ID / Haem / Immuno / Allergies / Genetics

Question 1

Anaemia - cause categorization? Ix? Deficiency-related anaemia - causes & relevant deficiencies?

Answer 1

Hb normal range: 130-175

MCV normal range: 82-98

Categorization:

• MICROcytic - IDA, thalassaemia, anaemia of chr disease (can be normocytic)
• NORMOcytic - acute bleed, aplastic anaemia, mixed anaemia (micro & macro)
• MACROcytic - B12/folate def, alcohol excess, haemolytic anaemia

Ix: FBC

• Microcytic - haematinics (Fe profile), Hb electrophoresis (thalassemia/SCD Dx)
• Macrocytic - B12, folate, DAT test (AI haemolytic anaemia Dx)

Deficiency-related anaemia:

• Poor dietary intake - Fe, B12, folate
• Malabsorption (IBD) - Fe, B12
• Pernicious anaemia (AI parietal cell destruction -> don’t prod intrinsic factor -> escorts B12 to terminal ileum for absorption) - B12
• Crohn’s disease (most common in terminal ileum where B12 is absorbed) - B12
• Bleeding (GI, menstrual) - Fe

Question 2

Multiple myeloma - def? pathophysiology? Spectrum of disease? Ix? Dx? Mx?

Answer 2

Def: cancer of plasma cells –> excessive monoclonal Ig prod

• Plasma cell dyscrasia (humoral immune dysfunction) – clonal plasma cell population –> proliferate –> monoclonal Ig light chains (in blood = paraprotein, in urine = Bence Jones protein)
• Pathophysiology:
  
  • Normally e.g. 5 different types of plasma cells produce 5 different types of Ig
  • In MM - one type of plasma cell outcompetes the others so lots of 1 type of Ig produced

Spectrum of disease:

• Multiple Myeloma:
  
  • >1 focal lesion on MRI
  • BM plasma cells >60%
  • End organ damage (1+ of CRAB(S)):
    
    • Calcium (>2.75) - high: lytic bone lesions –> release Ca into circulation
      
      • NOTE: stones, bones, abdo groans, thrones, psychiatric overtones
    • Renal (from excess Ig) – creatinine clearance <40ml/min OR creatinine >177
    • Anaemia (Hb <100g/l) - BM supression
    • Bone lesions (lytic)
    • Signs of amyloidosis – damage from misfolded protein prod
• Smouldering/asymptomatic myeloma
  
  • Serum monoclonal protein >3g/dL
  • BM plasma cells 10-60% in marrow
  • NO end-organ damage (CRABS) BUT most progress to MM untreated
• Monoclonal gammopathy of unknown significance (MGUS)
  
  • Serum monoclonal protein <3g/dL
  • Plasma cells <10% in BM
  • No end-organ damage (CRABS)
  • NOTE: 1-2% progress to MM, very common in elderly (if low risk – yearly bloods)

Dx: plasma cells on BF + Rouleaux cells

Ix: ESR, Ca, U&E, serum & urine electrophoresis (to identify an excess of one type of Ig = 1 large band)

• Electrophoresis (spike in gamma region, isolated IgG Kappa):
  
  • Normally polyclonal bands, in myeloma = monoclonal band
• CD138= diagnostic

​Mx:

• MM:
  
  • Young –> chemo followed by autologous SCT
  • Old –> chemo followed by maintenance therapy
• Smouldering myeloma – treat
• MGUS – annual blood test

Question 4

Myeloproliferative disorders - characteristics? causes? Mx?

Answer 4

ALL = tyrosine kinase disorder (JAK2)

Essential thrombocythemia

• High Pls: >450 (other causes of raise: acute inf, chr infl, malig (5-10%), polycythaemia rubra vera)
• JAK2 mutation in 55%
• Mx: aspirin to reduce stroke risk, hydroxycarbamide to lower pl count

Polycythemia vera

• _High RBC_s:
  
  • Haematocrit >0.52 (M) /0.48 (F)
  • Often thrombocytosis – high risk of thrombotic event (MI, stroke, Budd-Chiari)
  • JAK2 mutation in 90%
• Causes:
  
  • Primary: polycythaemia rubra vera
  • Secondary: altitude, chr hypoxia (severe COPD, cyanotic HD), erythropoietin-secreting renal cancers (RCC)
    
    • NOTE: secondary polycythaemia = no JAK2 mutation
• Presentation: itchy (pruritus) after shower, peptic ulcers (increased histamine)
  
  • If very high RBC count –> hyperviscosity Sx, splenomegaly, thrombosis, gout
• Mx:
  
  • Aspirin to reduce stroke risk, hydroxycarbamide to lower pl count
  • Venesection (removing blood –> lowers haematocrit)

Myelofibrosis

• decrease all myeloid cell lines: MASSIVE SPLENOMEGALY
  
  • Clonal prolif of stem cells in BM –> cytokine release + fibrosis of BM –> pancytopenia
  • Features:
    
    • JAK2 mutation in 50%
    • Pancytopenia
    • Massive splenomegaly (extramedullary hematopoiesis)
    • Dry tap – on BM aspiration
    • Tear drop poikilocytes – on BF (leucoerythroblastic film)
• Mx: stem cell transplant = only cure, ruloxitinib (JAK inhibitor)
• NOTE: CML increases all myeloid cell lines (opposite)

Question 5

Myelodysplastic syndromes

Dx? Characteristics? Ix findings? Prognosis?

Answer 5

Myelodysplastic syndromes (MDS)

• Pre-malignant BM failure/’early AML’ (<20% blasts; NOTE: >20% blasts = AML)
  
  • All 3 myeloid cell lines can be affected (erythroid, megakaryocyte, granulocyte)
  • Asymptomatic –risk progression–> AML
  • Can be secondary to chemo
• Ix:
  
  • Hyposegmented + hypogranular neutrophils
  • Present w/ incidental pancytopenia, can have macrocytic anaemia (normal ferritin/B12/folate/erythropoietin –> suspicious of MDS)
• Prognosis: 30% progress to AML, risk assessed w/ IPSS score

Question 6

Classical Hodgkin’s lymphoma - peaks when? presentation? histology? most common type? assoc inf? Mx?

Answer 6

• Peaks: young, older adults
• Presentation: localised LNs (freq mediastinal), B-symptoms (fever, WL, NS)
  
  • NHL = multiple nodal sites
  • Pain in LNs after alcohol
  • Neck node “rubbery”
  • Possibly assoc w/ EBV inf
• Histology: Reed-Sternberg cells (“Owl’s eye” inclusions) = Dx (only 1 needed)
  
  • Other findings – eosinophils/macrophages, reactive fibrosis
  • Dx markers: CD30/15
• Nodular sclerosing = most common type
• Mx: ABVD chemo + radiotherapy –> good prognosis –> sometimes SCT

Question 7

MICROangiopathic haemolytic anaemia (MAHA)

• Haemolytic uraemic syndrome (HUS)
• Thrombotic thrombocytopenic purpura (TTP)
• Disseminated intravascular coagulation (DIC)

Answer 7

MICROangiopathic haemolytic anaemia (MAHA)

• Non-immune-mediated, small vessel disease, RBC breakdown
• Damage to endothelial BV lining –> fibrin deposition + platelet aggregation –> fragmentation of RBCs (Schistocytes)
• It is a mechanism NOT a disease

Haemolytic Uraemic Syndrome (HUS)

• Post-_diarrhoeal_ illness – do NOT give abx
  
  • E.coli O157:H7 –> Shiga-like toxin can cause glomerular endothelial injury –> platelet plug forms (platelet consumption) –> shearing of blood vessels (MAHA) + reduced renal perfusion –> renal failure
  • Can get type with complement factor H deficiency
• Diarrhoea in child –> triad:
  
  • MAHA (features on peripheral blood smear e.g. schistocytes)
    
    • Haemolysis signs - high LDH, low haptoglobins
  • Thrombocytopenia
  • acute renal failure (self-limiting in children)
• Supportive Mx, anti-C5 Ab (ecluzimab)

TTP

• Pathophysiology:
  
  • vWF multimers are normally broken down by ADAMTS13 but in TTP Abs against this –> reduced ADAMTS13
    
    • Causes: unknown, cancer, pregnancy
  • Increased vWF multimers = very sticky –> attach to endothelium & platelet plug forms (platelet consumption) –> shearing of blood vessels (MAHA) + reduced end-organ perfusion (can happen anywhere) –> confusion (brain), renal failure (kidneys)
• Pentad: MAHA, thrombocytopenia, acute renal failure, NEURO Sx, fever
  
  • Case: 40yrs, fever, headache, jaundice for 1wk, temp 39, confused
    
    • Purpura, bleeding gums, haemoglobinuria
    • Bilirubin & LDH high = MAHA
• Ab to metalloproteinase
• Supportive Mx - plasma exchange + FFP

DIC

• Trigger (sepsis, tumour, pancreatitis) –> increased exposure to Tissue factor –> factor 7 converted to 7a = coagulation cascade –> lots of miniclots formed throughout circulation - platelet & coagulation factor consumption​​
• Very bad bleeding, Low platelets, PT & aPTT low (all coagulation factors low), low fibrinogen

Question 8

Myelodysplasia vs Myelofibrosis

Answer 8

In normal BM - stem cells –> differentiate & proliferate

Myelodysplasia - abn differentiation of myeloid progenitor cells

• Def: BM disorder resulting in pancytopenia AND production of functionally immature blood cells (essentially it is ‘early AML’, <20% blasts)
• Chemo is a RF
• Key facts:
  
  • Pancytopenia (all 3 myeloid lines can be affected)
  • 1/3 cases –> AML

Myelofibrosis

• Def: clonal BM disorder characterised by deposition of fibrous scar tissue (over time, less and less tissue in BM that can produce blood cells)
• Key facts:
  
  • Pancytopenia
  • Tear drop cells
  • Dry tap (due to level of fibrosis)
  • Massive splenomegaly (a site where body tries to compensate for low blood cell production in BM)

Question 9

Hereditary haemorrhagic telangiectasia (HHT) - Def? Dx criteria?

Answer 9

Aka Osler-Weber-Rendu syndrome - AD condition characterised by multiple telangiectasias over skin & mucous membranes

• 20% cases spontaneous wo/ FHx

Dx criteria (2 = possible; 3 = definitive Dx):

• Epistaxis: spontaneous, recurrent nosebleeds
• Telangiectases: multiple @lips/oral cavity/fingers/nose
• Visceral lesions: GI telangiectasia, pulmonary (increased stroke risk)/hepatic/cerebral/spinal AV malformations (AVM)
• FHx: first-degree relative w/ HHT

Question 10

Haematinics - constituents? interpretation?

Iron studies - constituents? interpretation?

Answer 10

Haematinics - serum B12, folate, Intrinsic factor, ferritin

• Low IF –> consider pernicious anaemia (cause of B12 def)

Iron studies - MCV, Fe, ferritin, TIBC, transferrin, transferrin saturation

• Low MCV, low Fe, low ferritin & high TIBC/transferrin –> IDA (iron def anaemia)
• Normal MCV, low Fe, high ferritin & low TIBC/transferrin –> consider Anaemic of chronic disease/haemoglobinopathy (SCD)

Question 11

Coagulation screen - constituents? interpretation?

Answer 11

PT, aPTT, Fibrinogen - light blue test tube

• PT /INR measures extrinsic pathway (factor 7) and common pathway - measures overall clotting factor consumption as factor 7 rarely def in isolation
  
  • Raised in liver disease, DIC, vit K def, Warfarin
• aPTT measures intrinsic pathway (factor 8/9/11) & common pathways
  
  • Raised by same as above + intrinsic pathway issues:
    
    • Haemophilia A (factor 8 def - X-linked recessive)
    • Haemophilia B (factor 9 def - X-linked recessive)
    • von Willebrand disease (as vWF pairs with factor 8)
    • NOTE: antiphospholipid syndrome can cause high aPTT despite causing clots as inactivates phospholipid used in intrinsic pathway
• DIC - PT & aPTT raised, fibrinogen & platelets low

Question 12

Amyloidosis - def? types? Presentation? Ix? Mx?

Answer 12

Def: aggregates of proteins with fibrillar morphology & beta-pleated sheet structure depositing in body tissues

Types: occurs as a complication of other conditions

• AA - serum amyloid A - chronic inflammation
  
  • RFs:
    
    • Inflammatory conditions (e.g. RA, psoriatic arthritis, ankylosing spondylitis, IBD esp. Crohn’s)
    • Chr infections (bronchiectasis, TB, chr UTIs, osteomyelitis)
• AL - Ig light chain - multiple myeloma
  
  • RF: monoclonal gammopathy of undetermined significance (MGUS)
• ATTR - TransThyRetin - familial, wild-type (elderly)

Presentation:

• Purpura around the eyes, eyelid petechiae, enlarged tongue
• Carpal tunnel syndrome (bilateral)
• Peripheral neuropathy (not in AA) - symmetrical sensory loss of feet initially (temp, pain –> proprioceptive)
• Autonomic neuropathy (not in AA) - erectile dysfunction/orthostatic HTN, GI/urinary dysfunction
• Fatigue (amyloid cardiomyopathy/nephrotic syndrome), weight loss (cardiac/hepatic amyloidosis), dyspnoea on exertion (amyloid cardiomyopathy)
• Exam: proteinuria, high JVP + pitting oedema (from restrictive cardiomyopathy)

Ix:

• Serum & urine immunofixation (monoclonal protein in AL)
• Ig free light chain assay (abn kappa to lambda ratio in AL)
• FBC (anaemia), metabolic profile (hypoalbuminaemia, high ALP, low Ca)
• 24hr-urine collection (>3g/day = nephrotic syndrome)

Mx: treat underlying condition

Question 13

Case:

• 45yrs, tingling in arms & legs, loss of balance
• Exam: loss of vibration sense in both feet
• Ix: macrocytic anaemia, gastric antrum biopsy - achlorhydria & atrophic gastritis

Dx? Presentation? Ix? Mx?

Answer 13

Dx: pernicious anaemia aka atrophic gastritis/AI gastritis

Presentation: >60yrs, female

• Subacute combined degeneration of spinal cord from B12 def:
  
  • Weakness, lethargy
  • Paraesthesia, difficulty ambulating
  • Ataxia, shuffling gait, decreased proprioception, decreased vibration sense
  • Memory loss, irritability, depression, dementia
  • Exam: koilonychia, macroglossia
• Assoc w/ AI conditions e.g. Hashimoto’s thyroiditis
• Risk of gastric adenocarcinoma

Ix:

• Bloods:
  
  • FBC, haematinics (megaloblastic anaemia from B12 def), increased serum gastrin (increases PUD)
  • Abs: anti-IF (60% but more specific) & parietal cell abs (90% but can be normal variant)
• Imaging:
  
  • Biopsy of corpus/fundus stomach (absence of parietal cell-containing oxyntic glands, achlorhydria, atrophic gastritis) + intra-gastric pH (ph>6 @rest rules out Dx)

Mx:

• If PUD with H. pylori –> triple therapy (PPI + 2abx)
• Replace deficiency (Fe, B12, Ca/Vit D)

Question 14

Sickle cell crisis - Mx?

Answer 14

ACUTE (PAINFUL CRISES)

• Oxygen
• IV Fluids
• Strong analgesia (IV opiates)
• Antibiotics
• Cross match blood
• Give transfusion if Hb or reticulocytes fall sharply

Question 15

Blood transfusion reactions - Immediate? Delayed?

Answer 15

Immediate (<24hrs):

• Immune:
  
  • Acute haemolytic transfusion reaction (ABO incompatibility)
    
    • Anti-A/B abs activating complement pathway –> inflammatory cytokine release
    • Features:
      
      • Early - fever, low BP, anxiety, red urine
      • Late - low BP, widespread haemorrhage secondary to DIC
  • Transfusion-related acute lung injury (TRALI)
    
    • Donor abs against recipient HLA antigens (neutrophil, leukocyte)
    • Within 6hrs - sudden dyspnoea, severe hypoxemia, low BP, fever
    • Resolves with supportive care within 2-4 days
  • Anaphylaxis - allergic to protein components in donor transfusion
    
    • Itchy rash, angioedema, SoB, vomiting, lightheaded, low BP
• Non-immune:
  
  • Bacterial infection
  • Transfusion-associated circulatory overload (TACO)
    
    • Acute/worsening resp compromise/pul oedema up to 12hrs post-transfusion

Delayed (>24hrs):

• Immune:
  
  • Delayed haemolytic transfusion reaction (DHTR)
    
    • Abs to antigens e.g. Rhesus/Kidd
    • 3-13 days post-transfusion
    • Sudden drop in Hb, fever, jaundice, haemoglobinuria
  • Febrile non-haemolytic transfusion reaction (FNHTR)
    
    • Abs against donor leukocytes/HLA antigens
    • Fever during transfusion, no haemolysis
    • Normally if received multiple transfusions/women with multiple pregnancies
  • Post-transfusion purpura (PTP)
    
    • Adverse reaction to blood/platelet transfusion when body produces allo-abs to introduced platelets’ antigens –> destroy patient’s platelets –> thrombocytopenia
    • 5-12 days post-transfusion
  • Graft versus host disease (GvHD)
    
    • After receiving transplanted tissue from a genetically different person
    • WBCs in donated tissue (graft) recognise recipient as foreign –> attack host cells
    • Can also occur in blood transfusion if blood has not been irradiated/treated with approved pathogen reduction system
• Non-immune:
  
  • Viral infection
  • Malaria
  • Prions

Question 16

Treatment of high INR? Target?

Answer 16

• Any bleeding: stop Warfarin AND IV vit K slowly
  
  • If major bleed = ADD dried PCC/FFP
  • INR @24hrs –> continue Tx if INR high, continue Warfarin when INR <5
• INR >8: stop Warfarin AND oral Vit K
  
  • INR @24hrs –> continue Tx if INR high, continue Warfarin when INR <5
• INR 5-8: miss dose of Warfarin –> reduce maintenance dose

Target: 2.5 (2-3 range)