Everything You Need To Know (at least) for

SEQs and FLMs

Name Year Matric no. Batch -

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IRON DEFICIENCY ANAEMIA Definition is 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. Causes Chronic Blood Loss Uterine Gastrointestinal tract Peptic Ulcer Esophageal varices Aspirin (NSAID) Urinary tract Haematuria Haemoglobinuria Haemosiderosis Increase iron demand Prematurity Adult male Postmenopausal Menstruating Pregnancy Children Female (12-15) Malabsorption Gastrectomy Gluten-induced enteropathy Poor diet Malnutrition

Normal iron regulation

Dietary intake in the form of: 1) haem-protein complex 2) ferric hydroxides 3) ferric protein

Breakdown to

In iron deficient

no of hepcidin

no of DMT-1 absorption of inorganic iron by duodenal enterocyte

ferroportin level of the macrophages, intestinal epithelial cell and placental syncytiothropoblast

iron release to the plasma Serum iron level back to normal

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Iron in anaemia
Iron Iron deficiency anaemia Protorporphyrin

Haem

Globin

Haemoglobin

Clinical features of anaemia 1. 2. 3. 4. Smooth and glistening tongue (atrophic glossitis) Angular Stomatitis Koilonychia (spoon-shaped nails) Dysphagia due to the formation of pharyngeal web

Lab findings of Iron deficiency anaemia 1. 2. 3. 4. 5. 6. 7. See blood film in Haematological Presentation [soft copy] (slide 6) Low MCH (<27 pg) hypochromic anaemia Low MCV (<80 fl) microcytic anaemia Pencil-shaped/cigar shaped poikilocytes Occasional target cell Serum iron falls but increase total iron binding capacity Reduce serum ferritin (normal in latent iron deficiency)

Treatment 1. Oral ferrous sulphate 2. Intravenous ferric hydroxide-sucrose

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

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ANAEMIA OF CHRONIC DISEASE Definition Decrease in the amount of haemoglobin below normal in patient with chronic inflammatory disease or malignancy Causes Chronic inflammatory disease Infectious Non-infectious Pulmonary abscess Rheumatoid Arthritis Tuberculosis Systemic Lupus Osteomyelitis Erythematosus Pneumonia Sarcoidosis Bacterial endocarditis Crohns Disease Urinary Tract Infections Pathogenesis
Infections Cytokines (IL-1 and TNF-) 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

Malignancy Carcinoma Lymphoma Sarcoma

Anaemia of Chronic disease (reduction in serum iron)

TNF- suppressed bone marrow from producing blood cell Paraneoplastic Syndrome

Release of cytokines Attracted macrophages New growth of the tissue/cell (foreign body) Malignancy (Neoplasia)

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Lab investigations 1. 2. 3. 4. 5. 6. See blood film in Haematological Presentation [soft copy] (slide 7) Normochromic Anaemia (MCH normal) Normocytic Anaemia (MCV normal) Mild and progressive anaemia Reduce TIBC (total iron binding capacity) and serum iron Increase serum ferritin or normal

Treatment 1. Remove the underlying cause of malignancy or infections

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

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SIDEROBLASTIC ANAEMIA 1. Definition is 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 Mutation of aminolaevulinic acid synthase (ALA-S) gene on Xchromosome Primary Myelodysplasia Acquired Secondary Malignancy myelofibrosis, myeloid leukemia, myeloma Drugs antituberculous drugs Lead poisoning Benign condition haemolytic anaemia, malabsorption, Rheumatoid arthritis

Pathogenesis Lead poisoning

Inhibit haem and globin synthesis

Inhibit the enzyme pyrimidine 5 nucleotidase Disturbed the breakdown of RNA

Hypochromic anaemia Accumulation of denatured RNA in the red cell Appearance of basophilic stippling (Romanowsky stain)

Ring sideroblast at the marrow

1

Is a red blood cell precursor (erythroblast)

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MEGALOBLASTIC 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 synthesis 2. Folate deficiency defective DNA synthesis 3. Abnormalities in B12 and Folate metabolism cobalamin deficiency, Nitrous oxide or antifolate drugs 4. Other defects of DNA synthesis congenital enzyme deficiency (orotic aciduria) or acquired enzyme deficiency (alcohol, hydroxyurea etc)

Normal B12 and Folate metabolisme

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Clinical features 1. Gradually progressive symptoms signs of anaemia 2. Mildly jaundice increase ineffective erythropoiesis leads to increase breakdown of Haemoglobin hyperbilirubinaemia 3. Glossitis 4. Angular stomatitis 5. Loss of weight 6. Purpura

Lab investigations In peripheral blood 1. 2. 3. 4. 5. 6. See blood film in Haematological Presentation [soft copy] (slide 9 and 10) Macrocytic anaemia Dual shaped macrocytes Low reticulocyte count Decrease TWBC and platelet Hypersegmented neutrophils (slide 11)

In bone marrow 1. Hypercellular 2. Large erythroblast, failure of nuclear maturation 3. Giant and abnormal metamyelocyte (slide 12)

Treatment 1. Large doses of vitamin B12 2. Large doses of folic acid

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HAEMOLYTIC ANAEMIA Definition Anaemia results from increase red cell destruction Causes Inherited Membrane Hereditary spherocytosis Hereditary elliptocytosis Metabolisme G6PD deficiency Pyruvate kinase deficiency Haemoglobin Genetic abnormalities (Hb S, Hb C) Acquired Autoimmune Warm antibody type Cold antibody type Alloimmune Haemolytic transfusion reactions Haemolytic disease of newborns Red cell fragmentation syndrome March haemoglobinuria Infections Malaria Clostridia Chemical and physical agents Drugs, industrial/domestic substance Burns Secondary Liver and renal disease Paroxysmal nocturnal haemoglobinuria

Clinical features 1. 2. 3. 4. 5. Pallor of the mucous membrane Mild fluctuating jaundice Splenomegally Dark urine (increase urobilinogen) Ulcers

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Laboratory findings 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

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G6PD deficiency Definition 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 illness 2. Drugs - Antimalarials - Sulphonamides and sulphones - Other antibacterial agents - Analgesics - Antihelminths - Others vitamin K analogues, naphtalenes, mothballs - Fava beans

Pathogenesis

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Clinical features 1. Acute haemolytic anaemia refers haemolytic anaemia 2. Neonatal jaundice hyperbilirubinaemia

Lab investigations Refer Slide 13 1. Bite cells and blister cells 2. Contracted and fragmented cell 3. Heinz body (clumps of oxidized haemoglobin within the RBC)

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

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SICKLE CELL ANAEMIA Definition Is a group of haemoglobin disorder which the sickle -cell gene is inherited. Classification 1. Homozygous sickle cell anaemia (Hb SS) 2. Doubly heterozygote condition of Hb SC and Hb Sthal Pathogenesis and pathophysiology
Substitution of valine for glutamic acid in position 6 in -chain Produce sickle cell (Hb S or Hb22S) 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)

Clinical features 1. 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

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3. Aplastic crises Anaemia as a results of infection with parvovirus or from folate deficiency 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 Investigation 1. Hb level 6-9 g/dl 2. Sickle cell and target cell in blood (slide 14) 3. Features of splenic atrophy 4. Screening test for sickling becomes positive when blood is deoxygenated 5. Hb electrophoresis Hb SS, no Hb A and Hb F is variable (5-15%) Treatment 1. Prophylactic avoid precipitating factors 2. Folic acid 3. Good general nutrition and hygiene 4. Regular oral penicillin avoid infections 5. Stem cell transplantation

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

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AETIOLOGY OF HAEMATOLOGICAL MALIGNANCIES 1. Inherited factors Incidence increase greatly in some genetic disease such as Down Syndrome, Bloom Syndrome, Fanconis Anaemia, ataxia telangiectasia, Klinefelters syndrome and Wiskott-Aldrich Syndrome Incidence increase weakly in familial history of AML, CLL, Hodgkin and NonHodgkins 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 Virus i) HTLV-1 ii) Epstein-Barr virus iii) HHV-8 iv) HIV-1 Bacteria Helicobacter pylori Protozoa Malaria Associated with i) ii) iii) iv) Adult T-cell leukaemia/lymphoma Burkitts and Hodgkins Lymphoma Primary effusion lymphoma High grade B-cell lymphoma

Gastric lymphoma (MALT) Burkitts Lymphoma

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LEUKAEMIA Definition Is a group of disorders characterized by accumulation of malignant white cells in marrow and blood. It can be symptomatic due to i) Bone marrow dysfunction ii) Organ infiltration by leukaemic cells

Classification Is classify based on the rate of progression of this disease

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)

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ACUTE LYMPHOBLASTIC LEUKAEMIA 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 L1 L2 L3 Description Blast cells small, uniform high nuclear to cytoplasmic ratio Blast cell larger, heterogenous, lower nuclear to cytoplasmic ratio Vacuolated blast, basophilic cytoplasm (B-ALL) Reference Slide 15 Slide 16 Slide 17

Clinical features Bone marrow failure 1. Anaemia pallor, lethargy, dyspnoea etc 2. Neutropenia fever, malaise, features of infections 3. Thrombocytopenia bruising, purpura, gum bleeding, menorrhagia) Organs infiltration 1. 2. 3. 4. 5. 6. 7. 8. Tender bones Lymphadenopathy Moderate splenomegally Hepatomegaly Meningeal syndrome headache, nausea, vomiting, blurring of vision Pappiloedema and haemorrhage Testicular swelling Mediastinal compression (thymic enlargement)

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Investigations 1. 2. 3. 4. 5. 6. 7. 8. 9. Normocytic anaemia Normochromic anaemia Thrombocytopenia White cell count normal, reduce or increase white cell count Variable number of blast cell in film Hypercellular marrow with more than 20 % leukaemic blood Lumbar puncture increase pressure, contains leukaemic cell Serum analysis shows increase uric acid, lactate dehydrogenase, hypercalcaemia X-ray shows lytic bone lesion, mediastinal mass (thymus or lymph nodes)

Treatment 1. 2. 3. 4. 5. 6. Alkylating agents cyclophosphamides Antimetabolites methotrexate Cytotoxic antibiotics Purine analogues Hydroxyurea Chemotherapy and radiotherapy

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ACUTE MYELOBLASTIC LEUKAEMIA 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 M1 Blast cells show few granules but may show Auer rods Refference Slide 18 Causes Almost all type nucleotide insertion, mutation and internal tandem duplication t(8;21), t(6;9) t(5;17) Inv(16), del(16q) Del(11q), t(9;11), t(11;19) Almost all type nucleotide insertion, mutation and internal tandem duplication Almost all type nucleotide insertion, mutation and internal tandem duplication

M2 M3 M4 M5 M6

Blast cells show multiple cytoplasmic granules Blast cells contains prominent granules or multiple Auer rods Blast cells have some monocytoid differentiation Monoblastic leukaemia in which more than 80 % of the blast are monoblasts Preponderance of erythroblast

Slide 19 Slide 20 Slide 21 Slide 22 Slide 23

M7

Megakaryoblastic leukaemia showing cytoplasmic blebs on blast

Slide 24

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)

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Tissue infiltration 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)

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

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HODGKINS LYMPHOMA 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 Nodular sclerosis Description 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 Numerous Reed-Sterberg cell Intermediate numbers of lymphocyte refer slide 28 Reticular pattern with dominance Reed-Sterberg cell Low number of lymphocytes Diffuse fibrosis pattern (lymph nodes replaced by connective tissue Scanty Reed-Sterberg cell Multiple small lymphocyte with few eosinophils and plasma cell Nodular and diffuse type Absence of Reed-Sterberg cell Abnormal polymorphic B-cells

Mixed cellularity

Lymphocyte-depleted

Lymphocyte-rich

Nodular lymphocytepredominant Pathogenesis

Unknown aetiology Prevent synthesis of full length immunoglobulin Mutation of B-cell (Reed-Sterberg cell)

Neoplastic

Ebstein-Barr virus (50% of total cases)

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Clinical features 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. 3. 4. 5. 6. 7. Moderate hepatosplenomegally Signs and symptoms of pleural effusion and superior vena cava obstruction Fever cyclical or continuous pattern Pruritus Alcohol-induced pain Others loss of appetite, night sweats, weakness, fatigue, anorexia and cachexia

Laboratory investigations 1. 2. 3. 4. 5. 6. Normocytic anaemia Normochromic anaemia Leukoerythroblastic anaemia when involving bone marrow failure Neutrophilia Eosinophilia Lymphopenia and loss of cell-mediated immunity in advanced progression of disease 7. Platelet count initially normal or raised, reduced latter 8. ESR and C-Reactive Protein raised 9. Serum Lactate Dehydrogenase increase

Treatment 1. Chemotherapy adriamycin. Bleomycin, vinblastine etc 2. Radiotherapy 4000 rad (40 Gy) dose
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 owls eyes Explain aetiology, pathology and pathophysiology, clinical manifestation and treatment

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NON-HODGKINS LYMPHOMA 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-Hodgkins Lymphoma Follicular lymphoma Is 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 Lymphocytic lymphoma Is a disease closely related to the Chronic Lymphoblastic Anaemia and its characteristic similar with the tissue phase of CLL See slide 31 High Grade Non-Hodgkins Lymphoma Diffuse large B-cell lymphoma Is a heterogenous group of disorder, typically presents with rapidly progressive lymphadenopathy associated with a fast rate of cellular proliferation See slide 33 Burkitts lymphoma Lymphomatous 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 Lymphoblastic lymphoma Occurs mostly in children and young adults which the condition is similar clinically and morphologically to that of ALL

Lymphoplasmacytid lymphoma Associated with production of monoclonal IgM which give rise to certain complication such as anaemia and hyperviscosity syndrome Mantle cell lymphoma Is 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 blood See slide 32 Marginal zone lymphoma Is extranodal and usually localized. Clinical presentation includes splenomegally and may be associated with circulating villous lymphocytes

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Clinical features 1. 2. 3. 4. 5. 6. 7. 8. Superficial lymphadenopathy Constitutional symptoms fever, night sweats and weight loss Oropharyngeal involvement Weldeyers ring causing sore throat and wheezing Anaemia Neutropenia with signs and symptoms of infections Thrombocytopenia with purpura Hepatosplenomegally Rarely, skin, brain, testis and thyroid involvement

Investigation 1. 2. 3. 4. 5. 6. 7. Normocytic normochromic anaemia Autoimmune haemolytic anaemia may occurs Neutropenia Thrombocytopenia Leukoerythroblastic features Increase Lactate Dehydrogenase 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) Burkitts lymphoma sheets of lymphoblast, starry sky tangible body macrophages

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

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POLYCYTHAEMIA 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 Polycythaemia (rubra) vera JAK2 mutation del(9p) and del(20q) Secondary Compensatory erythropoietin increase High altitude Pulmonary disease Alveolar hypoventilation Cardiovascular diseae Increase affinity haemoglobin Heavy cigarette smoking Inappropriate erythropoietin increase Renal disease (hydronephrosis, vascular impairment, cyst, carcinoma) Tumors (uterine leiomyoma, hypernephroma, hepatocellular carcinoma, cerebellar hemangioblastoma)

Congenital polycythaemia

Pathogenesis Compensatory erythropoietin increase Kidney Stressor Erythrogenin Globulin Liver

Erythropoietin Stem cell sensitive to erythropoietin Proerythroblast Normoblast Reticulocytes

Erythrocytes

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Clinical features 1. Headaches, dyspnoea, blurred vision and night sweats 2. Pruritus after taking hot bath 3. Plethoric appearance 4. Ruddy cyanosis 5. Conjunctival suffusion 6. Retinal venous engorgement 7. Splenomegally 8. Haemorrhage (GI bleed, uterine etc) 9. Hypertension 10. Gout 11. Peptic ulceration

Investigations 1. Increase haematocrit, haemoglobin and red cell count increase 2. Neutrophilia and increase circulating basophil 3. Raised platelet count 4. JAK2 mutation in marrow and peripheral blood granulocytes 5. Increase neutrophil alkaline phosphatase score 6. Serum B12 and B12 binding capacity - increase haptocorrin 7. Hypercellular bone marrow with prominent megakaryocytes 8. Low serum erythropoietin 9. Expression of PRV-1 increase, decrease Mpl expression 10. Increase blood viscosity 11. Increase plasma urate 12. Normal serum Lactate Dehydrogenase 13. 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. 2. 3. 4. 5. Venesection Cytotoxic myelosuppression hydroxyurea Phosphorus-32 therapy -interferon Aspirin

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MYELOFIBROSIS Definition Is a progressive generalized reactive fibrosis of the bone marrow in association with the development of extramedullary haemopoiesis Clinical features 1. 2. 3. 4. 5. 6. Insidious onset of anaemia (elderly) Massive Splenomegally Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats Increase bleeding tendency Bone pain Gout

Lab investigations 1. 2. 3. 4. 5. 6. 7. 8. Anaemia High white cell (initially), later became low Thrombocytopenia JAK2 mutation Increase neutrophil alkaline phosphatase score High serum urate High serum lactate Dehydrogenase 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 substance 10. Increase bone density

Treatment 1. 2. 3. 4. Blood transfusion and regular folic therapy Hydroxyurea Splenectomy Allupurinol to prevent gout

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ESSENTIAL THROMBOCYTHAEMIA Definition A sustained increase in platelet count due to increase megakaryocyte proliferation and platelet overproduction Clinical features 1. 2. 3. 4. Mostly asymptomatic Erythromelalgia burning sensation of hands or feet Palpable Splenomegally Infarction splenic atrophy

Lab investigations 1. Blood film (see slide 38) - Abnormal large platelets - Nucleated megakaryocytic fragments 2. Abnormal platelet function test

Treatment 1. 2. 3. 4. 5. 6. Hydroxyurea -interferon Anagrelide Busulfan and 32P Platelet pheresis Aspirin

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THROMBOCYTOPENIA Definition A reduction in the number of platelets in the blood Causes Failure of platelet production Selective megakaryocytes depression Congenital defects Drugs, chemical, viral infections Part of general bone marrow failure Cytotoxic drugs Radiotherapy Aplastic anaemia Myelofibrosis Marrow infiltration HIV infections Megaloblastic anaemia Pathogenesis Present of abnormal IgG (platelets autantibody) Premature removal of platelet by macrophages of reticuloendothelial system Increase consumption of platelets Immune Autoimmune Infections (HIV, malaria) Drug-induced Heparin DIC Thrombotic thrombocytopenic purpura Others Splenomegaly Massive transfusion of stored blood to bleeding patient

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

Increase destruction of the platelet

Splenomegaly

Pooling of platelet at the spleen (90% total)

Abnormal distribution of the platelet

Thrombocytopenia

Viral infections

Suppress bone marrow from producing platelets

Drugs toxicity

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Clinical features 1. 2. 3. 4. 5. Petechial haemorrhage Easy bruising Menorrhagia Mucousal bleeding epistaxes or gum bleeding Intracranial haemorrhage (rarely)

Lab investigations 1. Prolonged reduction of platelet count <400 x 109 2. Present of large platelet in the peripheral blood 3. Increase or normal number of marrow megakaryocytes

Treatment Depending on the cause thrombocytopenia 1. 2. 3. 4. 5. 6. Splenectomy High dose of intravenous immunoglobulin therapy Corticosteroid or immunosuppressive drugs vincristine, cyclophosphamide etc Monoclonal antibody - Rituxinab Platelet transfusion Stem cell transplantation

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HAEMOPHILIA A Definition Congenital deficiencies (X-link recessive) of factor VIII Pathogenesis

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

Clinical features Applied to haemophilia A, B and von Willebrand disease 1. 2. 3. 4. Infant post-circumcision haemorrhage Develops joint, soft tissue bleeds and excessive bruising when start to be active Recurrent painful haemarthroses Haematoma can leads to joint deformities, entrapment neuropathy and ischaemic necrosis 5. Prolonged bleeding after dental extractions 6. Spontaneous haematuria and gastrointestinal bleed 7. 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 Platelet count Bleeding time Prothrombin time Partial thomboplastin time Factor VIII Factor IX vWF Ristocetin-induced platelet aggregation Results Normal Normal Normal Prolonged Low Normal Normal Normal

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Treatment 1. Factor VIII replacement therapy 2. Recombinant factor VIII and immunoaffinity-purified factor VIII 3. DDAVP (desmopressin) mild haemophilia

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.

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HAEMOPHILIA B Definition A congenital (X-link recessive) deficiency of factor IX and also known as Christmass disease Clinical features See haemophilia A clinical features

Lab investigations Tests Platelet count Bleeding time Prothrombin time Partial thomboplastin time Factor VIII Factor IX vWF Ristocetin-induced platelet aggregation Treatment High purity factor IX concentrates Results Normal Normal Normal Prolonged Normal Low Normal Normal

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VON WILLEBRAND DISEASE 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 Type 2 Type 3 Clinical features See haemophilia A clinical features Quantitative partial deficiency Functional abnormalityYTYPE 3 complete deficiency

Lab investigations Tests Platelet count Bleeding time Prothrombin time Partial thomboplastin time Factor VIII Factor IX vWF Ristocetin-induced platelet aggregation Treatment 1. Local measures and antifibrinolytic agent 2. DDAVP infusion for type I1 vWF disease 3. High-purity vWF concentrates
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.

Results Normal Prolonged Normal Prolonged or normal Moderately reduced Normal Low or abnormal function Impaired

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DISSEMINATED INTRAVASCULAR COAGULATION Definition 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 Hypersensitivity reactions Anaphylaxis Incompatible blood transfusion Malignancy Widespread mucinsecreting adenocarcinoma Acute promyelocytic leukaemia Obstetric complications Amniotic fluid embolisme Premature separation of placenta Eclampsia retained placenta Septic abortion Vascular abnormalities Kasabach-Meritt syndrome Leaking prostatic valve CABG Vascular aneurysm

Widespread tissue damage Post-operative Trauma Burns

Pathogenesis

Endotoxaemia Severe trauma Widespread endothelial damage and collagen exposure Platelet aggregation and deposition to the damaged endothelial wall

Entry of procoagulant material in the circulation

Aggregation of platelet forming microthrombi

Intravascular thrombin formation produce large amount of circulating fibrin monomers

Widespread platelet aggregation and deposition in the vessel

Disseminated Intravascular Coagulation (DIC)

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Clinical features 1. Bleeding from venipuncture sites or recent wound 2. Generalized bleeding 3. Rarely, renal failure, skin lesion, gangrene of finger or toes, cerebral ischaemia cause by microthrombi

Lab investigations 1. 2. 3. 4. 5. 6. Low platelet count Low fibrinogen concentration Prolonged thrombin time High level of fibrin degradation products such as -dimer in serum and urine PT and APTT time prolonged in acute syndromes Peripheral blood smear (slide 41) - Microangiopathic haemolytic anaemia - Prominent fragmentation of red cells

Treatment 1. Remove the underlying causes 2. Cryoprecipitate 3. Heparin and antiplatelet drugs

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

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