.
96 1/23/2023 12:49 PM
ACUTE MYELOBLASTIC LEUKAEMIA
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LEARNING OBJECTIVES
 At the end of this lecture you should be able to:
1. Define AML
2. List 5 risk factors
3. Discuss the pathogenesis of AML
4. List 3 translocations in AML
5. Enumerate 3 diagnostic investigations
6. Enumerate the variables addressed by WHO Classification of AML
7. List 4 Supportive and 2 Specific treatments for AML
8. Write short notes on APL
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OUTLINE
 INTRODUCTION
 DEFINITION
 ETIOLOGY
 PATHOGENESIS
 EPIDEMIOLOGY
 CLINICAL FEATURES
 INVESTIGATIONS
 CLASSIFICATION
 TREATMENT
 APL
 PROGNOSIS
 CONCLUSION
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INTRODUCTION
100 1/23/2023
DEFINITION
 AML is defined as acquired clonal disorders of the haemopoietic
stem cells characterized by the accumulation (≥20%) of
immature cells derived from the GEMM lineage in the blood and
or bone marrow . AML-specific cytogenetic and/or molecular
markers are DIAGNOSTIC even in the absence of increased
myeloblasts.
 GEMM Granulocytic, Erythroid, Megakaryocytic or Monocytic
Lineage.
 Acute Nonlymphocytic Leukaemia - more precise. Acute
Myeloid Leukaemia (AML) is the recommended term.
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ETIOLOGY
 No known cause however risk factors can be grouped into
two – GENETIC and ENVIROMENTAL
 GENETIC risk factors include:
1. Down Syndrome
2. Bloom Syndrome
3. Klinefelter Syndrome
4. Turner Syndrome
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5. Fanconi Anaemia
6. Dyskeratosis Congenita
7. Shwachman-Diamond Syndrome
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ENVIROMENTAL
1. Solvents (Benzene)
2. Smoking
3. Ionizing Radiation
4. Chemotherapy
- Alkylating therapy
- Topoisomerase II inhibitors
5. CML, MDS, PNH
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PATHOGENESIS
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PATHOGENESIS (CONTD)
 A myriad of factors result in three end results
1. Loss of apoptosis
2. Proliferation and
3. Failure to Differentiate
 Blast cells accumulate in the bone marrow and
‘crowd-out’ the normal ‘inhabitants’. This leads to bone
marrow failure characterized by anaemia,
thrombocytopaenia and leucopaenia.
106 1/23/2023
PATHOGENESIS (CONTD)
 Although the leukaemic cells may be many leading to
leucocytosis, they are immuno-incompetent. Their high
number may even be deleterious
(Hyperleucocytosis)
 Leukaemic cells may infiltrate the skin, gums, liver,
spleen, testes and the CNS.
107 1/23/2023
EPIDEMIOLOGY
 Predominant form of leukaemia in the neonatal period
 Commonest form of leukaemia in adults
 More in males
 Peak age is 60 years
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CLINICAL FEATURES
These depend on the predominant pattern of bone marrow failure
 The patient is usually acutely ill-looking and may present with various
combinations of the following
1. Features of anaemia
2. Features of Thrombocytopaenia
3. Fever (from infections or granulocytopaenia)
4. Gum hypertrophy and bleeding (M4/M5)
5. Splenomegaly, Hepatomegaly
6. Skin swellings (Chloroma or Granulocytic sarcoma)
7. Features of DIC (APL/M3)
8. CNS Disease
109 1/23/2023
INVESTIGATIONS
 Low PCV
 Thrombocytopaenia
 WBC may be high, low or normal
 *Peripheral Myeloblasts at least 20% is diagnostic*
 Bone marrow aspiration may reveal increased Myeloblasts
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INVESTIGATIONS (CONTD)
 Cytochemistry
MPO, SBB and Chloroacetate are positive
Non-specific esterase is positive in M4 and M5
 Flow cytometry
-CD13+, CD33+ and CD117+ (c-kit),TdT- (specific myeloid
antigens)
-Glycophorin (positive in erythroid lineage)
-CD 41 (Megakaryoblastic lineage)
-CD14, CD64 (Monocytic markers)
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INVESTIGATIONS (CONTD)
 Cytogenetics
t(15;17)
t(8;21)
t(16;16)
Inv(16)
Deletion 5
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 Molecular studies: CEBPA , NPM
 OTHERS
- PT,APTT
- U&E,Cr Uric Acid, LDH, LFTs
- Blood Culture
- As may be determined by patient’s presentation
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CLASSIFICATION
1. French-American-British (FAB) Co-operative
Group. Based on two criteria - morphology and
cytochemistry.
2. WHO classification addressed the shortcoming of FAB by
adding Clinical, cytogenetics, immunophenotypic
and molecular variables to the initial FAB criteria.
Diagnostic blast count was reduced from 30% (FAB) to
20% (WHO).
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FAB CLASSIFICATION
Type of AML
M0 Minimally differentiated
M1 Without Maturation
M2 With Maturation
M3 -Hypergranular Promyelocytic Leukaemia
- Hypogranular (Microgranular) Promyelocytic Leukaemia (M3 Variant)
M4 -Acute Myelomonocytic Leukaemia
-Acute Myelomonocytic Leukaemia with bone marrow eosinophilia (M4
Eo)
M5 -Monoblastic (M5a)
- Monocytic (M5b)
M6 Acute Erythroleukaemia
M7 Acute Megakaryocytic Leukaemia
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SUMMARY OF WHO CLASSIFICATION
AML with recurrent genetic abnormalities

-AML with t(8:21)
-AML with t(16:16) or inv(16)
-AML with t(15;17)
-Provisional entity: AML with mutated NPM1

-Provisional entity: AML with mutated CEBPA
AML with Myelodysplasia-related changes
Therapy-related myeloid neoplasms (t-AML)
AML not otherwise specified
-AML with minimal differentiation
-AML without differentiation
-AML with maturation
-Acute myelomonocytic Leukaemia
-Acute Monoblastic/Monocytic Leukaemia
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-Acute Erythroid Leukaemia
WHO (CONTD)
-Acute Megakaryoblastic Leukaemia
-Acute Basophilic Leukaemia
-Acute panmyelosis with myelofibrosis
Myeloid Sarcoma
Myeloid proliferations related to Down syndrome
-Transient abnormal myelopoiesis
-Myeloid leukaemia
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TREATMENT
1. General supportive therapy
 Counseling
 Hydration
 Allopurinol
 Blood products and components
 Antibiotics
 Antifungals
 Antivirals
 G-CSF
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TREATMENT (CONTD)
2. Specific
 Chemotherapy
- Induction
- Consolidation
- Maintenance (Only in Acute Promyelocytic Leukaemia
[APL] )
- all-trans retinoic acid (ATRA) is added to the
chemotherapy in APL (M3)
 SCT – Autologous, Allogeneic
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TREATMENT ALGORITHM
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SOME TERMINOLOGIES
 REMISSION
- Normal Clinical Status
- Normal Blood Counts
- Less than 5% blasts in the bone marrow
 RELAPSE
- Recurrence of symptoms, signs and laboratory features of
AML in a patient who was in remission
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 MINIMAL RESIDUAL DISEASE – Disease that cannot be
seen by conventional microscopy of the blood and bone
marrow.
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ACUTE PROMYELOCYTIC LEUKAEMIA
 Acute Promyelocytic Leukaemia (APL) is a variant of AML that
corresponds to M3. Primary granules form Auer rods in
the promyelocytes. It is defined by t(15;17) which results in
PML-RARα fusion protein that acts as a transcriptional
repressor. Differentiation is thus arrested at the
Promyelocytic stage. APL may present with DIC due to
release of Thromboplastin-like materials from the leukaemic cells.
ATRA is a differentiating agent that ‘removes the block’.
123 1/23/2023
124 1/23/2023
APL (CONTD)
 The use of ATRA may be associated with ATRA Syndrome
(Differentiating Syndrome). This is characterised by
fever, pulmonary infiltrates, hypoxia and fluid
overload.
 Whereas Dexamethasone is used in mild cases, ATRA
is discontinued in severe cases.
125 1/23/2023
PROGNOSIS
126 1/23/2023
127 1/23/2023
CONCLUSION
 AML remains one of the most difficult haematological
malignancies to manage especially in the developing world.
128 1/23/2023
REFERENCES
 Hoffbrand AV, Moss PAH. Acute Myeloid Leukaemia. In: Essential
Haematology 6th Edition Blackwell Publishers Ltd Massachusetts,
2011.179-189
 Kawthalkar SM. Acute Myeloid Leukamia. In:Essentials of Haematology
1st Edition JAYPEE Brothers Medical Publishers (P) LTD New Delhi,
2006.250-260.
 Durosinmi MA. Acute Leukaemias. In: A Design Handbook of Haemato-
Oncology Chemotherapy for Medical Students and Doctors 3rd Edition.
Amkra Books Lagos, 2013. 7-14
129 1/23/2023
THAN
K YOU
130 1/23/2023

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HAEMATOLOGIC AND

DEPT OF PATHOLOGY, FACULTY OF BASIC

Pluripotent Stem Cell

Myeloid Multipotent Common Lymphoid

 Red Blood Cells

Brady; Paramedic Care Principles and Practice

Brady; Paramedic Care Principles and Practice

DR. G.D WAZIRI

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

HEPATOBILLIARY PIGMENT (BILIRUBIN) GALLSTONES

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

 APLASTIC CRISES: THIS IS CAUSED BY INFECTION

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

DEPT OF PATHOLOGY, FACULTY OF BASIC

characterized by proliferation of lymphoblasts in the

bone marrow/peripheral blood and associated with a

short rapidly progressive and fatal outcome if untreated

 ≥ 20% lymphoblasts or characteristic mutation

 Acute Myeloblastic Leukaemia (AML)

 Leukaemic phase of a lymphoblastic lymphoma

 Metastasis: Neuroblastoma, Ewing’s Sarcoma, lung cancer

 Depends on factors already discussed

 Additional limitations in our setting

AML with recurrent genetic abnormalities

-Provisional entity: AML with mutated NPM1

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