Dr Rishi Banerjee BSc Hons MBBS Dist Foundation Year 1 Doctor Manchester University Foundation Trust Content Anaemia Haemoglobinopathies Haemostasis and thrombosis Obstetric haematology ID: 1045086
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1. Haematology: Non-MalignantDr Rishi Banerjee BSc (Hons.) MBBS (Dist.)Foundation Year 1 DoctorManchester University Foundation Trust
2. ContentAnaemiaHaemoglobinopathiesHaemostasis and thrombosisObstetric haematologyTransfusion medicine
3. QuestionA pregnant lady is in her first trimester, and is found to have a High MCV, and a low Hb. She informs you that she hasn’t started taking any multivitamins, or supplements, since finding out she is pregnant.What is the likely cause?Folate Deficiency
4. QuestionA 5 year old boy presented to A&E with fatigue and shortness of breath. Patient is also mildly jaundiced. Peripheral blood film shown below. His father had a splenectomy when he was younger. What is most sensitive investigation?Answer: Eosin-5-maleimide test
5. QuestionAn 18-year-old man has just returned from a holiday to Malawi and arranges a GP appointment. He said during the holiday he turned yellow, his urine turned brown and he felt more tired than normal. No PMH. He took antimalarial prophylaxis as directed.Blood tests reveal a normocytic anaemia with unconjugated bilirubinemia. DAT negative.What is the most likely reason for the intravascular haemolysis?Malaria Beta ThalassemiaG6PD DeficiencyHereditary SpherocytosisWarm autoimmune hemolytic anemia
6. Question Which lab finding would you not expect to see in autoimmune haemolytic anaemia?Reticulocytes Raised conjugated bilirubin Positive DAT Low HbRaised LDH
7. QuestionA confused patient presents to A&E. She is noted to be extremely lethargic, and she is oliguric. Blood film shows schistocytes. Her bloods show a thrombocytopenia and a rapid rise in urea and creatinine What is the most likely diagnosis?MAHA DIC TTP HUSAcute Intermittent Porphyria
8. Question How do you manage TTP?Plasma exchange
9. 1. Anaemia
10. BackgroundReduced ability to deliver oxygen due to a lower number of RBCs or a decreased amount of haemoglobin.Men Hb < 130 g/ml Women Hb < 120g/ml
11. BackgroundThere are three mechanisms for anemia to occurBlood loss Decreased RBC production Increased RBC destructionAnemia can be classified by sizeMicrocytic Normocytic Macrocytic
12. Microcytic anaemia work-upKey differentialsIron deficiency anaemiaThalassaemiaSideroblastic anaemiaKey investigationsPeripheral blood smearIron studies
13. Iron deficiency anaemiaCommonest cause is blood lossKey featuresPeripheral blood smear – pencil cellsIron studies – ↓iron, ↓ferritin, ↑transferrin, ↑TIBCFBC – reactive thrombocytosisManagement – investigate underlying cause, iron supplementation
14. Thalassaemiaα-thalassaemia, β-thalassaemia, thalassaemia traitKey featuresPeripheral blood smear – basophilic stippling, target cellsIron studies – all normalManagement – iron supplementation, regular transfusions, iron chelation
15. Hematinic Interpretation
16. Sideroblastic anaemiaCongenital or acquiredKey featuresPeripheral blood smear – basophilic stipplingIron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBCBone marrow – ringed sideroblastsManagement – treat underlying cause, regular transfusions
17. Macrocytic anaemia work-upKey differentialsMegaloblastic anaemia: vitamin B12 deficiency, folate deficiencyAlcoholHypothyroidismKey investigationsPeripheral blood smear LFTsTFTs
18. Megaloblastic anaemiaVitamin B12 or folate deficiencyHow to differentiate?Duration – months for folate deficiency, years for vitamin B12 deficiencyClinical findings – vitamin B12 deficiency associated with neurological changesSerum methylmalonic acid – elevated in vitamin B12 deficiencySchilling test – positive in vitamin B12 deficiency 2º to pernicious anaemiaDrug history – phenytoin inhibits folate absorptionManagement – vitamin supplementation
19. Non-megaloblastic anaemiaAlcohol, hypothyroidism, pregnancyHow to differentiate?History – features of hypothyroidismClinical findings – hepatomegaly, gynaecomastia, abdominal veins, ascites, jaundiceLFTs – ↑AST, ↑ALT, ↑GGT, AST:ALT >2:1TFTs – ↑TSH, ↓T3/T4, anti-thyroid peroxidase antibodiesManagement – treat underlying cause
20. Normocytic anaemia work-upKey differentialsHaemolytic: inherited or acquired (immune-mediated, non-immune-mediated)Non-haemolytic: anaemia of chronic disease, failure of erythropoiesisKey investigationsPeripheral blood smearDAT CRP, ESR
21. Anaemia of chronic diseaseInfection, inflammation, malignancyKey featuresInflammatory markers – raised CRP, ESRIron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBCManagement – treat underlying cause
22. Haemolytic anaemia - ClassificationInheritedMembrane: Hereditary spherocytosisCytoplasm/ Enzymes: Glucose-6-phosphate dehydrogenase deficiencyHaemoglobinAcquiredImmuneAutoimmune: warm vs cold haemolytic anaemiaAlloimmune: ABO or Rhesus incompatibilityNon-immune Microangiopathic vs macroangiopathicInfectionInherited vs acquired (immune-mediated vs non-immune-mediated)
23. Haemolytic anaemia - ClassificationIntravascular vs ExtravascularIntravascular- destroyed in the circulation Alloimmune AutoimmuneHereditary SpherocytosisExtravascular- destroyed in the reticuloendothelial systemMalaria G6PD Deficiency Drugs PNH
24. Hereditary spherocytosisAutosomal dominantDefect in the vertical interaction of the red cell membraneKey featuresPeripheral blood smear: spherocytes, polychromasiaPositive osmotic fragility testPositive eosin-5-maleimide (most sensitive test)Management – folate supplementation, splenectomy
25. G6PDX-linked recessiveG6PD generates NADPH via pentose phosphate pathway Key featuresEpisodes of acute haemolysis following exposure to oxidative stress (e.g. fava beans, mothballs, drugs)Peripheral blood smear: Heinz bodies, bite cellsIntravascular haemolysis: ↑unconjugated bilirubin, ↓haptoglobin, haemoglobinuriaManagement – avoidance of triggers, supportive care
26. AIHAImmune-mediated destruction of red blood cells, DAT positiveWarmMediated by IgG Associated with CLL, SLE, methyldopaExtravascular haemolysisColdMediated by IgMAssociated with Mycoplasma, EBV, hepatitis CIntravascular haemolysisManagement – treat underlying cause, steroids, rituximab
27. Non Autoimmune HADAT will be negative The red cell breakdown is NOT caused by the immune system Infection (such as malaria) can cause red cell haemolysis This can also be caused by Microangiopathic Haemolytic Anaemia (MAHA)
28. MAHANon-immune-mediated, small vessel disease Damage to endothelial cells within the vasculature fibrin deposition and platelet aggregation fragmentation of red blood cellsKey featuresPeripheral blood smear: schistocytes, thrombocytopeniaDisorders – HUS, TTP, DICDistinguish from DIC with normal APTT, PT, fibrinogenManagement – treat underlying cause, supportive
29. HUSCommonly caused by Escherichia coli O157:H7 – Shiga-like toxinMore frequent but less severe in childrenKey featuresSymptoms occur after a diarrhoeal illness – do not give antibiotics to treatTriad of MAHA, thrombocytopenia, acute renal failure – self-limiting in childrenFeatures of MAHA on peripheral blood smearManagement – supportive care
30. TTPDeficiency of ADAMTS13 decreased break down of multimers of vWFCan be inherited or acquiredKey featuresPentad of MAHA, thrombocytopenia, acute renal failure, neurological symptoms, feverHigh mortality rateManagement – supportive care, plasma exchange
31. DICThis is an EMERGENCY Activation of both coagulation and fibrinolysis is triggered by: Sepsis (MOST COMMON) Trauma (e.g. head injury, fat embolism) Obstetric complications (abruptio placentae, amniotic fluid embolism) Malignancy (e.g. APML)↓ platelets, ↓ Fibrinogen, ↑ PT and ↑ APTT, ↑ D-dimer
32. Clotting Studies for DICProlonged APTT Prolonged PT Prolonged TT Decreased fibrinogen Increased FDP Decreased platelets Schistocytes Due to fragmentation of red blood cells as they pass through the fibrin mesh in the small blood vessels
33. MAHA/ DIC/ TTP/ HUSMAHAThink: E. coli, renal failure, thrombocytopenia, MAHAThink neurological symptoms, MAHA, renal failure, feverThink: clotting is screwed + MAHA + ↑ APTT + ↑PT, Amniotic Fluid Embolus
34. Haemolytic Anaemia Work UpDAT - Check for autoimmune haemolysis Urinary haemosiderin/haemoglobin - Suggests intravascular haemolysis Osmotic fragility - Suggests hereditary spherocytosis , the dye binding test is being used more frequently now G6PD +/- PK activity - characterised by episodic haemolysis, where as PK deficiency causes chronic haemolytic anaemia Haemoglobin separation A and F% Heinz body stain - suggests oxidative haemolysis Ham's test/Flow cytometry of GPI-linked proteins Thick and thin blood film - Check for malaria
35. Lab/ Clinical Features of HA Clinical FeaturesPallorJaundice Splenomegaly PigmenturiaFamily HistoryLab FeaturesAnaemia Reticulocyte Polychromasia Hyperbilirubinaemia (unconjugated)Increased LDH Reduced/ absent haptoglobin Haemoglobinuria Haemosiderinuria
36. Anaemia Summary
37. QuestionWhich of these is true about alpha thalassemia?Caused by a defect on Chr 11There is increased destruction of beta globin chainsDecreased gamma-globin chains4 mutated genes can lead to hydrops fetalisIncreased production of alpha globin chains
38. QuestionMohammed is a 4-year-old boy who was born in Bangladesh. He presents to your pediatric clinic. What is the likely diagnosis?Beta Thalassemia
39. QuestionWhat is the best investigation to diagnose beta thalassaemia?High performance liquid chromatography
40. Haemoglobinopathies
41. BackgroundGenetic disorders of globin chain synthesisHaemoglobinHbF (α2ɣ2) – foetus, infantHbA (α2β2) – late foetus, infant, child and adultHbA2 (α2δ2) – infant, child and adultDiagnosis made with Hb electrophoresisDisorders – thalassaemia, sickle cell disease
42. β-thalassaemiaReduced synthesis of β globin chain (Chromosome 11) Major (homozygous), intermedia and minor (heterozygous)Key featuresMajor – severe anaemia requiring regular blood transfusionsIntermedia – genetically complex, moderate reduction in β globin chain productionMinor – benign but important geneticallyDiagnosed with high performance liquid chromatographyManagement – regular blood transfusions, iron chelation, folate supplementationβ-globinβ-globinChr 11
43. α-thalassaemiaReduced synthesis of α globin chain (Chromosome 16) Hb Barts (x4), HbH (x3), trait (x2), silent (x1)Key featuresHb Barts – fatal in utero, hydrops foetalisHbH – severe anaemia in childhood, hepatosplenomegalyTrait – mild anaemiaSilent – asymptomaticManagement – regular blood transfusions, iron chelation, folate supplementationα-globinα-globinChr 16α-globinα-globin
44. Sickle cell diseaseAutosomal recessiveGlu Val mutation at codon 6 on the β globin chain HbSHbSS, HbAS, HbSC, HbSβKey featuresHaemolytic crisis, sequestration crisis, aplastic crisis, infection (Streptococcus pneumoniae – sepsis, Salmonella – osteomyelitis)Peripheral blood smear: sickle cellsSickle solubility test positive in HbSS and HbASManagement – vaccination, folate supplementation, hydroxyurea, supportive for acute crisis
45. QuestionA 19-year-old boy comes in with an acutely swollen knee. He does not recollect any trauma. He has been known to have history of bleeding after dental extraction. What is the most likely factor deficiency? Factor XFactor VIIFactor IXFactor VIIIFactor XI
46. QuestionWhat is the most common inherited Thrombophilia?VWDHereditary Activated Protein C ResistanceAnti-Thrombin Deficiency Hemophilia BProtein S Deficiency
47. Haemostasis and thrombosis
48. Quick Recap: Haemostasis
49. Quick Recap: Coagulation CascadeInitiationAmplificationPropagation
50. BackgroundDisorders of primary or secondary haemostasisPrimary – platelet adhesion and aggregation (quantitative and qualitative defects)Secondary – coagulation cascade (inherited and acquired)Disorders of thrombosis occur as a result of Virchow’s triadInherited – factor V Leiden, anti-thrombin deficiency, protein C/S deficiencyAcquired – HIT, malignancy, immobilisation
51. HaemostasisDysfunction in primary haemostasis bleeding disorders (superficial bleeding)Qualitative defect in platelets – von Willebrand disease Quantitative defect in platelets – ITP, HITDysfunction in secondary haemostasis coagulation disorders (deep bleeding)Inherited disorders – haemophilia A, haemophilia BAcquired disorders – liver disease, vitamin K deficiency
52. Platelet DisordersDecreased Number (Thrombocytopaenia) Decreased production Decreased survival (ITP) Increased consumption (DIC) Dilution Defective Platelet Function Acquired (e.g. aspirin, end-stage renal failure) Congenital (e.g. thrombasthenia)
53. Causes of Platelet DisordersImmune-Mediated Idiopathic Drug-induced (e.g. quinine, rifampicin, vancomycin) Connective tissue disease (e.g. rheumatoid arthritis, SLE) Lymphoproliferative disease Sarcoidosis Non-Immune Mediated DIC MAHA
54. von Willebrand diseaseSubtypesType I – autosomal dominant, quantitative defect Type II – autosomal dominant, qualitative defectType III – autosomal recessive, quantitative and qualitative defectsKey featuresMucocutaneous bleeding↓platelet adhesion, ↓factor VIII, abnormal ristocetin↓platelet count, ↑bleeding time, ↑APTT, normal PTDifferentials include Bernard-Soulier disease (large platelets) and Glanzmann’s thrombasthaenia (normal ristocetin)Management – desmopressin, vWF and factor VIII concentrates
55. ITPAcute and chronic formsAcutePredominantly children, M:F 1:1Preceding infectionSelf-limiting, treatment with steroids and IVIG if platelet count ↓↓↓, major bleeding ChronicCommonly adults, M:F 1:3No triggerLong-term relapsing-remitting, treatment with steroids, IVIG or splenectomy
56. Haemophilia AX-linked recessiveFactor VIII deficiencyKey featuresSpontaneous, deep bleeding, haemarthrosisNormal platelet count, normal bleeding time, ↑APTT, normal PTMore common than Haemophilia BManagement – factor VIII concentrate
57. Haemophilia BX-linked recessiveFactor IX deficiencyKey featuresSpontaneous, deep bleeding, haemarthrosisNormal platelet count, normal bleeding time, ↑APTT, normal PTManagement – factor IX concentrate
58. Vitamin K deficiencyVitamin K necessary for synthesis of factors II, VII, IX and X, protein C/SSecondary to malabsorption, warfarin, antibiotic therapyKey featuresFactor VII first factor to be depletedNormal platelet count, normal bleeding time, ↑APTT, ↑PTDifferentials include liver disease (↓platelet count), scurvy (corkscrew hair)Management – vitamin K replacement, PCC, FFP
59. Factor V LeidenAutosomal dominant – most common inherited prothrombotic disorder Key featuresResistance to protein C failure to degrade factor V hypercoagulable statePredisposition to venous thromboembolism (arterial thromboembolism rare)Management – long-term anti-coagulation
60. Anti-thrombin deficiencyAutosomal dominant Key featuresCarries highest risk of thrombosisDevelop thromboembolism in unusual locations (e.g. splenic or mesenteric veins)Anti-thrombin assay used to make diagnosisKey differentials include protein C/S deficiencyManagement – long-term anti-coagulation with warfarin and argatroban
61. Protein C/S deficiencyAutosomal dominant Key featuresPredisposition to venous thromboembolism (arterial thromboembolism rare)Associated with warfarin-induced skin necrosis – initial pro-coagulant state ischaemia of skin vesselsProtein C/S assayManagement – long-term anti-coagulation with argatroban
62. QuestionA 35-year-old female who is 34 weeks pregnant presents with a swollen, painful right calf. A deep vein thrombosis is confirmed on Doppler scan. What is the preferred anticoagulant?Subcutaneous Low Molecular Weight Heparin
63. QuestionWhich of the following is low during pregnancy?FibrinogenFactor 7Protein SPlasminogen activator inhibitor 1Von Willebrand’s factor
64. Obstetric haematology
65. BackgroundVolume expansion ↑cardiac output, dilutional anaemiaThrombocytopenia – returns to normal post-partumHypercoagulable and hypofibrinolytic state ↑risk of venous thromboembolism
66. Haematological changes Plasma volume↑↑Red cell mass↑Haemoglobin↓MCV↑Haematocrit↓Platelets↓WCC↑Factors VII, VIII, IX, X, XII↑Factor XI↓Protein S↓
67. HDFNPrior sensitisation of Rh-negative women from previous pregnancyKey featuresIgG-mediatedFoetal anaemia, hydrops foetalis, neonatal jaundice, kernicterusMonitor foetus for anaemia with MCA doppler ultrasoundManagement – prevent sensitisation with anti-D Ig routinely at 28 weeks and within 72 hours of sensitising event, intra-uterine transfusion
68. HELLP syndromeHaemolysis, elevated liver enzymes, low plateletsLife-threatening complication associated with pregnancyKey featuresMAHA, ↑↑AST, ↑↑ALT, ↓platelets, normal APTT, PTDifferentials include DIC (↑APTT, ↑PT, ↓fibrinogen), AFLP (marked transaminitis)Management – supportive, delivery of foetus
69. QuestionA 15-year-old boy with Beta Thalassemia Major undergoes a bloods transfusion. Shortly after the blood transfusion is started, he feels feverish and has the chill. His observation prior to the transfusion were taken. HR 82, BP 118/80, RR 16, Temp 36.7 and O2 97 (RA). His observation were taken as soon as he complained of the symptoms HR 84, BP 114/78, RR 17, Temp 37.6, O2 97 (RA). What is the likely cause of his symptoms?Acute Haemolysis Transfusion related acute lung injury Transfusion associated circulatory overloadNon – hemolytic transfusion reaction Anaphylaxis
70. QuestionA 40-year-old man who was involved in a major trauma is receiving a blood transfusion in hospital. Within 10 minutes of starting the transfusion, he becomes acutely unwell, with fevers, rigos and significant abdominal pain.Observations: HR 124bpm, BP 94/62 mmHg, O2 Sats 96% on air, RR 24/min, Temp 38.6ºCWhat is the likely diagnosis?Acute Hemolytic Transfusion Reaction
71. QuestionA 63-year-old man is an inpatient on a gastroenterology ward after being admitted for an upper gastrointestinal bleed secondary to oesophageal varices. He has become short of breath over the last 20 minutes. HR 90 beats /min, RR 32 /min, BP 85/56 mmHg, O2 Saturations 92% on air, temperature 39.7ºC. On examination he has bilateral inspiratory crepitations. Heart sounds are normal and JVP is not raised. No rash or swelling is noted. The patient had completed a blood transfusion of 1 unit of blood 2 hours ago.What is the most likely transfusion reaction?Acute Haemolysis Transfusion related acute lung injury Transfusion associated circulatory overloadNon – haemolytic transfusion reaction Anaphylaxis
72. Transfusion medicine
73. BackgroundMinutesHoursDaysAnaphylaxisABO incompatibilityBacterial contaminationFebrile non-haemolytic transfusion reactionTransfusion-associated circulatory overloadTransfusion-related acute lung injuryDelayed haemolytic transfusion reactionGvHD
74. Acute (≤24 hours)AnaphylaxisSymptoms occur within minutesRisk increases in patients with IgA deficiency ABO incompatibilitySymptoms occur within minutes to hoursIntravascular haemolysis – IgM-mediatedBacterial contaminationSymptoms occur within minutes to hoursMore commonly occurs with platelet transfusion
75. Acute (≤24 hours)Febrile non-haemolytic transfusion reactionRise in temperature of ≤1ºC without circulatory collapseCaused by release of cytokines by leukocytes and prevented by leukodepletionTransfusion-associated circulatory overloadSymptoms of pulmonary oedema/fluid overload occur within hoursLook for signs of heart failure: ↑JVP, ↑PCWP, ↑BPTransfusion-related acute lung injurySymptoms similar to TACOCaused by interaction with anti-HLA antibodies in donor blood with recipientOccurs < 6 hoursAbsence of heart failure
76. Delayed (>24 hours)Delayed haemolytic transfusion reactionOccurs within 1 weekExtravascular haemolysis – IgG-mediatedGraft vs host diseaseSymptoms include diarrhoea, liver failure, skin desquamation and bone marrow failureDonor lymphocytes recognise recipient’s HLA as foreign and attack gut, liver, skin and bone marrowPrevent by irradiating blood components for immunosuppressed recipients
77. Warfarin reversalINR ≤5 – lower or omit next doseINR 5-9 – either omit next dose or oral vitamin KINR >9 – omit next dose + oral vitamin KAny bleeding – omit next dose + IV vitamin K + PCC or FFP
78. ResourcesMedEd Path GuideMedEd Lecture SeriesPathology Course Lectures SlidesFlashcards (Wakana Yasuda)Course Lead LecturesPathbase (https://candidate.speedexam.net/signin.aspx?site=pathbase) Haematology + ID sections on Passmed
79. Thank yourishi.banerjee@mft.nhs.uk