Basics to Brilliance: Haematology Podcast

FeedbackWelcome to the Red Cell Series!Timestamps and notes to follow...'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

FeedbackTimestamps to follow!'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

FeedbackThis is a discussion about possible factors and strategies to consider and should not be used as a guideline for clinical practice. Always discuss complicated cases with the attending H&T consultant.00:52 Intro01:30 Case 1: 41M Severe Haemophilia A, acute MI needing PCITry the 4 steps!Bleeding RiskAnticoagulant characteristicsIntensity of anticoagulant (prophylactic vs therapeutic)Duration of anticoagulant therapy11:20 Cardiac Disease in Haemophilia: thoughts and considerations 20:40 Case 1: a potential algorithm in action24:15 Case 2: 60M Moderate Haemophilia A, positive cardiac Hx, AF on ECG33:30 Case 3: Moderate Haemophilia A, lobectomy, DVT on USS doppler of leg40:00 Golden nuggets with a side of ffries'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro and chuckles01:40 Case study: 75M, left calf swelling, put on DOAC, 24 hrs later haematoma and deep bleed on CT06:00 General informationElderly (>65), Mortality 8-40%Common presentations: GI and UG bleeding, Retroperitoneal and muscle bleeds (compartment syndrome)Ptegnancy, TTP, Malignancy (15%), Autoimmune disease (17%)08:56 Pathogenesis and diagnosis: AutoAb against F8*Bethesda units do not correlate with bleeding phenotype in Acquired HA- second orfer kinetics*HistoryAPTT, PT (isolated raised APTT)Mixing studies: 50/50 or 80/20 mixFactor Assays (**Intrinsic**)Decreased Factor VIII + Non-paralellism -> Bethesday Assay20:20 Non-clotting investigations22:05 TreatmentMDT + Comprehensive Care Center escalationRICE., TXA, Bypassing agentsLimit iatrogenic bleedingReview medicationsPregnancy: birth plan!!!  inhibitor can cross palcentaSteroid +/- Cyclophosphamide27:10 Bypassing Agents in Acquired Haemophilia AFENOC + EACH2 study: FEIBA vs NovoSeven = No difference in bleeding/thrombosis rates- more info at 33:25 for EACH2Obizor can be titrated according to response whereas FEIBA and NovoSeven cannotEmicizimab +/- Immunosuppression  = Not currently licesnsed in the UK 32:25 Inhibitor eradicationMean time to remission: 5 weeksGood prognostic markers: FVIII 1 or more, Inhibitor titre < 20EACH 2 Study: Steroids -> Steroids + Cyclophosphamide -> Steroids + Cyclo + RituximabBiggest cause of death: infection36:45 Follow up Weekly FVIII levels and inhibitor monitoring till remission then monthly for 6 months then 2-3 monthly for a yearPlanned procedure; FVIII level38:45 Golden Nuggets'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro - very important topic02:00 Case Study: Haem/Obstetrics clinic, Family Hx Severe Haemophilia A, 12wks pregnant04:15 Clotting changes in pregnancyIncreased: FVII, FVIII, FX, VWF, FibrinogenDecreased: FXIII   Protein S, Antithrombin Stable: FIX07:57 New born to 6 months clotting:FVIII (8) similar to adultFIX (9) lower and rises after 6 months09:30 GUEST STARRINGDr. William Jones MRCP FRCA St6 Anaesthetics SpR with a special interest in Obstetrics10:25 Will speaks about Delivery, Instrumentations,  Anaesthetics/Analgesia aspects of Obstetrics.13:28 David asks about big needles, bleeding risks and Will explains Spinal vs Epidural15:40 Three Stages of Labour (briefly, very briefly) ***‘Haematologists advise active management of the third stage’ means:Management of process of delivering the placenta ie.Uterotonic - Syntometrine IM- helps reduce bleeding and get placenta outPlacental traction?Cord clampingThanks Will.17:40 All the nuggets you'll need **avoiding a traumatic ICH to a baby boy**1/ Pre-conception: baseline factor levels, family Hx (genetic mutations), discussion of treatments and risks  2/ Antenatal: Male identification (IVF, fetal free DNA testing in maternal blood from 9 wks)Offer CVS (11-14 wks, miscarriage risk) or Amniocentesis (15-20 wks, pre-term delivery risk)Faetal anomaly scan @ 20wksCheck FVIII/FIX at booking, pre-procedure, 28wks and 34 wksMDT (haematologist, anaesthetist, obstetrician, nenonatolgist, lab) haemophilia centre, 24hr access to haenostasis labClear delivery plan by 37 weeks3/ Labour/deliverAvoid instrumentationRisk of bleeding: Forceps > Ventouse > Vaginal > C Section (high mortality for mother)FVIII >50 IU/dL : TXAFVIII <50 IU/dL: TXA + DDAVP (avoid in pre-eclampsia)Neuro-axial anaesthesia needs FVII > 80 IU/dLAvoid faetal blood sampling, fetal scalp electrodes, ventouse, forceps, external cephalic version4/ Post partumUncomplicated: maintain FVIII >50 for three daysComplicated/C-Section: maintain FVIII >50 for five daysContinue TXA till minimal Lochia If FVIII >50 needs VTEpNewborn: PT/APTT, FVIII and FIX (cord blood),Newborn: Routine screen for bleed with USS, Give factor if ANY suspicion of ICH- don't wait for a scan. CT/MRI head.Newborn: if ICH, maintain FVIII approx 80-100 for first 3 days, then above 50 for 2 weeks and will need prophylaxis going forwards. ?Vitamin K. SC vaccinations not IM. Give parent info. 40:15 David attempts the case study44:20 How to write the delivery plan:A Practical Guide to the Management of the Fetus and Newborn With Hemophilia - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Suggested-Contents-of-the-Written-Delivery-Plana_tbl2_328606634 [accessed 10 Jan 2026]47:20 Summary 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro02:10 DefinitionCommon: Alloantibody neutralizes FVIIIRare: causes increased clearance of FVIII1/3 of Severe Haemophilia A patientsMedian time 10-15 emergency dosesRF: Mutation types (INSIGHT study), <5 or >60, African/Hispanic, HIVneg, large rFVIII doses, FVIII + inflammatory stimulus07:05 Inhibitor classificationsTitres: Low (<5 BU) vs. High (>5 BU)Responder: Low vs HighTime: Dependent (FVIII inh.) vs Independent (FIX inh.)09:50 Presentation in practiceTreatment failure, change in bleeding pattern, anaphylaxisScreening: prior to invasive procedures, before/after treatment changesRoutine surveillance:Mild- moderate: Yearly + 2-3 wks after emergency treatmentSevere: Every 3rd emergency dose or 3 monthly13:55 Tests (needs repeat)Mixing studyFVIII assay (48 hours post dose)Bethesda assay (if 80-100% residual FVIII = no inhibitor)Specialist: ELISA, In-vivo recoveryMost sensitive: FVIII half-life studiesInhibitor Assays (Bovine chromogenic assay)19:45 Preventative measures?Mild to moderate: DDAVP when possibleSevere: prophylaxis 23:40 TreatmentsBypass agent: skips intrinsic pathway, straight to extrinsic F.I.B.A: activated PCC (II, VIII, IX, X)Onset 15-30 minsDose: 50-100IU/kgHalf life 8-12 hrsNB: Plasma derived: FVIII contamination, infectionContraindicated: EmicizimabNovoSeven: activated rFVIIaPeak 15 minsDose: 270ug/kg, fixed dose, can’t titrateNB: Half life 2 hours, can’t titrateObizor: Porcine rVIIIPeak 30 minsDose: 200IU/kg and titrateablePorcine Bethesda before use34:35 ProphylaxisEmicizumabImmune tolerance induction pts: Emicizumab, NovoSeven > FIBABreakthrough bleeding: increase frequency38:22 Immune Tolerance Induction: start ASAP if inhibitor presentUKHCDO: Long term FVIII tolerance induction and maintenance is key for severe Haemophilia A - don't rely on Emicizumab Success rate: 70%, consistent treatment, fewer emergency doses prior to starting, Historic peak titre <200 BU, <10 BU titres at the start, < 5yrs from inhibitor presentationSuper responder antibody, >500 BU titres46:20 International Immune Tolerance Study (Hay, DiMichele)- Blood 201247:50 Monitoring and Response Assessment Success: FVIII half-life  >7 hours BU negativeMeasurable trough levels at 48 hoursFailure: escalated to max rFVIII but still uptrending titres or fall of <20% in 6 months (alternative systemic agents)NB: rule out intercurrent infection50:33  VerITI-8 trial 51:28 Golden Nuggets'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro02:35 Structure of Haemophilia A care05:10 Key aspects of management (On-demand vs prophylaxis)07:00 Prophylaxis: reduce death rates from ICH and reducing joint bleeds- Primary prophylaxis: before the 2nd joint bleedSevere haemophiliaAny child spontaneous ICHModerate haemophilia A (1-3 IU/dL)- Secondary prophylaxis:After the 2nd joint bleedLimit joint damage and maximize long term functionESPRIT trial- Tertiary prophylaxis: If joint disease already establishedSlow progression, reduce pain and improve QOLSPINART study13:10 Phases of treatment in Primary Prophylaxis- Modify dose during according to needs at that stage of life- By adulthood, 30% of severe patients can safely stop primary prophylaxis!15:50 Prophylactic medications- IV Recombinant FVIII, 1 IU/kg increases by 2 IU/dL (2%)- Half life: 8-12 hrs - Primary Prophylaxis: (needs CVC)Aim trough level 1-3 IU/dL25-40 IU/kg approx 3-4x per weekTitrate clinically which is individual to the patient- Extended half life...ratio of regular:half-life should be at least 1:1.3- Cannot START them on this as can cause inhibitor25:40 Efanesoctocog (EFA) only needs once weekly IV dosing- Very extended half life- XTEND 1 and XTEND-KIDS trials27:52 Emicisimab: Bi-specific Ab, SC, half life 30 days- Binds FIXa to FX thereby replacing FVIII- Phenotypically makes patients have mild haemophilia A- Used for ANY haemophilia with inhibitor OR severe haemophilia without an inhibitor- HAVEN 3 study- Breakthrough bleeds ?management challenges at home- FIBA can cause MAHA (don't use together) - Thrombosis risk- Reduces APTT and interferes with measuring FVIII and inhibitor45:50 On-demand therapy (inhibitor dependent)47:50 Joint bleeds- Moderate bleed: Aim peak of 50- 60 IU/dL- Severe bleed: Aim peak of 60-80 IU/dL- Daily dosing- Assess within 15 mins , treat within 30 mins- TXA + analgesia, PT + PRICE 52:20 Other bleeds- Peak 80-100 IU/dL: Iliopsoas, ICH, GI bleeds, Neck/throat- Deep cut: aim peak 50 IU/dL- Keep at peak for 1-3 days then 50% decrease in peak level for the next week54:10 Case-study: 24M, swollen knee, FVIII 0.3 IU/L- Patients usually have an emergency plan- Assume severe if no info.01:00:15 Case study: 38M, Appendicectomy, FVIII 30 IU/dL- Hari tricks David, David is tricked- Give DDAVP because rFVIII can cause an inhibitor01:03:05 DDAVP (Vasopressin)- IV/SC- 3-5 fold increase of FVIII- 0.3micrograms/kg- Releases a pool of FVIII from endothelium *lung*- tachyphylaxis- Check protocol, side effects and contraindications1:08:36 Management planning in elective surgery (MDT)- TXA!- Calculate dose of Recomb. FVIII- Check levels at 15mins(pre-op), 4hrs (post-op), next morning- May need VTEp01:12:05 Comprehensive Care Centre Annual Review checklist- exam pearlNB: Target joint- 3 or more bleeds into one joint in a 6 month period1:16:24 Rap'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro02:00 What is Haemophilia A?03:00 Factor VIII, Pathogenesis of Haemophilia A07:10 Structure of Factor VIII (exam pearl)300kDHeavy (A1 A2, B) + Light Chain (A3, C1, C2) bound by a metal ions *Calcium*A subunits are 30% homologousB subunit (variable region) is cleaved by thrombin to get Factor VIIIaC1 and C2 help bind to VWFGood to r/o VWF10:55 Epidemiology and history taking- X-linked recessiveFactor VIII is (mostly) feminist.....Turners syndrome, Androgen Insensitivity syndrome, Consanguinity etc. can present with HA  Hari talks about cats 50% of severe haemophilia A have an Intron 22 mutation (non-coding)1/3 de-novo mutationsAmount of Factor VIII negatively correlates with severity (less VIII= more severe)21:55 Presentation of Haemophilia ASpontaneous Joint and Muscle bleeds + Op bleedingYounger presentation = more severeSpontaneous ICH in baby/child inc. in birth traumaThink about On/Off recurrent oromucosal bleeding (can become anaemic)30:00 Non-accidental injury in pre-mobile child- check BSH guidance**33:35 DiagnosisFactor VIII < 40 IU/dL in general (units useful to think as percentages- 40%)Mild 6-40%Moderate 1-5%Severe <1%, presents < 2 yo and diagnosed < 4 yo35:50 InvestigationsBleeding and Family HxFBC, PT/APTT (expect normal PT, abnormal APTT correcting with mixing studies)severe  eg. APTT 100moderate eg. APTT 60-100Factor VIII, IX, XI , XII assay (intirnsic)1 stage and 2 stage chromogenic assay VWF assay (antigen and activity)VW Factor VIII binding assay to r/o VWF 2MGenetic testing (HCDO)- mutational analysis. Can inform likelihood of inhibitor formation and **female carrier identification**Factor V and VIII can be co-inherited in an autosomal inherited pattern*** Biggest cause of death is intracranial death ****** Biggest cause of disability is target joint deformation ***47:52 Summary 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback01:45 Case: Neonate with repeated umblical bleeding. IC haemorrhage.  Normal Factors (so far), Normal VW screen, Normal FBC and normal film.05:35 Factor XIII (13): function and presentations in deficiency 09:45 Testing, testing! ELISA/Ammonia Release Assay then a Mutational Analysis Honarable mention: Clot Solubility Assay16:00 Fibrinolysis definition and pathway21:00 Activators of Fibrinolysis: tPA vs. uPA 23:23 Inhibitors of Fibrinolysis: PAI-1, PAI-2, TAFI, α2-antiplasmin, and Factor XIII (13)26:28 Thrombolysis: defintion, examples and uses32:20 Case: Thromboembolic stroke, thrombolysis 24 hours prior, haemorrhagic transformation36:19: Tranexamic Acid (Hari’s favourite drug)Honarable mention: Dr Utako Okamoto and the WOMAN trialCRASH 2 and CRASH 3 trialsHALT-IT trial41:22 D-Dimer 44:00 Summary'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro: definition and prompts04:25 Intro to Case 1: Haemophilia B, 3rd dose of BeneFix Anaphylaxis 06:03 Intro to Case 2: Severe Haemophilia A, joint bleed, non-responsive to emergency Factor VIII07:30 Initial screening tests NB: Inhibitors: Time Dependent vs. Immediate Acting14:54 Flash examples of Mixing Study importance16:35 Bethesda Assay **Bethesda Studios made the Elder Scrolls and Fallout games: they Inhibit Haider from doing any work**28:45 Bethesda Assay Summary30:00 Nijmegen Modification of Bethesda Assay34:30 Heat Treatment of Bethesda Assay 36:25 ELISA Assay 40:30 Auto vs Allo Antibodies42:00 Kinetics of a Time Dependent Inhibtor 44:45 Case 1 results45:50 Case 2 results51:00 Case 3 (real-life scenario): young girl, subdural bleed after fall, deranged clotting found incidentally 59:30 Summary 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:52 Intro (shoutuout to the BSH anticoagulant monitoring guidelines)02:15 Practical relevance of testing and monitoring anticoagulants 07:30 Heparin: The Basics 09:00 Unfractionated Heparin vs. Low Molecular Weight Heparin 10:24 Mechanism of action of Heparin (UfH vs. LMWH)LMWH: more Anti-Xa activityUfH Anti-IIa acitivity = Anti-Xa activity15:30 Pharmacokinetic differences (UfH vs. LMWH)23:28 Unfractionated Heparin uses and monitoring34:34 Anti Xa Assay42:32 Activated Clotting Time (POCT)46:56 Anti Xa in LMWH: Practical considerations52:03 LMWH uses and dosing55:30 Summary'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:54 Intro and table of contents1:48 Case 1: pre-op, prolonged PT and ++ prolonged APTT…thrombin time done03:44 Case 2: post-op, normal PT and prolonged APTT…thrombin time done04:46 Thrombin Time definition and ingredients (its all about the fibrinogen!)10:45  Differentiating causes of prolonged thrombin time- protamine, reptilase, ecarin17:24 Case 3: Major Haemorrhage (Variceal), due OGD, Derived PT Fibrinogen normal20:45 Clauss Fibrinogen- methodology, causes of change and treatment of deranged fibrinogen30:09 Derived PT Fibringoen31:20 ELISA, TEG and ROTEM (brief)33:07 Summary 36:56 David’s request (email us your questions!)'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback0:52 Intro and table of contents2:36 CASE 1- Infection, due surgery and a prolonged APTT  ft. a refresher on APTT prolongation08:00 Mixing studies- definition and uses ft. Hari’s exam nugget17:00 Factor assays (1 stage, 2 stage and chromogenic assays) ft. David’s humorous humility43:30 David applies his new-found knowledge to our first case45:45 CASE 2-  Infection, hx of weight loss and bleeding and a prolonged APTT 47:36 Summary   https://practical-haemostasis.com/Factor%20Assays/1_stage_pt_factor_assay.htmlhttps://practical-haemostasis.com/Factor%20Assays/chromogenic_factor_assays.html'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback00:00 Intro04:25 Automated Methods of Measuring a Clot05:50 Scenario 1 & Pre-Analytical Variables11:50 HIL Index & Patient Factors15:55 Blood Tube Basics21:10 Nitty Gritties- What Happens When We Send a PT?23:20 PT vs INR for Warfarin- Going Down The Rabbit Hole...26:35 Heparin Neutralising Buffer29:00 APTT 33:05 Summary (& an honorable mention)'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback0:00 Intro2:45 What is Haemostasis?3:55 Stages of Haemostasis (summary)4:45 Primary Haemostasis 8:35 Secondary Haemostasis11:10 The Clotting Cascade12:20 Common + Extrinsic Pathway13:50 Intrinsic Pathway (TwelvEleveNinEight)14:25 Clotting Tests16:30 Hari Pops The Bubble18:05 In-Vivo vs. In-Vitro22:20 Isolated PT Prolongation- causes25:46 Isolated APTT Prolongation- causes27:43 Paired PT/APTT Prolongation- causes28:50 Best Test for Bleeeding (David makes Hari proud)30:24 Bleeding History Pearls and Questionnaires33:55 When The PT/APTT Screen Doesn't Work37:25 NICE Guidelines Reference for Surgery38:15 David's Scenarios 42:00 Summary 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

FeedbackPolycythaemia-  red cell #Erythrocytosis – in red cell massAbsolute Erythrocytosis- M: Hct >0.60 or >0.52 + RCM >25% of mean- F: Hct >0.56 or >0.48 + RCM >25% of meanApparent Erythrocytosis- Men: Hct >0.52 + normal RCM- Women: Hct >0.48 + normal RCMRelative erythrocytosis-Normal RCM + Reduced plasma volume (pathological dehydration)M>FMedian >60yo2' PRV: treat underlying cause +/- venesection (higher hct threshold)Classification of Absolute:EPO dependent-        Appropriate: High altitude, chronic hypoxia, localised hypoxia, congenital-        Inappropriate: Tumors, EPO doping, Testosterone replacement, diabetic medsEPO independent:-        Acquired: Primary PRV  (low EPO level, feedback)-        Congential Polycythemia= mutations in EPO receptorsInv:- Tumor Hunt- Hx + Exam: ?True vs. Apparent- FBC, U+E, LFTs, Ca2+ - Blood film- Ferritin: low in 1’ PRV- EPO- Imaging- NB:  Normal Hct + High Red Cell # + Low MCV + Low ferritin –> Masked PRV- Molecular Testing:JAK2 (V617F)(96-97%)...SAMURAI JACK=BLOODY)EXXON 12 (3%)Del (13q), Del (20q), Del (1q), Tris. 8/9- *SV thrombus 50% chance MPN- BMBx: Tri-lineage myeloid expansion- Familial screen for congenital(young) Sx of primary PRV:-  Arterial*+ Venous clot (splanchnic*)- Hyperviscosity sx- Splenic sx- GoutIndications for urgent venesection...Hyperviscosity sxBSH diagnostic:JAK2 Pos - Hct M >0.52, F > 0.48. Or RCM >25% above baseline OR Splanchnic vein thrombus - JAK2 positive  JAK2 Neg= A1-4 + either ≥ 1 A or 2 B’sA1: Hct M >0.60, F > 0.56. Or RCM >25% above baselineA2: No JAK2 A3: No 2' cause A4: BMBx posA5: Palpable splenomegalyA5: Acq. genetics in BM cellsB’s: Plt >450, Neut >10 (>12.5 in smokers), Radiological splenomegaly, Low EPO Congenital testing Risk Stratification:- Thrombi.. ECLAP studyHigh Risk:>65 + prev clotsLow Risk: <65 + no prev clot-  Malignant Transformation to MF (5-15% in 10 years), AML (2% at 10 year) markers:Splenomegaly, LDH, HVAF burden >50% at diagnosisManagement:- Lifestyle...CV factors decrease- Aspirin +PPI for all (after confirmed)- decrease CV events 60% (ECLAP) - Venesection first line (?isovolemic)- sx***CYTO-PV trial: Hct aim <0.45, make iron def.400-450ml offWeekly -> 3-4x/year- If previous clots: Lifelong anticoag (w/out aspirin)- NB: if plt>1000 (acq. VWF) bleeding risk, 1st cytoreduceCytoreduction: (once confirmed primary PRV)- High risk- Progressive Hepatosplenomegaly- Plts >1500- WCC >15- Constitutional Sx- Poor tolerance of venesection1st line: (OHC then/or IFN)OHC- Risk:  Macrocytosis, ulcers, SCC, Malignant transformationNB: pregnancyPeg IFN-AYoung + fertileLowers HVAFPROUD PV study (2020)Continuation PV study (2022)SE: flu like sx, AI disease (*thyroid), mood disturbances'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback-       Synchronous CNS and systemic lymphoma at initial presentation (treatment-naïve; TN-SCNSL)-        CNS relapse without recurrent systemic lymphoma (relapsed isolated CNS lymphoma; RI-SCNSL)-        Relapsed concomitant systemic and CNS disease following treatment for systemic lymphoma (RC-SCNSL) Generally hybrid disease Investigations-  MRI Head w gadolinium-  PET-CT-  Testicular US (blood testes barrier influences treatment)-  Opthalmoscopy/fundoscopy +/- Vitreal biopsy +/- subretinal aspirate – could need RT-  Lymph node Biopsy NB: Worthwhile to remember patient hx re relapses-  ?Stereotactic Brain Biopsy w/ Intraoperative rapid cytology and rv of frozen sections......NB: Steroids pre-biopsy may yield non-diagnostic results (1/3 if 7 days steroids)- Correlate with imaging and timescale-   LPo   Good for leptomeningeal (15%) which can be missed on MRIo   CSF protein levels are prognostico   Flow cytometry o   Cytospino   PCR for IGHV rearrangement: sens.Trial: MARIETTA study, or also known as the IE LSG 42-        Single arm prospective trial, 75 patients-        +/- Steroid pre-phase –>MATRIX + RICE alternating induction x3–>CR/PR ->Carmustine-Thiotepa AutoSCT-        Pre-morbid performance status <=3-        2-year overall survival for all of those patients included in the trial just under 50%-        NB: cytaribin omissions if poor performance status-        RICE (Ritux isophosphamide, carboplatin and etoposide)…NB, peripheral neuropathy and neurotoxicitiy-        TN-SCNSL best 70% 2 year PFS-        RI-SCNSL 40% 2 year PFS... can also be given just MATRIX-        RC-SCNSL 14% 2 year PFS-        NB if frail elderly, change MATRIX to MARTAResponse assessment : -        TN-SCNSL and RC-SCNSL o   Brain MRI +/- Spine every 2 cycleso   PET scan every 2-3 cycleso   PET and MRI pre-auto, determine least partial responseo   End of treatment PET (6-8 weeks post) and MRI-        RI-SCNSL : MRI brain +/- spine every 2 cycles…PET only if suspicion of progression elsewhereRelapse post MARIETTA :-BTKi ?compassionate access vs Trial-ZUMA7 trial: CAR-T (anti CD19) NB : ICANS/CRS….Approved for DLBCL 12 relapse within 12 months and primary refractory disease that hasn’t responded-        PALLIATIVE CARE NB Immuno-privileged sites :-        Primary Intraocular Lymphoma :o   Stage w PET, MRI head, US Testeso   MATRIX vs MARTA vs PREMAINE as frailty allows (like 1’ CNS) –> AutoSCTo   +/- Occular RTo   Frail++ +-> Intravitreal MTX-        Primary Testicular Lymphomao   If 1 testicle involved 1/3 of patients have the other involved tooo   US Testes –> Orchidectomy + histopathology…if lymphoma ->imaging and investigations as aboveo   LP with above investigations as 1/3 have CNS involvemento   ?skin lesions sometimes in testicular lymphomao   RCHOP vs RPolaChP + CNS prophylaxis w MTXo   Radiotherapy (30gy) to contralateral testes to reduce contralateral Relapse risk and/or  BL orchidectomy- fertility discussiono   Systemic chemotherapy because 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

FeedbackCNS Lymphomas1% of all NHL3% of all Brain tumoursMost common subtype (90%) is DLBCL Clinical division:1.  1* CNS lymphoma, 2.  2* CNS lymphoma- TN-SCNSL- RI-SCNSL- RC-SCNSL3.  Immune deficiency assoc- HIV; better prog. Presentation:  -    SOL Sx -    Raised ICP: morning headaches w N+V-    Neuropsych, Behavioural, Memory, Language-    Focal motor + Stroke Sx-    Seizures-    Visual Sx and uveitis Investigations:-    FBC + Blood film (exclude 2* CNS lymphoma and BM), GFR, U&Es-    LDH (prog.)-    Virology (Hep+HIV)-    IGs, SPEp (paraprotein)-    Stereotactic Brain Bx w/ IO rapid cytology and rv of frozen sectionsNB: Steroids pre-biopsy  ?non-diagnostic results -    LP:.Leptomeningeal*.CSF protein- prognostic.Flow.Cytospin.PCR for IGHV r.-    CT Head-    MRI H (w gadolinium) +/- spine Staging:-R/O systemic lymphoma-PET/CT-US Testes-Opthalmoscopy/fundoscopy +/- Vitreal biopsy +/- subretinal aspirate-?BMBxPre-treatment:-Baseline neuropsych + cognitive ax-Premorbid performance status: ECOG, Echo, GFR, PMHxDx w/o Bx-MRI-Clinical features-Clonal B cells in CSF/Vitreous fluid    and/or   PCR IGHV rearrangementTreatment:Induction main: - MATRIX- younger <70- MARTA- older >65Consolidation: -  Whole brain RT-  BCNU Thiotepa AutoSCT- gold standard if fit...Within 6-8 weeks of the 1st day of final induction: consider for all patients with non-progressive disease (EOT MRI)Trials: IELSG32 study (Leukemia, 2022)- induction + consolidation choices for < 70Induction: 3 arms, MTX + Cyt main-   MATRIX- MTX +Cyt + Thiotepa + Ritux -> AutoSCT…..best choice (4 cycles)...7yr 70% survivalConsolidation: efficacy equal AutoSCT and WB-RT, favoured AutoSCT for Sx....MATRIX regimen available on NSSG:- Dose ++ to cross BBB- Folinic Acid rescue*- IVF till MTX levels <0.1 umol/L (1st lvl 48hrs after MTX)- EF >45%- GFR >50NB: stop co-trimoxazole, penicillins, aspirin, NSAIDs, PPIs (inhibit MTX clearance)- MTX  build up in 3rd spaces- Stem cell harvest post #2- Treatment related mortality 4-7% mostly in #1- Dose reduce Cytaribin (2/3instead of 4 cycles) if pre-morbid, 25-50% totalMARTA study (Blood, Nov 22): fit for autosct and >65-   2x MTX, cytarabin and rituximab ->AutoSCTPRIMAIN study(2017): not fit for autosct >= 651.     4x MTX, Ritux + PO procarbazine2.     6mo of PO procarbazine as maintenance?WB-RT for residual disease-   Palliative if unfit and older:DexTemozolomideWB-RT?IT Chemo in leptomeningealIELSG43 study…  favoured AutoSCT PFS and OS to de-escalation consol. Follow Up:- Response Ax with contrast enhanced MRI scan: 1-2mo after consol.- Rpt MRI every 3-4mo for 2 years ++-       - CR: MRI NAD, normal eye, clear CSF- Stable: <50% decrease, <25% increase- PR: 50% tumor reduction ?persistent CSF- Progressive: >25% incre'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

Feedback Chronic MyeloMonocytic Leukemia (not CML)Persistently high monocyte count- 3 months Most frequent MDS/Myeloproliferative neoplasms – a cross between the twoMedian age 72Median survival 20-40 months Transformation to AML (15-30%) WHO definition of CMML:1. Excess monocytes- persistent over 3 months, ≥ 1                - Monocytes 10% of total WC count2. Dysplasia: morphological difference (blood film on BMBx) OR3. Genetic abnormalites ( on cytogenetics or molecular)WHO Addition in 2022:Persistent 3 months Monocytes  ≥  0.5  over 10% of WC countAND Dysplasia AND Genetic Abnormalities No single diagnostic test- Exclude MPNs: CML, MF, pre-fibrotic MF, PRV and ET- Exclude Genetics: PDFGR A and B, FGFR 1, JAK-2 rearrangement- Ensure less than 20% blastsCommon Presentation: - Constitutional Sx- Cytopenias and sequelae- Effusions pericardial or pleural (inflammation and infiltration)- Skin deposits- Autoimmune disorders (higher incidence of CMML) Classification: -Myelodysplastic CMML- WC<13o Cytopenias**- Myeloproliferative CMML – WC ≥ 13o   Activate RAS pathway mutationso   Leukostasis**(*brain and lung*)o   More adverse clinical outcomeso   More splenomegaly and extra-medullary (infiltrative) PROGNOSTIC CLASSIFICATION: Blast Count-   CMML-1:  BMBx <10% blasts-   CMML-2: BMBx <20% blasts OR Presence of Auer Rods (trumps blast %)OTHER:o   CPSS-Mol: cytogenetics, "NARS”, blast count, WBC count, transfusion dependence Investigations-  R/O infection-  FBC and trend -  Blood film-  Flow of Peripheral blood (immunophenotyping): Chronic Panel       o   Classical Monocyte MO1: CD14 +ve and CD16 -ve           - If >=94% MO1 on flow specific and sensitive for malignant          - Can help differentiate reactive monocytes MO3 (CD14 weak +ve, CD16 +ve)          -BMBx if appropriate as per age and fitness       o   Aspirate: Dysplasia, Excess monocytes       o   Flow: Acute panel (check blasts percentage)       o   Cytogenetics:            - Poor cytogenetics: Trisomy 8, Chrom. 7 abnormalities, complex cytogenetics (3 or more cytogenetic abnormalities)           -Good cytogenetics: Isolated loss of chromosome Y       o   Molecular: PCR in EDTA- “NARS”.....NRAS, ASXL1, RUNX1, SETBP1Treatment decisions: - High risk (AML risk) + Tx eligible -> Intensive chemo (AML style) and Tx- Transplant outcomes: Overall survival approx. 30% but curable -  Low risk and not transplant eligible: QOL improvement o   Watch and wait o   Cytopenia supportive treatment w/ transfusions o   CMML-1 with raised WC count: ->Hydroxycarbimide as long as it provides benefit but  can worsen cytopenias in patients with stable countso   CMML-1 with significant cytopenias MML-2 with WC <13 with high risk of AML -> Azacytidine (hypomethylating agent) Subcutaneous 'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!

FeedbackChronic Lymphocytic Leukemia (CLL)- Chronic Relapsing RemittingMost  common leukemia in adultsIncurable but treatable*Remember Supportive Care*Median age of 72M > F80% incidentalSLL: lymphocytes in lymph nodes and spleen instead of blood Presentation: 1) Fatigue2) B symptoms3) High WC4) Cytopenias (Marrow infiltrate, AIHA, ITP, Hyposplenism)Rule out: Reactive (viral serology)- Hepatitis, HIVInvestigate: 1) FBC + blood film (mature lymphocytes) w/ trend2) Haemolysis screen + Coombs test3) B2 Microglobulin (prognostic marker)4) IGs + serum electrophoresis5) Flow cytometry (immunophenotyping)6) LN Bx (core) especially if lymphadenopathy (*SLL)7) BMBx8) Tp53 (17p del or mut)9) CTNTAP if treatment indicated Confirm : 1) Lymphocyte morphology (blood film)- monomorphic mature small w/out nucleolous r/o aggressive pro-lymphocytes r/o prominent nucleoli in reactive lymphocytosis2) 5x10^9 / L circulating clonal B cells for over 3 months on Flow…if below, need annual FBC monitoring 3) Immunophenotype scoring out of 5 (1 point each): +ve CD5, +ve CD23, weak IG expression, absent/weak CD22, absence of FMC-7...need 4 or 5/5 Staging : 1) BINIT A/B/C2) RAI 0-4Prognosis: CLL International Prognostic Index1) Age2) B2 Microglobulin3) TP53 status- continuous therapy better if TP53 mut4) IGHV mutation- better if present5) RAI or BINITThe International Working Group for CLL (iwCLL) treatment- Risk vs. Benefit    1) Cytopenias Hb <100, Plts <100    2) Bulky disease >10cm LN length    3) Constitutional sx disease related    4) AIHA (10-20%) and ITP (2-5%)    5) Symptomatic or fnxnal extranodal involvement    6) Massive Splenomegaly >6cm from costal margin or progressive SM + Sx    7) Lymphocyte doubling time < 6 months or  > 50 percent rise in 2 months  WATCH and WAIT if not reaching criteriaInfection risk (bacterial):   1)   Vaccination (NB: NO LIVE VACCINES)   2)   IVIG in immune paresis   3)   Prophylactic Abx (azithromycin)   4)   PCP prophylaxis while on treatmentNeed IRRAD blood productsTrials for Traditional treatments vs. BTK1 and BCL21) Alliance 2) Mayo clinic study3) FLARE4) CLL14 (German) and Illuminate trials Treatment:1) Traditional:  FCR2) Targeted:    a.    1st gen BTK1- Ibrutinib 420mg OD (continuous)    b.    2nd gen BTK1- Acalabrutonib 100mg BD (continuous)    c.    BCL-2 inhibitor- Venetoclax 400mg OD            i.       Frontline : OVen.. Ven + Obinutuzumab (CD20 mAb) - 1 yr            ii.       Relapse: VenR... Ven + Rituximab (CD20 mAb)- 2 yrs    d.   PI3K inhibitor- Idelalisib - 3rd line as bridging for 2x refractory/2x exposed*High Risk*: Doublet therapy (targeted combined)i. Jain et al. – Phase 2 trialii. CAPTIVATE trial: Ibru + Ven <65,  TP53 mut/del OR unmutated IGHV TRIPLET Therapy trials-ALLO SCT- early referrals in high risk with first progression·   Primary Progression: <6m of response·   Relapse: >6m response and then….look at iwC'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK. Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning. Email: [email protected]: BasicstoBrillianceX: @basics_2_brillSend us your feedback!