Haematology Flashcards

Question

How long is anticoagulation required to prevent recurrence after VTE? State the cases for each circumstance.

Answer 1

* Post-surgery = no need for long-term anticoagulation * After minor precipitants = 3 months therapy * Idiopathic and age \> 60 years = offer CT scan to identify any underlying disease and at least 3 months anticoagulation * First VTE with known cause: 3 months * Cancer VTE: 3-6 months * 1st VTE unknown cause: 3-6 months, possibly lifelong * 1st VTE in thrombophilic patient: 3 months, possibly lifelong * Recurrent VTE: lifelong

Answer 2

* Treatment of DVT/PE * Atrial fibrillation * Cardiomyopathy * Symptomatic inherited thrombophilia * Systemic embolism after MI * Cardioversion * Bio-prosthetic mitral or mechanical aortic valve (mechanical mitral valve = 3) * MI

Answer 3

Recurrent DVT/PE in patients on anticoagulant therapy with INR \>2

Answer 4

* Stop warfarin * Give Vitamin K slow infusion * Prothrombin complex * If unavailable, can give FFP but not as effective

Answer 5

* Stop warfarin * Give Vitamin K and repeat if needed after 24 hours * Restart warfarin when INR \<5

Answer 6

Stop warfarin Give Vitamin K Restart warfarin with INR \<5

Answer 7

Withhold 1-2 doses of warfarin

Answer 8

Raised haemoglobin concentration and raised haematocrit.

Answer 9

Lack of plasma giving the appearance of polycythaemia - aka Relative polycythaemia

Answer 10

* Secondary/non-malignant * Primary/myeloproliferative neoplasm * Philadelphia chromosome -ve = Polycythaemia vera, Essential Thrombocythaemia or Myelofibrosis * Philadelphia chromosome +ve = Chronic myeloid leukaemia (CML)

Answer 11

True = suppressed Relative = raised

Answer 12

Alcohol Obesity Diuretics

Answer 13

Chronic = excess mature/differentiated cells Acute = excess immature/undifferentiated cells

Answer 14

JAK2 - most common is JAK2 V617F Calreticulin MPL

Answer 15

Transmit cell growth signals from surface receptors to nucleus Activated by transferring phosphate groups Normally held tightly in inactive state Promote cell growth but do NOT block maturation

Answer 16

JAK2 V617F is a single-point mutation- found in 100% of PV and 60% of ET and myelofibrosis

Answer 17

JAK2 is a tyrosine kinase that is normally bound to the inactive EPO receptor 1. EPO binds to the EPO receptor, receptor dimerises and autophosphorylates and phosphorylates JAK2 2. This activates the JAK2 signalling pathway resulting in the normal response to EPO - In JAK2 mutation, the JAK2 signalling pathway is constitutively active causing a EPO response in absence of EPO

Answer 18

* Clinical features * Symptoms * Splenomegaly * FBC ± bone marrow biopsy (increased cellularity) * EPO level (low) * Mutation testing (phenotype linked to acquired mutation)

Answer 19

* High altitude * Hypoxic lung disease (COPD) * Cyanotic heart disease * High affinity haemoglobin

Answer 20

* Renal disease * Uterine myoma * Other tumours (liver, lung)

Answer 21

* Incidental - most commonly 60 year old male * Symptoms of hyperviscosity - headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea * Symptoms of histamine release - aquagenic pruritus, peptic ulceration * High RBC, Hb, platelets, WCC * JAK2 V617F mutation

Answer 22

* Venesection * Hydroxycarbamide (cytoreductive therapy) - less DNA synthesis in RBCs * Keep plts \<400 x 10⁹/L * Keep Hct \<45% * Aspirin

Answer 23

Chronic myeloproliferative disorder involving megakaryocytic lineage - Sustained thrombocytosis \>600 x 10⁹/L

Answer 24

* Bimodal age distribution = 30 years (minor peak) then 55 years * 30yo (M = F) but at 55 years (F \> M)

Answer 25

M \> F Mean age at diagnosis = 60yo (5% \<40yo)

Answer 26

* Incidental (50% of cases) * Symptoms of thrombosis – *CVA, gangrene TIA, DVT/PE* * Symptoms of bleeding * Symptoms of hyperviscosity (headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea) * Splenomegaly * Mutations (JAK2, calreticulin, MPL)

Answer 27

* Aspirin (thrombosis prevention) * Hydroxycarbamide (antimetabolite that suppresses cell turnover) * Anagrelide (inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing)

Answer 28

* Normal life span in many patients * Leukaemic transformation in about 5% over 10 years

Answer 29

* Clonal myeloproliferative disease associated with reactive bone marrow fibrosis - Characterised by extramedullary haematopoiesis

Answer 30

60-70yo M=F 0.5-1.5/100,000/year

Answer 31

* Incidental in 30% * Presentations related to: * Cytopaenias (anaemia, thrombocytopaenia) * Thrombocytosis * Splenomegaly - Budd-Chiari syndrome * Hepatomegaly * Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia)

Answer 32

Blood film Bone marrow Liver and spleen analysis DNA analysis

Answer 33

* Leucoerythroblastic picture * Tear drop poikilocytosis * Giant platelets * Circulating megakaryocytes

Answer 34

* Dry tap * Trephine biopsy: * Increased reticulin or collagen fibrosis * Increased megakaryocytes with clustering * New bone formation

Answer 35

* Median 3-5 years survival (however, very variable) * BAD prognostic signs: * Severe anaemia \< 100 g/L * Thrombocytopaenia \< 100 x 109/L * Massive splenomegaly * High DIPPS score (score 6 à 1.3 years) * Other MPD (ET and PV) may transform into PMF

Answer 36

* Supportive - transfusion of RBC or platelets (often ineffective) * Cytoreductive Therapy - hydroxycarbamide (for thrombocytosis, may worsen anaemia) * HSCT - potentially curative (reserved for high risk eligible cases) * Splenectomy - symptomatic relief but a dangerous operation * Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)

Answer 37

Abnormal Ph Chr leads to synthesis of abnormal protein BCR-ABL with TK activity greater than the normal ABL protein

Answer 38

* M\>F * 40-60yo (however, affects any age) * Radiation is a major risk factor

Answer 39

* History: * Lethargy * Hypermetabolism * Thrombotic event (mono-ocular blindness, CVA, bruising, bleeding) * Massive splenomegaly/hepatomegaly

Answer 40

* Full Blood Count: * Hb and platelets are normal or raised * Leucocytosis (50-500 x 109/L) * Blood Film: * Neutrophils * Myelocytes * Basophilia

Answer 41

* ABL is a tyrosine kinase (normally, we do not express high levels of TK in the body) * However, BCR is a housekeeping gene that is constitutively expressed * This results in the BCR-ABL fusion gene being constitutively expressed and constitutively activated * This drives cell replication in cells containing the Philadelphia chromosome

Answer 42

* Conventional karyotyping * FISH * RT-PCR amplification and detection * Help determine response to therapy * FBC and leucocyte count

Answer 43

* Chronic phase tyrosine kinase inhibitor - Imatinib * 1^st Gen – Imatinib * 2^nd Gen – Dasatinib, Nilotinib * 3^rd Gen – Bosutinib * FAILURE 1 – switch to 2nd gen or 3rd gen tyrosine kinase inhibitor * Considered a failure if there is NO CCyR at 1 year OR if they respond but acquire resistance * FAILURE 2 – consider allogeneic stem cell transplantation * Considered a failure if there is an inadequate response to 2^nd generation TKIs OR if the disease progresses to accelerated or blast phase

Answer 44

* FBC - haematological response: * Complete Haematological Response (WBC\<10x10⁹/L) * Cytogenetics - cytogenetic response (on 20 metaphases) – very sensitive * Partial 1-35% Philadelphia positive * Complete 0% Ph positive * RQ-PCR - molecular response (reduction in % BCR-ABL transcripts) – most sensitive * Major Molecular response (MMR) \<0.1% (3 log reduction)

Answer 45

* Non-compliance * Side-effects (fluid retention, pleural effusion) * Loss of major molecular response * Acquisition of ABL point mutations leads to treatment resistance * Evolution of a blast crisis

Answer 46

* 95% 5 year survival * Annual mortality 2% * Complete Cytogenic Response at 12months = 97% * Failure to achieve CCyR at 6 years = 80%

Answer 47

Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells

Answer 48

* Home and infiltrate the bone marrow * Form bone expansile or soft tissue tumours called plasmacytomas * Produce a serum monoclonal IgG or IgA: paraprotein or M-spike * Produce excess of monoclonal (κ or λ) serum free light chains * Bence Jones protein: urine monoclonal free light chains

Answer 49

* Median age 67 years * Incidence increases with age - 1% of patients are younger than 40 years * Men \> women * Black \> Caucasian and Asians * Prevalence of myeloma in the community is increasing

Answer 50

* Obesity * Increasing age * Genetics * Incidence in black population * Sporadic cases of familiar myeloma

Answer 51

Monoclonal Gammopathy of Uncertain Significance (MGUS) - MGUS becomes smouldering myeloma and then MM - Both have NO symptoms - symptoms begin at MM

Answer 52

* Serum M-protein \<30g/L * Bone marrow clonal plasma cells \<10% * No lytic bone lesions * No myeloma-related organ or tissue impairment * No evidence of other B-cell proliferative disorder

Answer 53

* Most common premalignant condition * Incidence increases with age * 1% - 3.5% in elderly population * Average risk for progression = 1% annually * IgG or IgA MGUS → myeloma * IgM → lymphoma

Answer 54

* Higher incidence of osteoporosis * HIgher incidence of thrombosis * Increased risk of bacterial infection * Progression to MM or lymphoma * Reduce survival rate compared to matched control group - Kyle R, NEJM 2018

Answer 55

Mayo Criteria Risk Factors * Risk Factors * Non-IgG M-spike * M-spike \>15g/L * Abnormal serum free light chain (FLC) ratio

Answer 56

* Smouldering myeloma = **No CRAB S/S** * Monoclonal serum protein ≥ 30g/L * BM plasma cells ≥ 10% * Annual risk of progression to MM 10%

Answer 57

* Hyperdiploidy (60%) * Additional odd number Chr * IGH rearrangements (Chr 14q32) * t(11;14) IGH/CCND1 * t(4;14) IGH/FGFR3 * t(14;16) IGH/MAF

Answer 58

* KRAS, NRAS - 50% * t(8;14) IGH/MYC * 1q gain / 1p del * del 17p (TP53) * 13- / del 13q

Answer 59

Smouldering myeloma develops before becoming MM

Answer 60

CRAB * C: Hypercalcaemia - calcium \>2.75mmol/L * R: Renal disease - creatinine \>177μmol/L or eGFR \<40ml/min * A: Anaemia - Hb \<100g/L or drop by 20g/L * B: Bone disease - One or more bone lytic lesions in imaging

Answer 61

* Electrophoresis (dense band of **monoclonal proteins**, often IgG or IgA) * **Rouleaux stacks** on blood film * **Bence-Jones proteins** in urine * Blood * ESR high * \>10% plasma cells in BM

Answer 62

Durie-Salmon

Answer 63

* Immunoglobulin studies * Serum protein electrophoresis * Serum free light chain levels * 24h Bence-Jones protein * Bone marrow aspirates and biopsy * FISH * Flow cytometry immunophenotyping * Bence-Jones proteins in urine * Bloods * Rouleaux stacks on blood film * ESR high * \>10% plasma cells in BM

Answer 64

* Positive: * CD38 * CD138 * CD56/58 * Monotypic cytoplasmic Ig * Light Chain restriction (Kappa or Lambda positive) * Negative: * CD19 * CD20 * Surface Ig

Answer 65

* Proximal skeleton * Back (spine), chest wall and pelvic pain * Osteolytic lesions, never osteoblastic * Osteopenia * Pathological fractures * Hypercalcaemia

Answer 66

Cord compression Hypercalcaemia Myeloma kidney disease Infections - particularly pneumonia/chest infections

Answer 67

* Dexamethasone * Radiotherapy * Neurosurgery - rarely required * Stabilise unstable spine

Answer 68

* Serum creatinine \>177μmol/L (\>2mg/dL ) or eGFR \<40ml/min (CDK-EPI) * Acute kidney injury and result of myeloma * 20-50% acute kidney injury at diagnosis * 2-4% of newly diagnosed patients will require dialysis * 25% develop renal insufficiency at relapse

Answer 69

* Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria * Indirect consequences * Hypercalcaemia * Loop diuretics * Infection * Dehydration * Nephrotoxics

Answer 70

Misfolded free light chain aggregates into amyloid fibrils in target organs - Organised into solid, non-branching and randomly arranged with a diameter of 7 – 12 nm

Answer 71

* Kidney * Heart * Liver * Neurons

Answer 72

* Nephrotic syndrome (70%) * Proteinuria (not BJP!) * Peripheral oedema * Unexplained heart failure → determinant of prognosis * Raised NT-proBNP * Abnormal echocardiography and cardiac MRI * Sensory neuropathy * Abnormal liver function tests * Macroglossia

Answer 73

Alkylating agents Proeasome inhibitors Thalidomide Monoclonal Antibodies - daratumumab

Answer 74

Add alkyl groups to DNA - crosslinks and blocks DNA replication - lymphopenia

Answer 75

Autologous Haematopoietic Stem Cell Transplant: 1. Stem cells collected from blood and stored 2. High dose melphalan used to kill myeloma cells 3. Re-infusion of stem cells to rescue blood formation

Answer 76

* Induce apoptosis in myeloma cells * Strong synergy - part of almost all combination regimens

Answer 77

* Targets the turnover of transcription factors that are particularly important for myeloma cell survival * Often used alongside cyclophosphamide and dexamethasone * Newer more potent drugs exist - lenalidomide, pomalidomidem iberdomide

Answer 78

* Large enzyme complex degrades most intracellular proteins (i.e. damaged proteins) by ubiquinating (adding a functional group) and marking the protein for degradation * This is called ER-associated degradation (ERAD) * This is necessary to prevent cell death from accumulation * Inhibiting these proteasome, causes accumulation of misfolded proteins in the myeloma cells leading to myeloma cell death

Answer 79

* Bortezomib * Carfilzomib

Answer 80

IgG1k monoclonal antibody directed against CD38

Answer 81

Relapsed/refractory myeloma

Answer 82

* Microcytic hypochromic anaemia * Reduced Ferritin * Reduced TF saturation * Raised TIBC

Answer 83

Red and white cell anaemia with precursor cell, of variable degree, within the blood

Answer 84

* Teardrop RBCs – aniso and poikilocytosis * Nucleated RBCs * Immature myeloid cells

Answer 85

Bone marrow malignancy

Answer 86

* Malignant – primary or metastatic * Severe infection * Myelofibrosis

Answer 87

Anaemia due to shortened RBC survival

Answer 88

* Anaemia – may be compensated * Reticulocytosis = haemolytic – if reticulocytes then haemolytic * Unconjugated bilirubin raised – pre-hepatic * LDH raised * Haptoglobins reduced

Answer 89

* Inherited - defects of the red cell * **Membrane** – hereditary spherocytosis * **Cytoplasm/enzyme** – G6PD deficiency * **Haemoglobin** – SCD (structural) or thalassemia (quantitative) * Acquired - RBC is healthy but is due to defects in the environment/body * **Immune-mediated** – DAT-positive/Coombs test positive * **Non-immune mediated**

Answer 90

Immune-mediated haemolytic anaemia

Answer 91

* IgG and Extravascular haemolysis * Lymphoma * CLL * Drug allergy * SLE * Idiopathic * 80-90%

Answer 92

* IgG and Extravascular haemolysis * Lymphoma * CLL * Drug allergy * SLE * Idiopathic

Answer 93

* Steroids * Splenectomy * Immunosuprression

Answer 94

* Treat underlying condition * Avoid the cold - often associated with Raynaud's * Chemotherapy

Answer 95

* Infection - malaria (commonest WW) * Micro-angiopathic haemolytic anaemia (MAHA) * Adenocarcinoma * HUS * TTP * Paroxysmal nocturnal haemoglobinuria

Answer 96

* Parasite enters the RBC, causes it to die, shortening survival of RBC

Answer 97

1. Underlying adenocarcinoma releases granules into circulation 2. These are pro-coagulant and activate the coagulation cascade * Platelet activation, fibrin deposition, degradation 3. Red cell fragmentation due to low-grade DIC 4. Bleeding (low platelet and coagulation factor deficiency)

Answer 98

* Corticosteroids * Underlying neoplasia * Tissue inflammation - colitis or pancreatitis etc * Myeloproliferative or leukemic disorders * Pyogenic infection (most likely)

Answer 99

* Brucella * Typhoid * Viral infections

Answer 100

* Neutrophilia/basophilia + immature cells/myleocytes + splenomegaly = CML * Neutropenia + myeloblasts = AML * Malignancy causes a much higher/massive neutrophila

Answer 101

* Reactive * Parasitic infection * Allergic diseases - asthma, rheumatoid, polyarteritis, pulmonary eosinophilia * Underlying neoplasms - Hodgkin’s, T-cell NHL * Drugs - reaction erythema multiforme * Chronic eosinophilic leukaemia * Eosinophils part of clone * FIP1L1-PDGFRa fusion gene

Answer 102

* Pox viruses * CML

Answer 103

* Chronic infection * TB, brucella, typhoid * Viral, CMV, varicella zoster * Sarcoidosis * Chronic myelomonocytic leukaemia (CMML, myelodysplastic syndrome)

Answer 104

* EBV, CMV, Toxoplasma * Infectious hepatitis, rubella, herpes infections * Autoimmune disorder * Sarcoidosis * Lymphocytic leukaemia

Answer 105

* HIV * Auto immune disorders * Inherited immune deficiency syndromes * Drugs (chemotherapy)

Answer 106

* Mature lymphocytes (PB) * Reactive/atypical lymphocytes * Small lymphocytes and smear cells (CLL/NHL) * Immature lymphoid cells (PB) * Lymphoblasts (ALL)

Answer 107

* Polyclonal = kappa and lambda = Reactive * Monoclonal = kappa ONLY or lambda ONLY = Malignant

Answer 108

* Cellular proliferation - mutations in Tyrosine Kinase genes causing excess proliferation * BCR-ABL = CML * JAK2 = MPD * Impair/block cellular differentiation - mutations in transcription factors block differentiation (only cuases leukaemia if present with proliferation mutation) * PML RARA in APL * Prolong cell survival - mutations in apoptosis genes in leukaemia * BCL2 = follicular lymphoma

Answer 109

* **Morphology** * Malignant cells; large or small, mature or immature? * Lymph node diffuse invasion or forming follicles? * **Immunophenotype** (flow cytometry or Immunohistology) * Myeloid or lymphoid? T or B lineage? * Stage of maturation precursor or mature? * **Cytogenetics** (translocations or FISH studies) * Confirm genetic morphology e.g. Philadelphia Chromosome \> CML * Prognostic information e.g. 17p del in CLL * t(8;14) activates c-myc oncogene in Burkitt Lymphoma * **Molecular genetics** (PCR, pyro sequencing)

Answer 110

* **BM mets from breast cancer** * *IDA - wouldn't expect jaundice or nucleated RBCs* * *MAHA - Not get leucoerythroblastic problems in blood as BM is healthy* * *AIHA - AIHA is DAT-positive*

Answer 111

* Mature B cell lymphoproliferative disorder (e.g. CLL) * No abnormal cells in the blood (all mature cells) * *Infectious mononucleosis (e.g. EBV)* * *IgG serology is historical (past infection), IgM is current* * *Would expect 50/50 proliferation of Kappa/Lambda* * *T cell acute leukemic lymphoma*

Answer 112

* Neoplastic tumour of lymphoid cells; usually found in: * Lymph nodes, bone marrow and/or blood (the lymphatic system) * Lymphoid organs; spleen or the gut-associated lymphoid tissue * Skin (often T cell disease; e.g. Mycoses Fungoides) * Rarely “anywhere” (CNS, ocular, testes, breast, etc.)

Answer 113

* Acute Lymphoblastic Leukaemia (ALL) * Non-Hodgkin Lymphomas (B-cell lineage) * Non-Hodgkin Lymphomas (T and NK cell lineage) * Hodgkin Lymphoma

Answer 114

* Recombination – *DNA molecules cut and recombined (deliberate point mutations to provide diversity)* * Unwanted point mutations * Rapid cell proliferation in germinal centres * Replication errors * Apoptosis dependency - *90% lymphocytes die in germinal centres* * Acquired DNA mutation in apoptosis-regulating genes

Answer 115

2 STAGES * 1) **VDJ recombination** – creates a molecule that recognises an epitope: * *Occurs in bone marrow* * *Involves enzymes: RAG1 and RAG2* * 2) **Class switch recombination** * Somatic hypermutation in germinal centre * *Ig promotor highly active in B-cells to drive AB production* * *Recombination errors occur* * *Oncogenes brought close to the promotor* * *Bcl2* * *Bcl6* * *(C-)MYC* * *CyclinD1*

Answer 116

* Immune system diseases * B-cell NHL Marginal Zone Lymphoma sub-type = H. pylori, syndrome, Hashimoto’s * Enteropathy associated T-cell NHL = Coeliac disease * Viral infection (direct viral integration of lymphocytes) * HTLV1 retrovirus * Loss of T-cell function * EBV infects B-cells stimulating proliferation → EBV switches on at later life and drives proliferation through HIV or immunosuppression

Answer 117

* Generative → generation/maturation of lymphoid cells * Bone marrow and thymus * Reactive → development of immune reaction * Lymph nodes and spleen * Acquired→ development of local immune reaction * Extra-nodal lymphoid tissue (e.g. skin, stomach, lung)

Answer 118

* Lymphocytes * B lymphocytes * T lymphocytes * Accessory Cells: * Antigen-presenting cells * Macrophages * Connective tissue cells

Answer 119

* Rounded areas = B cell follicles * Between B cell follicles = T cell areas * Central medulla = where mature B cells eventually end up

Answer 120

* CD19, CD20 = B-cells * CD3, CD5 = T-cells

Answer 121

* Cytology * Histology * Architecture (nodular, diffuse) * Cells – *large cells are suggestive of a high-grade lymphoma* * Immunophenotyping → identify proteins on/in the cells – i.e. determine cell lineage * Cytogenetics * FISH – identify chromosome translocations * DIAGNOSTIC – i.e. t (11; 14) = Mantle Cell Lymphoma * PROGNOSTIC – i.e. t (2; 5) = Anaplastic Large Cell Lymphoma * PCR – identify chromosome translocations, clonal T cell receptor or Ig gene rearrangement

Answer 122

* Low-grade: * Follicular lymphoma * Small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL) * Marginal zone lymphoma (MALT) * High-grade: * Diffuse large B cell lymphoma * Mantle zone lymphoma * Aggressive: * Burkitt’s lymphoma

Answer 123

Lymphadenopathy in the middle-aged or elderly

Answer 124

* Follicular pattern: * Follicles are neoplastic * Often these follicles spread out of the node into the adjacent tissues * Germinal centre cell origin: * Positive stain for CD10 and BCL-6

Answer 125

* t (14;18) translocation involving BCL-2 gene * Usually indolent, but can transform into high grade lymphoma

Answer 126

Middle-aged or elderly

Answer 127

* Small lymphocytes * Arises from naïve B cells or post-germinal centre memory B cells (CD5 and CD23 positive) * They replace the entire lymph node so that you no longer see follicles or T cell areas

Answer 128

* Multiple genetic abnormalities * Indolent, but can transform into a higher-grade lymphoma (Richter transformation)

Answer 129

* Middle-aged or elderly * Lymphadenopathy

Answer 130

* Arise from germinal centre or post-germinal centre B cells * LARGE lymphoid cells * The lymph node is effaced so it is not possible to identify germinal centres and follicles

Answer 131

* Having a germinal centre phenotype is associated with a GOOD prognosis * p53 positive and high proliferation fraction is associated with a POOR prognosis

Answer 132

* Middle-aged males * Affects lymph nodes and the GI tract * Disseminated disease

Answer 133

* Located in the mantle zone of the lymph node * Arise from pre-germinal centre cells * Aberrant expression of **CD5** and **cyclin D1**

Answer 134

* t(11;14) translocation * Cyclin D1 over-expression

Answer 135

* Having a germinal centre phenotype is associated with a GOOD prognosis * p53 positive and high proliferation fraction is associated with a POOR prognosis

Answer 136

* Jaw/abdominal mass * Endemic (children/young adults) * Sporadic (elderly) or immunodeficiency ± EBV

Answer 137

* Starry-sky appearance

Answer 138

* C-myc translocation (8;14, 2;8 or 8;22)

Answer 139

* Middle-aged and elderly * Presenting with lymphadenopathy and extra-nodal sites * Large T lymphocytes * Often found with an associated reactive cell population (especially eosinophils) * **AGGRESSIVE**

Answer 140

* Children and young adults * Lymphadenopathy

Answer 141

* Large epithelioid lymphocytes * T cell or null phenotype (i.e. anaplastic)

Answer 142

* **t (2;5)** translocation = better prognosis * **Alk-1 protein expression** = better prognosis

Answer 143

* Classical Hodgkin Lymphoma * Nodular sclerosing * Mixed cellularity * Lymphocyte rich/depleted * Nodular Lymphocyte Predominant * *Has some relationship to NHL*

Answer 144

* Young and middle-aged * Single group of lymph nodes * Associated with EBV → symptoms related to EBV infection

Answer 145

* Sclerosis * Mixed cell population with REED-STERNBERG (binucleate ‘owl’s’ eyes) * Lymphoma cells are relatively few in number and tend to be scattered around * Eosinophils

Answer 146

* Moderately aggressive

Answer 147

* CD30 * CD15

Answer 148

* Isolated lymphadenopathy

Answer 149

* B cell rich nodules * Scattered around L&H cells

Answer 150

Can transform to high grade B cell lymphoma (so it can transform into a non-Hodgkin lymphoma)

Answer 151

Classical Hodgkin's Lymphoma * Reed-Sternberg cell in bottom left

Answer 152

* GCSF given and obtain a CD34+ population of cells from the bone marrow * These are preserved in the freezer * A high dose of chemotherapy is given to eradicate the bone marrow → reinfuse the stem cells

Answer 153

* Acute leukaemia * Myeloma * Solid tumours * Lymphoma * Autoimmune disease * CLL

Answer 154

* High dose chemoradiotherapy is given to ablate the bone marrow * Bone marrow from a healthy donor is transplanted in

Answer 155

Used when patient's disease is unlikely to be eradicated from the bone marrow by standard chemotherapy * Acute leukaemia * Chronic leukaemia * Thalassaemia * Myeloma * Lymphoma * SCD * Bone marrow failure * Congenital immune deficiencies

Answer 156

* Serological = Low-resolution → A\*02 * DNA = High-resolution → A\*0201, A\*0202, A\*0203, …, A\*0260 * More likely to match at high resolution in a sibling match * Allele frequencies vary depending upon the ethnicity of the patient (for each allele – i.e. A\*0202)

Answer 157

1-(3/4)^{number of siblings}

Answer 158

* 1.5L, 1% CD34+ → 15mL CD34 * Puncturing the bone and getting into the medulla damages it, meaning that the first few millilitres that you collect will contain stem cells, however, the rest of it will be blood flooding into the damages site * So, you keep re-puncturing the bone, collecting a small amount at a time until you have a good harvest * Difficult → involves anaesthetising the patient and sampling some bone marrow from their pelvis

Answer 159

* 10L, 1% CD34+ → 100mL CD34 * Hormones (e.g. G-CSF) can be used to stimulate granulocyte production *(given 5 days before)* * Leads to the bone marrow releasing some white cells as well as some stem cells * The donor is connected to a centrifuge device which spins the blood, removes the white cell component, reassembles the red cells and plasma and reinfuses it into the patient

Answer 160

0. 1L, 1% CD34+ → 1mL CD34 * Stem cells can be harvested at the time of delivery

Answer 161

* Graft failure * Infections * Graft-versus-host disease - *allografting only* * Relapse

Answer 162

**EBMT** risk score: * **Age** = 20-40=1, \>40=2 * **Disease phase** = Int=1, Late=2 * **Gender of R/D** = Female into male = 1 * **Time to BMT** = \>1 yr = 1 * **Donor** = VUD = 1 * Overall success rate * 80% survival in 0-1 score * 70% survival in 2 score * 50% survival in 3 score * 30% survival in 4 score * 15% survival in 5-7 score

Answer 163

* This is ubiquitous → opportunistic infection * Only really affects severely immunocompromised * Invasive aspergillosis = high mortality * 10-15% deaths after SCT are due to aspergillosis → 92% mortality

Answer 164

* Member of the herpes family * Remains latent because T cells are able to keep it under control * CMV pneumonia is a large cause of deaths in HSCT

Answer 165

* Patient's serological status * Donor's serological status * Type of stem cells donor (monocytes) * Type of transplant * CMV viral load

Answer 166

An immune response when the donor cells recognise the patient as foreign.

Answer 167

* Acute → \<100 days * Skin - rash, itchy, red * GI tract - diarrhoea * Liver - hepatitis, jaundice * Chronic → \>100 days * Skin - rash * Liver - hepatitis, jaundice * Mucosal membranes - dry, mouth ulcers * Lungs - SoB * Eyes - dry * Joints - arthritis

Answer 168

* Degree of HLA disparity * Recipient age * Conditioning regimen * R/D gender combination *(D : M → R : F get worse GvHD)* * Stem cell source * Disease phase * Viral infections

Answer 169

* Corticosteroids * Cyclosporin A * FK506 * Mycophenolate mofetil * Monoclonal antibodies * Photopheresis * Total lymphoid irradiation

Answer 170

* Corticosteroids * Ciclosporin A + methotrexate * FK506 * T-cell depletion * Post-transplant cyclophosphamide

Answer 171

**CAR-T cells** → engineer autologous T cells

Answer 172

1. Leukapheresis - *T-cells are collected* 2. T-cell activation - *engineered chimeric-TCR put into a virus which infects the collected T-cells)* 3. Modified T-cell expansion - *new T cells are expanded* 4. Quality and release testing 5. Chemotherapy 6. Modified T-cell infusion

Answer 173

* Retains the more effective intracellular components of the TCR (CD28 and CD3 intracellular components) * Extracellular portions are engineered in * These extracellular portions recognise CD19

Answer 174

* **Tumour lysis syndrome** * **Cytokine release syndrome** * Potentially fatal – chimeric T-cells can release massive amounts of cytokines * **Neurologic toxicity** * **Cytopaenia** - *macrophage activation syndrome* * **B-cell aplasia** - *hypogammaglobulinaemia*

Answer 175

* Painless progressive lymphadenopathy * Palpable node * Extrinsic compression of any ‘tube’ * Infiltration/Impairment of organ function * Skin rash, liver failure etc * Recurrent infections * Constitutional symptoms * Coincidental

Answer 176

* Painless enlargement of lymph nodes → may cause obstructive symptoms/signs * Constitutional symptoms: * B symptoms * Fever * Night sweats * Weight loss * Rarely: pruritis, alcohol-induced pain

Answer 177

* F \> M (20-29yo) * Neck nodes and a mediastinal mass * May have B symptoms * Spreads contiguously * Needs tissue diagnosis

Answer 178

* Classical HL: * Nodular sclerosing - *80% → Good prognosis (causes the peak incidence in young women)* * Mixed cellularity - *17% → Good prognosis* * Lymphocyte rich - *rare → Good prognosis* * Lymphocyte depleted - *rare → Poor Prognosis* * Nodular Lymphocyte predominant HL - *5% → disorder of the elderly multiple recurrences*

Answer 179

* FDG-PET / CT scan * Biopsy * Diaphragm is key for staging

Answer 180

* 1^st line = **Chemotherapy = ABVD** (given at 4-weekly intervals) and **Radiotherapy** * Adriamycin * Bleomycin * Vinblastine * DTIC (Dacarbazine) * *Complications = Pulmonary fibrosis,* *Cardiomyopathy* * 2^nd line for relapse = **Salvage chemotherapy + high-dose chemotherapy + autologous HSCT** * 3^rd line for relapse = **Post-salvage** → anti-CD30 (Brentuximab Vedotin) + anti-PD1 (nivolumab)

Answer 181

* Risk of damage to normal tissues - collateral damage * Associated with increased risk of breast/lung/skin cancer, leukaemia/myelodysplasia * Combined modality carries the greatest risk (two mechanisms of DNA damage)

Answer 182

* Highly curable disease, but the prognosis depends on stage * Over 80% in stage I or II disease are cured * 50% of stage IV are cured * Curable: * Overall, 80% will be long-term survivors * 10% will die of relapse within 10 years * 10% will die from long-term treatment complications after 10 years → *after 5 years, patients are more likely to die of a secondary malignancy or cardiovascular complications*

Answer 183

* Painless lymphadenopathy * Compression symptoms * B symptoms * Fever * Night sweats * Weight loss

Answer 184

* Stage the disease * CT scan * PET scan * Bone marrow biopsy * Lumbar puncture (if risk of CNS involvement) * Prognostic markers and important tests * Prognosis * LDH (marker of cell turnover) * Performance status * Viral infections: * HIV serology → HIV may have predisposed to NHL * Hepatitis B serology (many patients are asymptomatic carriers of hepatitis B) * NHL patients may be given treatments that deplete B cells * This may cure the lymphoma, but the patient might then present with fulminant liver failure because you have reactivated any asymptomatic hepatitis B

Answer 185

* T-cell NHL seen in patients with Coeliac disease * Mature T cells * Involves the small intestines (jejunum and ileum) * Aggressive → quick clinical course but isn't responsive to treatment * Caused by chronic antigenic stimulation (gluten/gliadin)

Answer 186

* Abdominal pain * Obstruction * Perforation * GI bleeding * Malabsorption * Systemic symptoms

Answer 187

* Lymphocytosis (5-300 x 10⁹/L) * Smear cells - break when on slide * Normocytic normochromic anaemia * Thrombocytopaenia * Bone marrow lymphocytic replacement of normal marrow elements

Answer 188

* Normal Mature B Cells: * CD19 POSITIVE * CD5 NEGATIVE * Normal Mature T Cells: * CD3 positive * CD4 or CD8 positive * Th-cell * CTL cell * CD19 NEGATIVE * CD5 POSITIVE * In CLL, the B cells continue to express CD5 * This immunophenotyping assay shows a third population of lymphocytes co-expressing CD19 and CD5

Answer 189

* Supportive *(50% of CLL-related deaths due to infections)* * Vaccination (flu, pneumococcus) – no live vaccines (i.e. VZV) * Anti-infective prophylaxis and treatment * (2) Specific Scenarios * High-Grade (Richter) Transformation → treat as high grade lymphoma (R-CHOP) * Leukaemia-directed Treatment * FCR or R-Bendamustine * Fludarabine * Cyclophosphamide * Rituximab (anti CD20 moab) * Obinutuzumab (anti CD20) + Chlorambucil

Answer 190

* Progressive lymphocytosis (count doubling \< 6 months) * Progressive bone marrow failure (Hb \< 100; Platelets \< 100; Neutrophils \< 1) * Massive or progressive lymphadenopathy/splenomegaly * Systemic symptoms (B symptoms)

Answer 191

Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukaemia

Answer 192

IgG antibodies which do not cause direct agglutination of RBCs → cause a delayed haemolytic transfusion reaction – *i.e. not an immediate haemolysis*

Answer 193

* Pregnancy * Anti-D made by an Rh -ve mother exposed to Rh +ve blood * Haemolytic disease of the newborn * Severe fetal anaemia and heart-failure (hydrops fetalis)

Answer 194

* **Column Agglutination Technology:** use known anti-A, anti-B and anti-D reagents against the **patient's RBCs** * **Reverse group:** known A and B groups red blood cells are mixed with the **patient's plasma** (IgM antibodies) * This group acts as an internal control – if it does not match, this is an anomalous result * New-borns often have a weak reverse group as their ABs have not developed fully yet

Answer 195

* A positive result causes agglutination at the top * A negative result will mean that the red cells stay suspended at the bottom of the vial

Answer 196

* Uses 2 or 3 reagent RBCs containing all important RBC antigens between them * Incubate patient’s plasma and screening cells using the Indirect Antiglobulin Technique (IAT) * Patient serum containing specific antibody added to reagent RBCs → * Add Anti-Human Globulin (AHG) to promote agglutination → * If +ve, reaction creates bridges between RBCs coated in IgG antibodies → visible clumps

Answer 197

Avoid a delayed transfusion reaction with IgG antibodies

Answer 198

* ABO and RhD-type - *always select correct type* * Kell - *select K -ve in females of child-bearing age* * Other Rh antigens - *patient-dependant selection*

Answer 199

* **Full Crossmatch** (uses IAT): * Patient's plasma is incubated with donor red cells at 37 degrees for 30-40 mins * Detects antibody-antigen reaction that destroys the RBCs leading to extravascular haemolysis * Add antiglobulin reagent to cause cross-linking * IgG antibodies bind to RBCs but do not crosslinking * **Immediate Spin** (EMERGENCY Only): * Incubate patient’s plasma and donor red cells for 5 minutes only and spin * Will only detect ABO incompatibility * IgM anti-A and/or anti-B bind to RBCs, fix complement and lyse the cell

Answer 200

* Compatibility is determined by an IT system without physical testing of donor cells against plasma * This is a quick process, requiring fewer staff which allows better stock management

Answer 201

* Serological * Full cross-match * Immediate Spin - *emergency only* * Electronic

Answer 202

* RBCs = 4° for 35 days * Platelets = 22° for 7 days * Plasma = Frozen * Cryorecipitate = Frozen

Answer 203

* RBCs = 2-3 hrs * Platelets = 20-30 mins * Plasma = 20-30 mins * Cryorecipitate = 20-30 mins

Answer 204

* Major blood loss - *\>30% of blood volume* * Peri-op or Critical care - *Hb \<70g/L* * Post-chemo - *Hb \<80g/L* * Symptomatic anaemia * *IHD* * *Breathless* * *ECG changes*

Answer 205

* **Pre-operative autologous deposit** * Patient's own blood is donated before a planned operation * *Not done in the UK* * **Intra-operative cell salvage** * Blood is collected during surgery * It is then centrifuged, filtered and washed before being reinfused * **Post-operative cell salvage** * Collect blood that is lost post-operatively into a wound drain * This is filtered and re-infused * Mainly done for orthopaedic operations * *NOTE: all the coagulation factors and platelets are removed from cell salvage blood* * Cell salvage is useful in people with rare blood groups and Jehovah's witnesses

Answer 206

* Rare blood groups * Jehovah's witnesses

Answer 207

* Pregnancy * Required for intra-uterine and neonatal transfusions * Also used for elective transfusion in pregnant women

Answer 208

* Highly immunosuppressed patients * Patients cannot destroy incoming donor lymphocytes * Presence of these lymphocytes → fatal transfusion-associated graft-versus-host disease (TA-GvHD)

Answer 209

* IgA-deficient patients * RBCs/platelets given to patients who had severe allergic reactions to some donors' plasma proteins * This takes 4 hours to happen so needs to be pre-planned

Answer 210

* Massive transfusion * Prevent bleeding post-chemo = \<10x10⁹/L * Prevent bleeding in surgery = 50x10⁹/L (100 if at critical site - eye, CNS etc) * Platelet dysfunction or immune cause - only if active bleeding

Answer 211

* 100g/L * 10g/L

Answer 212

* Heparin-induced thrombocytopaenia and thrombosis * Thrombotic thrombocytopenic purpura (TTP)

Answer 213

* 30-40 x 10⁹/L

Answer 214

* Massive transfusion - Blood loss \>150ml/min * DIC with bleeding * Liver disease + Risk - PT ratio \>1.5x normal * Coagulation factor replacement where factor concentrate isn't available

Answer 215

* All clotting factors

Answer 216

* Adult dose = 15 mL/kg * 1 unit of FFP contains 250 mL → enough for 16.6kg * 75kg (or so) = 5 doses needed

Answer 217

**Reverse warfarin** * Better treatment is PCC (prothrombin complex concentrate) * Contains factors 2, 7, 9 and 10

Answer 218

\<24hrs from transfusion * Acute haemolytic (ABO incompatible) * Allergic/anaphylaxis * Infection (bacterial) * Febrile non-haemolytic * Respiratory * Transfusion associated circulatory overload (TACO) - *most common* * Acute lung injury (TRALI)

Answer 219

\>24hrs from transfusion * Delayed haemolytic transfusion reaction (antibodies) - *Duffy and Kidd* * Infection (viral, malaria, vCJD) * TA-GvHD (week or 2 after transfusion) * Post transfusion purpura * Iron overload

Answer 220

* 1st signs (potentially, before the patient experiences any symptoms): * Increased temperature or pulse * Decreased BP * Monitoring may be the only way to detect a reaction if the patient is unconscious * Baseline temperature, pulse, RR, BP before transfusion * 0m → 15m → 1hr → 1hr… → end - most reactions start within 15 mins * Repeat hourly and at the end of the transfusion * Monitor for general symptoms * Fever * Rigors * Flushing * Vomiting * Dyspnoea * Pain at transfusion site * Loin pain/chest pain * Urticaria * Itching * Headache * Collapse

Answer 221

* *Mild/Moderate* * Occurs during/soon after transfusion → blood or platelets * May cause a rise in temperature by around 1 degree * Patient may have chills and rigors * Common before blood was leucodepleted * Caused by the release of cytokines from white cells during storage

Answer 222

* Transfusion stopped or slowed * May need paracetamol

Answer 223

* *Mild/Moderate* * Common, especially with plasma - proteins in plasma * Causes a mild urticarial or itchy rash sometimes with a wheeze * Caused by allergy to donor plasma proteins * Recipients have a history of atopy * Can occur during or after transfusion

Answer 224

* Stopping/slowing of transfusion if still ongoing * IV antihistamines

Answer 225

* Severe/Fatal * Symptoms and signs of acute intravascular haemolysis (IgM-mediated) * General * Restless * Chest/loin pain * Fever * Vomiting * Flushing * Collapse * Haemoglobinuria (later) * Monitoring * Low BP * High HR * High Temperature

Answer 226

* **Failure of bedside check/Human error** - *By far the most common* * Wrongly labelled blood sample * Laboratory error

Answer 227

* FBC * Biochemistry * Coagulation * Repeat X-match * Direct antiglobulin test (DAT)

Answer 228

* *Severe/Fatal* * General * Restless * Fever * Vomiting * Flushing * Collapse * Monitoring * Low BP * High HR * High Temperature

Answer 229

* **From the donor** → e.g. from low grade GI, dental or skin infection * **Introduced during processing** → environmental or skin

Answer 230

**Platelets** (stored at room temperature) \> RBCs \> FFP

Answer 231

* Donor questioning + Arm cleaning + Diversion of first 20 mL into a pouch for testing * Red Blood Cells * Store in a controlled fridge at 4 degrees * Shelf-life: 35 days * If it is kept out for \>30 mins it needs to go back in the fridge for 6 hours * Complete transfusion should take place within 4 hours of leaving the fridge * Platelets: * Stored at 22 degrees * Shelf-life: 7 days * Screened for bacteria before release * Transfused over 20-30 mins

Answer 232

* *Severe/Fatal* * Soon after the start of transfusion * Shock = Drop in BP + Rise in HR * Very breathless with wheeze * Often laryngeal and/or facial oedema

Answer 233

* **Mechanism = IgE antibodies** in the patient cause mast cell degranulation * Most allergic reactions are not severe, but some can be in the case of IgA deficiency * IgA deficiency = 1: 600 * In 25% of these, anti-IgA antibodies develop in response to exposure to IgA in the donor blood * Only a minority go on to have a severe transfusion reaction

Answer 234

* Pulmonary oedema/fluid overload as a consequence of transfusion * Often caused by lack of attention to fluid balance * More common in * Cardiac failure * Renal impairment * Hypoalbuminaemia * Extremities of age

Answer 235

* *Severe/Fatal* * SoB * Low O2 saturations * High HR * High BP * CXR * Fluid overloaded * Cardiac failure

Answer 236

* Diuretics - TRALI does NOT respond to diuretics * Reduced fluid intake * Carefully urine monitoring

Answer 237

* Anti-WBC antibodies in donor blood * These interact with WBCs in the patient * Aggregates WBCs stick to pulmonary capillaries → release neutrophil proteolytic enzymes and toxic O2 metabolites → lung damage

Answer 238

* Looks at bit like ARDS - more common in FFP or platelet transfusion * Clinical features: * SoB * Low O2 saturations * Fever * High HR * High BP * No clinical fluid overload

Answer 239

* Use male donors for plasma and platelets who haven't had transfusions * No pregnancy or previous transfusions → no HLA/HNA Abs

Answer 240

* 1-3% of all patients transfused will **develop an antibody against and RBC antigen** that they lack = **alloimmunisation** * Further transfusions with RBCs expressing same antigens → antibodies will lyse RBCs → **extravascular haemolysis** * This is IgG-mediated so takes 5-10 days

Answer 241

* Haemolysis Tests: * High bilirubin * Low Hb * High reticulocytes * Haemoglobinuria over a few days * U&Es = can cause renal failure * Repeat the group and screen → look for new antibodies

Answer 242

* Causes temporary red cell aplasia – *so affects those with RBCs of a shortened life span* * Affects foetuses and patients with haemolytic anaemias - *e.g. sickle cell, hereditary spherocytosis*

Answer 243

1. Donor's blood will contain some lymphocytes that are able to divide 2. Normally, the patient's immune system will recognises these donor lymphocytes as foreign and destroy them 3. In susceptible/very immunosuppressed patients these lymphocytes are NOT destroyed 4. Lymphocytes recognise patient's tissue HLA antigens as foreign and attack → gut, liver, skin and bone marrow

Answer 244

* **ALWAYS FATAL** – can take weeks to months post transfusion * Diarrhoea * Liver failure * Skin desquamation * Bone marrow failure

Answer 245

* Irradiation of blood components for very immunocompromised patients OR * HLA-matched components

Answer 246

* Appears 7-10 days after transfusion of blood or platelets * Usually resolves in 1-4 weeks but can cause life-threatening bleeding * Affects Human Platelet Antigen (HPA) 1a -ve patients previously immunised via pregnancy or transfusion (HPA-1a AB) * Treatment: IVIG

Answer 247

* Possible increased rate of infections post-operatively and increased recurrence of cancer in patients who have blood transfusions * Evidence is conflicting

Answer 248

* If someone has lots of transfusions (thalassaemia patients/sickle cell) iron will accumulate in their body * There is about 200-250 mg of iron per unit of blood * This can damage the liver, heart and endocrine organs * Requires chelation

Answer 249

* People lacking an RBC antigen (RhD) can form corresponding antibodies if exposed to the antigen * This can happen: * By receiving blood transfusions * In pregnancy → foetal red cells enter the mother's circulation during pregnancy or at delivery 1. The first RhD-positive foetus will not experience any issues, however, they will stimulate the development of anti-D antibodies in the mother 2. In a subsequent pregnancy, if the mother has another RhD-positive foetus, the antibodies will destroy foetal red cells leading to severe anaemia ± HDN

Answer 250

* High WCC * High neutrophils * High lymphocytes * High Hb * High MCV * Higher percentage of HbF * 50% the G6PD concentration of an adult

Answer 251

* Twin-to-twin transfusion * Intrauterine hypoxia * Placental insufficiency

Answer 252

* Twin-to-twin * Foetal-to-maternal transfusion (rare) * Parvovirus infection * Haemorrhage from cord or placenta

Answer 253

* The first mutation that subsequently leads to childhood leukaemia often occurs in utero * Pre-leukaemic cells carrying this mutation can even spread to a twin * Congenital leukaemia is particularly common in Down syndrome = Transient Abnormal Myelopoiesis (TAM) * This is different from leukaemia in older children * Disease tends to remit spontaneously within the first 2 months of life → tends to relapse 1-2 years later in 25% * Capacity for spontaneous remission is similar to neuroblastoma

Answer 254

Defects in the globin chain * Thalassaemia = reduced rate of synthesis of ≥1 globin chain as a result of a genetic defect * Haemoglobinopathy = structurally abnormal Hb - *some think thalassemia a form of haemoglobinopathy*

Answer 255

**Chromosome 11** and **Chromosome 16** * Chromosome 11 (beta cluster) = deletion of LCRB → reduced downstream globin expression * Beta, delta, gamma gene * Epsilon is an embryonic globin gene * Chromosome 16 (alpha cluster) * Alpha 1 and alpha 2 gene * HbA2 = \<3.5% of total adult Hb * Zeta is an embryonic globin gene

Answer 256

* Specific foetal haemoglobins are present in the first 16 weeks - HbF predominates * After around 32 weeks you get a rapid increase in HbA production * At birth → 1/3rd of haemoglobin is HbA → rapidly increases after birth

Answer 257

1. Hypoxia → polymerisation of haemoglobin S → crescent shaped RBCs and blocked blood vessels (occurs in **post-capillary venules -** reversible if the hypoxic state is resolved) 2. If circulation slows, cells sickle and become adherent to the endothelium which causes obstruction 3. Retrograde capillary obstruction → **arterial obstruction**

Answer 258

* bb = Normal * bb^S / AS = Sickle cell trait (not SCD) → *totally asymptomatic* * b^Sb^S / SS = Sickle cell anaemia * b^Sb^C / SC = Sickle cell / haemoglobin C → *milder than HbSS* * b^Sb^Thal = Sickle cell / beta thalassaemia * bb^Thal = Beta thalassaemia

Answer 259

* Depends on whether it is a: * **Beta-0 gene** (no beta globin production) * **Beta+ gene** (a little bit of beta globin production)

Answer 260

* 3-6 months of age * Gamma chain production and HbF synthesis decreases * HbS production increases

Answer 261

* UK = birth → Guthrie spot test * Antenatal screening is based on risk → Family Origins Questionnaire * Neonate diagnosis allows prevention and anticipation of some of the complications

Answer 262

* Red bone marrow: * Adult haematopoietic BM = restricted to axial skeleton * Child haematopoietic BM = axial skeleton + extends to bones of hands and feet * **Hand-foot syndrome** – from infarction * Developing RBCs and white cell need vascular, glucose and requires an oxygen supply = susceptible to infarction * Different spleen types: * Adult / older-child spleen – spleen is small and fibrotic from recurrent infarction * Suffer from sequalae of hyposplenism (i.e. pneumococcal infection) * Child spleen – still has a functioning spleen * **Splenic sequestration** → acute pooling of a large % of circulating RBCs in spleen (**Splenomegaly**) → severe anaemia, shock and death * Parents should be taught how to palpate the spleen and to seek medical attention if needed * Blood transfusion required * **Acute chest syndrome** * **Painful crisis** * **Stroke -** most common cause of stroke in childhood * **Bacteraemia** * **Parvovrius**

Answer 263

* **Increased folic acid** demands due to: * Hyperplastic erythropoiesis * Growth spurts - *have an additive effect* * Red cell lifespan is shorted so anaemia can rapidly worsen

Answer 264

* **Educate parents** – splenomegaly, pale pallor, breathlessness, fever * **Vaccinate** * **Folic acid** * **Penicillin**

Answer 265

Hyposplenism

Answer 266

Parvovirus B19 infection

Answer 267

Condition resulting from reduced synthesis of beta globin chain - and so, HbA * No HbA = major * Some HbA = intermedia

Answer 268

* **3-6m** of life because of decline of synthesis of HbF and the increased production of HbA * Can be suspected at birth through the Guthrie spot test

Answer 269

* bb = Normal * b^thalb = trait - *harmless but genetically important* * b^thalb^thal = major - *severe anaemia → fatal without transfusions* * b^thalb^thal = intermediate - *‘+’ forms of beta (instead of ‘0’)*

Answer 270

* Anaemia * Heart failure * Growth retardation * Erythropoietic drive * Bone expansion * Hepatomegaly * Splenomegaly * Iron overload * Heart failure * Gonadal failure

Answer 271

* **Accurate diagnosis** * **Family counselling** * **Blood transfusion ± Iron chelation** *(desferrioxamine, deferiprone)*

Answer 272

* Red cell membrane - *hereditary spherocytosis/eliptocytosis* * Haemoglobin molecule - *sickle cell anaemia* * Glycolytic pathway enzymes (rare) - *pyruvate kinase deficiency* * Pentose-phosphate shunt - *G6PD deficiency* * G6PDD = X-linked (recessive) → more common in males

Answer 273

* **Autoimmune haemolytic anaemia** * Spherocytosis * Positive DAT (Coombs' test) * **Haemolytic uraemic syndrome:** * Haemolysis * Uraemia

Answer 274

* Infections * Drugs * Naphthalene – moth balls (banned in EU) * Fava beans (broad beans)

Answer 275

* Red cells are damaged in capillaries forming small angular fragments and micro-spherocytes

Answer 276

* Bleeding following circumcision * Haemarthroses when starting to walk * Bruises * Post-traumatic bleeding * Family history

Answer 277

* Inherited thrombocytopaenia or platelet functional defect * Acquired defects of coagulation (e.g. ITP, acute leukaemia) * Non-accidental injury * Henoch-Schönlein purpura

Answer 278

* Platelet count = normal * aPTT = prolonged * PT = normal * Bleeding time = normal

Answer 279

* Treatment of bleeding episodes * Use of prophylactic coagulation factors * Counselling the family

Answer 280

Biologically heterogenous group of acquired haematopoietic stem cell disorders.

Answer 281

* Development of a clone of marrow stem cells with abnormal maturation resulting in: * Functionally defective blood cells * Numerical reduction * Leads on to: * Cytopaenia * Functional abnormalities of erythroid, myeloid and megakaryocyte maturation * Increased risk of transformation to leukaemia

Answer 282

* Elderly * Signs of BM failure developing over weeks-months * Weight loss * Fatigue * Infections * Bleeding

Answer 283

* **Pelger-Huet** - bilobed neutrophils * **Dysgranulopoiesis of neutrophils** - low granule number * **Dyserythropoiesis of red cells** * Lack of separation between red cell precursors → abnormal ring of cytoplasm around the nucleus * **Dysplastic megakaryocytes** * **Increased proportion of blast cells in marrow** - normal \< 5% * **Ringed sideroblasts** - iron granules in red cell precursors

Answer 284

**Dyserythropoiesis** → abnormal ring of cytoplasm around nucleus due to lack of red cell precursor seperation

Answer 285

Myeloblasts + Auer rods → classical in AML

Answer 286

**Myelokathexis →** fragmented neutrophil nucleus

Answer 287

Normal neutrophil

Answer 288

**Pelger-Heut** → bilobed neutrophil (MDS)

Answer 289

**Ringed sideroblasts →** iron granules in red cell precursors / ineffective erythropoiesis

Answer 290

* **1. Deterioration of blood count** * Worsening consequences of marrow failure * **2. Development of acute myeloid leukaemia (AML)** * Develops in 5-50% \<1 year (depends on subtype) * Some cases of MDS are much slower to evolve * AML from MDS has an extremely poor prognosis and is usually not curable * **3. Death** * 1/3 die from infection * 1/3 die from bleeding * 1/3 die from acute leukaemia

Answer 291

* Treatments to prolong survival - only benefit a small minority → that vast majority of which are young: * Allogenic Stem Cell Transplant (A-SCT) * Intensive chemotherapy * **Supportive care** * Blood products * Antimicrobial therapy * Growth factors (EPO, G-CSF) * **Biological modifiers** * Immunosuppressive therapy * Hypomethylating agents (Azacytidine, Decitabine) * Lenalidomide – in del(5q) variant * **Chemotherapy** * Oral = hydroxyurea * Low dose = SC low dose cytarabine

Answer 292

**(c) One third of MDS patients can be expected to die from leukaemic transformation**

Answer 293

All blood cell types - pluripotent HSC is affected

Answer 294

* Primary * **Congenital**: Fanconi’s anaemia (multipotent stem cell), Dyskeratosis congenita * **Acquired**: Idiopathic aplastic anaemia (multipotent stem cell) → VAST MAJORITY (70-80%) * **Diamond-Blackfan anaemia** (red cell progenitors) * **Kostmann’s syndrome** (a form of SCID; neutrophil progenitors) * Secondary * Marrow infiltration * Leukaemia / Lymphoma / Myelofibrosis * Non-haematological / Solid tumours * Radiation * Drugs * Cytotoxic drugs * Phenylbutazone * Gold salts * Chloramphenicol * Sulphonamide * Thiazides * * Carbimazole * Chemicals (benzene) * Autoimmune * Infection (Parvovirus, Viral hepatitis)

Answer 295

* Failure of BM to produce blood cells because of: * “Stem cell” problem - CD34, LTC-IC (long-term culture-initiating cells) * Immune attack - humoral or T cell attack against multipotent haematopoietic stem cell

Answer 296

* Classic triad of BM failure: * **Anaemia** – fatigue, breathlessness * **Leucopaenia** – infections * **Thrombocytopaenia** – bleeding/bruising * Bimodal age distribution – 15-25 and \>60

Answer 297

* Peripheral blood → cytopaenia * Bone marrow → hypocellular + fat

Answer 298

**Camitta criteria** → 2 out of 3 peripheral blood features + Bone marrow of \<25% cellularity * Reticulocytes = \< 1% (\<20 x 10⁹/L) * Neutrophils = \< 0.5 x 10⁹/L * Platelets = \< 20 x 10⁹/L

Answer 299

* Hypoplastic MDS/AML * Hypocellular ALL * Hairy cell leukaemia * Mycobacterial (usually atypical) infection * Anorexia nervosa * Idiopathic thrombocytopenic purpura (ITP) * *Unlikely to confuse aplastic anaemia with ITP* * *ITP = normal Hb and RBC*

Answer 300

* **Seek and remove a cause** - *requires a detailed drug and occupational exposure history* * Supportive: * **Blood/platelet transfusions** * **Antibiotics** * **Iron chelation therapy** * **Immunosuppressive therapy** - *anti-thymocyte globulin, steroids, Eltrombopag, cyclosporine A* * Tend to be used in older patients * Late complications following immunosuppressive therapy for AA * Relapse - 35% over 15 years * Blood disorders - 20% risk over 10 years * Solid tumours - 3% risk * **Drugs for marrow recovery** (androgens (oxymetholone), thrombopoietin receptor agonists (Eltrombopag)) * **Stem cell transplantation** * Young (\<40yo) + Sibling donor → 80% cure rate * Other treatments in refractory cases (e.g. alemtuzumab)

Answer 301

* Severity of illness * Age of patient * Stem cell transplantation tends to be used in younger patients (80% cure rate if a sibling donor) * Immunosuppressive therapy used in older patients (e.g. anti-lymphocyte globulin, ciclosporin) * Potential sibling donor * Androgens (oxymetholone) can also promote bone marrow recovery

Answer 302

**Cure rate of AA treated by sibling related allogeneic SCT in a patient under 40 years old is \> 70% → is around 80%**

Answer 303

* **Most common** form of inherited aplastic anaemia * Autosomal recessive or X-linked * Heterozygote frequency = 1:300 * Multiple mutated genes are involved which result in: * Abnormalities in DNA repair * Chromosomal fragility * Genes responsible → act through a final common pathway involved with DNA repair mechanisms: * FA-A * -B * -C * -D

Answer 304

* 60-70% * Short Stature * Hypopigmented spots and café-au-lait spots * Abnormality of thumbs * Microcephaly or hydrocephaly * Hypogonadism * Developmental delay * 30-40% * No abnormalities

Answer 305

* An inherited disorder characterised by * Marrow failure * Cancer predisposition * Somatic abnormalities * Leukoplakia * Nail dystrophy * Skin pigmentation

Answer 306

* Leukoplakia * Nail dystrophy * Skin pigmentation

Answer 307

* Fanconi anaemia * Dyskeratosis congenita

Answer 308

**Telomere shortening** * 3 patterns of inheritance * X-linked recessive = most common * *Mutant DKC1 gene leads to defective telomere functioning* * Autosomal dominant * *Mutant TERC gene encodes the RNA component of telomerase* * Autosomal recessive * *Mutant gene has NOT been identified*

Answer 309

* Dyskeratosis congenita * Idiopathic

Answer 310

(a) Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita

Answer 311

* **Mild anaemia** * Red cell mass rises (120-130%) * Plasma volume rises (150%) * *Both due to net dilution* * **Macrocytosis** * Normal * Folate or B12 deficiency * **Neutrophilia** * **Thrombocytopenia** * Increased platelet size from increase in turnover of platelets

Answer 312

* *300mg (foetus); 500mg (maternal RBC mass)* * Required Daily Average = 30mg * Increase in daily iron absorption 1-2mg to 6mg * Iron deficiency → IUGR, prematurity, PPH

Answer 313

* Folate requirement increase = +*200mcg/day* * Growth and cell division

Answer 314

* **WHO = 60mg iron** and **400ug folic acid daily** * **RCOG = 400ug folic acid** (and _no_ iron) * Supplement before conception and for more than 12-weeks’ gestation * High-dose folic acid = 5mg / 5000ug folic acid

Answer 315

* \<110 g/l in 1^st trimester * \<105 in 2^nd and 3^rd trimester * \<100 g/l postpartum

Answer 316

* Physiological / Gestational * Pre-eclampsia → HELLP – *Haemolysis, Elevated Liver enzymes, Low Platelets* * Immune thrombocytopenia (ITP) – *BM creates lots of platelets but there is peripheral destruction* * MAHA syndromes – *TTP, anti-phospholipid* * All other causes – *BM failure, hypersplenism, DIC, leukaemia*

Answer 317

Lower platelets = more likely it is pathological * \>70 x 109/L = gestational thrombocytopenia * \<70 x 109/L = Pre-eclampsia / HELLP or ITP

Answer 318

Physiological decrease in platelets affecting around 10% * Mechanism is poorly defined (dilution and increased consumption potentially) * Baby is not affected * Platelet count **rises 2-5 days post-delivery**

Answer 319

* \>50x10⁹/L = delivery * \>70x10⁹/L = epidural

Answer 320

* 50% get thrombocytopenia (proportionate to severity) → some of these suffer from HELLP * Association with increased activation and consumption - incipient DIC (normal PT, APTT) * Platelet count remits following delivery

Answer 321

Unpredictable → platelets \<20 in 5% * Avoid ventose and forceps if baby platelet count is unknown / low * Check cord blood and then daily → may fall for 5 days after delivery * Bleeding in 25% of severely affected – IVIG if low * Usually normal delivery

Answer 322

* TTP * HUS * AFLP * SLE * APLS

Answer 323

**Fragmentation (shistocytes) and Destruction of RBC within vasculature** * Thrombocytopenia, schistocytes * Organ damage – kidney, CNS, placenta (in pregnancy)

Answer 324

* MAHA * Fever * Renal impairment * Neurological impairment * Thrombocytopenia

Answer 325

* Pro-thrombotic * Factor 8 and VWF = Increases 3-5x * Fibrinogen = Increases 2x * Factor 7 and 10 = Increases 0.5x * Less fibrinolysis * Protein S = Falls to half basal * PAI-1 (plasminogen activator inhibitor) = Increases 5x * PAI-2 = Produced by placenta

Answer 326

* Procoagulant state * Increased thrombin generation * Increased fibrin cleavage * Reduced fibrinolysis * Interact with other maternal factors

Answer 327

* Biggest maternal killer in UK * Highest risk time = **post-partum and 1^st trimester** * High BMI is the largest predictor of incidence of PE * High risk patients need to be on heparin from the first trimester

Answer 328

* **Doppler and V/Q** * D-dimer is elevated in pregnancy → not useful for exclusion of thrombosis

Answer 329

* **All patients = Virchow’s triad** * **Changes in blood coagulation** * **Reduced venous return** → 85-95% in left leg * **Vessel wall** * Variable numbers of patients: * Hyperemesis or dehydration * Bed rest * BMI \>29 = 3x risk of PE * Pre-eclampsia * Operative/emergency delivery * Previous thrombosis or thrombophilia * Age (increases dramatically over 35) * Multiparity (\>4 = increased risk) * Multiple pregnancy * PMHx – HbSS, nephrotic syndrome

Answer 330

* Prevention: * Women with RFs = prophylactic heparin and TED stockings * Mobilise early * Maintain hydration * Treatment: * **LMWH** (OD or BD) - does not cross placenta * No Warfarin - DOES CROSS PLACENTA (teratogenic), avoid weeks 6-12 * After 1st trimester monitor anti-Xa * Stop medications for labour or planned delivery * Especially if a women wishes for an epidural * Wait 24 hours after treatment dose * 12 hours after prophylactic dose

Answer 331

**≥3 Miscarriages** + **lupus anticoagulant** or **anticardiolipin antibodies** * Adverse pregnancy outcomes → 3+ consecutive miscarriages before 10 weeks of gestation * 1 or more morphologically normal foetal losses after 10w of gestation * 1 or more preterm birth before 34-weeks of gestation * Treatment = unfractionated **heparin** and **aspirin** * Dramatically improved outcomes

Answer 332

* May or may not be associated with pregnancy complications * RCTs fail to demonstrate improvement in pregnancy outcome in unselected women with idiopathic recurrent pregnancy loss

Answer 333

* \>500ml blood loss (SVD) * 5% pregnancies have blood loss more than 1L * Requiring transfusion post-partum * 1% after vaginal delivery * 1-7% after C-section

Answer 334

* Major factors * **Uterine atony** * Trauma * Tissue * Thrombin * Haematological factors minor except * Dilutional coagulopathy after resuscitation * DIC in abruption, amniotic fluid embolism

Answer 335

* **Amniotic fluid embolism** * **Pre-eclampsia (severe/HELLP)** * Placental abruption * Sepsis * Retained dead foetus

Answer 336

S/S's = sudden onset shivers, vomiting, shock, DIC * Presumed due to tissue factor in amniotic fluid entering maternal bloodstream * Almost all 25yo+ * Usually in the 3^rd trimester * Drugs used to induce labour – misoprostol increase risk * Most **catastrophic event** in obstetrics * 86% mortality * 1 in 20,000-30,000 births

Answer 337

* Thalassaemia * Sickle cell disease

Answer 338

Avoid /counselling parents about birth of children with: * **Alpha 0 thalassaemia** / **Hb Barts** (4 gamma chains) - *death in utero, hydrops fetalis* * **Beta 0 thalassemia** - *transfusion dependent* * HbSS / **SCD** - *life expectancy 43yo* * Other compound HbS syndromes - *symptomatic, stroke* * Some compound thalassaemia’s - *transfusion dependent, iron overload*

Answer 339

* All disorders are recessive * **If mother is heterozygous = Partner tested** * Combinations important as homozygous states * Options: * Proceed * Prenatal dx * CVS sampling (10-12 weeks) * Amniocentesis (15-17 weeks) * cffDNA testing (NEW) * US screening for hydrops

Answer 340

Platelet count may fall following delivery in babies born to mothers with ITP

Answer 341

Improved targeted thromboprophylaxis

Answer 342

Uterine atony is a common cause of post-partum haemorrhage