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98 Cards in this Set
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HIT 4T score Points for different risk categories |
Thrombocytopenia 2 50% drop, nadir > 20 (rarely drops lower than this 1 30-50% drop, or nadir 10-20
Timing of platelet fall 2. 5-10 days after start of exposure, or within 24 hours and has had a separate heparin exposure within 1 month 1. Possibly within 5-10 days but missing counts; onset >10 days; or within 24 hours and has a separate heparin exposure within 30-100 days
Thrombosis or other sequelae 2. Confirmed, or skin necrosis, or systemic reaction to iv injection 1. Suspected/progressive thrombosis, non-necrotising skin lesion
Other causes 2. Non apparent 1. Possible
3 or less: low risk. Dont lab test unless missing data has led to this score 4-5: intermediate risk 6 or more: high risk |
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Raised INR from warfarin (2x3 categories) |
No bleeding <4.5: nil 4.5-10: consider vit K if high bleeding risk >10: Vit K. Consider prothrombinex Bleeding Minor: consider vit K if high bleeding risk or >4.5 Clinically significant: IV Vit K + prothrombinex Life-threatening: IV vit K + prothrimbinex + FFP |
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HIT mechanism |
Heparin normally binds with the cytokine, platelet-activating factor 4, forming a complex. In HIT, IgG forms against this complex and binds it, which changes the Fc domain of these IgG, causing them to activate platelets, causing them to degranulate |
(Not enough paf 4 me) |
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Reversal of dabigatran / apixaban / rivaroxaban |
Dabigatran: idarucizumab. Rapidly reverses dabigatran. MAB. Seems to be available Anti Xa: andexanet alpha is in phase 3. Not available |
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MDS subtypes |
1. MDS with single lineage dysplasia with or without ringed sideroblasts (>15%) - Blasts <5% 2. MDS with multi-lineage dysplasia with or without ringed sideroblasts (>15%) - Blasts <5% 3. MDS with excess blasts - Blasts 5-19% 4. Isolated del(5q) abnormality 5. Chronic myelomonocytic leukaemia (CMML) - Blood monocytes >1, <20% blasts 6. Juvenile myelomonocytic leukaemia (JMML) - RAS / NF-1 mutations |
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MDS diagnosis (4) |
1. 1 or more cytopenias - Anaemia is often macrocytic - Cells are hypofunctional also (neutrophils are hypogranular), so may be disproportionately symptomatic to cell count 2. >10% dysplasia in a cell line (on BMAT) 3. <20% blasts (BMAT) 4. Characteristic cytogenetic findings |
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MDS prognostic score - name and 4 factors |
IPSS score (low, intermediate, high) Blasts (<5, 5-10, 11-20, 21-30) Karyotype (good, intermediate, poor) Cytopenias (0/1; 2/3) Age |
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MDS treatment options - Low risk (3) - High risk (3) |
Low risk patients - supportive cares - Transfusions - EPO in select patients - Chelation in select patients (usually >20 transfusions) High risk patients - Young patients: stem cell transplant - Other: azacitidine - 5q syndrome: lenalidamide (strong response) |
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Most common cause of death in MDS |
Infection Then AML Then haemorrhage |
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Treatment of HIT (3 aspects) |
Stop heparin Alternative anti coagulant - Anti-Xa: lepirudin/argatroban - Direct thrombin: danaparoid (?fondaparinux & bivalirudin also options?) Start warfarin once platelet count improves and bridge. Continue for 1-3 months |
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ITP 2 types and associated ages Most common antibody |
Acute: more so children Chronic: more so adults. Can relapse and remit with unpredictable timecourse AntiGP2b3a |
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ITP acute treatment |
Plt >30 and no/mild bleeding: observation Plt >30 and symptoms: treat Plt <30: treat Prednisone 1-2mg/kg - good at inducing remission but relapse common IVIG - quicker induction Splenectomy - best difinitive treatment Rituximab Romiplostin (thrombopoietin receptor agonist) or eltrombopag (TPO mimetic) - mist be post-splenectomy, habing failed steroids/IVIG |
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ITP investigations |
Film to exclude pseudothrombocytopenia (plt clumping) or platelet abnormalities (should be normal or mildly enlarged in ITP) HIV, hepatitis C |
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Amyloidosis overview 3 major types 7 general possible features Diagnosis |
Types Over 36 forms of amyloid 3 most common are - AL (primary) - AA (secondary): - ATTR (cardiac only) Other: dialysis-related General possible features Waxy skin Enlarged muscles (tongue, deltoid) Cardiac: heart failure, conduction problems Hepatomegaly with greatly elevated ALP Proteinuria/nephrotic syndrome (see renal slide) Peripheral/autonomic neuropathy Coagulopathy Diagnosis Biopsy - If single organ involvement: biopsy that organ - If multi-organ, biopsy fat pad (less bleeding risk) |
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AA amyloid |
Most common form in resource-limited countries
Commonly complicates chronic inflammation (chronic infections or inflammatory diseases) Fibrils of SAA protein (serum amyloid A), an acute phase reactant Diagnosis: as per slide above Other investigations: - Raised CRP, ESR - Raised serum SAA (but often not available) Management: treat underlying condition |
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3 types of primary TMA 5 broad causes of secondary TMA 1 other atypical type to note |
TTP (ADAMTS13) Shiga-toxic associated HUS Complement-mediated TMA (AKA atypical HUS) Secondary TMA - Malignancy - Transplant - Infection - Drugs - Pregnancy
Renal-limited TMA - when there's TMA on renal biopsy without systemic features (probably like C3 bloke from ICU) |
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Complement mediated TMA (atypical HUS) Pathogenesis Treatment (1) - Side effect of |
5-10% of HUS cases Genetic mutations in complement regulatory proteins resulting in excessive complement activation. Can also be complement regular auto antibodies Ecalizumab or revalizumab - block cleavage (activation) of C5 to C5a. Result is susceptible to infection (especially neisseria), ?because of lack of C5b and therefore membrane attack complex Above is indicates in those where complemented mediated is the most likely cause for the TMA based on clinical features (see other card), while awaiting confirmation by complement testing |
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Shiga toxin-producing E coli HUS (STEC-HUS) Pathophysiology Effect on coagulation screen and D.dimer |
Shiga toxin binds Gb3 found most in glomerular endothelium (and more in children than adults) Results in platelet activation by unknown mechanism Also inacticates ADAMTS13 (?but doesn't cause a low level) Also causes complement activation Coags/D.dimer normal (as opposed to DIC) Diagnosis: clinically TMA with positive shiga toxin +/- negative ADAMTS13 deficiency Management: supportive. Uptodate recommends eculizumab (C5 MAB) for those with severe neurological impairment. It doesnt recommend plasma exchange as no evidence |
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Causes of MAHA |
Primary TMA (TTP, shiga toxin HUS, complement TMA) DIC Malignancy Autoimmune conditions (SLE) Antiphospholipid syndrome Malignant hypertension Valvular heart disease Drugs Pregnancy |
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MAHA and TMA definitions |
MAHA is any non-immune haemolysis resulting in fragmentation of red blood cells intravascularly producing schistocytes. Some sites say that thrombocytopenia is also part of the definition, but others not so necessarily (especially since it can be caused by valve problems) TMA is MAHA plus thrombocytopenia and organ damage. And it seems that pathologically it should show a characteristic endothelial injury |
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Similarities and differences between DIC and TMA |
Both have thrombocytopenia Both cause organ failure Both cause MAHA with schistocytes and helmet cells (but not as bad in DIC) Both can cause anaemia, but less common/severe in DIC BP low in DIC, high in TMA
DIC: Everything is activated from platelets to coagulation to fibrinolysis. Clot is fibrin rich Abnornal coags. High D dimer. Low fibrinogen (but can be normal in inflammatory conditions as it's an acute phase reactant)
TMA:Predominantly platelets alone are activated without so much coagulation and fibrinolysis. Clot is platelet rich/hyaline - rich (not fibrin rich) Normal coags and ?D dimer |
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Paroxysmal nocturnal haemaglobinuria Pathogenesis Clinical features Diagnosis Treatment Other condition it's associated with |
Pathogenesis Due to an acquired mutation in a glycolipid (glycosylphosphatidylinositol) needed to anchor other surface proteins (complement inhibitors), which protect red cells from the complement system. Specifically either DAT (CD55) or protectin (CD59) When these are lost, complement destroys cells intravascularly (CD59 prevents C9 from forming the membrane attack complex) The gene that encodes it is the PIGA gene The mutation has to happens in a haematopoetic stem cell for it to affect other cells Clinical features 1. Non-immune (normal direct coombs), non-microangiopathic haemolytic anaemia 2. Venous thrombosis (especially in uncommon areas like DVST, budd-chiari, portal vein thrombosis, mesenteric thrombosis 3. Characteristic red urine in the morning (due to urine being more concentrated then) is uncommon 4. Abdo pain, erectile dysfunction, fatigue, oesophageal spasm - due to vasoconstriction from loss of NO from free Hb which scavenges it 5. Bone marrow failure if aplastic anaemia also present Pathogenesis of thrombosis not known Diagnosis Suspected based on above Confirmed by flow cytometry for CD55 (DAF) and CD59 (protectin) Treatment 1. Mild symptoms: watchful waiting 2. Bad symptoms without aplastic anaemia/MDS: C5 inhibitor (ravalizumab or ecalizumab) 3. Bad symptoms with aplastic anaemia or MDS: consider SCT |
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When to suspect complement mediated TMA over other TMAs Confirmation of the diagnosis |
Renal failure-predominant TMA without recent diarrhoeal illness or culprit medications Family Hx of the same TTP is more neurological STEC-HUS is renal predominant but preceded by the diarrhoeal illness Medication induced is self explanatory Confirmed by complement testing |
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HIT 2 lab tests and their relative sensitivity/specificity |
ELISA to detect antibodies against the heparin/platelet-activating factor 4 complex (ELISA tubes coated with PAF4/heparin complex. Patient's serum added, then washed off. Enzume-linked animal ABs against human ABs added to the assay which bind any human ABs. Then a substrate is added which reacts to the linked enzym to create a colour change) - Doesn't tell you whether they're actually causing platelet activation tho Functional assays, where a platelet-rich assay is incubated with the patient's serum to see if the platelets activate or not Both are sensitive, the functional is more specific But functional takes longer and may not be available Uptodate suggests doing ELISA first only doing the second if equivocal/in a certain range. |
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Vaccination-induced thrombotic thrombocytopenia (VITT) Pathophys Clinical features / scores Lab testing Management |
Vaccine induces antibodies against PF4 (platelet-activating factor 4), the Fc domain of which causes platelet activation. Similar to HIT, except that the antibodies are to PF4 alone rather than the heparin/PF4 complex. Also very high d-dimer Causes a similar syndrome to HIT, where thrombosis is the primary issue rather than the thrombocytopenia Score is a modified 4T score with Timing post vaccine Degree of thrombocytopenia Presence of thrombosis Ruling out other causes Lab test is an ELIZA for PF4 antibodies, or a functional essay looking for platelet degranulation. Similar to HIT Management: - Anticoagulation in everyone, prefer to use non-heparin based - IVIG in everyone - Plasma exchange in refractory cases |
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ITP treatment Critical bleeding Severe bleeding Minor bleeding (plt <50) or no bleeding and plt <20) |
IV steroids + IVIG IV steroids or IVIG Consider IVIG or steroids, especially if plt <10 Above should be a single course, with a taper in the case of steroids. Then cease and observe |
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ITP secondary/further options |
If recurrence or lack of response to initial steroids / IVIG: Splenectomy If not a candidate for splenectomy (surg risk or infection risk) or pt prefers to avoid it, or splenectomy is ineffective, next line is rituximab as a single course over 4 weeks |
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Waldenstrom Macroglobulinaemia What is it Clinical features - 3-3-3: - Syndrome it causes and associated triad - 3 other features (2 are in a similar group) - 3 differences from myeloma 5 key investigation findings Treatment |
What is it B cell neoplasm (in the bone marrow) that secretes monoclonal IgM (IgM paraproteinaemia) Macroglobulin as in large immunoglobulin (i.e. IgM pentamer) Clinical features Hyperviscosity syndrome - Neuro problems - Visual problems - Bleeding
Autoimmune reactions: - AI haemolytic anaemia - cold subtype - Autoimmune neuropathy (AB agaibst myelin-associated glycoproteins) - Raynaud's syndrome from cyroglobulinaemia
Difference from myeloma - Rarely get bone pain - Enlarged lymph nodes - Hepatosplenomegaly (from the IgM?) Investigations Normocytic normochromic anaemia with positive coombs test Film: rouleaux SPEP: M spike. On immunofluorescence : IgM High serum viscosity
Bone marrow: >10% lymphocytic cells Treatment Chemo Plasma exchange if hyperviscosity syndrome IVIG |
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Hereditary haemochromatosis 3 most common gene mutations, and which 2 combos mostly cause symptomatic disease Ethnicity 6 main organ effects Diagnosis Features reversible with treatment Management Screening of relatives |
C282Y is the only one that can cause iron overload - either homozygous C282Y, less commonly C282Y/H63D heterozygote (specifically that heterozygote - C282Y when paired with a non-H63D has no risk of iron overload). Although deltamed says that his combo doesn't result in clinical significant haemochromatosis But not everyone homozygote has clinical iron overload Northern European Results in hepcidin deficiency/resistance
Cardiac: heart failure, arrythmias Liver: cirrhosis/HCC Pancreas: diabetes Joints: arthropathy Skin: pigmentation / bronze tan Pituitary - hypogonadism (erectile dysfunction) Diagnosis
High ferritin and transferrin saturation ,Low total iron binding capacity Then genetic testing Can do MRI to look for black liver, white pancreas Liver biopsy (if done): Perl's stain
Heart failure and skin pigmentation are reversible with treatment
Management Phlebotomy if ferritin >1000 or end organ damage. Target ferritin in low-normal range (~50)
Screen first degree relatives of homozygotes |
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Gilbert syndrome Cause Inheritance Diagnostic test (which isn't actually needed) |
Mutation in promotor of gene that conjugates (via glucuronidation) bilirubin Results in unconjugated hyperbilirubinaemia, especially during times of infection, exercise and fasting Diagnosed by persistent isolated high unconjucated bilirubin Can be confirmed by administration of nicotinic acid Autosomal recessive |
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Essential thrombocytosis Age Cause including 3 mutations in order 3 clinical symptoms 3 complications 1 clinical sign 3 main investigations and features Diagnostic criteria |
Middle to old (mean 50) Excessive clonal platelet production Somatic mutation (mostly sporadic) in - JAK2 60% - CALR 20% - MPL 5% Half are incidentally found Signs - Neuro: visual change, headache, dizziness - Complications: bleeding, thrombosis, 1st trimester fetal loss - Splenomegaly without hepatomegaly or lymphadenopathy (think pure platelet consumption) Film: playelet anisocytosis (variable size) Bone marrow: - Normal to moderate hypercellularity - Prominent large megakarycytes with hyperlobulated nuclei - Shouldnt be any highly displastic features , significant fibrosis or increased myeloblasts - suggests something else Genotype: mutations as above (but 10% have a different one). This differentiates from reactive thrombocytosis Test for BCR-ABL, and von willebrand disease (if plt >1000) Jak2 mutation more likely ro transform into polycythemia RV with high RBC and WCC Diagnosis Plt count over 450 BMAT showing the abovr Rule out BCR-ABL CMR and other alternatives A mutation is present |
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Essential thrombocytosis 2 things it can transform into Management |
AML and myelofibrosis (but most end up having a normal life expectancy) Use risk score Intermed-high risk: platelet lowering agent and asprin. If hx of VTE, use anticoagulation instead of aspirin Low risk: Aspirin (which also helos symptoms) or observation Main plt lowering agent of choice is hydroxyurea |
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CLL What is it Characteristic cells on smear How to diagnose when suspected off FBC/film |
Leukaemia of well differentiated cells, almost all are B cells Smear Smudge cells Diagnosis 1. Suspect from high lymphocyte count (with smudge cells on film) 2. Confirm with immunophenotyping by flow cytometry - CD19, CD20 (weak), CD23 (B cell markers) - CD5 (mostly T cell antigen) - Very low levels of surface membrane immunoglobulin (SmIg) that is restricted (is only either light or heavy chain) 3. BMAT not necessary unless unexplained cytopenias 4. SLL is diagnosed with LN biopsy (because they don't have the lymphocytosis to point you in that direction) |
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CLL indications for treatment |
1. B symptoms impacting on life 2. Massive/symptomatic splenomegaly, hepatomegaly or lymphadenopathy 3. Symptomatic extranodal disease 4. Progressive marrow failure: rough indications: anaemia <100 or theombocytopenia <100 (when excluded other causes) 5. Lymphocyte doubling rate less than 6 months, or >50% over 2 months
Treatment: FCR (fludarabine, cyclophosphamide, rituximab) |
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CLL treatment options |
Age <60: FCR 17p or P53 deletion: ibrutinib Frail elderly: Obinutuzumab (type 2 CD20 AB with enhancedantibody-dependent cytotoxicity) + chlorambucil
Relapsed disease: - Ibrutinib - Venetoclax: BCL2 inhibitor (aka BH3 mimetic, which is a natural BCL2 inhibitor that induces apoptosis in times of stress), which is an anti-apoptosis gene. Need graduated oral dosing to avoid tumour lysis syndrome |
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Monoclonal B cell lymphocytosis What distinguishes it from CLL |
Monoclonal lymphocyte count <5 No other clinical features of anything (B symptoms, lymphadenopathy, hepatosplenomegaly, cytopenias) And no secondary causes (infection, auto-immune) Do the usual flow cytometry as for CLL, to classify it into: - CLL-type: CD5+, CD19+, CD23+, SmIg +ve, CD20 dim/-ve - Atypical: as above but CD20 strongly positive. Nede to exclude mantle cell lympoma - Non-CLL type: different. Need to exclude marginal zone lymphoma Need to exclude atypical and non-CLL from mantel cell lympoma Rate of progression to CLL: 1-2% per year |
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Ibrutinib side-effects |
- Redistribution lymphocytosis (not so much aside-effect): initial worsening of lymphocytosis- Significant bruising (withhold 7 days prior tomajor surgery) - Diarrhoea - AF |
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Fludarabine mechanism |
Purine analogue |
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Acute intermittent porphyria - 3 classifications |
Inherited disorders of haem synthesis - accumulation of porphyrin precursors Except porphyria cutanea tarda which is due to an acquired inhibitor
8 enzymes in the pathway
Categorized into 3 ways they present clinically, with the 3 most common nicely slotting each into a different one of the 3
Neuro visceral or 'hepatic', although it doesn't seem to actually affect the liver? Symptoms are due to neuropathic effect Poster boy: acute intermittent porphyria (2nd) - Abdo pain is central symptom (neuropathic visceral pain) with normal exam findings - Vomiting, constipation - Psychosis, agitation, seizure, hyponatraemia (for which these symptoms are mistaken as a result of) - Peripheral neuropathy - In AIP, attacks occur acutely, precipitated by certain drugs - Diagnosis: urine porphobilinogen (remains elevated between attacks)
Blistering skin Poster boy: porphyria cutanea tarda (1st) - Blisters/scars/abnormal pigment on sun exposed areas - Triggers: haemochromatosis, hep C, HIV, liver damage - Diagnosis: urine porphyrins
Non-blistering skin Poster boy: erythropoietic protoporphyria (3rd) Pain/swelling immediately after sun exposure, but no lasting blisters or scars Diagnosis: erythrocyte total protoporphyrin |
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Acute intermittent porphyria treatment |
4 things to take at a bar - benzos, alcohol, selfie, OCP Avoid precipitants. Barbituates Benzos Alcohol OCP Sulphonamides Acute attacks: Haemin |
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Which thrombophilias you can test for during acute thrombosis |
Prothrombin gene mutation Factor 5 leiden (both of these are mutations so can test any time) APLS (but can be false pos, so repeat in 12 weeks) Cant test for protein C/S Leiden/prothrombin not affecting by anti coagulant Cardiolipin and b2micro arent Protein C/S |
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Blood film terms Pencil cells Howell-Jolly bodies Spur cells/acanthocytes |
Pencil cells: IDA Oval cells: megaloblastic Hypersegmented neutrophils: B12 deficiency Target cells: thalassaemia, hyposplenism, liver failure Rouleaux Auer rods: APML. Also, AML Helmut cells: schistocytest Spherocytes: AIHA or hereditary spherocytosis Note megaloblastic means large size relative to what you'd expect for nuclear material Teardrop cells: myelofibrosis (amongst other things) Heinz bodies: G6PD, A thalassaemia Blister cells - white blister on the edge of the cell (G6PD) Bite cells - the cell after the blister is popped or removed (G6PD) Howell-Jolly: hyposplenism Spur cells (severe acanthocytes, meaning very spiculated): haemolysis from advanced cirrhosis |
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Clotting cascade Which do APTT and INR provide info on |
Extrinsic (loner) is just tissue factor activating 7 Intrinsic 12 - 11 - 9 Factor 8 helps 9 -> 10 Factor 5 helps 10 -> 2 Protein C/S inhibit 8 and 5 INR - extrinsic (includes 7) - tissue is extrinsic APTT - intrinsic Warfarin mostly affects extrinsic, even though it also depletes factors 9 from intrinsic, because factor 7 has the shortest half life, so is the first to run out (according to google) |
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Thymoma associated with |
Myasthenia Gravis Red cell aplasia Dermatomyositis SLE SIADH |
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Methaemaglobinaemia What is it Features Common medication triggers |
What is it Haem has oxidised form of iron (Fe3+ instead of Fe2+) – unable to bind oxygen
Features 1. Usual signs of hypoxia (cyanosis, dyspnoea, endorgan effects) 2. Pulse oximeter sats are low - normally 85-90% regardless of actual Hb sats as it generally mucks up the interpretation - Doesn't change with supplementation oxygen 3. ABG PaO2 and sats are normal (ABG sats are based on the PaO2?) 4. Blood: chocolate brown hue Causes 1. Congenital - Fault in enzyme that reduces the haemoglobin 2. Drugs - Hydralazine, sulfur based drugs, nitrates Management Acquired: methylene blue. Ascorbic acid second line |
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Findings of methaemaglboin vs carbon monoxide poisoning vs cyanide |
Methaemaglobin - Low sats, normal pO2 CO poisoning - Low or falsely normal sats (depending on oximeter), low pO2 Cyanide poisoning - Normal pO2 and sats |
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Thymoma associated with |
Myasthenia Gravis Red cell aplasia Dermatomyositis SLE SIADH |
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CML diagnosis |
Elevated WCC/neutrophilia - low leukocyte alkaline phosphatase distinguises from reactive leukocytosis Immature granulocyes with myelocyte bulge Mild anaemia, raised platelets, raised basophils, raised eosinophils
Confirm by demonstration of Philadelphia chromosome by conventional cytogenetics or demonstration of mRNA for BCR-ABL |
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Causes of hyposplenism and hypersplenism |
Hyposplenism Splenectomy Sickle cell syndrome Coeliac disease Hypersplenism - Cirrhosis |
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Polycythaemia diagnosis 3 major 1 minor if all of above not met |
3 major criteria 1. Persistently raised Hb (on repeated test) or Hct 2. JAK2 mutation (V617F or exon 12) 3. Bone marrow: hypercellularity with panmyelosis(trilineage growth), including pleomorphic megakaryocytes Minor criterion: low EPO (only done if not all of abovemet) |
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Polcythaemia management |
For all - Phlebotomy for all, aiming haematocrit <0.45(reduces thrombosis) - Aspirin – at least daily (twice daily if prevvascular event or microvascular symptoms or high CVD risk) High risk (previous thrombosis / age >60 / plt>1500/WCC >15 / uncontrolled systemic symptoms / increasing splenomegaly) - Previous arterial thrombosis: BD aspirin - Previous venous thombosis: anti-coagulation(warfarin preferred as insufficient evidence for DOAC, but some use) - Cytoreductive therapy: hydroxyurea (akahydroxcarbamide) or interferon |
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Translocations Burkitt CML Mantle cell Follicular APML |
8 - 14 (B looks like 8) - C-myc 9 - 22 11 - 14 Follicular: 14 - 18 (fourlicular): BCL-2 (anti-apoptosis) with Ig heavy chain promotor 15 - 17 |
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Viruses that cause lymphomas Connective tisse disease Endocrine causes |
EBV - hodgkin lymphoma and burkitt NHL HIV - Burkitt Sjogrens: non-hodgkin Hashimoto: non-hodgkin thyroid lymphoma |
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Causes of microcytic anaemia |
Common: IDA Thalassaemia Less common: Anaemia of chronic disease Siderblastic anaemia Hyperthyroidism Heavy metal poisoning |
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Key regulator of iron metabolism |
Hepcidin - released from liver, acts on intestinal epithelium to down regulate ferroportin, preventing release of iron-bound transferrin into circulation
Also traps iron in macrophages Correlates with ferritin levels - high in iron overload, low in iron deficiency |
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Drugs that cause macrocytic anaemia |
Anti-folate: trimethoprim, methotrexate, pentamidine DNA-synthesis: azathioprine, hydroxyurea, |
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B12 deficiency 3 findings on FBC Finding on film 3 other organ effects apart from blood Most common cause and 2 blood tests for this |
Pancytopenia Hypersegmented neutrophils, irregularly-shaped cells. Severe cases can have haemolysis Subacute combined degeneration of the cord (demyelination) - this is the reason to replace first before folate Glossitis + angular stomatitis Neuropsych symptoms Pernicious anaemia Anti-intrinsic factor ABs - specific, not sensitive Anti-parietal cell ABs - sensitive but not specific (remember because parietal cells do other things) |
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Causes of fragmented red cells |
MAHA - TTP, HUS, complement associated TMA HELPP Malignant HTN DIC Valvular heart disease Pre-eclampsia Direct damage by heat/toxins |
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Cut off of ADAMTS13 for TTP |
<5% |
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4 causes of intravascular haemolysis |
MAHA G6PD Paroxysmal nocturnal haemoglobinuria Paroxysmal cold haemoglobinuria |
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Investigations for someone with iron deficiency anaemia that: 1. Is persistently iron deficiency despite ORAL supplementation 2. Is persistently microcytic anaemic despite normalisation of iron stores |
Rule out coeliac Rule out thalassaemia |
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Sickle cell anaemia treatment (3) |
Hydroxyurea (increased HbH) Red cell exchange Vaccinations if hyposplenism |
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Things causing prolongation of: Isolated APTT (4) Isolated INR (2) Both (4) |
Isolated APTT Lupus anticoagulant Deficiencies of the intrinsic factors (12, 11, 9, 8) Von Willebrand disease Isolated INR Vit K deficiency/antagonist Factor 7 deficiency Both prolonged Liver failure (all factors deficient) Fibrinogen deficiency (DIC) Deficiencies of common factors (10, 2, 5) Inhibitors of common factors (direct thrombin / 10a) |
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Which of INR, APTT, thrombin time to the NOACs prolong % renal clearance % protein bound Metabolism enzyme effects Severe bleeding |
Dabigatran - APTT, TCT prolonged - INR dose dependent increase - 80% renal. 35% protein bound - P-GP substrate - Bleeding: idaracizumab, dialysis Rivaroxaban - APTT: dose-dependent prolongation - INR: sometimes. TCT no - 1/3 renal clearance, 95% protein-bound - Bleeding: consider FFP Apixaban - APTT: dose-dependent - INR & TCT both no - 1/4 renal, 87% protein bound - Bleeding consider FFP |
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Transfusions reactions - pathophys and clinical features |
FNHTR - 1-6 hours: fever with no haemolysis - Cytokines from donor WBCs (the 3 macrophage cytokines) - cytokines released during storage, so increased storage times = higher risk - Prevent by leukodepletion Acute haemolytic - Within 15 mins. Fever, flank pain, bleeding - Do a DAT - Pathophys: ABO / rhesus incompatibility TACO - Pulmonary infiltrates with hypertension and no fever TRALI - Pulmonary infiltrates with fever and hypotension - Pre-transplant stress activates lung PMNs. Donor anti-HLA ABs attack primed PMNs Sepsis - More likely in platelets Urticaria / anaphylaxis - Recipient IgE to donor proteins (e.g. in IgA deficiency) - Prevent by washing TA-GVHD - 2 days to 6 weeks - Pancytopenia, diarrhoea, rash, liver failure - Prevent with irradiation |
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Blood transfusions - purpose of the following:
Radiation Red cell washing Main cause of anaphylaxis to red cell transfusions |
Radiation: depletes white cells, reduces chance of graft vs host disease. Used in immunocompromised patients. Red cell washing: removes immunoglobulin. Reduces the chance of anaphylaxis in patients with IgA deficiency Loucodepletion: routinely performed. Reduces chance of FNHTRs and CMV transmission Anaphylaxis is from a foreign substance in the donor bloods - e.g. IgA in IgA deficient people. Other example is haptoglobin-deficiency |
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Main organs involved in graft vs host disease Timecourse Main situations that it occurs in |
Skin, liver, gut and bone marrow (in patients that still have a bone marrow) 2 days to 6 weeks Blood transfusions to close relatives Allogenic stem cell transplants Usually, the host's WBCs kill any transfused white cells before they can engraft. In the above 2 situations, this doesnt occur (situation 1 - relatives have similar HLA and not recognised as foreign; situation 2 - host has no immune system with which to destroy donated white cells) Transfusion associated GVHD is 90% fatal |
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Melphalan mechanism Side effects |
Alkylates guanine Nausea Myelosuppression Pulmonary fibrosis |
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Lenalidomide Mechanism Side effects Uses |
Mechanism 1. Inhibits angiogenesis 2. Induces apoptosis 3. Immunomodulation Use: myeloma (not exhaustive) |
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2 Major complications of CAR T cell therapy
3 others |
Cytokine release syndrome - Fever, hypotension, hypoxia (think TRALI) - IL-6 key role in pathogenesis - Treat with tocalizumab +/- steroids ICANS - Immune-effector Cell Associated Neurotoxicity Syndrome - Neurological symptoms: headache, confusion, ALOC, seizures - Day 7 median onset. Commonly occurs after CRS - IL-1beta key role in pathogenesis. Disturbed blood brain barrier - Treat with dexamethasone/methylpred Tumour lysis syndrome B cell aplasia (B cells never recover) Relapse of leukaemia |
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TTP treatment options in rural centre |
1st line is PLEX + pred +/- ritux +/- caplacizumab for severe disease (anti-VWF, only new) If PLEX not available Pred should be Can also use FFP to replace the ADAMTS13 |
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APML Diagnosis Complication Management Management complication |
Film Prominent granulation with Auer rods Diagnosis Rapid diagnosis with PML-PARA PCR (protein produced from the below translocation) or FISH: t(15;17) Later confirmed with BMAT Complication DIC Management DIC control: platelet transfusion / fibrinogen Disease modifying - 'differentiation' therapy: - ATRA (modified vitamin A derivative), which acts on retinol (vit A) receptor to induce differentiation of the blasts into more mature myeloid cells - Arsenic Complication of treatment Differentiation syndrome - New differentiated promyelocytes abnormaly bind endothelium (particular lung) - Fever + TACO-like syndrome (oedema, lung infiltrates, hypoxia) + renal/liver dysfunction - Treatment: dexamethasone +/- delay chemo |
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MDS most frequently mutated genes Abormality that has treatment significance |
Most commonly mutated - SF3B1 - TET2 - SRSF2 - ASXL1 Treatment significant - 5q deletion: treat with leflunamide |
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Von Willebrand disease Inheritance 3 types 4 investigations Management |
Inheritance Autosomal dominant (think, it's the most common inherited bleeding disorder, so dominant makes sense) Types 1. Low (antigen) levels (75% of cases) 2. Normal levels, low function (10-20%) - Low activity:antigen ratio 3. Absent levels (rare) Clinical features Platelet pattern bleeding Investigations Plt: normal. Mildly low in 2 APTT mildly raised due to low factor 8 (VWF carries this) VWF antigen levels AND activity Management Severe bleeding: recombinant VWF TXA as adjunct DDAVP: triggers release of stored VWF from epithelial cells (not useful in type 2) - Small effect, only works in some people |
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Hodgkin lymphoma Age 2 random symptoms Characteristic cells Prognosis relative to NHL Diagnosis (2) |
Age: 20s and 60s 2 random symptoms - Itchy - Lymph pain after alcohol B symptoms are less common and imply worse prognosis Diagnosis Flow cytometry for CD15 and CD30 And I presume biopsy |
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Hodkin lymphoma 4 types Which is most common Which has worst prognosis and best prognosis Which 2 have particular blood film features |
Nodular sclerosing (70%) - lacunar cells Mixed cellularity (20%) - large number of reed-sternberg Lymphocyte predominant (5) - best prognosis Lymphocyte deplete (rare) - worst prognosis |
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Classical hodgkin lymphoma staging |
1. Single LN group 2. >1 LN group, one side of diaphragm 3. LN groups both sides of diaphragm 4. Extranodal or non-contiguous involvement |
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Hodgkin lymphoma 6 poor prognostic factors |
Male Age >45 Stage 4 Hb <105 Alb <40 WCC >15, or lymphocytes <8% of WCC (i.e. lymphocyte deplete form?) |
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Hodgkin lymphoma management |
Combination chemo + radiotherapy - Usually ABVD (i.e. DBVD – doxorubicin, bleomycin,vinblastine, dacarbazine) - BEACOPP is an alternative for advanced disease - Brentuximab or pembrolizumab for relapseddisease |
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MGUS risk of progression to myeloma |
1-2% per year (2% if restricted light chain) |
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Haemophilia A and B Diagnosis |
Inheritance X-linked recessive 1/3 are de novo mutations Diagnosis Gene mutation, or low factor 8/9 level - Mild: 5-40% of normal factor level - Mod: 1-5% - Severe: <1% Exclude Von Willeband disease as a cause (for haemophilia A) Management Prophylaxis Acute bleed Give factor 8/9, aiming for - Severe bleed: 80-100% of normal level - Minor bleeds: aim lower |
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Haemophilia - management of acute bleed |
Important point: when given the recombinant replacementfactor, the patient can develop antibodies to it, since he doesn’t normallyhave it, so it’s not ‘self’ No factor antibodies present- Give recombinant factor 8 or 9- Target activity: 80-100% of normal in severebleeding, lower in less severe bleeding or pre-emptive surgery (50% in haemarthrosis) Factor antibodies present – options:- FEIBA (factor eight bypassing products): bunchof activated factors that allow direct activation of factor 10- Factor 7a – directly activates factor 10 If unknown- Uptodate suggests giving recombinant factorfirst, but if activity is not coming up, then give bypassing products as above |
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Haemophilia prophylaxis |
- Low risk of bleeding: individualised. Can begiven, or given at certain times or not given- Mod-high risk – options:1. Emicizumab: MAB to factor 9 that activates it –i.e. the MAB does the role of factor 82. Previously factor 8 was given, but commonlyantibodies were developed against it (since the patient never has had factor 8,so it’s not ‘self’). When antibodies were present, activated factor 7 was givento activate the other pathways Cryoprecipitate can be used if factors aren’t available |
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How to remember which thrombophilia screens can be done during acute VTE, and on anticoagulation 4 are good for all 2 are good for one but not the other 1 is bad for all |
- 4 are good for all: 2 gene mutations (F5L,prothrombin), 2 APLS with antibody in their names - 2 are good for 1 thing only: lupus “anticoagulant”– bad for “anticoagulants”, protein C/S – okay for S/C anticoagulants - 1 is bad for all: AT (All Trash) |
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Follicular lymphoma Translocation and association mutated protein What is the function of this protein OVerall outlook of follicular |
14-18 (fourlicular) BCL-2 with Ig heavy chain promotor: inhibits apoptosis Indolent lymphoma 2nd most common NHL Treatment - Stage 1: radiotherapy (can be curative) - Stage 3-4: focus on alleviating symptoms as disease has 20 year survival |
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Universal donor for plasma products |
Universal donor is AB Opposite to PRB transfusions |
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Dilute Russell Viper venom test |
Detects lupus anticoagulants The venom activates factor 10 directly, in the presence of phospholipid Anti phospholipid antibodies (especially anti beta2 glycoprotein) interfer with the phospholipids, and so prolong the clotting time Which kind of doesn't make sense because antiphospholipids are supposed to be pro-coagulant |
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AML Pathogenesis 3 common mutations |
Pathogenesis Mutations lead to a leukaemic stem cell, which gives riseto blasts. The stem cell itself has a relatively small number of mutationscompared to other cancers, and is fairly quiescent. But the blasts that itgives rise to rapidly multiply. Chemo often can kill the blasts easily, butdoesn’t always get rid of the leukaemic stem cell. Initially, it’s oligoclonal. Chemo may knock out one ormore clonal populations, but another may persist 3 common mutations FLT3 (receptor tyrosine kinase) NPM1 DNMT3a |
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AML 4 risk factors |
1. Other haematological disease 2. Previous chemo or exposure to radiation/benzene 3. Age >65 (significantly increases after thisthreshold) 4. Genetic disorders (chromosomal) |
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AML 5 investigations |
Film: myeloid blasts with auer rods and phi bodies - Can be difficult to differentiate visibly fromALL blasts, so perform flow Flow cytometry - AML: myeloperoxidase positive (myel in both) - ALL: TdT (terminal deoxynucelotidal transferase)positive BMAT - >20% blasts Cytogenetics FLIT3 (rapid PCR) |
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AML diagnosis 4 criteria |
Confirmed by: 1. BMAT: >20% blasts 2. Flow cytometry: surface proteins consistent withAML 3. Genetics (genetic mutations and chromosomalabnormalities on karyotyping) 4. Clinicalsyndrome consistent |
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AML management |
Induction chemotherapy - For suitable candidates only – purpose is toachieve initial remission, to then assess options for further management - “7+3”. 7 days of cytarabine then 3 days of an anthracycline(daunorubicin or idarubicin)- If FLIT3 positive, add midostaurin If survive above, repeat BMAT. Remission = blasts <5% Not a candidate for induction chemoCharacteristics - Age >75 - Age >60 and ECOG 2, EF <50%, Cr Cl <45or DLCO <65% Options - Palliation - Low dose chemo: cytarabine +/- venetoclax; orazacitadine |
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AML post-induction assessment including mutations |
Favourable NPM1 without FLT3 Intermediate Unfavourable Secondary AML Wild type NPM1, with ?mutated FLT3 |
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Cryoprecipitate contains Use |
Fibrinogen VWF Factor 8, 13 Use: fibrinogen replacement (DIC) Only use in haemophilia A and von willebrand disease if nothing else available |
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Prothrombinex contains Indication |
Factors 2, 9, 10 Indications: warfarin reversal |
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FFP contains Indication |
All factors + fibrinogen Use: anything, but higher chance of transfusion reactions |
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Systemic Mastocytosis Mutation |
Kit (receptor that causes mast cell proliferation) - mutated in 90% of SM It is the receptor for 'stem cell factor' (Mast kit for your sailing boat) |
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What is the CD of haematopoietic stem cells in transplantation |
CD34 |
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