Everything You Need To Know (at least) for

SEQs and FLMs

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IRON DEFICIENCY ANAEMIA

Definitionis an aetiologic classification of reduction in Haemoglobin levels in blood due to the deficient in iron which is essential for the production of red blood cells.

Chronic Blood Loss Increase iron demand

Malabsorption Poor diet

Uterine Gastrointestinal tract

Peptic UlcerEsophageal varicesAspirin (NSAID)

Urinary tractHaematuriaHaemoglobinuriaHaemosiderosis

PrematurityAdult malePostmenopausalMenstruatingPregnancyChildrenFemale (12-15)

GastrectomyGluten-induced enteropathy

Malnutrition

Causes

Normal iron regulation

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Dietary intake in the form of:1) haem-protein complex2) ferric hydroxides3) ferric protein

Breakdown to

In iron deficient

↓no of hepcidin

↑ferroportin level of the macrophages,

intestinal epithelial cell and placental

syncytiothropoblast

↑iron release to the plasma

↑no of DMT-1

↑absorption of inorganic iron by

duodenal enterocyte

Serum iron level back to normal

Iron in anaemia

Clinical features of anaemia

1. Smooth and glistening tongue (atrophic glossitis)2. Angular Stomatitis3. Koilonychia (spoon-shaped nails)4. Dysphagia – due to the formation of pharyngeal web

Lab findings of Iron deficiency anaemia

1. See blood film in Haematological Presentation [soft copy] (slide 6)2. Low MCH (<27 pg) – hypochromic anaemia3. Low MCV (<80 fl) – microcytic anaemia4. Pencil-shaped/cigar shaped poikilocytes5. Occasional target cell6. Serum iron falls but increase total iron binding capacity7. Reduce serum ferritin (normal in latent iron deficiency)

Treatment

1. Oral ferrous sulphate2. Intravenous ferric hydroxide-sucrose

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Iron Protorporphyrin

Haem Globin

Haemoglobin

Iron deficiency anaemia

Case example

A 32 years old woman with a history of heavy menses presents to your clinic complaining fatigue upon exertion. You note that she is pale and decide to send her for serum studies. Lab results reveal a low serum iron levels, a high TIBC and mildly decrease serum ferritin level

ANAEMIA OF CHRONIC DISEASE

DefinitionDecrease in the amount of haemoglobin below normal in patient with chronic inflammatory disease or malignancy

Causes

Chronic inflammatory disease MalignancyInfectious Non-infectious

Pulmonary abscessTuberculosisOsteomyelitisPneumoniaBacterial endocarditisUrinary Tract Infections

Rheumatoid ArthritisSystemic Lupus ErythematosusSarcoidosisCrohn’s Disease

CarcinomaLymphomaSarcoma

Pathogenesis

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Infections

Cytokines (IL-1 and TNF-α)

Reduce release of iron macrophage; reduce red cell

lifespan and interference with erythropoiesis by reduction of

erythropoietin levels

Release of hepcidin by the liver

Inhibit iron release by macrophage and reduce absorption of iron by intestinal

epithelial cell

Release of cytokines

Attracted macrophages

New growth of the tissue/cell (foreign body)

Malignancy (Neoplasia)

TNF-α suppressed bone marrow from producing blood cell

Anaemia of Chronic disease (reduction in

serum iron)

Paraneoplastic Syndrome

Lab investigations

1. See blood film in Haematological Presentation [soft copy] (slide 7)2. Normochromic Anaemia (MCH normal)3. Normocytic Anaemia (MCV normal)4. Mild and progressive anaemia5. Reduce TIBC (total iron binding capacity) and serum iron6. Increase serum ferritin or normal

Treatment

1. Remove the underlying cause of malignancy or infections

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Case example

A 9 months old boy presented with history of high grade fever for 6 days prior to admission. He had decrease appetite and vomiting several times per day. He was also wet his pamper lesser than usual.

On physical examination, he was ill looking and lethargic. He was also pale. Lab investigations suggested a urinary tract infection with septicaemia.

1) Explain each pathophysiology of each signs presented above

2) List the relevant investigations you would like to performed and state your expected findings in this patient

3) State the non-pharmacological and pharmacological treatment for this patient

SIDEROBLASTIC ANAEMIA

1. Definitionis a refractory anaemia with hypochromic cells in the peripheral blood and increase marrow iron. It can be defined as presence of many pathological ring sideroblast1 in the marrow and clinically diagnosed when 15 % or more of marrow erythroblast are ring sideroblast See blood film in Haematological Presentation [soft copy] (slide 8)

Causes

Congenital AcquiredPrimary Secondary

Mutation of δ-aminolaevulinic acid synthase (ALA-S) gene on X-chromosome

Myelodysplasia Malignancy – myelofibrosis, myeloid leukemia, myeloma

Drugs – antituberculous drugs

Lead poisoning Benign condition –

haemolytic anaemia, malabsorption, Rheumatoid arthritis

Pathogenesis

MEGALOBLASTIC ANAEMIA

1 Is a red blood cell precursor (erythroblast)

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Lead poisoning

Inhibit haem and globin synthesis

Inhibit the enzyme pyrimidine 5’ nucleotidase

Disturbed the breakdown of RNA

Accumulation of denatured RNA in the red cell

Appearance of basophilic stippling (Romanowsky stain)

Ring sideroblast at the marrow

Hypochromic anaemia

Definition

Also known as macrocytic anaemia (MCV >95 fl), it can be defined as erythroblast in the bone marrow shows a characteristic abnormality which the maturation of nucleus delayed relative to that of cytoplasm

Causes

1. Vitamin B12 deficiency – defective in DNA synthesis2. Folate deficiency – defective DNA synthesis3. Abnormalities in B12 and Folate metabolism – cobalamin deficiency, Nitrous oxide or

antifolate drugs4. Other defects of DNA synthesis – congenital enzyme deficiency (orotic aciduria) or

acquired enzyme deficiency (alcohol, hydroxyurea etc)

Normal B12 and Folate metabolisme

Clinical features

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1. Gradually progressive symptoms signs of anaemia2. Mildly jaundice – increase ineffective erythropoiesis leads to increase breakdown of

Haemoglobin – hyperbilirubinaemia3. Glossitis 4. Angular stomatitis5. Loss of weight6. Purpura

Lab investigations

In peripheral blood

1. See blood film in Haematological Presentation [soft copy] (slide 9 and 10)2. Macrocytic anaemia3. Dual shaped macrocytes4. Low reticulocyte count5. Decrease TWBC and platelet6. Hypersegmented neutrophils (slide 11)

In bone marrow

1. Hypercellular2. Large erythroblast, failure of nuclear maturation3. Giant and abnormal metamyelocyte (slide 12)

Treatment

1. Large doses of vitamin B122. Large doses of folic acid

HAEMOLYTIC ANAEMIA

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Definition

Anaemia results from increase red cell destruction

Causes

Inherited Acquired Membrane

Hereditary spherocytosis Hereditary elliptocytosis

Metabolisme G6PD deficiency

Pyruvate kinase deficiencyHaemoglobin

Genetic abnormalities (Hb S, Hb C)

Autoimmune Warm antibody type Cold antibody type

Alloimmune Haemolytic transfusion reactions Haemolytic disease of newborns

Red cell fragmentation syndromeMarch haemoglobinuriaInfections

Malaria Clostridia

Chemical and physical agents Drugs, industrial/domestic substance Burns

Secondary Liver and renal disease

Paroxysmal nocturnal haemoglobinuria

Clinical features

1. Pallor of the mucous membrane2. Mild fluctuating jaundice3. Splenomegally4. Dark urine (increase urobilinogen)5. Ulcers

Laboratory findings

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1. Increase red cell breakdown Increase serum bilirubin Increase urine urobilinogen Increase stercobilinogen Absence of serum haptoglobulins

2. Increase red cell production Reticulocytosis Erythroid hyperplasia

3. Damage red cell Microspherocytes – reduce red cell survival Elliptocytosis Fragments

G6PD deficiency

Definition

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One of the causes of haemolytic anaemia which the deficiency renders the red cell susceptible to oxidant stress

Oxidant stress

1. Infections or other acute illness2. Drugs

- Antimalarials- Sulphonamides and sulphones- Other antibacterial agents- Analgesics- Antihelminths- Others – vitamin K analogues, naphtalenes, mothballs- Fava beans

Pathogenesis

Clinical features

1. Acute haemolytic anaemia – refers haemolytic anaemia

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2. Neonatal jaundice – hyperbilirubinaemia

Lab investigations

Refer Slide 13

1. Bite cells and blister cells2. Contracted and fragmented cell3. Heinz body (clumps of oxidized haemoglobin within the RBC)

SICKLE CELL ANAEMIA

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Case example

A 35-year-old Chinese man comes to your office after noticing that his urine has become tea-colored. He tells you that he has just returned from a trip to Kenya where he had taken primaquine to guard against contracting malaria. Peripheral blood smear found Heinz body as well as contracted cell

DefinitionIs a group of haemoglobin disorder which the sickle β-cell gene is inherited.

Classification1. Homozygous sickle cell anaemia (Hb SS)2. Doubly heterozygote condition of Hb SC and Hb Sβthal

Pathogenesis and pathophysiology

Clinical features1. Painful vaso-occlusive crises

The occlusion of blood vessels by crystals can be caused by infections, acidosis, dehydration or deoxygenation

It can cause infarction to bones, lungs, spleen, brain and spinal cord 1st presentation is ‘hand and foot syndromes’ (painful dactylitis caused by

infarction of small bones in the hand and foot) leads to abnormal digits varying lengths

2. Visceral sequestration crises Sickling within organ and pooling of blood – causing severe exacerbation of

anaemia Dyspnoea, falling arterial PO2, chest pains and pulmonary infiltrates on X-ray

3. Aplastic crises Anaemia as a results of infection with parvovirus or from folate deficiency

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Substitution of valine for glutamic acid in position 6 in β-chain

Produce sickle cell (Hb S or Hbα2β2S)

These cells are;1. Insoluble in nature

2. Forms crystal when expose to low oxygen tension

These crystals may blocks different areas of microcirculation or large vessels

Infarction of various organs

Become symptomatic and give rise to various clinical features (see below)

Causing sudden fall in Hb

4. Haemolytic crises Increase rate of haemolysis Fall in haemoglobin and rise in numbers of reticulocytes

5. Others Mild anaemia – Hb S gives up oxygen easily compared to Hb A Ulcers of the lower legs – due to vascular stasis and local ischaemia Enlarged spleen in infancy but becomes reduce in size as a results of infarction Gall stone Kidneys – medullary infarcts and pappilary necrosis Osteomyelitis

Investigation1. Hb level – 6-9 g/dl2. Sickle cell and target cell in blood (slide 14)3. Features of splenic atrophy4. Screening test for sickling becomes positive when blood is deoxygenated5. Hb electrophoresis – Hb SS, no Hb A and Hb F is variable (5-15%)

Treatment1. Prophylactic – avoid precipitating factors2. Folic acid3. Good general nutrition and hygiene4. Regular oral penicillin – avoid infections5. Stem cell transplantation

AETIOLOGY OF HAEMATOLOGICAL MALIGNANCIES

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Case example

An 8-year-old African-American boy presents to the emergency department complaining of severe pain in both leg. The pain began after the boy attended pool party and spent much of the day swimming and he reports that he has suffered from severe bouts of back and chest pain in the past.

Explain aetiology, pathology and pathophysiology, clinical manifestation and treatment

1. Inherited factors Incidence increase greatly in some genetic disease such as Down Syndrome,

Bloom Syndrome, Fanconi’s Anaemia, ataxia telangiectasia, Klinefelter’s syndrome and Wiskott-Aldrich Syndrome

Incidence increase weakly in familial history of AML, CLL, Hodgkin and Non-Hodgkin’s Lymphoma

2. Chemicals Chronic exposure to Benzene may cause marrow dysplasia and hypoplasia,

chromosome abnormalities, myelodysplasia as well as AML

3. Drugs Combination of alkylating agents (chlorambucil) with radiotherapy predispose to

AML Epipodophyllotoxins (etoposide) are antileukaemic agents and their use is

associated with the risk of developing secondary leukaemia

4. Radiation Leukaemogenic to marrow

5. Infections

Infections Associated withVirus

i) HTLV-1ii) Epstein-Barr

virusiii) HHV-8iv) HIV-1

i) Adult T-cell leukaemia/lymphomaii) Burkitt’s and Hodgkin’s Lymphomaiii) Primary effusion lymphomaiv) High grade B-cell lymphoma

BacteriaHelicobacter pylori Gastric lymphoma (MALT)ProtozoaMalaria Burkitt’s Lymphoma

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LEUKAEMIA

DefinitionIs a group of disorders characterized by accumulation of malignant white cells in marrow and blood. It can be symptomatic due to

i) Bone marrow dysfunctionii) Organ infiltration by leukaemic cells

ClassificationIs classify based on the rate of progression of this disease

ACUTE LYMPHOBLASTIC LEUKAEMIA

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Leukaemia

Acute Leukaemia (see next page)

Chronic Leukaemia (see next page)

Acute Myeloblastic Leukaemia (see

next page)

Acute Lymphoblastic

Leukaemia (see next page)

Chronic Myeloblastic

Leukaemia (see next page)

Chronic Lymphoblastic

Leukaemia (see next page)

Definition

Accumulation of lymphoblast in the bone marrow and it is the most common malignancy in childhood

Classification

French-American-British (FAB) classification of Acute Lymphoblastic Leukaemia

Grade Description Reference L1 Blast cells small, uniform high nuclear to cytoplasmic ratio Slide 15L2 Blast cell larger, heterogenous, lower nuclear to cytoplasmic

ratioSlide 16

L3 Vacuolated blast, basophilic cytoplasm (B-ALL) Slide 17

Clinical features

Bone marrow failure

1. Anaemia – pallor, lethargy, dyspnoea etc2. Neutropenia – fever, malaise, features of infections3. Thrombocytopenia – bruising, purpura, gum bleeding, menorrhagia)

Organs infiltration

1. Tender bones2. Lymphadenopathy3. Moderate splenomegally4. Hepatomegaly5. Meningeal syndrome – headache, nausea, vomiting, blurring of vision6. Pappiloedema and haemorrhage7. Testicular swelling8. Mediastinal compression (thymic enlargement)

Investigations

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1. Normocytic anaemia2. Normochromic anaemia3. Thrombocytopenia 4. White cell count normal, reduce or increase white cell count5. Variable number of blast cell in film6. Hypercellular marrow with more than 20 % leukaemic blood 7. Lumbar puncture – increase pressure, contains leukaemic cell8. Serum analysis shows increase uric acid, lactate dehydrogenase, hypercalcaemia9. X-ray shows lytic bone lesion, mediastinal mass (thymus or lymph nodes)

Treatment

1. Alkylating agents – cyclophosphamides2. Antimetabolites – methotrexate3. Cytotoxic antibiotics4. Purine analogues 5. Hydroxyurea6. Chemotherapy and radiotherapy

ACUTE MYELOBLASTIC LEUKAEMIA

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Definition

Accumulation of abnormal myeloblast in the bone marrow and its incidence increase with age

Causes and classification

French-American-British (FAB) classification of Acute Myeloblastic Leukaemia

Grade Description Refference CausesM1 Blast cells show few granules but may

show Auer rods Slide 18 Almost all type –

nucleotide insertion, mutation and internal tandem duplication

M2 Blast cells show multiple cytoplasmic granules

Slide 19 t(8;21), t(6;9)

M3 Blast cells contains prominent granules or multiple Auer rods

Slide 20 t(5;17)

M4 Blast cells have some monocytoid differentiation

Slide 21 Inv(16), del(16q)

M5 Monoblastic leukaemia in which more than 80 % of the blast are monoblasts

Slide 22 Del(11q), t(9;11), t(11;19)

M6 Preponderance of erythroblast Slide 23 Almost all type – nucleotide insertion, mutation and internal tandem duplication

M7 Megakaryoblastic leukaemia showing cytoplasmic blebs on blast

Slide 24 Almost all type – nucleotide insertion, mutation and internal tandem duplication

Clinical features

Anaemia Pallor Lethargy Dyspnoea

Thrombocytopenia Bruising, purpura, gum bleeding and menorrhagia. In M3 variant, there are increase bleeding tendency as well as disseminated

intravascular coagulation (DIC)

Tissue infiltration

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Gum hypertrophy and infiltration Skin involvement Central nervous system disease

Lab investigation

1. Test of DIC positive (M3 variant)2. FISH analysis (refer slide 25)

HODGKIN’S LYMPHOMA

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M4 and m5 types

Case example for Acute Leukaemia

A 6-year-old boy presents to your office complaining of fatigue, fever and a history of recurrent epistaxis and urinary tract infections. He has enlarged liver and spleen and a petechial rash over his entire body. Concerned, you send him for blood test which demonstrate pancytopenia with the multiple blast

Definition

Is a group of disease caused by malignant lymphocytes that accumulates in the lymph nodes characterized by clinical features of lymphadenopathy with presence of Reed-Sterberg cells on histological study

Classification

Classify based on histological finding as well as their prognosis. For clinical classification, see slide 26

Class Description Nodular sclerosis Collagen bands extend from the node capsule to encircle

nodules of abnormal tissue. Lacunar cell variant of Reed-Sterberg cell is often found. Type of cellular infiltrate – lymphocyte-predominant,

mixed cellularity or lymphocyte depleted type Refer slide 27

Mixed cellularity Numerous Reed-Sterberg cell Intermediate numbers of lymphocyte refer slide 28

Lymphocyte-depleted Reticular pattern with dominance Reed-Sterberg cell Low number of lymphocytes Diffuse fibrosis pattern (lymph nodes replaced by

connective tissueLymphocyte-rich Scanty Reed-Sterberg cell

Multiple small lymphocyte with few eosinophils and plasma cell

Nodular and diffuse typeNodular lymphocyte-predominant

Absence of Reed-Sterberg cell Abnormal polymorphic B-cells

Pathogenesis

Clinical features

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Ebstein-Barr virus (50% of total

cases)

Unknown aetiology

Prevent synthesis of full length

immunoglobulin

Mutation of B-cell (Reed-Sterberg

cell)Neoplastic

1. Lymphadenopathy- painless, non-tender, asymmetrical, firm, discrete and rubbery enlargement of

superficial lymph nodes- Involving cervical lymph nodes (60-70%), axillary lymph nodes (10-15%) and

inguinal lymph nodes (6-12%)- size of lymph nodes may increase or decrease spontaneously

2. Moderate hepatosplenomegally3. Signs and symptoms of pleural effusion and superior vena cava obstruction 4. Fever – cyclical or continuous pattern5. Pruritus6. Alcohol-induced pain7. Others – loss of appetite, night sweats, weakness, fatigue, anorexia and cachexia

Laboratory investigations

1. Normocytic anaemia2. Normochromic anaemia3. Leukoerythroblastic anaemia – when involving bone marrow failure4. Neutrophilia5. Eosinophilia6. Lymphopenia and loss of cell-mediated immunity – in advanced progression of

disease7. Platelet count – initially normal or raised, reduced latter8. ESR and C-Reactive Protein raised9. Serum Lactate Dehydrogenase increase

Treatment

1. Chemotherapy – adriamycin. Bleomycin, vinblastine etc2. Radiotherapy – 4000 rad (40 Gy) dose

NON-HODGKIN’S LYMPHOMA

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Case example

A 22 years old man presents to your office complaining of a painless lump in his neck. Upon further questioning, you discover that he has had low grade fever and drenching night sweats for 2 months. He also has lost 14 pounds over the pass 6 weeks. Physical examination reveals unilateral cervical lymphadenopathy and splenomegaly. A lymph node biopsy reveals a large multinucleated cell with prominent nucleoli resembling owl’s eyes

Explain aetiology, pathology and pathophysiology, clinical manifestation and treatment

Definition

A group of tumor, originates from B-cell, T-cell or NK cell characterized by irregular pattern of spread and extranodal disease

Classification

Based on aggressiveness, low grade are indolent, respond well to chemotherapy but very difficult to cure while high grade are aggressive, need urgent treatment but are often curable.see slide 29

Low Grade Non-Hodgkin’s Lymphoma High Grade Non-Hodgkin’s LymphomaFollicular lymphomaIs the most common and is caused by t(14;18) and constitute BCL-2 expression. Clinical features include painless lymphadenopathy and often widespread.See slide 30

Diffuse large B-cell lymphomaIs a heterogenous group of disorder, typically presents with rapidly progressive lymphadenopathy associated with a fast rate of cellular proliferationSee slide 33

Lymphocytic lymphomaIs a disease closely related to the Chronic Lymphoblastic Anaemia and its characteristic similar with the tissue phase of CLLSee slide 31

Burkitt’s lymphomaLymphomatous correlate to L3 variant of ALL. It is thought that Ebstein-Barrvirus infection as well as chronic malaria exposure to be the cause. Clinical presentation, usually a child with massive lymphadenopathy at the jaw. See slide 34

Lymphoplasmacytid lymphomaAssociated with production of monoclonal IgM which give rise to certain complication such as anaemia and hyperviscosity syndrome

Lymphoblastic lymphomaOccurs mostly in children and young adults which the condition is similar clinically and morphologically to that of ALL

Mantle cell lymphomaIs a tumor derived from pre-germinal center cell localized in the primary follicles or in the mantle region of secondary follicles.clinical presentation includes lymphadenopathy, bone marrow infiltration and tumor cell in the bloodSee slide 32Marginal zone lymphomaIs extranodal and usually localized. Clinical presentation includes splenomegally and may be associated with circulating villous lymphocytes

Clinical features

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1. Superficial lymphadenopathy2. Constitutional symptoms – fever, night sweats and weight loss3. Oropharyngeal involvement – Weldeyer’s ring causing sore throat and wheezing4. Anaemia5. Neutropenia with signs and symptoms of infections6. Thrombocytopenia with purpura7. Hepatosplenomegally8. Rarely, skin, brain, testis and thyroid involvement

Investigation

1. Normocytic normochromic anaemia2. Autoimmune haemolytic anaemia may occurs3. Neutropenia4. Thrombocytopenia5. Leukoerythroblastic features6. Increase Lactate Dehydrogenase7. Lymphoma cell (lymph node biopsies)

i) Follicular lymphoma – the follicles and nodules of neoplastic cell compress the surrounding tissue and lack of mantle of small lymphocytes (slide 30)

ii) Lymphocytic lymphoma – predominantly small lymphocytes with round nuclei containing densely clumped heterochromatin (slide 31)

iii) Mantle cell lymphoma – deformed pattern of small lymphocytes with angular nuclei (slide 32)

iv) Diffuse large B-cell lymphoma – neoplastic cell are larger than normal lymphocytes and have round nucleus with prominent nucleoli. Number of mitotic figures are seen (slide 33)

v) Burkitt’s lymphoma – sheets of lymphoblast, starry sky tangible body macrophages

POLYCYTHAEMIA

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A 57-year-old man presents to your office after noticing a large painless lump in his neck. Upon questioning, he tells you that he has been suffering from low grade fever a night sweats over the past 3 months. He has also lost 10 pounds during that time. Physical exams reveal painless cervical and inguinal lymphadenopathy and Hepatosplenomegally. When his blood test reveals elevated LDH levels, you fear the worst and immediately send him for a lymph node biopsy

Explain aetiology, pathology and pathophysiology, clinical manifestation and treatment

Definition

Polycythaemia is an increased in the haemoglobin concentration above normal limit due to the many causes while in Polycythaemia (rubra) vera, it is one type of primary polycythaemia, it is caused by clonal malignancy of marrow stem cell.

Causes

Primary SecondaryPolycythaemia (rubra) vera

JAK2 mutation del(9p) and del(20q)

Compensatory erythropoietin increase High altitude Pulmonary disease Alveolar hypoventilation Cardiovascular diseae Increase affinity haemoglobin Heavy cigarette smoking

Congenital polycythaemia Inappropriate erythropoietin increase Renal disease (hydronephrosis,

vascular impairment, cyst, carcinoma)

Tumors (uterine leiomyoma, hypernephroma, hepatocellular carcinoma, cerebellar hemangioblastoma)

Pathogenesis

Compensatory erythropoietin increase

Clinical features

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Normoblast

Liver

Erythrogenin Globulin

Erythropoietin

Stem cell sensitive to erythropoietin

Proerythroblast

Kidney

Reticulocytes Erythrocytes

Stressor

1. Headaches, dyspnoea, blurred vision and night sweats2. Pruritus after taking hot bath3. Plethoric appearance4. Ruddy cyanosis5. Conjunctival suffusion6. Retinal venous engorgement7. Splenomegally8. Haemorrhage (GI bleed, uterine etc)9. Hypertension10. Gout11. Peptic ulceration

Investigations

1. Increase haematocrit, haemoglobin and red cell count increase2. Neutrophilia and increase circulating basophil3. Raised platelet count4. JAK2 mutation in marrow and peripheral blood granulocytes5. Increase neutrophil alkaline phosphatase score6. Serum B12 and B12 binding capacity - increase haptocorrin7. Hypercellular bone marrow with prominent megakaryocytes8. Low serum erythropoietin9. Expression of PRV-1 increase, decrease Mpl expression10. Increase blood viscosity11. Increase plasma urate12. Normal serum Lactate Dehydrogenase13. Increase CFUE and BFUE

14. Iliac crest trephine biopsy reveals (slide 35)- Replacement of the fat space by the hyperplastic haemopoietic tissue- Increase haemopoietic cell line with prominent megakaryocytes

Treatment

1. Venesection2. Cytotoxic myelosuppression – hydroxyurea3. Phosphorus-32 therapy4. Α-interferon5. Aspirin

MYELOFIBROSIS

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Definition

Is a progressive generalized reactive fibrosis of the bone marrow in association with the development of extramedullary haemopoiesis

Clinical features

1. Insidious onset of anaemia (elderly)2. Massive Splenomegally3. Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats4. Increase bleeding tendency5. Bone pain6. Gout

Lab investigations

1. Anaemia2. High white cell (initially), later became low3. Thrombocytopenia4. JAK2 mutation 5. Increase neutrophil alkaline phosphatase score6. High serum urate7. High serum lactate Dehydrogenase 8. Blood film (slide 36)

- Leukoerythroblastic blood film- ‘tear drop’ poikilocytes

9. Trephine biopsies show (slide 37)- Loss of normal bone marrow architecture- Haemopoietic cell surrounded by increase fibrous tissue and intercellular

substance10. Increase bone density

Treatment

1. Blood transfusion and regular folic therapy2. Hydroxyurea3. Splenectomy4. Allupurinol – to prevent gout

ESSENTIAL THROMBOCYTHAEMIA

Definition

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A sustained increase in platelet count due to increase megakaryocyte proliferation and platelet overproduction

Clinical features

1. Mostly asymptomatic2. Erythromelalgia – burning sensation of hands or feet3. Palpable Splenomegally4. Infarction – splenic atrophy

Lab investigations

1. Blood film (see slide 38)- Abnormal large platelets- Nucleated megakaryocytic fragments

2. Abnormal platelet function test

Treatment

1. Hydroxyurea2. Α-interferon3. Anagrelide4. Busulfan and 32P5. Platelet pheresis6. Aspirin

THROMBOCYTOPENIA

Definition

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A reduction in the number of platelets in the blood

Causes

Failure of platelet production Increase consumption of platelets

Others

Selective megakaryocytes depression

Congenital defects Drugs, chemical, viral

infectionsPart of general bone marrow failure

Cytotoxic drugs Radiotherapy Aplastic anaemia Myelofibrosis Marrow infiltration HIV infections Megaloblastic anaemia

Immune Autoimmune Infections (HIV,

malaria) Drug-induced Heparin

DICThrombotic thrombocytopenic purpura

SplenomegalyMassive transfusion of stored blood to bleeding patient

Pathogenesis

Clinical features

1. Petechial haemorrhage2. Easy bruising

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Thrombocytopenia

Present of abnormal IgG (platelets autantibody)

Directed against antigen sites of platelets glycoprotein IIb-IIIa or Ib complex

Premature removal of platelet by macrophages of

reticuloendothelial system

Increase destruction of the platelet

Splenomegaly Pooling of platelet at the spleen (90% total)

Abnormal distribution of the platelet

Viral infections

Drugs toxicity

Suppress bone marrow from producing platelets

3. Menorrhagia4. Mucousal bleeding – epistaxes or gum bleeding5. Intracranial haemorrhage (rarely)

Lab investigations

1. Prolonged reduction of platelet count <400 x 109

2. Present of large platelet in the peripheral blood3. Increase or normal number of marrow megakaryocytes

Treatment

Depending on the cause thrombocytopenia

1. Splenectomy2. High dose of intravenous immunoglobulin therapy3. Corticosteroid or immunosuppressive drugs – vincristine, cyclophosphamide etc4. Monoclonal antibody - Rituxinab5. Platelet transfusion6. Stem cell transplantation

HAEMOPHILIA A

Definition

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Congenital deficiencies (X-link recessive) of factor VIII

Pathogenesis

Clinical features

Applied to haemophilia A, B and von Willebrand disease

1. Infant – post-circumcision haemorrhage2. Develops joint, soft tissue bleeds and excessive bruising when start to be active3. Recurrent painful haemarthroses4. Haematoma – can leads to joint deformities, entrapment neuropathy and ischaemic

necrosis5. Prolonged bleeding after dental extractions6. Spontaneous haematuria and gastrointestinal bleed7. Haemophilic pseudotumor – large encapsulated haematoma with progressive cystic

swelling and occurs commonly at fascial and muscle planes, large muscle groups, long bones, pelvis and cranium

Lab investigations

Tests ResultsPlatelet count NormalBleeding time Normal

Prothrombin time NormalPartial thomboplastin time Prolonged

Factor VIII LowFactor IX Normal

vWF NormalRistocetin-induced platelet aggregation Normal

Treatment

1. Factor VIII replacement therapy

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Mutation or deletion of X chromosome (Xq2.6) region or flip-tip inversion in X-chromosome

Absence or low level of plasma factor VIII

Defects in coagulation cascade

2. Recombinant factor VIII and immunoaffinity-purified factor VIII3. DDAVP (desmopressin) – mild haemophilia

HAEMOPHILIA B

Definition

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Case example

An 8 years old boy presents to the emergency department with uncontrollable bleeding into his right knee joint. Upon taking a family history, you learn that two of the boy maternal uncles suffer from bleeding disorder. Lab tests reveal a prolonged PTT, normal PT and normal bleeding time.

A congenital (X-link recessive) deficiency of factor IX and also known as Christmas’s disease

Clinical features

See haemophilia A clinical features

Lab investigations

Tests ResultsPlatelet count NormalBleeding time Normal

Prothrombin time NormalPartial thomboplastin time Prolonged

Factor VIII Normal Factor IX Low

vWF NormalRistocetin-induced platelet aggregation Normal

Treatment

High purity factor IX concentrates

VON WILLEBRAND DISEASE

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Definition

A disorder in which there is either reduced level or abnormal function of von Willebrand factor resulting from a point mutation or major deletion

Classification

Type 1 Quantitative partial deficiencyType 2 Functional abnormalityYTYPE 3Type 3 complete deficiency

Clinical features

See haemophilia A clinical features

Lab investigations

Tests ResultsPlatelet count NormalBleeding time Prolonged

Prothrombin time NormalPartial thomboplastin time Prolonged or normal

Factor VIII Moderately reduced Factor IX Normal

vWF Low or abnormal functionRistocetin-induced platelet aggregation Impaired

Treatment

1. Local measures and antifibrinolytic agent2. DDAVP infusion – for type I1 vWF disease3. High-purity vWF concentrates

DISSEMINATED INTRAVASCULAR COAGULATION

Definition

ONNAZLI0809

Case example

A 7-year-old girl was brought to the emergency department due to uncontrollable bleeding following deep laceration to her palm. Further questioning reveals that she has been taking aspirin for virus illness, that she has a history of prolonged bleeding, and that her brother and mother both suffer from bleeding disorder. Lab tests reveal a prolonged bleeding time, prolonged PTT and normal PT.

Inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelet due to several causes

Causes

Infections Gram-negative Meningococcal

septicaemia Clostridium welchii Falciparum malaria Viral – HIV, hepatitis

etc

Malignancy Widespread mucin-

secreting adenocarcinoma

Acute promyelocytic leukaemia

Obstetric complications Amniotic fluid

embolisme Premature separation

of placenta Eclampsia – retained

placenta Septic abortion

Hypersensitivity reactions Anaphylaxis Incompatible blood

transfusion

Widespread tissue damage Post-operative Trauma Burns

Vascular abnormalities Kasabach-Meritt

syndrome Leaking prostatic

valve CABG Vascular aneurysm

Pathogenesis

Clinical features

1. Bleeding from venipuncture sites or recent wound2. Generalized bleeding

ONNAZLI0809

Endotoxaemia

Widespread endothelial damage

and collagen exposure

Platelet aggregation and deposition to the damaged

endothelial wall

Intravascular thrombin formation produce large

amount of circulating fibrin monomers

Widespread platelet aggregation and

deposition in the vessel

Severe trauma

Entry of procoagulant material in the circulation

Aggregation of platelet forming microthrombi

Disseminated Intravascular

Coagulation (DIC)

3. Rarely, renal failure, skin lesion, gangrene of finger or toes, cerebral ischaemia – cause by microthrombi

Lab investigations

1. Low platelet count2. Low fibrinogen concentration3. Prolonged thrombin time4. High level of fibrin degradation products such as δ-dimer in serum and urine5. PT and APTT time prolonged in acute syndromes6. Peripheral blood smear (slide 41)

- Microangiopathic haemolytic anaemia- Prominent fragmentation of red cells

Treatment

1. Remove the underlying causes2. Cryoprecipitate 3. Heparin and antiplatelet drugs

ONNAZLI0809

Case example

A 28 years old woman who is at 33 weeks gestation presents to the emergency department with heavy vaginal bleeding. Evaluation reveals that she s suffering from premature separation of placenta from uterus wall. As she is being prepare for delivery, you notice that there is blood seeping from her intravenous and venipuncture sites and that she had a petechial rash. Concerned, you immediately order several blood test, which reveal a prolonged PT, prolonged PTT, prolonged bleeding time, prolonged thrombin time, thrombocytopenia and elevated D-dimer levels