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Medicine Year 3 > Week 4 - Haematology > Flashcards

Week 4 - Haematology Flashcards

1
Q

Describe the action of hydroxycarbamide in the treatment of essential thrombocytopenia

A

Gentle chemotherapy, ribonucleotide reductase inhibitor resulting in reduced production of deoxyribonucleotides, affects all blood cell lines

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2
Q

Describe the pharmacological characteristics of warfarin

A
  • Oral vitamin K antagonist (taken once daily)
    • Failure of gamma-carboxylation of Glu residues –> dysfunction of factors II, VII, IX and X
  • Delayed onset and offset
  • Effective half life approx. 36 hours
  • High inter-individual variability
  • Narrow therapeutic window
  • May drug and food interactions
  • Requires regular INR monitoring
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3
Q

What protein is produced by abnormal plasma cells in plasma cell myeloma?

A
  • In most myeloma patients, abnormal plasma cells produce an abnormal ‘monoclonal protein’ called a paraprotein or ‘M’ protein
    • 5 different types (IgG, A, M, D, E - G and A most common)
    • IgE very rare
    • IgM myeloma does exist but rare - more commonly associated with lymphoma e.g. Waldenstroms macroglobulinaemia
  • Sometimes only part of the Ig molecule is produced - ‘light chain myeloma’, hard to detect (present with renal impairment)
  • Rarely no Ig produced - ‘non-secretory myeloma’
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4
Q

What are the aims of management of acquired warm type haemolytic anaemia?

A

Primary duty of haematologist is to halt the haemolytic process and thereafter to exclude any possible underlying causes

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5
Q

Describe the mechanism of action of tPA derivatives

A
  • Alteplase, Tenecteplase, Reteplase
    • Activates plasminogen
    • Plasmin cleaved from plasminogen
      • Plasmin breaks down fibrin
    • Relatively selective for clot bound plasminogen
    • Minimal unwanted fibrinogenolysis
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6
Q

Describe the survival rates of ALL

A

5 year survival rate for children - 90%

5 year survival rate for adults - 40%

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7
Q

What are the indications for anti-platelet drugs?

A

Cardiovascular disease

  • Acute MI
    • Aspirin indefinitely
    • Ticagrelor/clopidogrel for up to 12 months
    • +/- tirofiban acutely
  • Secondary prevention CVD
    • Aspirin

Cerebrovascular disease (without AF)

  • Acute stroke/TIA/secondary prevention
    • Clopidogrel
    • Dipyridamole + aspirin if clopidogrel not tolerated

Peripheral vascular disease

  • Clopidogrel
  • Aspirin if clopidogrel not well tolerated
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8
Q

List the causes of warm type autoimmune haemolytic anaemia

A
  • 55-60% of cases idiopathic/primary
  • Secondary causes include
    • Lymphoproliferative disorders e.g. chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma
    • Other neoplasms
    • SLE (systemic lupus erythematosus) or other connective tissue disorders
    • Drugs
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9
Q

How is acute myeloid leukaemia managed?

A
  • Intensive chemotherapy +/- stem cell transplant
    • For patients <60-65
    • 5 year survival approx. 50%
  • Low dose chemotherapy
    • Patients >60-65
    • 5 year survival approx <10%
  • Supportive care only
    • Older patients only, major comorbidities
    • Median survival 3-6 months
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10
Q

What is required for blood coagulation?

A
  • Functioning platelets
  • Functioning endothelium
  • Coagulation factors
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11
Q

Define thrombocytosis

A

Too many platelets

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12
Q

How is myeloma treated?

A
  • Asymptomatic myeloma (smoldering) - watch and wait
  • Symptomatic myeloma (determined by CRAB criteria) - requires treatment
    • All patients receive chemotherapy usually including a steroid and thalidomide
    • Radiotherapy - e.g. severe bone pain
    • Supportive therapy
      • Bisphosphonates - reduce pain, pathological fractures, hypercalcaemia and need for radiotherapy
      • Blood transfusion/EPO
      • Surgery
      • Interventional radiology
  • Autologous transplant (younger, fitter patients) versus no transplant
    • Can receive transplant up to 70 y/o
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13
Q

How has the prognosis of chronic myeloid leukaemia been improved?

A

Prognosis improved by introduction of Imatinib - blocks transformation of BCR-ABL gene and so pathways which cause unregulated proliferation

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14
Q

How is Fanconi’s anaemia treated?

A
  • Gold standard therapy is allogenic stem cells transplant - related donors need to be screened for FA
  • Improve blood cell count - supportive care, corticosteroids, androgens (oxymethalone)
  • Lifetime surveillance for secondary tumours
  • Possibility of gene therapy in future where faulty FANC gene is replaced
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15
Q

Where is red bone marrow found?

A

Mainly in the inner mass of flat bones e.g. pelvis, sternum, skull, ribs, vertebrae and scapulae, also the spongey matrix at the proximal ends of the femur and humerus

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16
Q

When is streptokinase ineffective?

A
  • Derived from streptococci bacteria
  • Antigenic
    • Recent step infection/previous use of streptokinase - can be rendered ineffective
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17
Q

How is intermediate essential thrombocytopenia treated?

A

Aspirin +/- hydroxycarbamide (cytoreductive agent)

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18
Q

List the risks of splenectomy

A
  • Acute risks of surgical operation + long-term specific risks
    • ‘Sieves’ out microorganisms from the bloodstream, particularly encapsulated microorganisms - streptococcus pneumoniae, haemophilus influenzae and neisseria meningitis
    • Organisms can cause overwhelming post-splenectomy infections - patients must be vaccinated against these organisms pre-operatively + life long antibiotic prophylaxis (penicillin V) recommended
    • Patients must be informed of risk, understand they require prompt antibiotics in the event of infection and carry a splenectomy card with them at all times
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19
Q

How can secondary haemostasis be assessed?

A
  • Prothrombin time (PT)
  • Activated partial thromboplastin time (APTT)
  • Thrombin clotting time (TCT)
  • Individual coagulation factor assays
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20
Q

List the signs/symptoms of iron deficiency anaemia

A

Iron is required for all tissues - typical tissue signs seen as well as haematological symptoms

  • Koilonychia - spoon nails
  • Atrophic glossitis - pale, smooth, painless tongue
  • Angular stomatitis
  • Oesophageal web (Plummer Vinson syndrome) - web in oesophagus causes trouble swallowing
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21
Q

Describe the principles of coagulation testing

A
  • Add reagents to PPP
  • Perform assay at ‘body temperature’ - 37 degrees
  • Time to form clot
  • All results expressed as
    • Seconds
    • Ratio to normal plasma i.e. normal result = 1.0
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22
Q

How are autograft stem cells usually harvested?

A
  • Almost all autografts use mobilised peripheral blood stem cells harvested by aphaeresis
  • Patients receive G-CSF +/- chemotherapy to make the stem cells leave the bone marrow so that they can be collected from the blood 2 cannulas in arms, blood cycles into machine set to specific velocity, collect stem cells at interphase
  • More recently Mozobil has been used to collect stem cells in patients that have failed to mobilise - inhibits CXCR4
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23
Q

Describe the pharmacological characteristics of heparins

A
  • Bioavailability
    • UFH - 30%
    • LMWH - 95-100%
  • IV half life
    • UFH - 45-60 minutes
    • LMWH - 2 hours
  • Protein binding (plasma and platelet)
    • UFH - ++++
    • LMWH - +
  • Monitoring
    • UFH - APTTr 1,5-2.5
    • LMWH - none
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24
Q

How is the thrombin clotting time measured?

A
  • Add at 37 degrees - patient’s plasma, bovine thrombin
  • Less calcium or phospholipid dependent
  • Time to clot
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25
Q

Describe the pattern of inheritance of hereditary spherocytosis

A

Autosomal dominant

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26
Q

Describe the pathogenesis of sickle cell disease

A

Mutation in beta globin gene on chromosome 11 - single amino acid substitution at position 6:

  • Glutamine swapped for valine = Hb S
  • Glutamine swapped for lysine = Hb C
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27
Q

What tools can be used to assess co-morbidities in lymphoma?

A
  • CGA (comprehensive geriatric assessment)
  • CIRS (cumulative illness rating scale)
  • Haemato-oncology elderly care liaison service
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28
Q

How is folate absorbed?

A

Mostly in small bowel, 200-400ug, no carrier molecule required

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29
Q

What is thrombophilia?

A
  • Deficiencies of natural anticoagulants
    • Antithrombin
    • Protein C
    • Protein S
  • Specific genetic mutations
    • Factor V Leiden (resistance to APC)
    • Prothrombin gene mutation (increased prothrombin)
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30
Q

How does graft vs host disease usually present?

A
  • Most commonly manifests as a skin rash, jaundice or diarrhoea (skin, liver and gut are organs most commonly affected)
  • Can also have dry mouth, dry eyes and breathlessness (due to pulmonary fibrosis)
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31
Q

When does functional IDA with epo therapy occur?

A

Renal disease

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32
Q

Describe the role of RES macrophages in iron metabolism

A
  • At end of lifespan (120 days) RBC phagocytosed by macrophages of the RES
  • Iron released from Haem, stored in macrophages as ferritin (when there is little iron, soluble) or haemosiderin (when there is lots of iron, insoluble aggregates)
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33
Q

How does clonal haemopoiesis occur?

A

Progenitor acquires somatic mutation or through neutral drift in HSC population

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34
Q

Define myelodysplastic syndromes

A
  • Characterised by dysplasia (abnormal cells) and ineffective haemopoiesis in >1 of the myeloid series
  • May have increased myeloblasts
  • Multiple sub-types based on morphology and % blasts
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35
Q

Describe the pharmacological treatment of chronic lymphoblastic leukaemia

A

Chemoimmunotherapy - new combination treatments available have increased cases of complete remission

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36
Q

What can cause a purpuric rash?

A
  • Platelet problem, usually thrombocytopenia - spontaneous purpura seldom occurs with platelet count >20 x 109/l
  • Vasculitis i.e. Henoch Schonlein syndrome
  • Haemophilia doesn’t affect platelets so doesn’t cause purpuric rash
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37
Q

What is thromboplastin?

A

Mixture of phospholipids and tissue factor found in plasma, catalyses conversion of prothrombin to thrombin

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38
Q

Describe the structure of RBC and the functional relevance of this structure

A

Biconcave disc - squeeze in/out of small blood vessels, maximum surface area for gas transfer

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39
Q

Why is haemoglobin used by RBC to carry oxygen?

A

Able to reversibly bind O2 without undergoing oxidation or reduction

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40
Q

What influences prothrombin time?

A
  • PT depends on
    • Factors in extrinsic and common pathways
    • Factors VII
    • And Factors X, V, II and Fibrinogen
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41
Q

How are Hickman lines used in stem cell transplants?

A

Central line which goes into chest, over clavicle and feeds into the subclavian vein which is used to take samples, do reinfusions of cells, monitor patient and give antibiotics

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42
Q

What are the clinical consequences of folate deficiency?

A
  • Blood abnormalities - megaloblastic anaemia (leucopenia, thrombocytopenia), RBCs macrocytic (raised MCV) + anisopoiklocytosis
  • Growing foetus - 1st 12 weeks deficiency can cause neural tube defect (every woman pregnant/planning pregnancy needs folate supplement)
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43
Q

Describe haemoglobinopathies

A

Inherited conditions - two types:

1) Relative lack off normal globin chains due to absent genes (thalassaemias)
2) Variant (abnormal) globin chain e.g. sickle cell disease

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44
Q

Describe the side effects of chemotherapy used in AML

A
  • High morbidity - bleeding and infection
  • Hair loss, sterility, mucositis, prolonged inpatient stays, psychological element
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45
Q

Describe the clinical staging of chronic lymphoblastic leukaemia

A
  • Stage A
    • Features - <3 involved nodes
    • Survival 10 years
  • Stage B
    • Features - >3 involved nodes, liver, spleen
    • Survival 7 years
  • Stage C
    • Features - anaemia of thrombocytopaenia
    • Survival 2 years
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46
Q

List the types of division which haematopoietic stem cells can undergo and the consequences of this

A
  1. Symmetrical division - both daughter cells become mature RBC, contraction of stem cell numbers
  2. Asymmetrical division - one daughter cell is a self-renewing stem cell, one becomes a mature RBC, maintenance of stem cell numbers
  3. Symmetrical division - both daughter cells become self-renewing stem cells, expansion in stem cell numbers
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47
Q

Describe the markers and phenotype of plasma cells in plasma cell myeloma

A
  • Express plasma cell markers e.g. CD138
  • Show aberrant phenotype e.g.
    • CD19 negative
    • CD56 positive
    • Cyclin D1 positive
    • Light chain restriction
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48
Q

Describe the classification of leukaemia

A

Leukaemia

  • Acute
    • Myelodysplastic syndrome/myeloproliferative disease can progress to acute leukaemia
    • Myeloid - acute myeloid leukaemia
    • Lymphoid - acute lymphoblastic leukaemia
  • Chronic
    • Chronic lymphoblastic leukaemia (can progress to high grade non-Hodgkin’s lymphoma)
    • Chronic myeloid leukaemia (can progress to acute myeloid leukaemia/acute lymphoblastic leukaemia)
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49
Q

Describe the mechanism of action of clopidogrel/ticlidipine (irreversible blockers of ADP receptor)

A
  • Decreases expression of GPIIb/IIIa
  • Reduced binding of fibrinogen
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50
Q

At which age is acute lymphoblastic vs myeloid leukaemia most prevalent?

A
  • Acute lymphoblastic leukaemia more prevalent in 0-20 y/o (especially 0-4)
  • Acute myeloid leukaemia more prevalent in 40-85 y/o, prevalence increases with age
  • Approx. equal incidence in 20-35 y/o - low prevalence compared to young and old age groups
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51
Q

List causes of folate deficiency

A
  • Dietary
  • Extensive small bowel disease - coeliac/severe Crohn’s
  • Increased cell turnover - haemolysis, severe skin disorders, pregnancy
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52
Q

Describe the management of a major haemorrhage

A
  • 2222 - major haemorrhage call
    • State major haemorrhage
    • State location and extension number
    • Haematologist, lab staff and porter alerted
  • Request major haemorrhage pack
    • 6U PRC
    • 4U FFP
    • 1 pooled platelets
  • IV access - wide bore x 2
    • Grey/brown cannulae
    • Level one device - allows rapidly infusion of blood, can hang two units at same time (rate limiting step is size of cannula and vein)
    • Can also use dialysis catheter, pulmonary artery catheter sheaths or a rapid infusion catheter
  • Bloods - FBC, coagulation screen, fibrinogen, U+Es, LFT, calcium - near patient testing if available
  • Tranexamic acid (if trauma <3 hours ago)
  • KEEP PATIENT WARM
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53
Q

What is the 1st line treatment for myeloma? What are the side effects?

A
  • 1st line treatment - chemotherapy, MPT (melphalan, prednisolone and thalidomide) in elderly
  • Side effects - neuropathy, constipation, increased thrombosis –> LMW heparin
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54
Q

What are clonal haematological malignancies/pre-malignant conditions?

A

Haematological conditions arising from a single ancestral cell

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55
Q

How does the structure of foetal haemoglobin differ from adult haemoglobin?

A

Hb F (foetal) - 2 x alpha, 2 x gamma

Hb A (adult) - 2 x alpha, 2 x beta

Hb A2 (more rare adult) - 2 x alpha, 2 x delta

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56
Q

What is the purpose of investigations done in lymphoma?

A
  1. Staging - what areas are affected
  2. Help decide fitness for treatment - renal/liver/ bone marrow function, cardiac/respiratory disease
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57
Q

Describe the chemotherapy treatment used in acute myeloid leukaemia

A
  • Anthracycline and cytarabine based - heavy myelotoxicity
  • Most young patients entered into trials
    • MRC AML 17, UKALL14, UKALL2011
  • Aim to eradicate abnormal clone
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58
Q

Describe the half life, minimum creatinine clearance and side effects vs warfarin of dabigatran

A
  • Half life - 12 hours
    • Cmax - 2-3 hours
  • Minimum creatinine clearance
    • 30 (reduce dose if 30-50ml/min)
  • Side effects vs warfarin
    • Fewer ICH, possibly more GI bleeds
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59
Q

How is the risk of progression in myelodysplastic diseases determined?

A

Low risk vs high risk disease established by proportion of blast cells in marrow and cytogenetic profile (MDS vs AML, blast % cut-off is 20%)

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60
Q

Give examples of other myeloproliferative disorders

A

Mastocytosis

Clonal hypereosinophilic syndromes

Chronic neutrophilic leukaemia

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61
Q

List the causes of anaemia of chronic disease

A

Infection Inflammation Neoplasia

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62
Q

Where is transferrin synthesised?

A

Synthesised in hepatocytes - less iron more Tf made, more iron less Tf made

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63
Q

What is the function of the bone marrow stroma?

A

Provides requirements of the stem cell to enable it to grow and divide.

Cells e.g. macrophages, fibroblasts and fat cells secrete growth factors and adhesion molecules, released by cells into the bone marrow sinus in close proximity to stem cells.

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64
Q

Describe dietary sources of B12

A
  • Synthesised solely by microorganisms
  • Meat (esp. liver and kidney), small amount in dairy products
  • Normal western diet - 5-30ug/day
  • Strict vegan diet is B12 deficient
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65
Q

Give examples of classical myeloproliferative disorders

A

Polycythaemia rubra vera

Essential thrombocytosis

Myelofibrosis

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66
Q

Describe the risk of thrombosis in antithrombin deficiency

A
  • Antithrombin deficiency - 20-50% risk of thrombosis in Type 1 AT deficiency by age 50
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67
Q

Describe the absorption of iron in the GI tract

A

Iron absorbed by mature enterocytes in the small bowel

Haem iron (red meat) readily absorbed, non-haem iron (white meat, green vegetables, cereals) more difficult to absorb

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68
Q

Is the spleen enlarged in immune thrombocytopaenic purpura?

A

No

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69
Q

What new therapies are available for chronic lymphoblastic leukaemia?

A
  • New therapies for p53 mutation/deletion, 11q22 (ATM) mutation
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70
Q

What part of the coagulation cascade is tested by the activated partial thromboplastin time?

A

Stimulates activation via the intrinsic pathway

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71
Q

List the advantages and disadvantages of umbilical cord blood stem cell transplants

A
  • Advantages - more rapidly available than VUD, less rigorous matching to patient type as immune system naive
  • Disadvantages - small amount (adults will often require double cord transplant), slower engraftment, if relapse can’t go back for DLI, expensive (single cord transplant costs £30,000)
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72
Q

Describe the prevalence of chronic lymphocytic leukaemia

A
  • Commonest leukaemia
  • Incidence rises with age - median 67yrs
  • M:F ratio 2:1
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73
Q

Describe the types of sickle cell disease

A

Hb SS - more severe, two copies of sickle cell gene Hb SC - less severe

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74
Q

Describe the development of haemolytic disease of the newborn

A

Usually occurs in 2nd/3rd pregnancy Mother Rh-, father Rh +, baby Rh + Foetal and maternal circulations mix - Rh+ from foetus to maternal circulation Antibodies from mother against foetus

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75
Q

Define leukocytosis

A

Too many WBC

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76
Q

List rare bleeding disorders

A
  • Fibrinogen deficiency
  • FXIII deficiency
  • FX deficiency
  • FV deficiency
  • FII deficiency
  • FVII deficiency
  • FXI deficiency
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77
Q

How can primary haemostasis by analysed?

A
  • In vivo - bleeding time
  • Ex vivo - FBC (platelet count), platelet function
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78
Q

How does diffuse large B-cell lymphoma present?

A

Wide variation in presentation -

  • Lymphadenopathy - usually rapidly enlarging LN mass
  • Extra-nodal presentation common (30-40%) -
    • Waldeyer’s ring (tonsils)
    • GI tract
    • Skin
    • Bone
  • CNS PUO - pyrexia of unknown origin
  • Night sweats and weight loss
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79
Q

What causes diffuse large B-cell lymphoma?

A

High grade lymphoma associated with various translocations and genetic abnormalities, complex karyotype - heterogeneous entity (variable phenotype)

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80
Q

What does a positive direct Coombs test indicate?

A

AIHA or haemolytic disease of the newborn

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81
Q

What are the contraindications for all DOACs?

A
  • Pregnancy and breast feeding
  • Liver disease with cirrhosis +/- coagulopathy
  • Some drugs (mostly strong Pgp or CYP3A4 inhibitors or inducers)
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82
Q

What are the main indications for autologous stem cell transplant?

A

Relapsed Hodgkin’s disease, non-Hodgkin’s lymphoma and myeloma

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83
Q

What are the main indications for allogeneic stem cell transplants?

A
  • Half of all transplants done are for AML
  • Acute and chronic leukaemias, reduced lymphoma, aplastic anaemia, hereditary disorders
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84
Q

How is chronic myeloid leukaemia diagnosed?

A
  • Blood film and clinical features
  • Molecular test on blood (BCR-ABL PCR/FISH)
  • Cytogenetic analysis (‘karyotype’)
  • If BCR-ABL negative - not CML
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85
Q

Which patients are treated with transplants in ALL?

A
  • Relapsed patients
  • Refractory patients
  • Poor risk disease in first complete remission
  • Age less than 60 years
  • Good performance
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86
Q

What proportion of adult bone marrow is haemopoietically active?

A

30%

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87
Q

What are the complications of chronic myeloid leukaemia?

A
  • With modern therapy - very few
    • Imatinib resistance
    • Imatinib intolerance
    • Need for 2nd/3rd line TKI inhibitors
    • Accelerated phase/blast crisis
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88
Q

How is the prothrombin time tested?

A
  1. Add patient’s plasma, thromboplastin (tissue factor and phospholipids)
  2. Warm to 37 degrees
  3. Add calcium
  4. Time to form clot
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89
Q

How prevalent are bleeding complications with warfarin?

A
  • Bleeding complications with Warfarin:
    • Fatal haemorrhage - 0.25-0.64% per year
    • Major haemorrhage - 1.1-2.7% per year
  • Risk increases as achieved INR increases
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90
Q

How does B12/folate deficiency cause red cell abnormalities?

A

Disparity in rate of synthesis of precursors of DNA, abnormality of cell division, dissociation between nuclear and cytoplasmic development

Ineffective erythropoiesis - death of mature cells whilst still in marrow

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91
Q

List the absolute and relative contraindications to thrombolysis

A
  • Absolute -
    • Haemorrhagic stroke or stroke of unknown origin at any time
    • Ischaemic stroke in preceding 6 months
    • Central nervous system damage/neoplasms
    • Major trauma, surgery, head injury within preceding 3 weeks
    • GI bleeding within the last month
    • Known bleeding disorder
    • Aortic dissection
  • Relative (discuss with senior staff before withholding) -
    • Transient ischaemic attack in preceding 6 months
    • Oral anticoagulant therapy
    • Pregnancy or within 1 month postpartum
    • Non-compressible punctures <24 hours
    • Traumatic resuscitation
    • Refractory hypertension (systolic BP > 180mmHg)
    • Advanced liver disease
    • Infective endocarditis
    • Active peptic ulcer
    • Terminal illness
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92
Q

How is GvHD prevented?

A

Conditioning therapy before transplant includes drugs to prevent GvHD - usually immunosuppressive agents

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93
Q

What is the treatment for IDA?

A
  • Investigate cause
  • Iron replacement (not blood transfusion)
    • Ferrous sulphate/fumarate 200mg tabs ( = 60mg elemental iron)
    • Ferrous gluconate 300mg tabs ( = 36mg elemental iron)
    • IV iron - can give 1g over 2-3 hours, Hb rises no quicker than oral replacement
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94
Q

What influences the thrombin clotting time?

A
  • Depends on
    • How much fibrinogen present in plasma
    • How well that fibrinogen functions
  • Will also be prolonged by
    • Inhibitors of thrombin e.g. heparin, dabigatran
    • FDPs (fibrin degradation products)
    • Inhibitors of fibrin polymerisation (paraproteins)
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95
Q

Compare the severity of alpha and beta thalassaemia

A

Missing beta globin genes has more of an impact than missing alpha genes - only have two beta genes

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96
Q

What are the management options in splenic injury?

A
  • Conservative - if stable, watch and wait
  • Interventional radiology - block off bleeding vessel
  • Surgery - tie off bleeding vessel, splenectomy
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97
Q

List the complications of a major haemorrhage

A
  • Hypothermia
    • Exposure to elements during trauma (?) + transfusion with clear fluid = dilatational coagulopathy
    • Aggressively warmed - blood warmer, patient warmer, foil hat, monitor temperature, otherwise won’t clot
  • Acidosis
    • Blood loss means lower oxygen perfusion, tissue becomes hypoxic, more anaerobic respiration so more lactic acid production = lactic acidosis
    • Monitor with blood gases
  • Coagulopathy
    • FFP, platelets, cryoprecipitate - liaise with blood bank
  • Hypocalcaemia
    • Blood loss = calcium loss
    • Check ionised calcium on blood gas
    • Replace - need calcium to clot
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98
Q

Explain latent iron deficiency

A

If the RES iron store is slightly low, the serum ferritin will fall but the Hb is initially maintained (not anaemic) Present in 20% of pre-menopausal women

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99
Q

What is the major role of RBC?

A

Gas transfer - CO2 removal from tissues to lungs, O2 delivery from lungs to tissues

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100
Q

Describe the use of imaging in the diagnosis of myeloma

A
  • Historically plain X-rays used but may miss early lytic changes
  • MRI is better at identification of lytic lesions
  • May indicate incipient risk of fracture
  • Skeletal survey of all long bones done
    • Affects bones with active BM
    • Plasma cells produce OAF –> alters bone turnover
  • Multiple lytic lesions in skull and humerus
    • Osteolytic lesions, fractures, pain and hypercalcaemia
    • Pepper pot skull typical finding
  • Spinal MRI
    • Deformity more clear on MRI
    • Flattened vertebrae, bulging backwards towards disc
    • May present with spinal cord compression
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101
Q

Describe the phases which occur when you cut yourself

A
  1. Blood vessel damage
  2. Disruption of endothelium
  3. Exposure of
  • Tissue factor
  • Collagen
  1. Primary haemostasis
  2. Recruitment of platelets
  3. Secondary haemostasis
  4. Activation of coagulation factors

Occur simultaneously

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102
Q

Describe haemoglobin in sickle cell disease

A

HbS = 2 x alpha chains, 2 x beta chains (sickle)

Continuously polymerised/depolymerised, rate of polymerisation depends on:

  • Deoxygenation rate - low oxygen = polymerisation (cells sickle)
  • HbF - high levels of HbF protect against sickling Hb concentration
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103
Q

Describe the immune complications associated with chronic lymphoblastic anaemia

A
  • Autoimmune haemolytic anaemia - 5-10%
  • Autoimmune thrombocytopenia - <5%
  • At presentation, precipitated by treatment
  • Treat with steroids, treat CLL
  • Infection due to:
    • Hypogammaglobulinaemia - not enough gamma globulins produced, low antibodies
    • Cell mediated immunity impaired
    • T lymphopenia
    • Neutropenia
    • Defects in complement activation
  • Pulmonary infection common
    • Bacteria, encapsulated organisms
    • Viral
    • Pneumocytosis
    • Fungi
  • As likely to die from infection as from CLL
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104
Q

How is the indirect Coombs test carried out?

A

Plasma mixed with red cells from unit of blood to be transfused, if antibodies are present they will bind to red cells in transfused blood - look for antibodies in plasma/on RBC

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105
Q

Compare LMWH and UFH

A
  • LMWH have superior pharmacokinetic profile allowing predictable dose response
  • LMWH have safer side effect profile
  • LMWH clinical efficacy at least equal to UFH
  • LMWH have higher drug costs but lower consumable costs and do not require monitoring
  • LMWH can be used in out-patients
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106
Q

How are lymphomas staged?

A

Ann-Arbor classification system

  • Stage I: single lymph node group
  • Stage II: More than one lymph node group same side of the diaphragm
  • Stage III: lymph node groups both sides of the diaphragm (includes spleen)
  • Stage IV: extranodal involvement e.g. liver, bone marrow (spread via blood)

A or B added after to signify absence or presence of B symptoms

Early stage: 1 or 2A (no B symptoms)

Advanced stage: 2B or 3/4

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107
Q

Describe the mechanism of action of GPIIb/IIIa antagonsits

A
  • Monoclonal antibodies antagonise IIb/IIIa receptor
  • Reduced platelet aggregation
  • Reduced binding of fibrinogen
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108
Q

How is classic Hodgkin’s lymphoma treated?

A
  • Very effective
  • High cure rates (>90% in early stage, 75-85% in advanced stages)
  • Early stage - usually combined modality Rx i.e. chemotherapy followed by radiotherapy
  • Advanced stage - chemotherapy
  • Late effects important e.g. malignancy, cardiac, pulmonary, fertility, endocrine
  • Balance between effective treatment of disease against risk of effects for given individual
  • Chemotherapy = ABVD
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109
Q

What can cause B12 deficiency?

A
  • Pernicious anaemia
  • Low B12 in plasma (normal in tissues) - pregnancy, hormonal contraceptives, metformin, PPIs
  • Gastrectomy/achlorhydria - no parietal cells
  • Dietary
  • Terminal ileum problem - Crohn’s, resection
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110
Q

Describe immunochemotherapy used to treat advanced stage follicular lymphoma

A

Rituximab (anti-CD20 monoclonal Ab) + chemotherapy (CVP or CHOP or bendamustine)

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111
Q

Describe the grading of splenic injuries

A
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112
Q

List the types of stem cell transplant

A
  1. Autologous transplant (autograft) - patients own blood cells
  2. Allogenic transplant (‘allograft’) - any transplant in which stem cells come from a donor
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113
Q

To what extent can bone marrow compensate for reduced RBC lifespan in haemolytic conditions?

A
  • Normal lifespan is 120 days
  • If reduced down to 20 days can compensate by producing more RBC, any less and anaemia will develop
    • Lifespan 120 days - Hb normal
    • Lifespan 20-100 days - Hb normal, raised reticulocytes, raised unconjugated bilirubin = compensated haemolytic state
    • Lifespan <20 days - reduced Hb, raised reticulocytes, raised bilirubin, hypersplenism = haemolytic anaemia
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114
Q

Describe the AVBD chemotherapy regimen

A

A - Adriamycin (doxorubicin)

B - Bleomycin

V - Vinblastine

D - Dacarbazine

Given on days 1 and 15 of 28 day cycle

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115
Q

What is the treatment for hereditary spherocytosis?

A

If required - splenectomy

  • Destroys RBC so removal restores RBC lifespan to normal but at increased risk of infection from encapsulated organisms
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116
Q

How does leukaemogenesis occur?

A
  • Normal HCS (or myeloid/lymphoid cell) acquires changes through a multistep process to become leukaemic cell - requires 2 genetic hits to develop leukaemia
  • Dysregulation of cell growth and differentiation - associations with mutations
  • Proliferation of the leukaemic clone, differentiation blocked at an early stage (immature leukaemic blast cell population)
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117
Q

Give examples of causes of DIC

A
  • Sepsis
  • Malignancy
  • Massive haemorrhage
  • Severe trauma
  • Pregnancy complications e.g. pre-eclampsia, placental abruption, amniotic fluid embolism
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118
Q

How is the fate of a haematopoietic controlled?

A

Complex interaction between micro-environment signals (the niche) and internal cues - Wnt, notch and hedgehog signalling are important for controlling

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119
Q

List the different forms of graft vs host disease

A

Acute GvHD - within first 100 days of transplant Chronic GvHD - after first 100 days of transplant

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120
Q

How much dietary iron is required daily?

A
  • 1-2mg/day
  • Western diet - 15-20mg/day so nutritional IDA in adults v rare
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121
Q

What causes haemophilia A?

A
  • Classical haemophilia
  • Factor VIII deficiency
    • Severe <1iu/dl (spontaneous bleeds)
    • Moderate 2-5iu/dl (minor trauma bleeds)
    • Mild 6-40iu/dl (surgical bleeding)
  • X-linked inheritance
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122
Q

List the abnormalities seen in Fanconi anaemia

A
  • Microphthalmia
  • GU malformations
  • GI malformations
  • Mental retardation
  • Hearing loss
  • CNS e.g. hydrocephalus
  • Short stature
  • Digit abnormalities e.g. absent thumbs
  • Cafe au lait macules
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123
Q

Define thrombocytopenia

A

Reduction in the number of platelets

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124
Q

Describe the mechanism of action of kinases

A
  • Bind to plasminogen - releases plasmin, enhanced breakdown of fibrin
  • Activity on both clot bound and free plasminogen
    • Causes both fibrinolysis and systemic fibrinogenolysis
    • Significant bleeding risk
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125
Q

Describe menorrhagia

A

>80ml blood/period 20ml blood/period normal

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126
Q

What is the disadvantage of donor lymphocyte infusion?

A

1/3 of DLI recipients will develop graft vs host disease (donor cells attack the host tissue), unless measures are taken to reduce the risk

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127
Q

What are the requirements for samples used for coagulation tests?

A
  • Pre-analytical
    • Citrate sample (9:1 ratio)
    • Chelates all calcium
  • Centrifugation
    • Separates cellular component
    • Platelet poor plasma (PPP)
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128
Q

What is the effect of B12/folate deficiency on blood cells?

A
  • Macrocytic anaemia
  • Many large immature and dysfunctional red cells seen in bone marrow = megaloblasts
  • Hypersegmented neutrophils - 5-7 lobes
  • Erythroblasts destroyed in BM, v few reticulocytes but BM hypercellular
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129
Q

List the pros and cons of DOACS vs warfarin

A

Warfarin

  • Slow onset slow offset - results in smooth anticoagulation

DOACs

  • Rapid onset and offset - anti-coagulated within 3h of 1st dose

Warfarin

  • Requires very individualised dosing

DOACs

  • May require dose adjustment based on CrCl

Warfarin

  • Requires INR monitoring

DOACs

  • Requires annual review

Warfarin

  • Many drug, food and alcohol interactions

DOACs

  • Few drug and no food/alcohol interactions

Warfarin

  • Renal impairment may increase bleed risk

DOACs

  • Renal impairment may be a contra-indication

Warfarin

  • Rare side effects other than bleeding

DOACs

  • More minor side effects

Warfarin

  • Rapid reversal with PCC and Vitamin K

DOACs

  • Currently no rapid reversing agent
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130
Q

Describe the mechanism of action of dipyridamole

A
  • Increased platelet concentration of cAMP
  • Increased cAMP leads to decreased platelet responsiveness to ADP
  • Reduced platelet aggregation
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131
Q

List the types of antithrombotic agents

A
  • Anticoagulants
    • Inhibit one or several components of coagulation cascade
  • Fibrinolytic agents
    • Enhance lysis (breakdown) of fibrin clot
  • Anti-platelet agent
    • Inhibit platelet activation or aggregation
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132
Q

Describe the management of acquired warm type haemolytic anaemia

A
  • Corticosteroids
    • Mainstay of management
    • Usually Prednisolone, initially high dosage range of 60-100mg per day, subsequently reduced
    • Haemolysis should be dramatically reduced in 80% of patients within 3 weeks
  • Blood transfusion
    • Transfusion of packed red cells may be required dependent on patients symptoms
  • Folic acid
    • Demand for RBC so high that folic acid may be compromised and supplementation may be required in severe cases
  • Splenectomy
    • Treatment of choice in patients whose anaemia is refractory to prednisolone, or those who require long term high dose therapy to suppress the haemolytic state
    • Such patients liable to develop the serious complications of steroid therapy
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133
Q

Describe the typical natural history of multiple myeloma

A
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134
Q

Define pernicious anaemia

A

Autoimmune disease of gastric parietal cells - gastric parietal cell autoantibodies in 95%, intrinsic factor autoantibodies in 50%

Associated w/ other autoimmune diseases e.g. hypothyroidism

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135
Q

How is the coagulation cascade regulated?

A
  • ​Antithrombin inhibits VIIa, XIa, IXa, Xa, IIa
  • Tissue factor pathway inhibitor inhibits VII + TF –> VIIa
  • Protein S and APC (activated protein C) inhibit Va and VIII
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136
Q

Define a major haemorrhage

A
  • Loss of more than one blood volume within 24 hours (around 70mL/kg, >5 litres in a 70kg adult)
  • 50% of total blood volume lost in less than 3 hours
  • Bleeding in excess of 150mL/minute
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137
Q

How is cold AIHA treated?

A

Self limiting mycoplasma, idiopathic - keep warm

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138
Q

Describe the normal saturation of transferrin with iron

A

Normally 30% iron saturated with iron

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139
Q

What can cause intravascular haemolysis?

A
  • Can occur by mechanical trauma to red cell - red cell fragmentation syndromes i.e. RBC breakdown by defective mechanical heart valves (RBC fragmentation also seen in haemolytic uraemic syndrome and microangiopathic haemolytic anaemia
  • Can follow ABO incompatible blood transfusion (anti-A and anti-B are IgM antibodies)
  • Can also be due to malaria, cold (IgM) autoantibodies - cause RBC to agglutinate on blood film
    • Difficult to treat - advised to keep warm (antibody only fixes to RBCs in colder parts of the body i.e. cold hands etc.)
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140
Q

Define beta thalassaemia

A

Missing Beta globin genes - should have two

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141
Q

How does plasma cell myeloma present?

A
  • Majority of new cases have non-specific symptoms
    • Backache or rib pain (60%)
    • Fatigue
    • Symptoms of hypercalcaemia (30%)
    • Recurrent infections - chest
    • Renal impairment (25-30%)
  • Average GP will only see 1-2 cases in whole career
  • Diagnosis often unavoidably delayed with patients being referred via a variety of specialists
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142
Q

List the types of alpha thalassaemia

A
  • Normally 4 alpha globin genes - 2 from mother, 2 from father
  • Can be missing -
    • One alpha gene from one parent = alpha+ thalassaemia trait
    • One alpha gene from each parent = homozygous alpha+ thalassaemia trait
    • Two alpha genes from one parent = alpha0 thalassaemia trait
    • Two alpha genes from one parent, one from the other = HbH disease
    • Two alpha genes missing from each parent (no remaining genes) = alpha thalassaemia major
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143
Q

How can disorders of RBC enzymes cause haemolytic anaemia?

A
  • Pyruvate kinase (glycolysis) deficiency anaemia - chronic extravascular haemolytic anemia due to ATP depletion, autosomal recessive
  • Glucose-6-phosphate dehydrogenase (pentose phosphate pathway) deficiency - acute episodic intravascular haemolysis, X-linked recessive, acute haemolysis from oxidative stress (Favism, drugs e.g. anti-malarials, sulphonamides)
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144
Q

What evidence is there to support the concept of clonality in haematological conditions?

A
  • Almost all lymphoproliferative disorders and some AMLs carry a unique rearrangement of either an immunoglobulin or TcR gene (whereas non-malignant lymphoid proliferations are polyclonal)
  • X chromosome inactivation studies in women with leukaemia show the clonal proliferation carrier either an active maternal or paternal X chromosome (limited utility - many women develop skewed X inactivation with age)
  • Acquired cytogenic or molecular changes that arise during development of a malignancy e.g. Philadelphia translocation in CML
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145
Q

How do erythroblasts use iron?

A

Iron converted to haem in erythroblast mitochondria using enzyme ALA-S2, extra stored as ferritin

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146
Q

How is iron transported in plasma?

A

Transferrin - glycoprotein molecule with 2 iron binding domains Travels and binds to cells with transferrin receptors, delivers iron to all tissues, erythroblasts, hepatocytes, muscle etc

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147
Q

Define thalassaemia

A

Haemoglobinopathy due to relative lack of globin genes - alpha or beta

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148
Q

List the types of congenital haemolytic anaemias

A
  1. Abnormalities of RBC membrane
  2. Haemoglobinopathies
  3. Abnormalities of RBC enzymes
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149
Q

List the characteristics of myeloproliferative diseases

A
  • Clonal blood disorders
    • JAK2 mutation prevalent
  • Characterised by ‘effective’ haemopoiesis
    • Too many platelets - essential thrombocytopaenia
    • Too many red cells (+ platelets + WC) - polycythaemia vera or primary polycythaemia (same thing)
    • Too much fibrous tissue (+ platelets + WC) - myelofibrosis
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150
Q

What are the requirements for normal erythropoiesis?

A
  • Drive for erythropoiesis - erythropoietin produced by interstitial cells of kidney in response to tissue hypoxia
  • Genes required for erythropoiesis
  • Haematinics - iron, B12, folate, minerals
  • Functioning bone marrow - no increased loss/destruction of red cells
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151
Q

What effect does G-CSF have on haematopoietic stem cells?

A

Mobilises stem cells peripherally using growth factors - used for stem cell transplant

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152
Q

Compare myeloma and monoclonal gammopathy of undetermined significance (MGUS)

A
  • Difficult to differentiate
  • MGUS = common age related condition, plasma cell dyscrasia
    • Plasma cells or other antibody producing cells secrete a myeloma protein (abnormal antibody) into the blood/urine
    • Accumulation of bone marrow plasma cells derived from a single abnormal clone
  • Resembles multiple myeloma and similar diseases but lower levels of antibodies and lower levels of plasma cells in bone marrow
  • MGUS can lead to myeloma - monitoring needed
  • MGUS don’t experience any signs or symptoms usually
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153
Q

Which blood cells are derived from lymphoid stem cells?

A

B/T lymphocytes, NK cells

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154
Q

Who is the ideal VUD and why?

A

Young male donors are preferred - less exposure to antigens compared with women due to childbirth

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155
Q

Describe the molecular biology of Fanconi anaemia

A
  • Fanconi anaemia mutations cause
    • Up-regulation of pathways e.g. MAPKs –> TNF-alpha (inflammatory cytokine)
    • Altered DNA damage responses (FA-BRCA pathway)
    • Abnormal oxidative stress response
    • Other aberrations e.g. defective telomere maintenance
    • environmental factors (e.g. sunlight, smoking, infections, chemotherapy) = Genomic instability, altered cell checkpoints and survival - cells survive damage and go on to become malignant
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156
Q

What usually causes IDA in males/post-menopausal women?

A

Due to GI blood loss until proven otherwise

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157
Q

List the presenting features of chronic lymphocytic leukaemia

A
  • None
  • Lethargy, night sweats, weight loss
  • Symptoms of anaemia
  • Lymphadenopathy
  • Infection
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158
Q

List causes of macrocytosis other than folate/B12 deficiency

A
  • Reticulocytosis - 20% bigger than average mature red cell
  • Cell wall abnormality (lipids) - alcohol, liver disease, hypothyroidism (poorly understood)
  • With anaemia - bone marrow failure syndromes e.g. myelodysplastic syndromes
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159
Q

What is expressed by B cells in B cell lymphoma that can be the target for treatment?

A

B cells express CD20 antigen, target for treatment of B cell lymphoma with the monoclonal antibody Rituximab

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160
Q

Describe the process of a splenectomy

A
  • Trauma laparotomy for bleed into abdomen -
    • Incision from xiphoid sternum –> pubic symphysis
    • Usually find several litres of blood + clots - remove
    • Blood/clots have been acting as tamponade stopping blood flow, need to pack abdomen with highly absorbent swabs to create tamponade
    • Swabs into paracolic gutters, pelvis, above spleen and liver
    • Remove packs from area of least concern to area of most concern to find source of bleeding, full laparotomy circuit to find injuries that the CT may have missed
  • Spleen is end on organ - on a single vascular pedicle - so is relatively easy to detach and remove
    • Splenic artery from coeliac plexus, passes behind pancreas
    • Splenic vein back to join with the SMV forming the HPV
    • Endoscopic stapling gun can be used
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161
Q

Define haemolytic anaemia

A

Anaemia related to reduced RBC lifespan, no blood loss, no haematinic deficiency

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162
Q

Why is there often a small residual mass after diffuse B-cell lymphoma treatment?

A

Fibrosis

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163
Q

Describe the treatment of sickle cell disease

A
  • Prevent crises - hydration, analgesia, early intervention, prophylactic vaccination and antibiotics (hyposplenic infections), folic acid (BM inactive/ineffective)
  • Prompt management of crises - oxygen, fluids, analgesia, antibiotics, specialist care, transfusion/red cell exchange - reduce amount of HbS
  • Bone marrow transplantation
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164
Q

How can bone marrow be collected for investigation?

A

Aspiration - sample of bone marrow taken from back of iliac crest using hollow needle, under local anaesthetic - liquid component of bone marrow Trephine - solid core of bone

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165
Q

Describe the presentation of Burkitt lymphoma

A
  • Usually short history, marked B symptoms, rapidly growing tumours with massive tumour bulk
  • Most cases present with extra-nodal disease
    • Jaws and facial bone (endemic BL in African children)
    • Ileocaecal region of GIT - often primary site
    • Ovaries
    • Kidneys
    • Breast
    • Lymph nodes and bone marrow more frequently affected in immunosuppression-associated BL
    • CNS involvement at presentation or relapse is common in all types - brain, meninges or both
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166
Q

What is alcohol induced pain in lymph nodes a symptom of?

A

Rare feature of Hodgkin’s lymphoma

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167
Q

How are PET/CT scans used in the staging of lymphoma?

A

PET/CT scan with FDG tracer - taken up in areas that are metabolically active e.g. brain, heart, bladder

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168
Q

What is clonal haemopoiesis?

A

Common age related phenomenon in which HSC or other early blood progenitors contribute to the formation of genetically distinct subpopulations of blood cells (derived from single founding cell)

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169
Q

What causes warm AIHA?

A

Idiopathic in 30%, other autoimmune disease, lymphoproliferative disorder (NHL, CLL), drug induced

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170
Q

Where are haematopoietic stem cells found?

A

Bone marrow, peripheral blood after treatment with G-CSF, umbilical cord blood

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171
Q

How much iron is usually lost in pregnancy?

A

500mg/baby

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172
Q

How is myelodysplastic disorder managed?

A

Incurable (other than with SCT, <65 years), for rest supportive care, consider drug therapy e.g. azacitidine

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173
Q

Describe the process of an umbilical cord blood stem cell transplant

A

Blood stem cells collected from umbilical cord and placenta Cells tissue typed and frozen and liquid nitrogen in cord blood banks for future use

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174
Q

Where are most transferrin receptors found?

A

80% on developing RBCs - erythroblasts

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175
Q

Define anaemia

A

Reduction in the number of RBC

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176
Q

How do patients with B12/folate present?

A
  • Symptoms of anaemia/cytopenia - tired (macrocytic RBCs/megaloblastic marrow), easy bruising (thrombocytopenia - rare), beefy red tongue (B12 deficiency)
  • Mild jaundice - lemon yellow tint, due to ineffective erythropoiesis in marrow
  • Neurological problems - nerve disturbance as a result of B12 deficiency (subacute combined degeneration of cord)
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177
Q

List the causes of IDA

A
  • Dietary - premature neonates, adolescent females, v uncommon in adults
  • Malabsorption
  • Blood loss
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178
Q

Describe beta thalassaemia major

A
  • Missing both beta globin genes - unable to make adult haemoglobin
  • Autosomal recessive condition
  • Causes bone changes as bone marrow expands to try to compensate for missing beta globin
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179
Q

Describe the stratification of essential thrombocytopenia into risk groups for treatment

A
  • Low risk = age <40 with no risk features
  • Intermediate risk = aged 40-60 with no high risk features
  • High risk = aged >60, one or more high risk features - platelets >1500, previous thrombosis or thrombotic risk factors e.g. diabetes or hypertension
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180
Q

What is seen on electrophoresis in myeloma?

A

Monoclonal band

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181
Q

Describe abnormal destruction of red cells in haemolytic anaemia

A
  • Haemolysis = increased in RBC destruction
    • Bone marrow has ability to increase red cell production 6-8 x - RBC lifespan has to be reduced to <15-20 days before anaemia develops
  • Mechanism of destruction in haemolytic anaemia by two pathways:
    • Intravascular - destruction of red cells directly in the circulation
    • Extravascular - destruction of red cells in the RES of the spleen, liver and bone marrow
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182
Q

What are the indications for heparins?

A
  • Provides immediate but short acting anticoagulant effect
  • Acute DVT or PE (subcutaneous LMWH)
  • During cardiac bypass surgery (IV UFH)
  • Acute coronary syndromes (along with anti-platelet agents)
  • Medium term after VTE in cancer patients
  • Prophylaxis against VTE
    • Medical and post-op patients (low dose LMWH)
    • Obstetric patients
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183
Q

Describe the abnormalities in coagulation screen and clotting factors seen in Von Willebrand’s disease

A
  • Prolonged APTT
  • (Blood loss)
    • Haemolglobin low
    • MCV low
  • F VIII deficiency
  • VWF:RCo low
  • VWF:Ag low
184
Q

Describe the treatment of Burkitt lymphoma

A
  • Short survival unless treated but responds well to chemotherapy
  • Requires intensive chemotherapy (CODOX-M/IVAC)
  • Aim of treatment is to cure - 70-90% long term survival
  • Elderly unable to tolerate intensive therapy - poorer outcomes
185
Q

What are the clinical effects of Von Willebrand disease?

A
  • Mucosal type bleeding pattern
  • Reduced VWF +/- reduced platelet aggregation +/- reduced FVIII
186
Q

Describe the histological appearance of diffuse large B-cell lymphoma

A

Resemblance to activated B-cells (immunoblasts, centroblasts) High proliferation fraction, variable rate of cell death

187
Q

What is the purpose of the direct Coombs test?

A

To detect autoimmune haemolytic anaemia (detect antibodies on RBC surface) Cold AIHA easy to detect (IgM big), warm AIHA harder to detect (IgG small)

188
Q

List the characteristics of haematopoietic stem cells

A

Self renewal capacity, unspecialised, ability to differentiate into mature cells, rare (1 in 10,000 to 1 in 1 million in bone marrow), usually quiescent (only undergo occasional cell division, usually in G0)

189
Q

How prevalent is Fanconi anaemia?

A

10-20% of aplastic anaemia case

190
Q

Why is the use of ferritin as a measure of stored iron potentially problematic?

A

Serum ferritin is an acute phase protein (volume changes in response to inflammation)

191
Q

Which population are predominantly affected by myelodysplastic disorders?

A

The elderly

192
Q

Define leukopenia

A

Reduction in the number of WBC, or leukocytes

193
Q

How are bone marrow aspirates taken?

A

Posterior superior iliac spine can be easily palpated as a bony prominence at the posterior end of the iliac crest. Bone marrow needle should be inserted at the top of this prominence. It should be angled in the direction of the anterior superior iliac spine, a prominence found at the anterior end of the iliac crest.

194
Q

What is the effect of raised unconjugated bilirubin in chronic haemolytic states?

A

Can cause pigment gallstones

195
Q

Which part of the coagulation cascade is tested using prothrombin time (PT)?

A

Extrinsic pathway

196
Q

Describe the side effects of heparins

A
  • Heparin induced thrombocytopaenia
    • UFH - 4%
    • LMWH - <1%
  • Osteoporosis (3m use)
    • UFH - 17%
    • LMWH - 2.6%
  • Hyperkalaemia - rare with UFH/LMWH
197
Q

Describe the role of Von Willebrand factor

A
  1. Facilitates platelet adhesion and aggregation in primary haemostasis
  2. Binds FVIII and prolongs its half-life in plasma (influences secondary haemostasis)
198
Q

Describe secondary haemostasis

A
  • Activation of coagulation factors
  • Cascade of events
    • Initiation - extrinsic pathway
    • Propagation - intrinsic pathway
    • Thrombin generation
    • Fibrin production - the ‘clot’
199
Q

What is pancytopaenia and what can cause it?

A
  • Pancytopenia = reduced WBCs, Hb and platelets
    • Caused by variety of bone marrow diseases, hypersplenism and peripheral consumption of blood cells
200
Q

How is beta thalassaemia major treated?

A

Transfusion dependent from early life (first couple years) Iron overload has major effect on life expectancy - may need iron chelators (with each unit of blood receive 200-250ml of chelators, iron excreted in urine)

201
Q

Describe the process of fibrinolysis

202
Q

How is DIC treated?

A
  • Treat underlying cause
  • FFP +/- platelets if bleeding or high risk for bleeding
  • ?
    • Heparin 300-500u/h if thrombotic phenotype
    • AT concentrate (reduces mortality 56% –> 44%)
    • Protein C concentrate (meningococcal sepsis)
    • Activated protein C
203
Q

How is high risk essential thrombocytopenia treated?

A
  • First line therapy - hydroxycarbamide + aspirin
  • Second line therapy - anagrelide (inhibits megakaryocyte differentiation so doesn’t affect all blood lines) + aspirin
  • INF-alpha - used in pregnancy (don’t know teratogenicity of other drugs)
  • Busulphan, phosphorus-32 - associated with increased risk of leukaemogenesis, used in older patients who can’t tolerate other treatments
  • May need to consider combination therapy
  • JAK2 inhibitors e.g. Ruxolitinib
204
Q

List the most common lymphoma types

A
  1. Diffuse large B cell lymphoma (38%) 2. Follicular lymphoma (19%) 3. Classical Hodgkin’s lymphoma (10%) 4. Marginal zone lymphoma (7%)
205
Q

How are cytogenetics used in the diagnosis of acute myeloid leukaemia?

A
  • Essential to determine prognosis
  • Abnormalities correlate with response to treatment and survival
  • Allows decisions on management
206
Q

What usually causes IDA in young women?

A

Menstrual blood loss +/- pregnancy GI investigations only for GI symptoms or blood in stools

207
Q

How is the IPSS risk score for myelodysplastic disorders calculated?

A

Based on - BM blast %, karyotype, cytopenias

208
Q

What is the lupus anticoagulant and what clinical effects does it have?

A
  • Phospholipid dependent antibody
  • Interferes with phospholipid dependent tests i.e. APTT
  • APTT prolonged
  • If persistent, may be associated with prothrombotic state
  • Persisting lupus anticoagulant + thrombosis (or recurrent foetal loss) = antiphospholipid syndrome
209
Q

Describe the aetiology of acute myeloid leukaemia

A
  • Largely unknown
  • Chemicals
  • Chemotherapy
  • Radiotherapy
  • Genetic - Down’s syndrome, Fanconi Syndrome
  • Antecedent blood disorders (MDS, MPD)
  • Viruses?
210
Q

Describe the treatment of coagulation factor deficiency

A
  • Education - patients and doctor
  • Desmopressin (DDAVP) - causes release of Von Willebrand’s factor
  • Replacement therapy
    • FFP/cryoprecipitate
    • Plasma derived factor concentrate
    • Recombinant produced factor concentrate
  • Gene therapy
211
Q

What is the pathological result of sickled RBCs?

A

Reduced red cell survival - haemolysis Vaso-occlusion - tissue hypoxia/infarction (sickled rec cells occlude BVs)

212
Q

How is low risk essential thrombocytopenia treated?

A

Aspirin or anti-platelet agent

213
Q

How does the grade of splenic injury guide treatment?

A
  • Increasing grade = worsening splenic injury
  • Trauma doesn’t always require splenectomy - try to avoid if possible because asplenism causes higher risk of infection from encapsulated organisms
  • If grade IV/V will most likely require splenectomy, lower grades can also require depending on how the patient is clinically
214
Q

When in RBC development is haem synthesised?

A

Haem synthesis occurs from proerythroblast –> reticulocyte stage of RBC development

215
Q

Describe the features of Fanconi anaemia

A
  • Bone marrow failure (may present from birth into adulthood)
  • Somatic abnormalities
  • Short telomeres
  • Malignancy
  • Chromosome instability

Currently 7 genetic sub-types FANC A-G

216
Q

How is the activated partial thromboplastin time tested?

A
  • Add patients plasma, contact factor e.g. (Kaolin or Silica) and phospholipid (‘partial thromboplastin’
  • Warm to 37 degrees
  • Add calcium
  • Time taken to clot
217
Q

Describe the autologous transplant process

A
  1. Collection - stem cells collected from patient’s blood or bone marrow
  2. Processing - blood or bone marrow processed in the lab to purify and concentrate stem cells
  3. Cyropreservation - blood or bone marrow frozen to preserve it
  4. Chemotherapy - high dose chemotherapy and/or radiation therapy given to the patient
  5. Reinfusion - thawed stem cells are reinfused into the patient
218
Q

How does follicular lymphoma usually present?

A
  • Incidence increases with age, median age at diagnosis is 65 y/o
  • Often present w/ stage 4 disease (marrow involvement)
  • B symptoms less common, indolent clinical course
  • Usually incurable
219
Q

Describe the natural history of acute leukaemias

A
  • Clonal disorders
  • Blastic proliferation in bone marrow (‘maturation arrest’)
  • Rapid onset
  • Serious compromise of normal marrow elements (so normal counts fall)
  • Death within days or weeks if untreated
220
Q

Describe the prognosis of classic Hodgkin’s lymphoma

A

Dependent on stage of disease

221
Q

What is the mechanism of action of hepcidin?

A
  • Reduces the levels of iron in plasma
  • Binds ferroportin and degrades it, reducing iron absorption by enterocytes and decreasing iron release from the RES
222
Q

Describe the structure of adult haemoglobin

A

4 globin chains (2 alpha, 2 beta), 4 haem groups (1 iron per haem group, 1 per globin chain)

223
Q

How common is Von Willebrand disease?

A

Most common mild bleeding disorder - 1/1000

224
Q

What are the benefits/drawbacks of allogeneic stem cell transplants in malignant disorders?

A

Benefit of graft vs leukaemia effect in addition to the effect of high dose chemotherapy, but at the expense of graft vs host disease (donor cells attack host tissue)

225
Q

Describe the maturation of macrophages

A

Myeloid stem cell –> monoblast –> monocyte (in blood) –> macrophage (in tissues)

226
Q

How do the cells seen on a bone marrow aspirate differ from peripheral blood cells?

A

More immature cells seen in bone marrow aspirate

227
Q

What balance is required in coagulation? What are the consequences of imbalance?

A
  • Balance
    • Coagulant vs. anticoagulant factors
  • Imbalance –> thrombosis, bleeding
228
Q

What are the treatment options for acute lymphoblastic leukaemia?

A
  • Chemotherapy
  • Supportive treatment
    • Blood transfusion
    • Fresh frozen plasma
    • Platelet transfusion
    • Antibiotics/antifungals
    • Growth factors (G-CSF)
    • Granulocytes
  • Transplant procedures
229
Q

Describe the natural history of follicular lymphoma

A

Very responsive to treatment

Tendency to relapse - become more frequent and eventually resistant to treatment, will die of lymphoma

May transform to diffuse large cell B-lymphoma

Rituximab has increased average survival

230
Q

What are the clinical consequences of B12 deficiency?

A
  • Blood abnormalities - megaloblastic anaemia (leucopenia, thrombocytopenia), RBCs macrocytic (raised MCV) and anispoiklocytosis (variance in size/shape of RBCs)
  • Neurological manifestations - bilateral peripheral neuropathy or demyelination of posterior and pyramidal tracts of spinal cord (biochemical basis unclear)
231
Q

What are the disadvantages of VUDs?

A

Increased risk of GvHD compared to family donor, majority of VUDs are caucasian - shortage of donors from other ethnic groups

232
Q

How is warm AIHA treated?

A

Stop any drugs, steroids, immunosuppression, splenectomy

233
Q

What mutations cause essential thrombocytosis?

A

50% carry JAK2V617F, 50% carry calreticulin mutation

234
Q

What is HbH disease?

A
  • Missing 3 alpha genes, lack of alpha chains and excess beta chains
  • Beta chains join together
  • Blood transfusion required during periods of stress
  • Hb variable - 65-75g/l
235
Q

Describe the mechanism of action of warfarin

A
  • Inhibits VKOR - vitamin K oxide reductase
    • Needed for oxidation of vitamin K for conversion of prothrombin precursor to prothrombin
236
Q

Describe the half life, minimum creatinine clearance and side effects vs warfarin of apixaban

A
  • Half life - 12 hours
    • Cmax 2-3 hours
  • Minimum creatinine clearance
    • 15 (for AF reduce rose if 15-29ml/min)
  • Side effects vs warfarin
    • Fewer ICH
237
Q

List the types of classical Hodgkin’s lymphoma

A

Nodular sclerosing, mixed cellularity, lymphocyte rich and lymphocyte depleted

238
Q

How prevalent is haemophilia A?

A

Incidence - 1/20,000 (1/10,000 males)

239
Q

What causes graft vs host disease?

A

Can happen in patients who have received allogeneic transplant - new donor’s immune system recognises the host’s body as foreign and starts to attack it

240
Q

Describe RBCs in hereditary spherocytosis

A

RBCs spherocytic and polychromatic - reticulocyte count increased (appears blue colour under stain)

241
Q

How are abnormal RBC in IDA described?

A

Hypochromic (pale, MCH low), microcytic (small, MCV low)

242
Q

What common patterns of abnormalities are seen in coagulation screens?

A
  • PT only abnormal (prolonged) - low factor II
  • APTT only abnormal (prolonged) - low factor VIII, IX, XI or XII, lupus anticoagulant
  • PT and APTT abnormal (prolonged) - common pathway factor low or multiple factors low
243
Q

How do RBC appear in warm AIHA?

A

Spherocytic and polychromatic - same on blood film as hereditary spherocytosis Small and dark

244
Q

Describe life expectancy in those with sickle cell disease

A

Reduced Longer life expectancy in those with high HbF (foetal haemoglobin)

245
Q

What platelet count indicates essential thrombocytosis?

A

Platelets >600 x 10(9)/L persistently (upper limit of 400 is normal)

246
Q

Describe the histological appearance of Burkitt lymphoma

A
  • Resemblance to proliferating germinal centre cells
  • Very high rate of proliferation (nearly all cells in cell cycle)
    • Due to MYC translocation and over-expression
  • High rate of cell death (apoptosis)
    • Tumour lysis syndrome an issue
247
Q

Describe the typical presentation of acute lymphoblastic leukaemia

A
  • Limping child
  • Purpuric rash
  • Unexplained, sometimes severe bone pains not uncommon
  • ‘Lumps’ vs ‘liquid presentation’ (i.e. lymphoblastic lymphoma vs true ALL)
248
Q

Define polycythaemia/erythrocytosis

A

Too many RBC

249
Q

What imaging should be done in a suspected major bleed?

A
  • CT chest/abdomen/pelvis
    • Need to CT all cavities that they could be bleeding into - abdomen, chest , pelvis, femurs/long bones
250
Q

Define myeloproliferative disorders

A

Clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny - disorders of bone marrow in which excess cells are produced

251
Q

Name a haemolytic anaemia which is due to abnormalities of RBC membranes

A

Hereditary spherocytosis

252
Q

When could normal serum ferritin levels be seen in IDA?

A

Ferritin is an acute phase protein - in presence of tissue inflammation IDA can occur with normal serum ferritin (rheumatoid arthritis and inflammatory bowel disease)

253
Q

How is anaemia of chronic disease treated?

A

Treat underlying cause

254
Q

What is done on arrival to A&E in a major bleed?

A
  • Primary survey done again (ABCD)
  • Worry about DIC - consumptive coagulopathy
  • Initial investigations - FBC, coagulopathy screen, ROTEM (guides how to replace blood for individual patient), type and match for blood type (takes approx. 45 minutes)
  • Management
255
Q

What is the main function of anticoagulant drugs? Give examples

A
  • Main function - inhibit formation of fibrin clot
  • Heparins and Fondaparinux - injection, act via antithrombin, antagonise Factor Xa (+/- thrombin)
  • Oral warfarin - vitamin K antagonist (lowers Factors II, VII, IX and X)
  • Newer direct oral anticoagulants (DOACs) - dabigatran (thrombin), apixaban, rivaroxaban, edoxaban (Xa)
256
Q

How much B12 is lost per day?

A

1-2ug/day in urine/faeces

257
Q

At what stage are HL and NHL usually diagnosed?

A

Most HL diagnosed at early stage Most NHL diagnosed at advanced stage

258
Q

What does the thrombin clotting time measure?

A
  • Measurement of conversino of fibrinogen to fibrin clot
259
Q

Define plasma cell myeloma

A

Neoplasm of mature plasma cells with varied clinical course

260
Q

List the causes of cold autoimmune haemolytic anaemia

A
  • Usually IgM antibodies
  • Primary (idiopathic)
  • Secondary including
    • Infection - mycoplasma pneumoniae
    • Infections mononucleosis
    • Lymphoproliferative disorders
261
Q

Describe the microenvironment of bone marrow

A

Ideal environment for growth and development of stem cells, composed of stromal cells and a microvascular network

262
Q

Define B symptoms in lymphoma

A

Systemic symptoms e.g. fever, weight loss, night sweats Itch (pruritis) is not a B symptom - can occur in NHL and HL

263
Q

What is the main action of fibrinolytic drugs?

A
  • Main action - enhancement of fibrinolysis
    • Breakdown of a fibrin thrombosis
264
Q

Describe the typical presentation of acute myeloid leukaemia

A
  • Rapid onset of symptoms
  • Lethargy
  • Infection
  • Bleeding and bruising
  • Bone pain
  • Gum swelling
  • Lymphadenopathy, skin rash
265
Q

How can a patient with lymphoma present?

A
  • Lymphadenopathy - painless, rubbery (hard and craggy suggests carcinoma, pain suggests infection)
  • Splenomegaly
  • B symptoms - night sweats, weight loss (10% of body weight in last 6 months), unexplained fever 38/9, recurrent, doesn’t respond to antibiotics
  • Anaemia - several causes
266
Q

What is the clinical significance of alpha thalassaemia?

A
  • Missing one gene - mild microcytosis, no anaemia
  • Missing two genes - microcytosis, increased red cell count and sometimes v mild (asymptomatic) anaemia
  • Missing three genes - significant anaemia (Hb approx. 75g/L) and bizarre shaped small RBC, HbH disease (beta globins bind together)
  • Missing four genes - incompatible with life, hydrops foetalis (heart failure from severe anaemia foetally)
267
Q

Describe causes of acquired thrombophilia

A
  • Antiphospholipid syndrome
    • Presence of antiphospholipid antibodies
      • Lupus anticoagulant - actually a prothrombotic agent
      • Anti-cardiolipin antibodies
      • Beta-2 glycoprotein-1 antibodies
    • Mechanism
      • Disrupt Annexin V shield, expose excess phospholipid
    • Clinical scenario
      • Venous/arterial thrombosis
      • Recurrent miscarriage
268
Q

How can CML progress?

A

Have potential to transform into AML

269
Q

What is the most common cause of death in Fanconi anaemia?

A

Premature bone marrow failure, AML

270
Q

What is seen histologically in acute myeloid leukaemia?

A
  • Peripheral blood
    • Blasts
    • Anaemia, neutropaenia, thrombocytopaenia
  • Bone marrow
    • Blast cells >20%
    • Morphology important
271
Q

Describe the epidemiology of beta thalassaemia

A

1 in 7 Greek Cypriots 1 in 12 Turks 1 in 20 Asians 1 in 20-50 Africans/Afro-Caribbeans 1 in 1000 white English

272
Q

Define classic Hodgkin’s lymphoma

A

High grade lymphoma with prominent component of reactive cells

273
Q

What can be done when the INR is too high in Warfarin therapy?

A
  • Stop Warfarin or reduce dose
  • Give Vitamin K1 (oral or IV)
  • Give coagulation factors (II, VII, IX, X)
    • Prothrombin complex concentrates e.g. Beriplex, Octaplex
274
Q

What is disseminated intravascular coagulation?

A
  • Acquired, consumptive process
    • Activation of coagulation cascade - microthrombi
    • Exhaustion of coagulation cascade - bleeding
  • Systemic activation of coagulation
    • Depletion of platelets and coagulation factors - bleeding
    • Intravascular deposition of fibrin - thrombosis of small and midsize vessels and organ failure
275
Q

What causes cold AIHA?

A

Idiopathic in most patients, can develop after mycoplasma infection or in patients with lymphoproliferative diseases e.g. lymphoma

276
Q

How are normal RBC described?

A

Normochromic (normal colour, mean corpuscular haemoglobin normal) and normocytic (normal size, mean corpuscular volume normal)

277
Q

What investigations are done in the staging of lymphoma?

A
  • CT scan - neck, chest, abdomen and pelvis
  • PET/CT scan - HL, most DLBCL, FL/NLPHL (to confirm early stage)
  • Bone marrow aspirate and biopsy - no longer required in HL and many DLBCL
278
Q

What are the consequences of bone marrow failure?

A
  • Neutropenia - infections
  • Anaemia
  • Thrombocytopenia - bleeding
279
Q

How do myelodysplastic disorders present?

A
  • 20% incidental finding on FBC
  • 20% present with infections or bleeding e.g. ophthalmic herpes zoster, fungal infections in lungs
  • Majority (70-80%) present with fatigue due to anaemia
280
Q

How is follicular lymphoma treated?

A
  • Treatment aimed at alleviating symptoms
  • 1/3 of patients don’t require treatment at diagnosis
  • Early stage (1A, some 2A) - localised radiotherapy (curable?)
  • Advanced stage -
    • Asymptomatic, no bulk, no end organ compromise (porta hepatis impairing liver function, spinal cord, kidneys) - watch and wait
    • Symptomatic and/or organ compromise - treatment with immunochemotherapy
281
Q

Describe the characteristics of severe rare platelet disorders

A
  • Rare
  • Autosomal recessive
  • Mucosal type bleeding pattern
282
Q

List the types of NOACs

A
  • Factor IIa inhibitor - dabigatran etexilate (Pradaxa)
  • Factor Xa inhibitors
    • Rivaroxaban (Xarelto)
    • Apixaban (Eliquis)
    • Edoxaban (Lixiana)
283
Q

Where are the globin gene clusters found?

A

Alpha 1/2 - chromosome 16 Beta, delta, gamma - chromosome 11

284
Q

What are the two types of bone marrow?

A

Red - due to erythrocytes Yellow - due to fat cells Conversion of red to yellow with age but can interconvert (e.g. yellow –> red with blood loss)

285
Q

Define cytosis/cythaemia

A

Too many mature blood cells

286
Q

Describe myeloablative regimens

A
  1. Conditioning Eliminate host haematopoietic system and immune system - high dose chemotherapy and total body irradiation 1440cGy 2. Bone marrow transplantation
287
Q

What causes anaemia of chronic renal failure?

A

Combination of effects of ACD and reduced Epo production

288
Q

What are the important stages in management of a major haemorrhage?

A
  • Early recognition important
    • Remember estimated blood volume varies dependent on patient weight
    • Transfusion usually necessary after 30-40% loss
    • Hb not a reliable indicator in acute situation
  • Get help - need lots of people to keep up with rate of blood loss
  • Control bleeding
    • Surgery
    • Interventional radiology
  • Transfuse early - need to think about future blood loss and potential for deterioration
289
Q

Describe the natural history of chronic myeloid leukaemia

290
Q

What abnormalities are seen on the coagulation screen with lupus anticoagulant?

A
  • APTT - often prolonged
  • APTT 50:50 dilution - only partially corrects (inhibitor present)
  • DRVVT ratio prolonged
  • DRVVT ratio corrects with excess phospholipid
291
Q

Describe the clinical consequences of sickle cell anaemia

A

Multisystem disease:

  • Brain - stroke, Moya Moya (degeneration in and around basal ganglia)
  • Lungs - acute chest syndrome, pulmonary hypertension
  • Bones - dactylitis (swelling, pain), osteonecrosis
  • Spleen - hyposplenic
  • Kidneys - loss of concentration, infarction
  • Urogenital - priapism (acute/chronic)
  • Eyes - vascular retinopathy
  • Placenta - IUGR (intrauterine growth retardation), foetal loss
292
Q

Why are the number of stem cell transplants being carried out increasing?

A

Transplanting older patients and for more conditions

293
Q

What laboratory investigations should be done in DIC?

A
  • Look for underlying cause
    • Sepsis, trauma, cancer, obstetric disease
  • Coagulation - PT, APTT, fibrinogen
  • D-Dimers
  • FBC + film - platelets, RBC fragments
294
Q

Describe the possible pathogeneses of drug induced AIHA

A
  1. Hapten - drug binds to RBC and acts as antigen hapten, antibodies which destroy RBC raised in response
  2. Immune complex (innocent bystander) - antibodies raised against drug not RBCs, interaction of antibody with drug causes complement fixation = severe haemolysis e.g. cephalosporins
  3. Autoimmune - drug is introduced, antibodies against RBC develop (not sure why), rare + mild
295
Q

Describe the stages involved in the coagulation cascade

A
  • Initiation - extrinsic pathway
  • Propagation - intrinsic pathway

The coagulation system, is triggered by the tissue factor (TF)/factor VIIa complex, which activates FIX and FX. Activated FIX converts small amounts of prothrombin to thrombin, which is sufficient to amplify coagulation by activating factors V and VIII, platelets, and platelet-bound factor XI. Coagulation is propagated when FIXa binds to FVIIIa on the surface of activated platelets, forming intrinsic tenase, which, in turn, activates FX. Activated FX binds to activated factor V to form prothrombinase, which converts prothrombin (Factor II) to thrombin (Factor IIa). In the final step, thrombin converts fibrinogen to fibrin.

296
Q

Describe the histological appearance of chronic lymphocytic leukaemia

A
  • Peripheral blood - blasts
  • Bone marrow
    • Nodular infiltrate
    • Diffuse infiltrate
  • Diagnosis
    • Clonal population of B lymphocytes 9 (>5 x 109/L)
    • CD5, 19, 20, 23 positive, weak surface Ig
    • Unique immunophenotype
    • Co-expression CD5, CD19, CD23
297
Q

Describe the platelet receptors

A
  • VWF and collagen facilitate platelet adhesion to subendothelium
  • Fibrinogen (and VWF) facilitate crosslinking of activated platelets
298
Q

Describe the use of catheter directed thrombolysis

A
  • All fibrinolytic drug types effective
  • Pros
    • Smaller doses
    • Administered directly into vessel containing thrombosis
    • Less systemic effect
    • Paradoxically not necessarily less bleeding
  • Uses
    • Acute limb ischaemia
    • Massive CVT
    • Blocked CVC (central venous catheter)
299
Q

What are the triggers for treatment in chronic lymphoblastic leukaemia?

A
  • Symptoms
    • Sweats, weight loss, symptomatic nodes
  • Bone marrow failure
    • Anaemia, thrombocytopenia
  • Do not treat asymptomatic patients
300
Q

Where does haemopoiesis occur in infants?

A

Bone marrow (all bones) - during childhood there is a progressive replacement of marrow by fat in the long bones (conversion from red –> yellow marrow)

301
Q

Describe the incidence of lymphoma

A

5th most common cancer, commonest blood cancer Can occur at any age - commonest cancer in <30 y/o, accounts for 1 in 10 cancers in children

302
Q

What is the effect of beta thalassaemia major on RBCs?

A

Significant dyserythropoiesis, RBC are small and misshapen

303
Q

What causes myelodysplastic syndromes?

A

May be secondary to previous chemotherapy or radiotherapy - 3-10 years after initial treatment Can occur without clear underlying cause

304
Q

Describe the use of JAK2 inhibitors in the treatment of essential thrombocytopenia

A
  • JAK2 mutations result in continuous activation of JAK receptor regardless of ligand binding
  • JAK inhibitor Ruxolitinib approved for use in myelofibrosis with trials ongoing in ET and PRV - inhibits JAK1/2, no reduction in allelic burden, main side effect is thrombocytopenia
  • Responses seen in JAK2 positive and negative patients
305
Q

How is myeloma diagnosed?

A
  • Blood tests
    • FBC, ESR, U&Es, Calcium - serum protein electrophoresis, SFLC (serum free light chain) quantity
    • Can be anaemic - microcytic, hypochromic
    • ESR can be over 100
  • Urine tests (GP) - to look for Light chains in urine (Bence-Jones protein)
  • Bone marrow aspirate
  • Imaging
306
Q

Define neutropenia

A

Reduction in the number of neutrophils

307
Q

Describe the clinical presentation of chronic myeloid leukaemia

A
  • May be asymptomatic (20-50%)
  • Symptoms
    • Fatigue
    • Weight loss
    • Night sweats
    • Abdominal discomfort
  • Splenomegaly in 50-75%
308
Q

How are donor lymphocyte infusions given?

A

Following bone marrow transplant and subsequent relapse, give incremental increasing concentrations of donor lymphocytes

309
Q

Describe the clinical features of essential thrombocythaemia

A
  • Continuum with polycythaemia rubra vera
  • Thrombotic complications
  • Haemorrhagic complications - abnormal platelets also produced = abnormal clotting (can also develop Von Willebrand’s disease)
  • Splenomegaly
  • Transformation to PRV or myelofibrosis (fibrotic tissue replacing marrow, become pancytopaenic)
  • Leukaemic transformation in 3%
310
Q

Describe the graft vs leukaemia effect

A

Same cells which cause GvHD also attack remaining leukaemia cells - minimising GvHD carries an increased risk of relapse GvL is very effective, esp. in patients where a good remission has been difficult to maintain with chemotherapy alone Can work in other cancers e.g. lymphoma, myeloma Challenge is to minimise GvHD and maximise GvL

311
Q

Which blood cells are derived from myeloid stem cells?

A

RBC, platelets, monocytes, neutrophils, eosinophils and basophils

312
Q

Describe R-CHOP chemotherapy

A
  • R - Rituximab (monoclonal antibody)
  • C - Cyclophosphamide
  • H - Adriamycin (Doxorubicin)
  • O - Vincristine
  • P - Prednisolone (steroid for 5 days)

Given on day 1 of a 21 day cycle

313
Q

What causes symptoms in chronic and acute leukaemia?

A
  • Chronic - accumulation of cells
  • Acute - marrow failure
314
Q

Describe the role of ferroportin

A

Transmembrane protein for the exportation of iron, hepcidin blocks its activity

315
Q

What are the clinical consequences of myelodysplastic syndromes?

A

Majority characterised by progressive bone marrow failure, some progress to AML

316
Q

Describe the onset of acquired warm type haemolytic anaemia

A

Onset of warm antibody autoimmune haemolytic anaemia may be insidious or explosive

317
Q

What are the indications for DOACs?

A
  • Total hip replacement or total knee replacement
  • Atrial fibrillation
  • DVT and PE prophylaxis
318
Q

What is leukaemia?

A
  • Blood cancer
  • Accumulation of abnormal leucocytes in marrow +/- blood +/- other tissues
319
Q

Which cell is the precursor to mature platelets?

A

Megakaryocyte

320
Q

How much iron is released from stores per day?

A

30-40mg released from stores per day but only 4mg in plasma at any one time

321
Q

List the major classes of fibrinolytics

A
  • Kinases - streptokinase, urokinase
  • Tissue plasminogen activators (tPA) - alteplase, tenecteplase, reteplase
322
Q

What are blast cells?

A
  • Primitive cells
    • Can be malignant or normal primitive cells
    • Myeloid and erythroblasts in leucoerythroblastic blood sample are normal primitive cells, pushed out of bone marrow by fibrotic tissue (myelofibrosis) or malignant infiltration by carcinomas
323
Q

How is acute lymphoblastic leukaemia diagnosed?

A
  • Histology of bone marrow
  • Cytogenetics
    • T(9:22)
    • T(4:11)
324
Q

What measures are taken in those who have had a splenectomy to prevent further morbidity?

A

Hyposplenic prophylaxis - immunisations and long term penicillin V

325
Q

Describe the supportive management of ALL

A
  • Blood transfusion
    • Symptomatic patients
    • Improve QOL
  • Fresh frozen plasma
    • For coagulopathy/DIC (disseminated intravascular coagulopathy)
  • Platelet transfusion
    • Purpura and bleeding - e.g. retinal haemorrhage
    • During fever, sepsis, DIC
  • Antibiotics/antifungals - bacterial and fungal infections e.g. chest infections
  • Growth factors (G-CSF)
  • Granulocytes
    • Refractory infections
326
Q

Describe the histological features of classic Hodgkin lymphoma

A
  • Rees Sternberg cells - distinct, giant cells seen in Hodgkin’s lymphoma
  • Neoplastic cell resembles atypical activated B-cell as seen in some viral infections (e.g. EBV - approx. 40% of cases associated with EBV infection)
  • Characterised by strong expression of CD30 and loss of some B-cell antigens
327
Q

How does classic Hodgkin’s lymphoma present?

A
  • Bimodal age incidence - peak in 20-30s then later peak >50 yrs
  • Usually presents with painless lymphadenopathy (>70%)
    • Neck lump
    • Cough, shortness of breath
  • May present with CXR mass
  • Spreads from one nodal group to immediately adjacent nodes
  • Later, haematogenous spread to liver, lungs, BM
  • May have B symptoms
  • Itch may precede diagnosis for many months
  • Alcohol related pain - very rare
328
Q

What causes extravascular haemolysis?

A
  • More common than intravascular haemolysis, occurs in RES, particularly spleen
  • Often related to production of ‘warm’ (incomplete) antibodies, usually IgG
    • IgG attaches to red cell antigen and damages the RBC membrane, damaged RBCs become spherocytic and are phagocytosed by the RES, particularly the spleen - hypersplenism
329
Q

How is warfarin monitored?

A
  • By INR
    • INR = (PT patient/mean normal PT)^ISI
  • Normal INR = 1/0 (not on Warfarin)
  • Target INR on Warfarin = 2.0 - 3.0
330
Q

What is the most significant disorder of haemoglobin variance?

A

Sickle cell disease

331
Q

Why are volunteer unrelated donor transplants needed?

A

Majority of patients (70%) do not have a family donor

332
Q

Why do men and women require different amounts of iron?

A

Men need 1mg/day, women need 2mg/day due to loss in menstruation/pregnancy

333
Q

Describe the pattern of inheritance of Fanconi anaemia

A

Autosomal recessive inheritance

334
Q

Why does anaemia of chronic disease occur?

A

Failure of iron utilisation, iron trapped in RES - cause not clear

335
Q

How long does blood type matching take?

A

Group specific takes 10-20 minutes, full cross matching takes 30-40 minutes

336
Q

What influences the activated partial thromboplastin time?

A
  • Depends on
    • Factors in intrinsic and common pathways
    • Factors VIII, IX, XI and XII, X, V, II and fibrinogen
337
Q

Describe blood cell production in adults

A

Red blood cells produced in the red bone marrow throughout adult life, process is continuous. Specialist cells called haematopoietic stem cells are responsible for making all the different types of blood cells. Many blood cells die and are replaced every day.

338
Q

Describe the inheritance pattern of Von Willebrand disease

A

Mostly autosomal dominant with variable penetrance

339
Q

Define pancytopenia

A

Reduction in all types of blood cells - WBC, RBC, platelets

340
Q

Give an example of a classic GI cause of IDA without GI symptoms

A

Adenocarcinoma of the colon

341
Q

What is Burkitt lymphoma?

A
  • High grade lymphoma
  • Characterised by translocations involving MYC gene (but simple karyotype)
342
Q

Describe the normal body stores of iron

A

Total body - 4g Bone marrow and RBCs - 3g RES macrophages - 200-500mg Myoglobin - 200-300mg Essential enzymes - 100mg

343
Q

What chance is there that siblings are HLA matched?

A

Each sibling has a 1 in 4 chance of being a HLA match

344
Q

Describe the classifications of lymphoma

A

Hodgkin’s (15%) - classical (90%) or nodular lymphocyte predominant Non-Hodgkin’s - B cell (>90%) or T cell, indolent or aggressive

345
Q

How effective is chemotherapy in acute myeloid leukaemia?

A
  • Cures in 15-90% according to risk group
  • Some patients refractory, some only curable using allogenic transplant
346
Q

Which mutations are associated with myeloproliferative disorders?

A

JAK2V617F and calreticulin mutation

347
Q

How can allogeneic transplants be modified for older/less fit patients?

A

Can have full intensity ‘myeloablative’ (host bone marrow completely destroyed) or reduced intensity ‘mini’ transplant (usually for older patients)

348
Q

What is seen histologically in plasma cell myeloma?

A
  • Peripheral blood - Rouleaux
    • Stacks/aggregations of red blood cells
  • Bone marrow - excess plasma cells, pleomorphic
    • Eccentric nucleus, basophilic cytoplasm
  • The neoplastic plasma cells are monoclonal and therefore produce only produce one type of immunoglobulin light chain (kappa or lambda)
349
Q

List the uses of autologous stem cell transplants

A

Plasma cell dyscrasias Non-Hodgkin’s lymphoma, Hodgkin’s disease, chronic lymphocytic leukaemia Solid tumours - used for breast cancer commonly in the 90s, not shown to increase survival Leukaemia

350
Q

How is the direct Coombs test carrier out

A

Add antibodies e.g. to IgG on red cell surface, immunological lattice forms, red cell agglutination

351
Q

Describe the folate stores

A

Require a lot, stored poorly, if stop folate takes 4-6 weeks to run out (process quickened by alcohol)

352
Q

Describe the, dose, half life, minimum creatinine clearance and side effects vs warfarin of edoxaban

A
  • Dose
    • 60mg od
    • 5d LWMH 60mg od (or 30mg od)
  • Half life - 12 hours
    • Cmax - 1-2 hours
  • Minimum creatinine clearance
    • 15 (reduce dose if 15-50 ml/min, <60Kg or interacting drugs)
  • Side effects vs warfarin
    • Fewer ICH
353
Q

What are the consequences of BM failure?

A

Risk of bleeding, anaemia, infections

354
Q

How is chronic lymphocytic leukaemia often diagnosed?

A

Incidental Diagnosis:

  • Common - 50% cases
  • FBC - lymphocytosis
  • GP samples
  • Hospital patients - medical or surgical
  • Pre-symptomatic diagnosis
355
Q

Explain the terms responder and non-responder in reference to resuscitation of a major bleed

A
  • Responder vs. non-responder
    • Responder - bleeding stops, stabilises following transfusion of blood products and fluid
    • Non-responder - stays stable while blood is being replaced but when transfusion stops they deteriorate quickly as the bleeding continues
  • Stable enough for investigation? Or do they need intervention immediately?
  • Secondary survey
356
Q

What is the role of nursing in the management of ALL?

A
  • Key component to success
  • Need specialised experienced staff
  • Nursing bond important to patients
  • Demanding both physically and psychologically
  • Rewarding specialty
357
Q

What determines the severity of haemoglobinopathies?

A

Amount of abnormal haemoglobin Type of abnormal haemoglobin Ameliorating factors

358
Q

Describe the histological appearance of essential thrombocytopenia

A

Peripheral blood - platelets clumped together, different sizes Bone marrow - lots of megakaryocytes Myelofibrosis

359
Q

Describe the stores of B12

A

Absorb small amount per day but is stored well, if stop absorbing B12 will take 5 years to be deficient

360
Q

Describe the chemotherapy used to treat ALL

A
  • Complex, specialist units
  • Prednisolone, cyclophosphamide, anthracycline, asparaginase, vincristine, etoposide, cytarabine based
  • CNS directed treatment essential
  • Initial aggressive therapy, then oral maintenance (1-2 years)
361
Q

Describe primary haemostasis

A
  • Vasoconstriction
    • Reduces blood flow and limits blood loss
    • Collagen exposed at site of injury promotes platelet adhesion to the injury site
    • Platelets release cytoplasmic granules containing serotonin, ADP and thromboxane A2 - increase vasoconstriction
  • Platelet plug formation
    • Activated by von Willebrand factor, found in plasma
    • Platelets release cytoplasmic granules which creates positive feedback loop to continue the process of platelet aggregation
362
Q

Describe the mutation responsible for CML

A

Reciprocal translocation from long arm of chromosome 9 –> 22 BCR-ABL fusion gene (Philadelphia) produced is responsible for CML - ABL1 gene on chromosome 9 joined to a part of BCR (breakpoint cluster region) gene on chromosome 22 BCR-ABL causes permanent activation of tyrosine kinase - impaired DNA binding and unregulated cell division –> cancer

363
Q

Describe the uses of fibrinolytic drugs

A
  • Breakdown pathological thrombosis
    • Systemically
    • Locally - catheter directed
364
Q

What abnormalities are seen in the coagulation screen in haemophilia A?

A

Prolonged APTT

365
Q

From which cells are chronic leukaemias derived?

A
  • B lymphocytes - chronic lymphoblastic leukaemia
  • Neutrophils, eosinophils, basophils - chronic myeloid leukaemia
366
Q

What are the potential options for the fate of a haematopoietic stem cell?

A

Self-renewal to produce an identical copy, apoptosis, differentiation (maturation and specialisation)

367
Q

What is the purpose of the indirect Coombs test?

A

To detect RBC antibodies in plasma for screening/cross-matching (transfusion)

368
Q

Describe the coagulopathy in liver disease

A
  • Poor coagulation factor synthesis in liver
  • Vit K deficient (poor diet +/- obstructive component to jaundice)
  • Poor clearance of activated coagulation factors
  • DIC
  • Hypersplenism (–> low WBC and platelets)
  • Reduced thrombopoietin synthesis (–> low platelets)
369
Q

Why would IV iron replacement be used rather than oral tablets?

A

Iron intolerance (GI upset) - before starting IV try reducing elemental iron dose (use gluconate instead of sulphate/fumarate) Compliance e.g. psychiatric patients Renal anaemia + Epo replacement

370
Q

Compare warm and cold AIHA

A

Cold - IgM + complement, rarer, harder to treat Warm - IgG +/- complement, more common, easier to treat

371
Q

What causes follicular lymphoma?

A

Translocations involving BCL2 gene (18 –> 14 translocations) Slow growth but reduced apoptosis

372
Q

What is the internationalised normalised ratio? What is it used for?

A
  • Standardised form of prothrombin time
  • Monitoring of oral coumarins e.g. Warfarin
    • Vit K dependent coagulation factors - II, VII, IX and X
  • Patient’s INR identical in any laboratory
    • Patient’s PT/average of 20 normal PTs
    • Result factored by International Sensitivity Index
    • Every thromboplastin has its own ISI
      • Calculated form international standard thromboplastin
      • Should be close to 1.0
373
Q

How can the reason for a prolonged APTT be determined?

A
  • If reason for prolonged APTT is factor deficiency, 50:50 dilution will show full correction (factors replaced with those in normal plasma).
  • If reason for prolonged APTT is inhibitor, 50:50 dilution will show partial correction (inhibitor still present).
374
Q

How are myelodysplastic disorders managed?

A
  • Supportive care - blood and platelet transfusion (may need iron chelation in younger patients)
  • Growth factors - erythropoietin +/- granulocyte colony stimulating factor (G-CSF), reduce anaemia, improve quality of life
  • Immunosuppression - some success in treating low-risk MDS with anti-thymocyte globulin
  • Low dose chemotherapy if high blast counts - e.g. hydroxycarbamide, low dose cytarabine
  • Demethylating agents e.g. azacytidine, an epigenetic therapy
  • Intensive chemotherapy (BM transplant) - only in patients who can tolerate, AML type chemotherapy
  • Allogenic stem cell transplantation - only in selected patients (suitable donor, well enough to tolerate)
375
Q

Describe the genetics of chronic myeloid leukaemia

A
  • Philadelphia chromosome, t(9:22)
    • BCR-ABL gene produced
376
Q

List the potential problems with stem cell transplant

A
  • Limited donor availability, upper age limit <65 years
  • Mortality 10-50% depending on risk factors
  • Graft vs host disease - chronic GvHD has 30% mortality
  • Immunosuppression
  • Infertility in both sexes
  • Risk of cataract formation
  • Hypothyroidism, dry eyes and mouth
  • Risk of secondary malignancy
  • Risk of osteoporosis/avascular necrosis - reduction in androgens and steroids needed for GvHD
377
Q

How are volunteer unrelated donors identified?

A

Anthony Nolan Trust donor registry within the UK, several million volunteers worldwide 70% chance of finding a VUD for each patient

378
Q

What are the clinical consequences of hereditary spherocytosis?

A

Splenomegaly Jaundice (neonatal and adult)

379
Q

Give examples of organisms asplenic patients have a greater risk of infection from

A

Encapsulated organisms - pneumococcus, meningococcus, haemophilus

380
Q

Describe the types of acute leukaemia classified by the cells from which they originate

381
Q

What laboratory findings are seen in extravascular haemolysis?

A
  • Positive direct antiglobulin test indicates the presence of antibodies (or complement) on RBC surface
  • Serum bilirubin usually elevated and is unconjugated (hence acholuric jaundice)
382
Q

Describe the mechanism of action of heparins

A
  • Mixture of glycosaminoglycans of differing polysaccharide chain length
  • Augment activity of endogenous antithrombin (1000-2000 fold)
    • Particularly anti-IIa and anti-Xa activity
    • Anti-Iia effect influenced by longer saccharide chains
  • Do not cross placenta
  • Short half-life
  • Administered parenterally
383
Q

How is non-haem iron absorbed?

A

Converted from ferric to ferrous iron requiring cytochrome b, then absorbed through the divalent metal transporter DMT1

384
Q

List the types of Von Willebrand disease

A
  • Type 1 - partial quantitative deficiency of VWF
  • Type 2 - qualitative deficiency of VWF
    • 2A - qualitative variants with decrease platelet dependent function associated w/ absence of HMW VWF multimers
    • 2B - all qualitative variants with increased affinity for platelet glycoprotein 1b
    • 2M - qualitative variants with decreased platelet dependent function NOT caused by absence of HMW VWF multimers
    • 2N - qualitative variants with markedly decreased affinity for factor VIII
  • Type 3 - virtually complete deficiency of VWF
385
Q

What can cause hypochromic, microcytic RBCs?

A

Iron deficiency anaemia - not enough haem Thalassaemia - not enough globin Anaemia of chronic disease Sideroblastic anaemia (esp. congenital SA) - enough iron but not converted to haem

386
Q

Describe the pathogenesis of cold AIHA

A

Autoantibody IgM + complement IgM antibodies cause red cells to aggregate

387
Q

Describe the potency of haematopoietic stem cells

A

Multipotent - can produce several different cell types

388
Q

What are the retrieval team?

A
  • Team of emergency medicine, anaesthetic and ITU consultants
  • Attend serious emergencies
    • 999 call responder triages patient to decide if retrieval team are needed
  • Use helicopter, can go to rural areas
  • Carry lots of kit and blood products
  • Pass information to hospital
    • Code red - phone ahead from ambulance to have blood products waiting, can add FFP, platelets, cryoprecipitate (rich source of fibrinogen)
389
Q

What investigations should be done in patients with lymphoma?

A
  • History - symptoms, duration of symptoms (needs to be persistent lymphadenopathy), B symptoms (fever, night sweats, weight loss)
  • Clinical examination - lymph nodes, splenomegaly
  • Blood tests - FBC, U&Es, LFTs, Ca (can be high), ESR (HL), LDH
  • Imaging tests - CT scan, PET/CT scan - lessens need for biopsy, can show marrow infiltration
  • Bone marrow - aspirate and trephine
  • Additional tests (may be required pre-treatment) - echocardiogram, pulmonary function tests
390
Q

How is B12 absorbed?

A

Binds to intrinsic factor (made by gastric parietal cells in fundus/body of stomach) Absorbed in ileum Binds to transcobalamin in plasma

391
Q

What is the disadvantage of syngeneic stem cell transplants?

A

Doesn’t give desired graft vs leukaemia effect

392
Q

How much B12 is required daily?

393
Q

How is iron recycled by the RES?

A

Effete RBC removed by the macrophages of the RES RES stored around 500mg of iron as ferritin/haemosiderin RES releases iron to transferrin in plasma when required Tf-iron complex taken up via Tf receptors on erythroblasts, hepatocytes etc.

394
Q

Describe the appearance of bone marrow in aplastic anaemia

A

Normal haematopoietic tissue replaced by fat spaces Fat spaces increase with age - 70y/o have 70% replaced w/ fat spaces

395
Q

List the pre-leukaemic conditions

A
  1. Myelodysplastic disorder
  2. Myeloproliferative diseases
396
Q

How does the appearance of bone marrow aspirate differ from a trephine sample?

A

Trephine is solid rather than liquid so shows the architecture more clearly

397
Q

How does haemoglobin production change throughout life?

A

Foetal haemoglobin produced during gestation, gamma chain production switched off just before birth - replace foetal haemoglobin with adult haemoglobin

398
Q

Describe the normal mechanism of red cell destruction

A
  • Senescent red cells (100 days+ old) are destroyed by the cells of the reticuloendothelial system particularly in the spleen
  • Intravascular haemolysis (breakdown of RBC in the general circulation) normally has little or no role in RBC destruction
399
Q

What does Moya Moya appear as on imaging?

A

‘Puff of smoke’

400
Q

Describe the stroma of bone marrow

A

Stromal cells include macrophages, fibroblasts, endothelial cells, fat cells and reticulum cells. They secrete extracellular molecules such as collagen, fibronectin, haemonectin, laminin and proteoglycans including growth factors and adhesion molecules - essential for growth, division and differentiation into mature blood cells.

401
Q

Give an example of a relatively benign myelodysplastic disorder

A

Refractory anaemia with ring sideroblasts Patients can live for years but are transfusion dependent - iron overload is problem

402
Q

Describe the prevalence and features of factor deficiencies (other than Haemophilia A)

A
  • Rare bleeding disorders
    • Represent 3-5% of all congenital bleeding disorders
  • Often manifest clinically in autosomal recessive form only
  • Prevalence of homozygous or double heterozygous cases - 1/500,000 - 1/2,000,000
  • Lower factor levels doesn’t necessarily mean higher bleeding severity
403
Q

Describe non-myeloablative stem cell transplants

A

Low-dose, less toxic preparative regimens Provides immune suppression to allow donor cells to engraft, while graft vs leukaemia effect eradicates tumour Permits SCT use in patients not eligible for conventional SCT

404
Q

What is leukaemogenesis?

A

The development of leukaemia cells from normal haematopoietic stem cells

405
Q

Describe the treatment of bleeding in inherited platelet disorders

A
  • Pressure
  • Tranexamic acid/Desmopressin
  • Platelet transfusion (HLA matched)
  • rFVIIa
406
Q

Describe the synthesis of haem in RBC development

A

Globin genes contain 3 coding sequences (exons) and 2 intervening sequences (introns) Transcription of genes controlled by promoter genes at 5’ end, influenced by upstream locus elements (LCR regions) After translation introns excised Globin chains produced on ribosomes Control of production mainly at transcription level and depends on availability of haem

407
Q

What are the consequences of clonal haemopoiesis?

A

Linked to increased risk of haematological disease

408
Q

Give examples of hereditary conditions which impair bone marrow function

A

Thalassaemia Sickle cell anaemia Fanconi anaemia Dyskeratosis congentia Schwann-Diamond syndrome Diamond Blackfan anaemia Thrombocytopenia with absent radii Hereditary leukaemia (rare)

409
Q

What is the best lab test to confirm iron deficiency anaemia?

A

Serum ferritin - low serum ferritin always indicates low RES iron stores

410
Q

List the characteristics of myelodysplastic disorder

A
  • Clonal blood disorder
  • Characterised by
    • Failure of effective haemopoiesis (low blood counts)
    • Most common in elderly
    • ‘Dysplastic’ blood and marrow appearances
    • Approx. 25% rate of transformation to AML
    • Consequences of marrow failure
411
Q

Describe the use of allogenic transplants in ALL

A
  • HLA matched stem cells
  • Sibling or unrelated donor
  • Procedure more complex
  • GVHD but GVL
  • Higher early mortality
  • Less risk of relapse
412
Q

Describe the main laboratory findings in intravascular haemolysis and the pathological mechanisms which lead to this

A
  • After intravascular haemolysis, free haemoglobin saturates plasma haptoglobin (binding protein), resulting in disappearance of plasma haptoglobin
  • Excess free haemoglobin in plasma filtered at the glomerulus leading to haemoglobinuria, tubules reabsorb some haemoglobin from urine, broken down to form haemosiderin (can also appear in urine)

Main laboratory findings in intravascular haemolysis are:

  • Anaemia, reticulocytosis and raised unconjugated bilirubin
  • Haemoglobinaemia and haemoglobinuria
  • Haemosiderinuria
413
Q

Give an example of a myelodysplastic disorder which has a high chance of progressing to AML

A

Refractory anaemia with excess blasts - increased number of blast cells with expanded chromatin and prominent nucleoli

414
Q

How is diffuse B cell lymphoma treated?

A

Requires aggressive chemotherapy with intention to cure Response is variable, subset of tumours resistant to conventional treatments Early stage (1A) - R-CHOP x 3 + radiotherapy All other stages - R-CHOP x 6 Elderly/unfit patients - need assessment of general frailty and co-morbidities

415
Q

Where can stem cells used for allogeneic transplants come from?

A

Can use peripheral blood stem cells, bone marrow or umbilical cord blood

416
Q

Which tissues are commonly invaded in ALL?

A

CSF and testicular infiltration

417
Q

Describe the, dose, half life, minimum creatinine clearance and side effects vs warfarin of rivaroxaban

A
  • Dose
    • 10mg od, 20mg od (15mg bd d21)
  • Half life - 12 hours
    • Cmax 2-4 hours
  • Minimum creatinine clearance
    • 15 (for AF reduce dose if 15-49 ml/min)
  • Side effects vs warfarin
    • Fewer ICH, possibly more GI bleeds
418
Q

Define follicular lymphoma

A

Indolent type of B cell lymphoma, low grade Accounts for 20-25% of lymphomas, 2nd commonest subtype of lymphoma, commonest subtype of low grade lymphoma

419
Q

Describe the prognosis of myeloma

A
  • Incurable
  • Variable - median 5.5 years (<6 months to >10 years)
  • Overall 5 year survival approaching 50%
  • Females survive longer
420
Q

Describe the mechanism of action of aspirin

A
  • Blocks conversion arachidonic acid –> thromboxane A2
  • Decreased platelet activation
421
Q

Describe the process of reduced intensity SCT (mini-transplant)

A
  1. Conditioning - low dose chemo, total body irradiation 200cGy 2. Bone marrow transplant - patient mixed chimera (mixture of own cells and donor cells in haematopoietic system)
422
Q

Describe the indications for tPA derivatives and which would be used in each

A
  • Acute MI (alteplase, tenecteplase, reteplase) for patients not suitable for PCI
    • Within 12 hours of onset of symptoms
    • 30 day mortality reduced compared to streptokinase or placebo
  • Ischaemic stroke (alteplase)
    • Within 4.5 hours of onset of symptoms
    • Reduced disability at 90 days
  • Massive pulmonary embolism with haemodynamic instability (alteplase)
    • Reduced thrombus size and cardiac strain
    • Effect on overall mortality unknown
423
Q

List the possible mechanisms of action of antiplatelet drugs

A
  • Irreversible blockage of ADP receptor (P2Y12) - clopidogrel, ticlidipine
  • GPIIb/IIIa antagonists - abciximab, tirofiban
  • Irreversible inhibition of cyclooxygenase - aspirin
  • Phosphodiesterase III inhibitor - dipyridamole
  • Thromboxane synthetase inhibitors and thromboxane receptor blockers - picotamide (combined), ifetroban (receptor blocker)
424
Q

Describe the lab values seen in anaemia of chronic disease

A

MCV/MCH - normal/reduced (RBCs can be normochromic and normocytic or hypochromic and microcytic) ESR - raised (inflammation) Ferritin - normal/high (iron stores not affected, just can’t utilise iron) Iron - low TIBC (measure of transferrin) - low (not normal for anaemia)

425
Q

What typifies myeloma?

A
  • Increased plasma cells in bone marrow
  • Clonal immunoglobulin or paraprotein
  • Lytic bone lesions
426
Q

How are iron levels regulated?

A

No regulatory excretory mechanism for iron, regulated by amount of absorption from GI tract, controlled by hormone hepcidin (decreases amount absorbed)

427
Q

Where does haemopoiesis occur in the foetus?

A

0-2 months - yolk sac 2-7 months - liver, spleen 5-9 months - bone marrow

428
Q

What is the aim of investigations in plasma cell myeloma?

A
  • Diagnosis
  • Extent of organ damage
  • Prognosis (Beta 2 microglobulin is important prognosis indicator - raised in myeloma)
429
Q

Describe the epidemiology of alpha thalassaemia

A

Alpha+ thalassaemia trait - Southern Europe, Middle East, Africa, South East Asia Alpha0 thalassaemia trait - South East Asia, Greece, Turkey

430
Q

Why is serum ferritin important?

A

Small amount of total body ferritin in serum but amount of serum ferritin directly related to how much iron is stored - important clinical marker 1mmol/l serum ferritin = 8mg RE iron

431
Q

Describe dietary sources of folate

A

Colourful foods e.g. green vegetables (destroyed by cooking), orange juice

432
Q

How is CO2 removed from the body?

A

Involves the renal tubules, lungs and RBCs Chloride shift and carbonic anhydrase reaction important for CO2 removal

433
Q

Describe the transferrin iron saturation in iron deficiency anaemia and hereditary haemochromatosis compared with normal transferrin iron saturation

A

Normal - 30% Iron deficiency anaemia - liver senses low iron, makes more transferrin, transferrin saturation can be <15% HH - liver senses high iron, makes less transferrin, transferrin saturation can be up to 100%

434
Q

Describe the survival rate of acute myeloid leukaemia

A
  • Childhood AML - 5 year survival rate approx. 60-70%
  • Adult AML (<60 years) - 5 year survival rate approx. 50%
  • Adult AML (>60 years) - 5 year survival rate approx. 10-20%
435
Q

What is the genetic cause of leukaemia?

A
  • Acquired genetic abnormalities
    • 1 gene vs 2 genes or more?
    • Cell type in which mutation arises likely to be crucial - allow diagnostic testing, monitoring, research, pharmaceutical targeting
436
Q

Describe the hierarchy of normal haemopoiesis

A

Pluripotent haematopoietic stem cell –> lymphoid or myeloid stem cell –> maturation –> mature cells

437
Q

Give examples of acquired conditions which impair bone marrow function

A

Aplastic anaemia Leukaemia Myelodysplasia Myeloproliferative disorders Lymphoproliferative disorders Myelofibrosis Metastatic malignancy e.g. breast, prostate Infections e.g. TB/HIV Drugs and toxins Chemotherapy Haematinic deficiencies

438
Q

Give an example of a cause of mechanical fragmentation haemolysis

A

Ventricular assist device for heart failure, forces blood out of heart, causes mechanical damage to RBC and fragmentation

439
Q

Describe pre-hospital resuscitation for a major bleed

A
  • Need to replace blood lost and maintain intravascular volume
  • Access
  • Replace blood lost w/ fluid + blood products
    • O negative blood used - universal donor
  • Also give tranexamic acid - fibrinolytic inhibitor
    • Binds to plasminogen, prevents conversion of plasminogen to plasmin, preventing fibrin breakdown
440
Q

List the types of donor in allogenic stem cell transplants

A

Syngeneic transplant - between identical twins Allogeneic sibling - HLA identical (match HLA A, B, C, DR, DQ) Haplotype identical - half matched family member, usually patent or half matched sibling Volunteer unrelated/match unrelated donor

441
Q

Mutation of what gene causes hereditary haemochromatosis? What is the effect?

A

HFE gene mutation - causes iron overload Liver cirrhosis, skin bronzing, arthritis, diabetes

442
Q

List the essential enzymes which contain iron

A

Cytochromes Perioxidases Xanthine oxidase Catalases RNA reductase

443
Q

Why are B12 and folate relevant to haematological disorders?

A

Haematinics - required for RBC production Required for DNA synthesis

444
Q

How can platelet function be assessed?

A

Light transmission aggregometry to assess platelet function

445
Q

What is the purpose of donor lymphocyte infusion?

A

T-cells obtained by leukapharesis from the original bone marrow donor have an anti-tumour effect Used to prevent/treat relapse after allogeneic SCT - can induce a graft vs leukaemia effect with complete cytogenetic and haematological remission in 2/3 patients

446
Q

Describe the diagnostic criteria for myeloma

A
  • Clinical spectrum of disease
    • Asymptomatic to highly aggressive disease
  • Diagnosis based on combination of features
    • Neoplastic plasma cells in bone marrow, >10% of total cells plus at least one of the following:
      • Evidence of end-organ damage attributable to the plasma cell proliferation (CRAB criteria)
        • Hypercalcaemia
        • Renal insufficiency
        • Anaemia
        • Bone lesions - >1 lytic lesion on skeletal X-ray, CT or PET/CT
      • Biomarkers of malignancy
        • Clonal plasma cell percentage >=60%
        • Serum free light chain ratio >=100
        • >1 focal lesion on MRI
447
Q

Define cytopenia

A

Reduction in the number of mature blood cells

448
Q

Which tissues are affected by macrocytic anaemia?

A

All rapidly growing, DNA synthesising cells - bone marrow, epithelial surface (painful red glossitis), stomach, small intestine, urinary, female genital tracts

449
Q

List the types of acquired haemolytic anaemia

A

Autoimmune - warm type (IgG) and cold type (IgM) Isoimmune - haemolytic disease of the newborn (HDN) Non-immune - mechanical fragmentation haemolysis

450
Q

Describe the progression and management of myeloproliferative disorders

A
  • Essential thrombocytopaenia and polycythaemia rubra vera - good outcome, risk of vascular events (prescribe aspirin), cytoreduction (hydroxycarbamide, venesection or interferon), 5-10% risk of AML, 10% progress to myelofibrosis
  • Myelofibrosis - difficult, large spleen, systemic symptoms, blood counts high or low, incurable other than with SCT. New class of drugs = JAK2 inhibitors
451
Q

What are the side effects of tPA derivatives?

A
  • Significant risk of haemorrhage
  • Any organs, particularly intracerebral
    • Stroke - large ischaemic or small stroke
  • Risk of bleeds increased in
    • Elderly
    • Later administration
    • Uncontrolled diabetes
452
Q

Describe the actions of antiplatelet drugs

A
  • Actions
    • Inhibit platelet activation
    • Inhibit platelet aggregation
  • Achieved via
    • Platelet receptor inhibition
    • Platelet signalling pathway inhibition
453
Q

Compare the pharmacological properties of tPA derivatives

A
  • Alteplase/Tenecteplase
    • Very short half life (4-5 mins)
    • Given as bolus, then infusion
  • Reteplase
    • Longer half life
    • Bolus only
454
Q

What factors affect choice of treatment in lymphoma?

A

Type of lymphoma Stage of lymphoma Age Performance status Co-morbidities Support e.g. family circumstances Patient’s preference

455
Q

Give examples of severe inherited platelet disorders

A
  • Glansmanns thrombasthenia
    • Absent/defective GP IIb/IIIa (alpha-IIb-beta3)
    • Normal platelet count
  • Bernard Soulier syndrome
    • Absent/defective GP Ib/V/IX
    • Macrothrombocytopenia
456
Q

Describe the morphology of RBC when ESR is raised?

A

RBC rouleaux form - ‘stack of coins’ RBC

Medicine Year 3 (15 decks)

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