Week 03 Haematology

• Requirements
• Drive for erythropoeisis
• Correct genes
• Ingredients [Folate, B12, iron etc]
• Functioning Bone Marrow

Balance between too much [polycythaemia] & too little [anaemia]

• Anaemia
• can be ^^ destruction
• underproduction

• Req ~1-2mg/day
• Absorbed in gut [HFe, duodenum & upper jejunum]
• Trasnport via Transferrin [hepatic glycoprotein, 2Fe, norm = 30% sat]
• Transport to all TfR tissues [BM, RBC, myoglobin enzymes]
• RBC [Menstrual losses for Females]
• Degraded in RES [t-port via serum ferritin, ^^^Fe sites]
• No regulated excretion [Enterocyte shedding]

**should be able to draw picture**

Caused by B12 & folate [B9] deficiency

• B12 [Cobalamin]
• convert homocysteine → methionine [all prot AA precursor]
• Absorbed w intrinsic factor [parietal] in ileum

• Folate [B9]
• Absorbed in majority of small bowel
• Thymine formation

• Both are involved in DNA synthesis so deficiency → cell abnormalities
• ineffective erythropoeisis → lysis, ^bilirubin & LDH

• Causes of deficiency
• Malabsorption → UC, Crohns, Pernicuous Anaemia
• Dietary → vegan

• Iron deficient anaemia [IDA] <15% Tf saturation
• Less Hb → microcytic & hypochromic

• Causes → TAILS
• Thalassaemia
• Any Chronic Disease
• IDA
• Lead Poisoning
• Sideroblastic Anaemia → BM prod ringed sideroblasts [abn nucleated erythrocytes]

Ix → Low SF Pt = IDA

CF → spooned nails, angular stomatitis, atrophic glossitis [pale & painless] Oesophageal web [Plummer Vinson]

• Replace iron, but not BTx
• Ferrous sulphate/ IV iron
• Discover cause → males/ post menopausals, GI unless proven otherwise, young women, menstrual

• Pathophysiology
• failure of Fe utilisation, trapped in RES
• reduced response to EPO → depressed marrow activity
• Common

• Laboratory Results
• Normochromic, normocytic
• ^ESR
• normal/ high SF
• TIBC [Total iron binding capacity (Tf)] → low
• Histology → RBC rouleaux [stack of coins]

• inherited condition
• relative lack of globin gene [missing alpha/beta]
• No genes -> Thalasaemia Major

• 4 genes involved
• Missing 1 → mild microcytosis
• Missing 2 → Microcytosis, ^RBC, mild anaemia
• Missing 3 → Significant anaemia [Hb-H disease]
• Missing 4 → death

• Hb-H disease [3 genes missing]
• lack of alpha genes, excess beta
• beta join → Hb-H
• Hb ~75g/l
• Req BTx during times of stress

2 genes involved [B = 2]

• Beta-Thalasaemia Major
• AR inheritence
• unable to make adult Hb
• Significant Dyserythropoeisis
• Bone marrow expands → hair on end in skull [@ CXR]
• Anaemia & Splenomegaly
• BTx dependant → Fe overload [chelation Therapy]

• Beta-Thalasaemia Minor
• Only 1 Mt → microcytic

• Abnormal Beta Hb [Glu for Val]
• HbS formed
• continuous polymerisation/depolymerisation
• cells do not flow well

• CF
• Multisystem disease
• Brain → CVA/ Moya Moya [Abn cerebral vasculature]
• Lungs → Acute chest syndrome [cells sickle in lungs, deoxygenation → ^^sickle]
• Bones → swollen hands & fingers
• Spleen → hypospleenic due to infarcts

• Prevent Crisis
• Hydration, analgesia & early intervention
• Education
• Prophylactic vaccinations & AntiB
• Folic Acid

• Acute Mx
• O2, fluids, analgesia, specialist care [OFAC....Oh Fuck]
• BTx [Exchange BTx]

• Haemolysis → ^ RBC destruction
• BM can ^^ RBC output so lifespan <15-20d before anaemia

• Intravascular → destruction in circulation
• Extravascular → occurs in RES [Spleen, Liver & BM]

• Abnormalities of RBC Membrane
• Hereditary Spherocytosis
• AD inheritance
• CF → RBC spherical & Polychromatic, Jaundice [adulat & Neonatal], Splenomegaly
• Tx → Splenectomy & Hyposplenic prophylaxis [encapsulated orgs → minigococcus, haemphilus & pneumococcus]

• Haemoglobinopathies
• SCD
• Thalasaemias

• Abnormal RBC Enzymes
• Pyruvate kinase deficient → AR inheritance, ATP depletion, extravascular [Chronic]
• G6P dehydrogenase deficient → XL-R inherit, acute IV haemolysis from oxidative stress [favabeans, drugs]

• Autoimmune
• Warm Type [IgG]
• idiopathic/ autoimmune assoc, lymphoproliferative disease [NHL, CLL] Drugs [cephalosporins]
• RBC → spherocytic & polychromatic
• Tx → stop culprit drug, steroids, splenectomy

• Cold Type [IgM]
• haemolysis in peripherys/ cold conditions
• mostly idiopathic [some PMH mycoplasma infection]
• Blood film → cold agglutinins, +ve direct Coombs
• Tx → Keep Warm

• Isoimmune
• Haemolytic disease of Newborn
• +ve direct coombs

• Non-immune
• Fragmentation Haemolysis → Mechanical Heart Valves

• Direct Coombs
• To detect if Ab/Complement have bound to RBC
• [Monoclonal Ab to FcR]
• Agglutination = +ve [Immune mediated haemolytic disease]

• Indirect Coombs Test
• invitro antibody-antigen reactions prior to BTx [Crossmatching]
• Compatability test, RBC phenotyping etc.

• Lymphoid/Myeloid
• occurs in bone marrow

HSc→ selfrenewal/ daughter cells [differentiate]

• Myeloproliferative Disorders
• Clonal Disorder of blood, ≥ 1 Myeloid Progeny
• Spectrum of disease
• e.g. Polycythaemia rubra vera [^RBC], essential thrombocytosis, myelofibrosis [BM replaced by scar]
• ~ transform to AML

• JAK2 Mt
• Results in continuous activation of JAK2 [Regardless of ligand e.g. EPO]
• inhibited by Ruxolitinib → reduces splenomegaly, no reduction in alleilic burden, causes thrombocytopenia

• ET
• Plts >600 [megakaryocyte proliferation]

• CF
• Thrombotic complications [microvascular occlusion]
• Some present w haemorrhage
• Splenomegaly
• Can transform to PRV/ Myelofibrosis
• ~3% transform to leukaemia
• High risk features → PLTs >1500, previous thrombosis, thrombotic RF [diabetes/ HBP]

• Tx
• Low risk → [<40yo, no ^ risk features] Antiplatelet e.g. aspirin/clopidogrel
• Intermediate → [40-60yo, no ^ risk features] Aspirin +/- hydroxycarbamide
• High risk → [>60yo, >1 risk feature] Aspirin + hydroxycarbamide/ Anagrelide [2nd line, inhibit MK differentiation]

• Aplastic Anaemia, underproduction [bone marow failure]
• AR inheritance → 7 subtypes [FANC A-G]

• CF
• Appearance → short stature, cafe au lait, GU & GI malformed, LDs, hearing loss, micropthalmos, may look normal
• CNS → Hydrocephalus
• Haemo → petechiae, bruising, pallor, fatigue, infections

• Tx
• Allogenic SC TPx
• Supportive care [blood & PLTs]
• Corticosteroids
• Surveillance for 2ndry tumours

• Myelodysplastic Syndromes
• Dysplasia & ineffective haemopoeisis in >1 myeloid
• ~prev Ct/Rt
• Various subtypes [morphology & % blasts]
• Acquired cytogenetic abn → monosomy 5 & 7
• Progressive BM failure
• May progress to AML

• CF
• elderly
• incidental
• recurrent infections
• fatigue [anaemia]

• Tx
• supportive care [Blood PLTs]
• Growth factors [G-CSF & EPO]
• ?Immunosuppression [Low Grade]
• Low dose Ct → demthylating agents

• Lymphoma
• Ca of lymphoid Cells
• develop in lymph nodes [also extra nodal]

• Classification
• Hodgkin's
• Non-Hodgkins → B-cell, T-cell, NK cell

• Excision Biopsy → ideal [invasive, slow turn over]
• Core Biopsy → [no scar, easier]
• Pre-Tx evaluation → FBC [anaemia → BM infiltration], LDH, ESR, U&E
• Staging investigations → CT [ neck, chest, abdo-pelvis], PET/CT [radiolabelled Glucose] ~ BM aspirate & trephine

• Ann Arbor Staging
• I → single LN region
• II → 2 LN same side of diaphragm
• III → both sides of diaphragm, incl 1 organ/ area near LN/Spleen
• IV → diffuse involvement of >1 extralymphatic organs [liver, BM, Lungs]

• Modifiers → B symptoms
• Fever [>38]
• Night sweats
• weight loss [10% in 6m]

• CF
• Bimodal age [young adults & older peeps]
• Painless Lymphadenopathy [above diaphragm usually]
• May have B Symptoms [fever, night sweats, weight loss]
• Also → generalised itch, ~alcohol induced lymph node pain

• Pathology
• Majority = classical HL
• Malignant cell = Reed Sternberg cell, bi-nucleate [owl head]
• Majority of cellularity in node = reactive to RS
• Initial spread from one node to next
• Later haematogenous spread [liver, lungs & BM]

• CF
• wide variety of Pc
• extra-nodal may mimin carcinoma
• Low Grade → indolent clinical course, incurable, painless peripheral adenopathy e.g. follicular lymphoma
• High Grade → more localised, rapid growth, ^^extranodal sites e.g. Diffuse Large B cell lymphoma

• Pathophysiology
• progressive clonal expansion of B/T/ NK cells
• 90% = B cell
• Malignant lymphocytes can look normal → immunocytochemistry

• Diffuse Large B Cell Lymphoma
• Commonest high grade
• Aggressive, but curable
• CF → painless lymphadenopathy, hepatosplenomegaly, systemic upset
• Ix → Bloods [LDH], CT [neack, abdo & pelvis], BM aspirate [infiltration common]
• Tx → R-CHOP [Rituximab + Ct] [Rituximab target CD20 → expressed on B cells]

• T cell Lymphoma
• Uncommon
• Multiple subtypes
• Poor Prognosis
• No CD20 [cant use rituximab]

• Follicular Lymphoma
• ~ responsive to Tx, but recurrent relapsing
• can convert to High grade
• CF → painless lymphadenopathy, widespread LNs, hepatosplenomegaly, B symptoms
• Ix → Bloods [LDH/Anaemia] CT [chest, neck, abdo & pelvis] BM aspirate [infiltration paratrabecullar]
• Tx → ?early [localised Rt] ?Late [watch & wait, symptomatic Rituximab + Ct R-CHOP]

• Multiple Myeloma
• Neoplasm of plasma cells in BM

• Patho
• >10% of BM
• Mature B cells
• Skeletal Destruction

• CF
• Lytic Lesions in bones
• anaemia
• renal failure
• Hypercalcaemia [confusion, constipation, Abdo pain]
• Infections [Pneumonia]

• Ix
• FBC, Biochem [^^Ca]
• Ig Electrophoreisis [Monoclonal band → 1 abn prot]
• BM aspirate [ ^^plasma cells]
• Skeletal Survey [multiple lytic lesion, pepperpot skull]

• Tx
• Incurable, median 3-4yr
• Thalidomide based Tx

• Based on cell lineage
• 4 types:
• ALL → acute lymphoblastic → ALL children get leukamia
• AML → acute myeloblastic
• CLL → chronic lymphoblastic
• CML → chronic myeloblastic → Philedelphia chromosome
• CML

• Hx
• rapid onset
• lethargy
• infections
• bruising & bleeding
• bone pain
• gum swelling
• Lymphadenopathy

• Peripheral Bloods
• Anaemia
• Neutropenia
• Thrombocytopenia
• Blasts [immature cells]

• Bone Marrow
• Hypercellular
• Dysplasia
• Blasts 20-100%

• Supportive
• BTx → if symptomatic [^QoL], FFP [for DIC]
• Prophylactic Antibiotics → [AML no granulocytes], common infections → HSV, VZV, CMV, Discitis, cellulitis

• Chemotherapy
• Most Pt into trials [ALL]
• Aim to iradicate abn clone
• ^morbidity [bleeding, infections, hair loss, sterility, mucousitis]
• AML → Anthracycline & cytarabine, ^^myelotoxic, ~allogenic TPx
• ALL → Complex, CNS Tx = vital, polypharma incl steroids

• Chronic Leukamia
• more mature cells
• CML → neutrophils, eosinophils & basophils [rare]
• CLL → B lymphocytes, Commonest, ~67yo

• CF
• ~none [incidental FBC → lymphocytosis]
• lethargy, night sweats, weight loss
• lymphadenopathy
• recurrent infections

• Bloods
• Mature Lymphocytosis [Clonal expansion, CD5,19, 20]
• condensed chromatin
• ^n:c ratio
• no blasts

• BM
• Diffuse nodular infiltration

• Cytogenetics
• 11q22 deletions → ~20%, ^^aggressive, younger. Refractory to Tx
• 17p deletions → 5-10%, ^^ aggressive, loss of p53, trasnform to CLL/PLL [really bad CLL]

• Transformation [Richter Transform]
• CLL → high grade B cell lymphoma [esp if loss p53]
• <5%
• ^^Aggressive + B symptoms

• Beware
• CLL → AIHA & Immune thrombocytopenia, limits treatment [precipitated by Ct/Rt]
• ^^infections → hypo Ig, low T cells, neutropenia, poor compliment = serious morbidity & mortality, Tx can worsen

• Philadelphia Chromosome
• 9:22 translocation
• switches on receptor tyrosine kinase [Brc-ABL]
• results in cell proliferation & failure of apoptosis
• Diagnostic of CML, but assoc w ALL
• Tx → Imatinib [Block ABL]

• Intrinsic → 12, 11, 9, 8
• Extrinsic → 7 & TF
• Common → 10, 5, 2, fibrinogen → fibrin

Vit K dependant → 2, 7, 9, 10

• DIC [Disseminated Intravascular coagulation]
• massive activation of clotting cascade [uses everything up]
• give anticoagulants
• Causes → brain inj, meningococcal septisaemia, trauma, malignancy]