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Y5 Pathology > Haematology > Flashcards

Haematology Flashcards

1
Q

What 3 factors make up Virchow’s triad?

A
  • Blood composition (viscosity, coagulability etc)
  • Vessel wall
  • Blood flow
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2
Q

What factors affect the bloods viscosity?

A
  • Polycythaemia - high haematocrit
  • Protein/paraprotein
  • Thrombocytosis - high platelets
  • Excess procoagulants
  • Reduced anti-coagulants - Protein C, S and anti-thrombin deficiency
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3
Q

What causes the vessel wall to switch from anti-thrombotic to thrombotic?

A
  • Infection
  • Malignancy
  • Vasculitis
  • Trauma
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4
Q

What are the mechanism that causes the vessel wall to become more thrombotic?

A
  • Anti-coagulant molecules down-regulated
  • Adhesion molecules upregulated
  • Tissue factor expressed
  • Prostacyclin reduced
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5
Q

What causes stasis to occur?

A
  • Immobility - surgery, air travel
  • Compression - tumour, pregnancy, obesity
  • Viscosity - polycythaemia, paraprotein
  • Congenital - vascular abnormalities
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6
Q

What are the mechanisms that causes stasis?

A
  1. Accumulation of activated factors
  2. Promotes platelet adhesion
  3. Promotes leukocyte adhesion and transmigration
  4. Hypoxia produces inflammatory effect on endothelium
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7
Q

What is the mechanism of heparin?

A
  • Potentiate antithrombin 3 - inhibits thrombin and factor X
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8
Q

What are the long-term disadvantages of unfractionated heparin?

A
  • Infections
  • Osteoporosis
  • Heparin induced thrombocytopenia (HIT)
  • Variable renal dependence
  • Complicated pharmacokinetics
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9
Q

What is the advantage of LMWH heparin over unfractionated?

A

Reliable pharmacokinetics - Doesn’t need monitory unless renal impairment or extreme weight/risk or late pregnancy

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10
Q

What is the antidote of heparin?

A

Protamine sulphate

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11
Q

What is the target for rivaroxaban?

A

Anti-10a

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12
Q

What is the target for apixaban?

A

Anti-10a

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13
Q

What is the target for dabigatran?

A

Anti-2a

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14
Q

What are the properties of DOACs?

A

Immediate; peak 3-4 hours Useful in long-term too Short half-life No monitoring needed Can be given orally

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15
Q

What is the mechanism of warfarin?

A

Indirect effect by inhibiting Vitamin K epoxide reductase so cant regenerate active vitamin K

  • Reduces pro-coagulant factors 2, 7, 9 and 10 (2-3 delay in anti-coagulant effect)
  • Also reduces levels of protein C, S and Z anti-coagulants (immediate procoagulant effect)
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16
Q

What is the antidote of warfarin?

A

IV Vitamin K - 6-12 hour delay Replacement of factors (prothrombin complex concentrate) - immediate

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17
Q

What are the disadvantages of warfarin?

A
  • Requires monitoring
  • Dietary vitamin K
  • Variable absorption Interactions with other drugs
  • Crosses placenta and is teratogenic
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18
Q

What scoring system is used for suspected PE?

A

Wells score

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19
Q

What is the next investigation for a Wells score for a suspected PE?

A
  • High - Doppler USS or CTPA
  • Intermediate - D-dimer - if high = ultrasound/CTPA
  • Low - consider alternative diagnosis
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20
Q

What is the treatment of DVT/PE?

A
  1. Immediate anti-coagulation - start LMWH and Warfarin (or a NOAC) (stop LMWH when INR >2 for 2 days (INR 2-3)) 2. Continue for 3-6 months Supplementary oxygen ect
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21
Q

When is thrombolysis (tPA) used in the context of PE or DVT?

A
  • Life-threatening PE
  • Limb-threatening DVT
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22
Q

What is the mechanism of thrombolysis?

A

Potentiates body fibrinolytic system

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23
Q

How is thrombosis recurrence prevented?

A

Long-term anti-coagulation - Consideration of bleeding must be done

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24
Q

What group of patients are at high risk of a recurrence in a thrombosis?

A
  • Post-surgery = very low recurrence
  • Non-surgical/flight/COCP = higher risk
  • Idiopathic/unprecipitated = highest risk of recurrence
  • Males have higher recurrence risk than women
  • Site dependent - distal sites = lower risk than proximal
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25
Q

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

A
  • Post-surgery = no need for long-term anticoagulation
  • After minor precipitants = 3 months therapy
  • Idiopathic and age > 60 years = offer CT scan to identify any underlying disease and at least 3 months anticoagulation
  • First VTE with known cause: 3 months
  • Cancer VTE: 3-6 months
  • 1st VTE unknown cause: 3-6 months, possibly lifelong
  • 1st VTE in thrombophilic patient: 3 months, possibly lifelong
  • Recurrent VTE: lifelong
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26
Q

What patients are given an INR target of 2.5?

A
  • Treatment of DVT/PE
  • Atrial fibrillation
  • Cardiomyopathy
  • Symptomatic inherited thrombophilia
  • Systemic embolism after MI
  • Cardioversion
  • Bio-prosthetic mitral or mechanical aortic valve (mechanical mitral valve = 3)
  • MI
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27
Q

What patients are given an INR target of 3.5?

A

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

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28
Q

What management must occur for a patient on warfarin who is suffering from major bleeding?

A
  • Stop warfarin
  • Give Vitamin K slow infusion
  • Prothrombin complex
    • If unavailable, can give FFP but not as effective
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29
Q

What management must occur for a patient on warfarin who has an INR <8 but isn’t bleeding?

A
  • Stop warfarin
  • Give Vitamin K and repeat if needed after 24 hours
  • Restart warfarin when INR <5
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30
Q

What management must occur for a patient on warfarin with an INR 5-8 who is suffering from minor bleeding?

A

Stop warfarin Give Vitamin K Restart warfarin with INR <5

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31
Q

What management must occur for a patient on warfarin with an INR 5-8 but isn’t bleeding?

A

Withhold 1-2 doses of warfarin

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32
Q

Define polycythaemia.

A

Raised haemoglobin concentration and raised haematocrit.

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33
Q

What is pseudopolycythaemia?

A

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

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34
Q

What are the causes of true polycythaemia?

A
  • Secondary/non-malignant
  • Primary/myeloproliferative neoplasm
    • Philadelphia chromosome -ve = Polycythaemia vera, Essential Thrombocythaemia or Myelofibrosis
    • Philadelphia chromosome +ve = Chronic myeloid leukaemia (CML)
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35
Q

What happens to EPO in true and relative polycythaemia?

A

True = suppressed

Relative = raised

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36
Q

What are the causes of relative polycythaemia?

A

Alcohol

Obesity

Diuretics

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37
Q

What is the difference between chronic and acute leukaemias?

A

Chronic = excess mature/differentiated cells

Acute = excess immature/undifferentiated cells

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38
Q

What genetic mutations exist in myeloproliferative disorders?

A

JAK2 - most common is JAK2 V617F

Calreticulin

MPL

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39
Q

What is the role of tyrosine kinases?

A

Transmit cell growth signals from surface receptors to nucleus

Activated by transferring phosphate groups

Normally held tightly in inactive state

Promote cell growth but do NOT block maturation

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40
Q

How common are JAK2 mutations in MPDs.

A

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

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41
Q

Describe the mechanism of JAK2.

A

JAK2 is a tyrosine kinase that is normally bound to the inactive EPO receptor

  1. EPO binds to the EPO receptor, receptor dimerises and autophosphorylates and phosphorylates JAK2
  2. This activates the JAK2 signalling pathway resulting in the normal response to EPO
    - In JAK2 mutation, the JAK2 signalling pathway is constitutively active causing a EPO response in absence of EPO
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42
Q

What is the diagnosis of MPD based on?

A
  • Clinical features
    • Symptoms
    • Splenomegaly
  • FBC ± bone marrow biopsy (increased cellularity)
  • EPO level (low)
  • Mutation testing (phenotype linked to acquired mutation)
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43
Q

What causes of true polycythaemia have appropriately raised EPO?

A
  • High altitude
  • Hypoxic lung disease (COPD)
  • Cyanotic heart disease
  • High affinity haemoglobin
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44
Q

What causes of true polycythaemia have inappropriately raised EPO?

A
  • Renal disease
  • Uterine myoma
  • Other tumours (liver, lung)
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45
Q

What is the clinical presentation of polycythaemia vera?

A
  • Incidental - most commonly 60 year old male
  • Symptoms of hyperviscosity - headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea
  • Symptoms of histamine release - aquagenic pruritus, peptic ulceration
  • High RBC, Hb, platelets, WCC
  • JAK2 V617F mutation
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46
Q

What is the treatment of polycythaemia vera?

A
  • Venesection
  • Hydroxycarbamide (cytoreductive therapy) - less DNA synthesis in RBCs
    • Keep plts <400 x 109/L
    • Keep Hct <45%
  • Aspirin
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47
Q

Define essential thrombocythaemia?

A

Chronic myeloproliferative disorder involving megakaryocytic lineage

  • Sustained thrombocytosis >600 x 109/L
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48
Q

What is the epidemiology of essential thrombocythaemia?

A
  • Bimodal age distribution = 30 years (minor peak) then 55 years
  • 30yo (M = F) but at 55 years (F > M)
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49
Q

What is the epidemiology of polycythaemia vera?

A

M > F

Mean age at diagnosis = 60yo (5% <40yo)

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50
Q

WHat is the clinical presentation of essential thrombocythaemia?

A
  • Incidental (50% of cases)
  • Symptoms of thrombosis – CVA, gangrene TIA, DVT/PE
  • Symptoms of bleeding
  • Symptoms of hyperviscosity (headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea)
  • Splenomegaly
  • Mutations (JAK2, calreticulin, MPL)
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51
Q

What is the treatment of essential thrombocythaemia?

A
  • Aspirin (thrombosis prevention)
  • Hydroxycarbamide (antimetabolite that suppresses cell turnover)
  • Anagrelide (inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing)
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52
Q

What is the prognosis of essential thrombocythaemia?

A
  • Normal life span in many patients
  • Leukaemic transformation in about 5% over 10 years
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53
Q

Define primary myelofibrosis.

A
  • Clonal myeloproliferative disease associated with reactive bone marrow fibrosis
  • Characterised by extramedullary haematopoiesis
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54
Q

What is the epidemiology of primary myelofibrosis?

A

60-70yo

M=F

0.5-1.5/100,000/year

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55
Q

What is the clinical presentation of primary myelofibrosis?

A
  • Incidental in 30%
  • Presentations related to:
    • Cytopaenias (anaemia, thrombocytopaenia)
    • Thrombocytosis
    • Splenomegaly - Budd-Chiari syndrome
    • Hepatomegaly
    • Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia)
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56
Q

What tests are ordered for suspected primary myelofibrosis?

A

Blood film

Bone marrow

Liver and spleen analysis

DNA analysis

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57
Q

What blood film results would be expected for primary myelofibrosis?

A
  • Leucoerythroblastic picture
  • Tear drop poikilocytosis
  • Giant platelets
  • Circulating megakaryocytes
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58
Q

What bone marrow results would be expected for primary myelofibrosis?

A
  • Dry tap
  • Trephine biopsy:
    • Increased reticulin or collagen fibrosis
    • Increased megakaryocytes with clustering
    • New bone formation
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59
Q

What is the prognosis of primary myelofibrosis?

A
  • Median 3-5 years survival (however, very variable)
  • BAD prognostic signs:
    • Severe anaemia < 100 g/L
    • Thrombocytopaenia < 100 x 109/L
    • Massive splenomegaly
    • High DIPPS score (score 6 à 1.3 years)
  • Other MPD (ET and PV) may transform into PMF
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60
Q

What is the treatment of primary myelofibrosis?

A
  • Supportive - transfusion of RBC or platelets (often ineffective)
  • Cytoreductive Therapy - hydroxycarbamide (for thrombocytosis, may worsen anaemia)
  • HSCT - potentially curative (reserved for high risk eligible cases)
  • Splenectomy - symptomatic relief but a dangerous operation
  • Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)
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61
Q

Define chronic myeloid leukaemia.

A

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

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62
Q

What is the epidemiology of chronic myeloid leukaemia?

A
  • M>F
  • 40-60yo (however, affects any age)
  • Radiation is a major risk factor
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63
Q

What is the clinical presentation of CML?

A
  • History:
    • Lethargy
    • Hypermetabolism
    • Thrombotic event (mono-ocular blindness, CVA, bruising, bleeding)
  • Massive splenomegaly/hepatomegaly
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64
Q

What will be the results of full blood count and blood films for a CML patient?

A
  • Full Blood Count:
    • Hb and platelets are normal or raised
    • Leucocytosis (50-500 x 109/L)
  • Blood Film:
    • Neutrophils
    • Myelocytes
    • Basophilia
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65
Q

Describe the phases of CML?

A
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66
Q

Describe the mutation causing CML?

A
  • ABL is a tyrosine kinase (normally, we do not express high levels of TK in the body)
  • However, BCR is a housekeeping gene that is constitutively expressed
  • This results in the BCR-ABL fusion gene being constitutively expressed and constitutively activated
  • This drives cell replication in cells containing the Philadelphia chromosome
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67
Q

What are the diagnostic techniques needed to diagnose CML?

A
  • Conventional karyotyping
  • FISH
  • RT-PCR amplification and detection
    • Help determine response to therapy
  • FBC and leucocyte count
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68
Q

WHat is the treatment of CML?

A
  • Chronic phase tyrosine kinase inhibitor - Imatinib
    • 1st Gen – Imatinib
    • 2nd Gen – Dasatinib, Nilotinib
    • 3rd Gen – Bosutinib
  • FAILURE 1 – switch to 2nd gen or 3rd gen tyrosine kinase inhibitor
    • Considered a failure if there is NO CCyR at 1 year OR if they respond but acquire resistance
  • FAILURE 2 – consider allogeneic stem cell transplantation
    • Considered a failure if there is an inadequate response to 2nd generation TKIs OR if the disease progresses to accelerated or blast phase
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69
Q

How is imatinib effectiveness assessed?

A
  • FBC - haematological response:
    • Complete Haematological Response (WBC<10x109/L)
  • Cytogenetics - cytogenetic response (on 20 metaphases) – very sensitive
    • Partial 1-35% Philadelphia positive
    • Complete 0% Ph positive
  • RQ-PCR - molecular response (reduction in % BCR-ABL transcripts) – most sensitive
    • Major Molecular response (MMR) <0.1% (3 log reduction)
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70
Q

What are the issues of tyrosine kinase inhibitors, such as imatinib, for CML?

A
  • Non-compliance
  • Side-effects (fluid retention, pleural effusion)
  • Loss of major molecular response
    • Acquisition of ABL point mutations leads to treatment resistance
      • Evolution of a blast crisis
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71
Q

With the introduction of tyrosine kinase inhibitors what is the prognosis of CML?

A
  • 95% 5 year survival
  • Annual mortality 2%
  • Complete Cytogenic Response at 12months = 97%
    • Failure to achieve CCyR at 6 years = 80%
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72
Q

What is multiple myeloma?

A

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

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73
Q

Describe myeloma plasma cells.

A
  • Home and infiltrate the bone marrow
  • Form bone expansile or soft tissue tumours called plasmacytomas
  • Produce a serum monoclonal IgG or IgA: paraprotein or M-spike
  • Produce excess of monoclonal (κ or λ) serum free light chains
  • Bence Jones protein: urine monoclonal free light chains
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74
Q

Describe the epidemiology of multiple myeloma.

A
  • Median age 67 years
  • Incidence increases with age - 1% of patients are younger than 40 years
  • Men > women
  • Black > Caucasian and Asians
  • Prevalence of myeloma in the community is increasing
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75
Q

What are the risk factors for multiple myeloma?

A
  • Obesity
  • Increasing age
  • Genetics
    • Incidence in black population
    • Sporadic cases of familiar myeloma
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76
Q

What always preceeds multiple myeloma?

A

Monoclonal Gammopathy of Uncertain Significance (MGUS)

  • MGUS becomes smouldering myeloma and then MM
  • Both have NO symptoms - symptoms begin at MM
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77
Q

What are the diagnostic criteria for MGUS?

A
  • Serum M-protein <30g/L
  • Bone marrow clonal plasma cells <10%
  • No lytic bone lesions
  • No myeloma-related organ or tissue impairment
  • No evidence of other B-cell proliferative disorder
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78
Q

What is the epidemiology of MGUS?

A
  • Most common premalignant condition
  • Incidence increases with age
  • 1% - 3.5% in elderly population
  • Average risk for progression = 1% annually
    • IgG or IgA MGUS → myeloma
    • IgM → lymphoma
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79
Q

What are the complications of MGUS?

A
  • Higher incidence of osteoporosis
  • HIgher incidence of thrombosis
  • Increased risk of bacterial infection
  • Progression to MM or lymphoma
  • Reduce survival rate compared to matched control group - Kyle R, NEJM 2018
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80
Q

How is the risk of progression to MM from MGUS stratified and monitored?

A

Mayo Criteria Risk Factors

  • Risk Factors
    • Non-IgG M-spike
    • M-spike >15g/L
    • Abnormal serum free light chain (FLC) ratio
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81
Q

What is the definition of smoulding myeloma?

A
  • Smouldering myeloma = No CRAB S/S
    • Monoclonal serum protein ≥ 30g/L
    • BM plasma cells ≥ 10%
    • Annual risk of progression to MM 10%
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82
Q

What are the primary genetic events that evolve into MM?

A
  • Hyperdiploidy (60%)
    • Additional odd number Chr
  • IGH rearrangements (Chr 14q32)
    • t(11;14) IGH/CCND1
    • t(4;14) IGH/FGFR3
    • t(14;16) IGH/MAF
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83
Q

What happens after a primary genetic mutation in the pathogenesis of MM?

A
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84
Q

What are the common secondary genetic events that evolve into MM?

A
  • KRAS, NRAS - 50%
  • t(8;14) IGH/MYC
  • 1q gain / 1p del
  • del 17p (TP53)
  • 13- / del 13q
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85
Q

What happens after a secondary genetic mutation in the pathogenesis of MM?

A

Smouldering myeloma develops before becoming MM

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86
Q

What are the diagnostic criteria of MM?

A

CRAB

  • C: Hypercalcaemia - calcium >2.75mmol/L
  • R: Renal disease - creatinine >177μmol/L or eGFR <40ml/min
  • A: Anaemia - Hb <100g/L or drop by 20g/L
  • B: Bone disease - One or more bone lytic lesions in imaging
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87
Q

What investigations should be carried out for suspected MM?

A
  • Electrophoresis (dense band of monoclonal proteins, often IgG or IgA)
  • Rouleaux stacks on blood film
  • Bence-Jones proteins in urine
  • Blood
    • ESR high
    • >10% plasma cells in BM
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88
Q

What is the staging for MM?

A

Durie-Salmon

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89
Q

What investigations should be done for suspected MM?

A
  • Immunoglobulin studies
    • Serum protein electrophoresis
    • Serum free light chain levels
    • 24h Bence-Jones protein
  • Bone marrow aspirates and biopsy
  • FISH
  • Flow cytometry immunophenotyping
  • Bence-Jones proteins in urine
  • Bloods
    • Rouleaux stacks on blood film
    • ESR high
    • >10% plasma cells in BM
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90
Q

What will be positive and negative for plasma cell immunophenotyping in MM?

A
  • Positive:
    • CD38
    • CD138
    • CD56/58
    • Monotypic cytoplasmic Ig
    • Light Chain restriction (Kappa or Lambda positive)
  • Negative:
    • CD19
    • CD20
    • Surface Ig
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91
Q

What are the clinical presentations/presenting complaints of MM?

A
  • Proximal skeleton
  • Back (spine), chest wall and pelvic pain
  • Osteolytic lesions, never osteoblastic
  • Osteopenia
  • Pathological fractures
  • Hypercalcaemia
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92
Q

What are the emergencies that occur in MM?

A

Cord compression

Hypercalcaemia

Myeloma kidney disease

Infections - particularly pneumonia/chest infections

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93
Q

What is the management of cord compression?

A
  • Dexamethasone
  • Radiotherapy
  • Neurosurgery - rarely required
  • Stabilise unstable spine
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94
Q

What is the definition of myeloma kidney disease?

A
  • Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)
  • Acute kidney injury and result of myeloma
    • 20-50% acute kidney injury at diagnosis
    • 2-4% of newly diagnosed patients will require dialysis
    • 25% develop renal insufficiency at relapse
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95
Q

What are the causes of myeloma kidney disease?

A
  • Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria
  • Indirect consequences
    • Hypercalcaemia
    • Loop diuretics
    • Infection
    • Dehydration
    • Nephrotoxics
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96
Q

What are amyloid fibrils?

A

Misfolded free light chain aggregates into amyloid fibrils in target organs

  • Organised into solid, non-branching and randomly arranged with a diameter of 7 – 12 nm
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97
Q

What stain is used for amyloid fibrils?

A

Congo red

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98
Q

What organs are commonly affected by amyloidosis?

A
  • Kidney
  • Heart
  • Liver
  • Neurons
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99
Q

What is the clinical presentation of amyloidosis?

A
  • Nephrotic syndrome (70%)
    • Proteinuria (not BJP!)
    • Peripheral oedema
  • Unexplained heart failure → determinant of prognosis
    • Raised NT-proBNP
    • Abnormal echocardiography and cardiac MRI
  • Sensory neuropathy
  • Abnormal liver function tests
  • Macroglossia
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100
Q

What are the treatment options for MM?

A

Alkylating agents

Proeasome inhibitors

Thalidomide

Monoclonal Antibodies - daratumumab

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101
Q

How do alkylating agents work in the treatment of cancer/MM?

A

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

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102
Q

How can alkylating agents be used in conjunction with surgery?

A

Autologous Haematopoietic Stem Cell Transplant:

  1. Stem cells collected from blood and stored
  2. High dose melphalan used to kill myeloma cells
  3. Re-infusion of stem cells to rescue blood formation
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103
Q

How are dexamethasone and prednisolone used in the treatment of MM?

A
  • Induce apoptosis in myeloma cells
  • Strong synergy - part of almost all combination regimens
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104
Q

How does thalidomide work in the context of treating in the context of MM?

A
  • Targets the turnover of transcription factors that are particularly important for myeloma cell survival
  • Often used alongside cyclophosphamide and dexamethasone
  • Newer more potent drugs exist - lenalidomide, pomalidomidem iberdomide
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105
Q

What is the mechanism of proteasome inhibitors in MM?

A
  • Large enzyme complex degrades most intracellular proteins (i.e. damaged proteins) by ubiquinating (adding a functional group) and marking the protein for degradation
    • This is called ER-associated degradation (ERAD)
    • This is necessary to prevent cell death from accumulation
  • Inhibiting these proteasome, causes accumulation of misfolded proteins in the myeloma cells leading to myeloma cell death
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106
Q

Name 2 proteasome inhibitors.

A
  • Bortezomib
  • Carfilzomib
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107
Q

What is the mechanism of daratumumab?

A

IgG1k monoclonal antibody directed against CD38

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108
Q

When is daratumumab monotherapy used in the treatment of MM?

A

Relapsed/refractory myeloma

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109
Q

What blood test results would occur for iron deficicency anaemia?

A
  • Microcytic hypochromic anaemia
  • Reduced Ferritin
  • Reduced TF saturation
  • Raised TIBC
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110
Q

What is leucoerythroblastic anaemia?

A

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

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111
Q

What morphology is found in peripheral blood films of leucoerythroblastic anaemia?

A
  • Teardrop RBCs – aniso and poikilocytosis
  • Nucleated RBCs
  • Immature myeloid cells
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112
Q

What is leucoerythroblastic anaemia usually the first sign of?

A

Bone marrow malignancy

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113
Q

What are the causes of leucoerythroblastic anaemia?

A
  • Malignant – primary or metastatic
  • Severe infection
  • Myelofibrosis
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114
Q

What is haemolytic anaemia?

A

Anaemia due to shortened RBC survival

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115
Q

What are the common lab features of haemolytic anaemia?

A
  • Anaemia – may be compensated
  • Reticulocytosis = haemolytic – if reticulocytes then haemolytic
  • Unconjugated bilirubin raised – pre-hepatic
  • LDH raised
  • Haptoglobins reduced
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116
Q

What are the causes of haemolytic anaemia?

A
  • Inherited - defects of the red cell
    • Membrane – hereditary spherocytosis
    • Cytoplasm/enzyme – G6PD deficiency
    • Haemoglobin – SCD (structural) or thalassemia (quantitative)
  • Acquired - RBC is healthy but is due to defects in the environment/body
    • Immune-mediated – DAT-positive/Coombs test positive
    • Non-immune mediated
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117
Q

What do DAT and/or Coombs test positive results indicate?

A

Immune-mediated haemolytic anaemia

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118
Q

What are some causes of warm AIHA?

A
  • IgG and Extravascular haemolysis
    • Lymphoma
    • CLL
    • Drug allergy
    • SLE
    • Idiopathic
  • 80-90%
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119
Q

What are some causes of cold AIHA?

A
  • IgG and Extravascular haemolysis
    • Lymphoma
    • CLL
    • Drug allergy
    • SLE
    • Idiopathic
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120
Q

What is the management of warm AIHA?

A
  • Steroids
  • Splenectomy
  • Immunosuprression
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121
Q

What is the management of cold AIHA?

A
  • Treat underlying condition
  • Avoid the cold - often associated with Raynaud’s
  • Chemotherapy
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122
Q

What are the causes of non-immune mediated anaemia?

A
  • Infection - malaria (commonest WW)
  • Micro-angiopathic haemolytic anaemia (MAHA)
    • Adenocarcinoma
    • HUS
    • TTP
  • Paroxysmal nocturnal haemoglobinuria
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123
Q

How does malaria causes non-immune mediated anaemia?

A
  • Parasite enters the RBC, causes it to die, shortening survival of RBC
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124
Q

How does adenocarcinoma cause MAHA?

A
  1. Underlying adenocarcinoma releases granules into circulation
  2. These are pro-coagulant and activate the coagulation cascade
    • Platelet activation, fibrin deposition, degradation
  3. Red cell fragmentation due to low-grade DIC
  4. Bleeding (low platelet and coagulation factor deficiency)
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125
Q

What are the causes of neutrophilia?

A
  • Corticosteroids
  • Underlying neoplasia
  • Tissue inflammation - colitis or pancreatitis etc
  • Myeloproliferative or leukemic disorders
  • Pyogenic infection (most likely)
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126
Q

What infections don’t produce neutrophilia?

A
  • Brucella
  • Typhoid
  • Viral infections
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127
Q

How can malignant neutrophilias be distinguished from each other and reactive/infective?

A
  • Neutrophilia/basophilia + immature cells/myleocytes + splenomegaly = CML
  • Neutropenia + myeloblasts = AML
  • Malignancy causes a much higher/massive neutrophila
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128
Q

What are the causes of eosinophilia?

A
  • Reactive
    • Parasitic infection
    • Allergic diseases - asthma, rheumatoid, polyarteritis, pulmonary eosinophilia
    • Underlying neoplasms - Hodgkin’s, T-cell NHL
    • Drugs - reaction erythema multiforme
  • Chronic eosinophilic leukaemia
    • Eosinophils part of clone
    • FIP1L1-PDGFRa fusion gene
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129
Q

What are some causes of basophilia?

A
  • Pox viruses
  • CML
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130
Q

What are some causes of monocytosis?

A
  • Chronic infection
    • TB, brucella, typhoid
    • Viral, CMV, varicella zoster
  • Sarcoidosis
  • Chronic myelomonocytic leukaemia (CMML, myelodysplastic syndrome)
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131
Q

What are some causes of lymphocytosis?

A
  • EBV, CMV, Toxoplasma
  • Infectious hepatitis, rubella, herpes infections
  • Autoimmune disorder
  • Sarcoidosis
  • Lymphocytic leukaemia
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132
Q

What are some causes of lymphopenia?

A
  • HIV
  • Auto immune disorders
  • Inherited immune deficiency syndromes
  • Drugs (chemotherapy)
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133
Q

What does lymphocyte morphology tell you about the cause of lymphocytosis?

A
  • Mature lymphocytes (PB)
    • Reactive/atypical lymphocytes
    • Small lymphocytes and smear cells (CLL/NHL)
  • Immature lymphoid cells (PB)
    • Lymphoblasts (ALL)
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134
Q

What does lymphocyte clonality tell you about the cause of lymphocytosis?

A
  • Polyclonal = kappa and lambda = Reactive
  • Monoclonal = kappa ONLY or lambda ONLY = Malignant
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135
Q

What acquired somatic mutation cause leukaemia and lymphoma?

A
  • Cellular proliferation - mutations in Tyrosine Kinase genes causing excess proliferation
    • BCR-ABL = CML
    • JAK2 = MPD
  • Impair/block cellular differentiation - mutations in transcription factors block differentiation (only cuases leukaemia if present with proliferation mutation)
    • PML RARA in APL
  • Prolong cell survival - mutations in apoptosis genes in leukaemia
    • BCL2 = follicular lymphoma
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136
Q

What analysis can be done on a tissue biopsy (blood for haemtological) for suspected cancer?

A
  • Morphology
    • Malignant cells; large or small, mature or immature?
    • Lymph node diffuse invasion or forming follicles?
  • Immunophenotype (flow cytometry or Immunohistology)
    • Myeloid or lymphoid? T or B lineage?
    • Stage of maturation precursor or mature?
  • Cytogenetics (translocations or FISH studies)
    • Confirm genetic morphology e.g. Philadelphia Chromosome > CML
    • Prognostic information e.g. 17p del in CLL
    • t(8;14) activates c-myc oncogene in Burkitt Lymphoma
  • Molecular genetics (PCR, pyro sequencing)
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137
Q
  • IDA
  • Anaemia of chronic disease
  • BM mets from breast Ca
  • MAHA
  • AIHA
A
  • ​BM mets from breast cancer
    • ​IDA - wouldn’t expect jaundice or nucleated RBCs
    • MAHA - Not get leucoerythroblastic problems in blood as BM is healthy
    • AIHA - AIHA is DAT-positive
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138
Q
  • B cell acute lymphoblastic leukaemia
  • Mature B cell lymphoproliferative disorder (e.g. CLL)
  • Infectious mononucleosis (e.g. EBV)
  • T cell acute leukemic lymphoma
A
  • Mature B cell lymphoproliferative disorder (e.g. CLL)
    • No abnormal cells in the blood (all mature cells)
      • Infectious mononucleosis (e.g. EBV)
        • IgG serology is historical (past infection), IgM is current
        • Would expect 50/50 proliferation of Kappa/Lambda
      • T cell acute leukemic lymphoma
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139
Q

Define Lymphoma.

A
  • Neoplastic tumour of lymphoid cells; usually found in:
    • Lymph nodes, bone marrow and/or blood (the lymphatic system)
    • Lymphoid organs; spleen or the gut-associated lymphoid tissue
    • Skin (often T cell disease; e.g. Mycoses Fungoides)
    • Rarely “anywhere” (CNS, ocular, testes, breast, etc.)
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140
Q

What are the classifications of lymphoma?

A
  • Acute Lymphoblastic Leukaemia (ALL)
  • Non-Hodgkin Lymphomas (B-cell lineage)
  • Non-Hodgkin Lymphomas (T and NK cell lineage)
  • Hodgkin Lymphoma
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141
Q

What processes lead to lymphoma?

A
  • Recombination – DNA molecules cut and recombined (deliberate point mutations to provide diversity)
    • Unwanted point mutations
  • Rapid cell proliferation in germinal centres
    • Replication errors
  • Apoptosis dependency - 90% lymphocytes die in germinal centres
    • Acquired DNA mutation in apoptosis-regulating genes
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142
Q

Describe TCR gene recombination.

A

2 STAGES

  • 1) VDJ recombination – creates a molecule that recognises an epitope:
    • Occurs in bone marrow
    • Involves enzymes: RAG1 and RAG2
  • 2) Class switch recombination
    • Somatic hypermutation in germinal centre
      • Ig promotor highly active in B-cells to drive AB production
      • Recombination errors occur
      • Oncogenes brought close to the promotor
        • Bcl2
        • Bcl6
        • (C-)MYC
        • CyclinD1
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143
Q

What are the risk factors for lymphoma?

A
  • Immune system diseases
    • B-cell NHL Marginal Zone Lymphoma sub-type = H. pylori, syndrome, Hashimoto’s
    • Enteropathy associated T-cell NHL = Coeliac disease
  • Viral infection (direct viral integration of lymphocytes)
    • HTLV1 retrovirus
  • Loss of T-cell function
    • EBV infects B-cells stimulating proliferation → EBV switches on at later life and drives proliferation through HIV or immunosuppression
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144
Q

Describe the lymphoreticular system.

A
  • Generative → generation/maturation of lymphoid cells
    • Bone marrow and thymus
  • Reactive → development of immune reaction
    • Lymph nodes and spleen
  • Acquired→ development of local immune reaction
    • Extra-nodal lymphoid tissue (e.g. skin, stomach, lung)
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145
Q

What are the cells of the lymphoreticular system?

A
  • Lymphocytes
    • B lymphocytes
    • T lymphocytes
  • Accessory Cells:
    • Antigen-presenting cells
    • Macrophages
    • Connective tissue cells
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146
Q

Describe this lymph node histology.

A
  • Rounded areas = B cell follicles
  • Between B cell follicles = T cell areas
  • Central medulla = where mature B cells eventually end up
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147
Q

Name the lymphoma CD markers.

A
  • CD19, CD20 = B-cells
  • CD3, CD5 = T-cells
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148
Q

What are the appropriate investigations for suspected lymphoma?

A
  • Cytology
  • Histology
    • Architecture (nodular, diffuse)
    • Cells – large cells are suggestive of a high-grade lymphoma
  • Immunophenotyping → identify proteins on/in the cells – i.e. determine cell lineage
  • Cytogenetics
    • FISH – identify chromosome translocations
      • DIAGNOSTIC – i.e. t (11; 14) = Mantle Cell Lymphoma
      • PROGNOSTIC – i.e. t (2; 5) = Anaplastic Large Cell Lymphoma
      • PCR – identify chromosome translocations, clonal T cell receptor or Ig gene rearrangement
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149
Q

What are the most common types of low, high and aggressive grade B-cell NHL?

A
  • Low-grade:
    • Follicular lymphoma
    • Small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL)
    • Marginal zone lymphoma (MALT)
  • High-grade:
    • Diffuse large B cell lymphoma
    • Mantle zone lymphoma
  • Aggressive:
    • Burkitt’s lymphoma
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150
Q

What are the specific signs and symptoms of follicular lymphoma?

A

Lymphadenopathy in the middle-aged or elderly

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151
Q

What is the histopathology of follicular lymphoma?

A
  • Follicular pattern:
    • Follicles are neoplastic
    • Often these follicles spread out of the node into the adjacent tissues
  • Germinal centre cell origin:
    • Positive stain for CD10 and BCL-6
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152
Q

What is the molecular pattern in follicular lymphoma?

A
  • t (14;18) translocation involving BCL-2 gene
  • Usually indolent, but can transform into high grade lymphoma
153
Q

What are the specific signs and symptoms of small lymphocytic lymphoma?

A

Middle-aged or elderly

154
Q

What is the histopathology of small lymphocytic lymphoma?

A
  • Small lymphocytes
  • Arises from naïve B cells or post-germinal centre memory B cells (CD5 and CD23 positive)
  • They replace the entire lymph node so that you no longer see follicles or T cell areas
155
Q

What is the molecular pattern in small lymphocytic lymphoma?

A
  • Multiple genetic abnormalities
  • Indolent, but can transform into a higher-grade lymphoma (Richter transformation)
156
Q

What are the specific signs and symptoms of diffuse large B-cell lymphoma?

A
  • Middle-aged or elderly
  • Lymphadenopathy
157
Q

What is the histopathology of diffuse large B-cell lymphoma?

A
  • Arise from germinal centre or post-germinal centre B cells
  • LARGE lymphoid cells
  • The lymph node is effaced so it is not possible to identify germinal centres and follicles
158
Q

What is the prognosis of diffuse large B-cell lymphoma?

A
  • Having a germinal centre phenotype is associated with a GOOD prognosis
  • p53 positive and high proliferation fraction is associated with a POOR prognosis
159
Q

What are the specific signs and symptoms of mantle-cell lymphoma?

A
  • Middle-aged males
  • Affects lymph nodes and the GI tract
  • Disseminated disease
160
Q

What is the histopathology of mantle-cell lymphoma?

A
  • Located in the mantle zone of the lymph node
  • Arise from pre-germinal centre cells
  • Aberrant expression of CD5 and cyclin D1
161
Q

What is the molecular pattern in mantle-cell lymphoma?

A
  • t(11;14) translocation
  • Cyclin D1 over-expression
162
Q

What is the prognosis of diffuse large B-cell lymphoma?

A
  • Having a germinal centre phenotype is associated with a GOOD prognosis
  • p53 positive and high proliferation fraction is associated with a POOR prognosis
163
Q

What are the specific signs and symptoms of Burkitt’s lymphoma?

A
  • Jaw/abdominal mass
  • Endemic (children/young adults)
  • Sporadic (elderly) or immunodeficiency ± EBV
164
Q

What is the histopathology of Burkitt’s lymphoma?

A
  • Starry-sky appearance
165
Q

What is the molecular pattern in Burkitt’s lymphoma?

A
  • C-myc translocation (8;14, 2;8 or 8;22)
166
Q

What are the general features of T-cell lymphoma?

A
  • Middle-aged and elderly
  • Presenting with lymphadenopathy and extra-nodal sites
  • Large T lymphocytes
  • Often found with an associated reactive cell population (especially eosinophils)
  • AGGRESSIVE
167
Q

What are the specific signs and symptoms of large cell lymphoma?

A
  • Children and young adults
  • Lymphadenopathy
168
Q

What is the histopathology of Burkitt’s lymphoma?

A
  • Large epithelioid lymphocytes
  • T cell or null phenotype (i.e. anaplastic)
169
Q

What is the molecular pattern in Burkitt’s lymphoma?

A
  • t (2;5) translocation = better prognosis
  • Alk-1 protein expression = better prognosis
170
Q

What are the type of Hodgkin’s lymphoma?

A
  • Classical Hodgkin Lymphoma
    • Nodular sclerosing
    • Mixed cellularity
    • Lymphocyte rich/depleted
  • Nodular Lymphocyte Predominant
    • Has some relationship to NHL
171
Q

What are the specific signs and symptoms of classical Hodgkin’s lymphoma?

A
  • Young and middle-aged
  • Single group of lymph nodes
  • Associated with EBV → symptoms related to EBV infection
172
Q

What is the histopathology of Burkitt’s lymphoma?

A
  • Sclerosis
  • Mixed cell population with REED-STERNBERG (binucleate ‘owl’s’ eyes)
  • Lymphoma cells are relatively few in number and tend to be scattered around
  • Eosinophils
173
Q

What is the prognosis of classical Hodgkin’s lymphoma?

A
  • Moderately aggressive
174
Q

What are the diagnostic markers for classical Hodgkin’s lymphoma?

175
Q

What are the specific signs and symptoms of nodular lymphocyte predominant Hodgkin’s lymphoma?

A
  • Isolated lymphadenopathy
176
Q

What is the histopathology of nodular lymphocyte predominant Hodgkin’s lymphoma?

A
  • B cell rich nodules
  • Scattered around L&H cells
177
Q

What are the diagnostic markers for nodular lymphocyte predominant Hodgkin’s lymphoma?

178
Q

What can nodular lymphocyte predominant Hodgkin’s lymphoma transform into?

A

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

179
Q

What is the diagnosis?

A

Classical Hodgkin’s Lymphoma

  • Reed-Sternberg cell in bottom left
180
Q

What is an Autologous Stem Cell Transplant?

A
  • GCSF given and obtain a CD34+ population of cells from the bone marrow
  • These are preserved in the freezer
  • A high dose of chemotherapy is given to eradicate the bone marrow → reinfuse the stem cells
181
Q

What are diseases are autologous transplants appropriate for?

A
  • Acute leukaemia
  • Myeloma
  • Solid tumours
  • Lymphoma
  • Autoimmune disease
  • CLL
182
Q

What is an Allogenic Stem Cell Transplant?

A
  • High dose chemoradiotherapy is given to ablate the bone marrow
  • Bone marrow from a healthy donor is transplanted in
183
Q

What are diseases are allogenic transplants appropriate for?

A

Used when patient’s disease is unlikely to be eradicated from the bone marrow by standard chemotherapy

  • Acute leukaemia
  • Chronic leukaemia
  • Thalassaemia
  • Myeloma
  • Lymphoma
  • SCD
  • Bone marrow failure
  • Congenital immune deficiencies
184
Q

Compare serological and DNA matching in donor selection.

A
  • Serological = Low-resolution → A*02
  • DNA = High-resolution → A*0201, A*0202, A*0203, …, A*0260
    • More likely to match at high resolution in a sibling match
    • Allele frequencies vary depending upon the ethnicity of the patient (for each allele – i.e. A*0202)
185
Q

What is the probability of matching with a sibling (as a donor)?

A

1-(3/4) number of siblings

186
Q

Describe bone marrow sampling.

A
  • 1.5L, 1% CD34+ → 15mL CD34
    • Puncturing the bone and getting into the medulla damages it, meaning that the first few millilitres that you collect will contain stem cells, however, the rest of it will be blood flooding into the damages site
      • So, you keep re-puncturing the bone, collecting a small amount at a time until you have a good harvest
    • Difficult → involves anaesthetising the patient and sampling some bone marrow from their pelvis
187
Q

Describe peripheral blood sampling.

A
  • 10L, 1% CD34+ → 100mL CD34
    • Hormones (e.g. G-CSF) can be used to stimulate granulocyte production (given 5 days before)
      • Leads to the bone marrow releasing some white cells as well as some stem cells
    • The donor is connected to a centrifuge device which spins the blood, removes the white cell component, reassembles the red cells and plasma and reinfuses it into the patient
188
Q

Describe umbilical cord stem cells.

A
  1. 1L, 1% CD34+ → 1mL CD34
    * Stem cells can be harvested at the time of delivery
189
Q

What are the complications of stem cell transplants?

A
  • Graft failure
  • Infections
  • Graft-versus-host disease - allografting only
  • Relapse
190
Q

What tool is used to assess a patients outcomes from a stem cell tranplant?

A

EBMT risk score:

  • Age = 20-40=1, >40=2
  • Disease phase = Int=1, Late=2
  • Gender of R/D = Female into male = 1
  • Time to BMT = >1 yr = 1
  • Donor = VUD = 1
  • Overall success rate
    • 80% survival in 0-1 score
    • 70% survival in 2 score
    • 50% survival in 3 score
    • 30% survival in 4 score
    • 15% survival in 5-7 score
191
Q

Describe Aspergillosis.

A
  • This is ubiquitous → opportunistic infection
    • Only really affects severely immunocompromised
  • Invasive aspergillosis = high mortality
    • 10-15% deaths after SCT are due to aspergillosis → 92% mortality
192
Q

Describe CMV infection.

A
  • Member of the herpes family
    • Remains latent because T cells are able to keep it under control
    • CMV pneumonia is a large cause of deaths in HSCT
193
Q

What are the risk factors for CMV after a SCT?

A
  • Patient’s serological status
  • Donor’s serological status
  • Type of stem cells donor (monocytes)
  • Type of transplant
  • CMV viral load
194
Q

Define Graft vs Host Disease.

A

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

195
Q

What are the signs and symptoms of graft vs host disease?

A
  • Acute → <100 days
    • Skin - rash, itchy, red
    • GI tract - diarrhoea
    • Liver - hepatitis, jaundice
  • Chronic → >100 days
    • Skin - rash
    • Liver - hepatitis, jaundice
    • Mucosal membranes - dry, mouth ulcers
    • Lungs - SoB
    • Eyes - dry
    • Joints - arthritis
196
Q

What are the risk factors for graft vs host disease?

A
  • Degree of HLA disparity
  • Recipient age
  • Conditioning regimen
  • R/D gender combination (D : M → R : F get worse GvHD)
  • Stem cell source
  • Disease phase
  • Viral infections
197
Q

What is the treatment of graft vs host disease?

A
  • Corticosteroids
  • Cyclosporin A
  • FK506
  • Mycophenolate mofetil
  • Monoclonal antibodies
  • Photopheresis
  • Total lymphoid irradiation
198
Q

What is the given to prevent graft vs host disease?

A
  • Corticosteroids
  • Ciclosporin A + methotrexate
  • FK506
  • T-cell depletion
  • Post-transplant cyclophosphamide
199
Q

What future therapy exist are there to improve future therapy?

A

CAR-T cells → engineer autologous T cells

200
Q

Describe CAR-T cell therapy?

A
  1. Leukapheresis - T-cells are collected
  2. T-cell activation - engineered chimeric-TCR put into a virus which infects the collected T-cells)
  3. Modified T-cell expansion - new T cells are expanded
  4. Quality and release testing
  5. Chemotherapy
  6. Modified T-cell infusion
201
Q

Describe the chimeric antigen receptor?

A
  • Retains the more effective intracellular components of the TCR (CD28 and CD3 intracellular components)
  • Extracellular portions are engineered in
  • These extracellular portions recognise CD19
202
Q

What are the side effects of CAR-T?

A
  • Tumour lysis syndrome
  • Cytokine release syndrome
    • Potentially fatal – chimeric T-cells can release massive amounts of cytokines
  • Neurologic toxicity
  • Cytopaenia - macrophage activation syndrome
  • B-cell aplasia - hypogammaglobulinaemia
203
Q

What are the presenting signs and symptoms of lymphoma?

A
  • Painless progressive lymphadenopathy
    • Palpable node
    • Extrinsic compression of any ‘tube’
  • Infiltration/Impairment of organ function
    • Skin rash, liver failure etc
  • Recurrent infections
  • Constitutional symptoms
  • Coincidental
204
Q

What are the signs and symptoms of Hodgkin’s lymphoma?

A
  • Painless enlargement of lymph nodes → may cause obstructive symptoms/signs
  • Constitutional symptoms:
    • B symptoms
      • Fever
      • Night sweats
      • Weight loss
    • Rarely: pruritis, alcohol-induced pain
205
Q

Describe nodular sclerosing HL.

A
  • F > M (20-29yo)
  • Neck nodes and a mediastinal mass
  • May have B symptoms
  • Spreads contiguously
  • Needs tissue diagnosis
206
Q

What are the classifications of Hodgkin’s lymphoma?

A
  • Classical HL:
    • Nodular sclerosing - 80% → Good prognosis (causes the peak incidence in young women)
    • Mixed cellularity - 17% → Good prognosis
    • Lymphocyte rich - rare → Good prognosis
    • Lymphocyte depleted - rare → Poor Prognosis
  • Nodular Lymphocyte predominant HL - 5% → disorder of the elderly multiple recurrences
207
Q

How is Hodgkin’s lymphoma staged?

A
  • FDG-PET / CT scan
  • Biopsy
  • Diaphragm is key for staging
208
Q

What is the management of Hodgkin’s lymphoma?

A
  • 1st line = Chemotherapy = ABVD (given at 4-weekly intervals) and Radiotherapy
    • Adriamycin
    • Bleomycin
    • Vinblastine
    • DTIC (Dacarbazine)
      • Complications = Pulmonary fibrosis, Cardiomyopathy
  • 2nd line for relapse = Salvage chemotherapy + high-dose chemotherapy + autologous HSCT
  • 3rd line for relapse = Post-salvage → anti-CD30 (Brentuximab Vedotin) + anti-PD1 (nivolumab)
209
Q

What are the disadvantages to radiation for cancer treatment?

A
  • Risk of damage to normal tissues - collateral damage
  • Associated with increased risk of breast/lung/skin cancer, leukaemia/myelodysplasia
  • Combined modality carries the greatest risk (two mechanisms of DNA damage)
210
Q

What is the prognosis of Hodgkin’s lymphoma?

A
  • Highly curable disease, but the prognosis depends on stage
    • Over 80% in stage I or II disease are cured
    • 50% of stage IV are cured
  • Curable:
    • Overall, 80% will be long-term survivors
    • 10% will die of relapse within 10 years
    • 10% will die from long-term treatment complications after 10 years → after 5 years, patients are more likely to die of a secondary malignancy or cardiovascular complications
211
Q

What are the signs and symptoms of Non-Hodgkin’s lymphoma?

A
  • Painless lymphadenopathy
  • Compression symptoms
  • B symptoms
    • Fever
    • Night sweats
    • Weight loss
212
Q

What are the appropriate investigations for Non-Hodgkin’s lymphoma?

A
  • Stage the disease
    • CT scan
    • PET scan
    • Bone marrow biopsy
    • Lumbar puncture (if risk of CNS involvement)
  • Prognostic markers and important tests
    • Prognosis
      • LDH (marker of cell turnover)
      • Performance status
    • Viral infections:
      • HIV serology → HIV may have predisposed to NHL
      • Hepatitis B serology (many patients are asymptomatic carriers of hepatitis B)
        • NHL patients may be given treatments that deplete B cells
        • This may cure the lymphoma, but the patient might then present with fulminant liver failure because you have reactivated any asymptomatic hepatitis B
213
Q

Describe Enteropathy associated T-cell lymphoma.

A
  • T-cell NHL seen in patients with Coeliac disease
    • Mature T cells
    • Involves the small intestines (jejunum and ileum)
    • Aggressive → quick clinical course but isn’t responsive to treatment
  • Caused by chronic antigenic stimulation (gluten/gliadin)
214
Q

What are the signs and symptoms of enteropathy associated T-cell lymphoma?

A
  • Abdominal pain
  • Obstruction
  • Perforation
  • GI bleeding
  • Malabsorption
  • Systemic symptoms
215
Q

What are the lab findings of chronic lymphocytic leukaemia?

A
  • Lymphocytosis (5-300 x 109/L)
  • Smear cells - break when on slide
  • Normocytic normochromic anaemia
  • Thrombocytopaenia
  • Bone marrow lymphocytic replacement of normal marrow elements
216
Q

What is the immunophenotyping for normal B and T cells?

A
  • Normal Mature B Cells:
    • CD19 POSITIVE
    • CD5 NEGATIVE
  • Normal Mature T Cells:
    • CD3 positive
    • CD4 or CD8 positive
      • Th-cell
      • CTL cell
    • CD19 NEGATIVE
    • CD5 POSITIVE
    • In CLL, the B cells continue to express CD5
    • This immunophenotyping assay shows a third population of lymphocytes co-expressing CD19 and CD5
217
Q

What is the treatment of CLL?

A
  • Supportive (50% of CLL-related deaths due to infections)
    • Vaccination (flu, pneumococcus) – no live vaccines (i.e. VZV)
    • Anti-infective prophylaxis and treatment
  • (2) Specific Scenarios
    • High-Grade (Richter) Transformation → treat as high grade lymphoma (R-CHOP)
  • Leukaemia-directed Treatment
    • FCR or R-Bendamustine
      • Fludarabine
      • Cyclophosphamide
      • Rituximab (anti CD20 moab)
    • Obinutuzumab (anti CD20) + Chlorambucil
218
Q

What are the indication for CLL treatment?

A
  • Progressive lymphocytosis (count doubling < 6 months)
  • Progressive bone marrow failure (Hb < 100; Platelets < 100; Neutrophils < 1)
  • Massive or progressive lymphadenopathy/splenomegaly
  • Systemic symptoms (B symptoms)
219
Q
  • 57-year-old woman originally from Jamaica
    • Hb 92g/L
    • WBC 130 x109/L
    • Platelets 90x109/L
    • Recurrent Chest infections
  • Further investigations:
A

Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukaemia

220
Q

What are anti-RhD?

A

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

221
Q

When is rhesus blood groups particularly important?

A
  • Pregnancy
    • Anti-D made by an Rh -ve mother exposed to Rh +ve blood
      • Haemolytic disease of the newborn
      • Severe fetal anaemia and heart-failure (hydrops fetalis)
222
Q

What tests are ran in the group part of group and screen/save?

A
  • Column Agglutination Technology: use known anti-A, anti-B and anti-D reagents against the patient’s RBCs
  • Reverse group: known A and B groups red blood cells are mixed with the patient’s plasma (IgM antibodies)
    • This group acts as an internal control – if it does not match, this is an anomalous result
    • New-borns often have a weak reverse group as their ABs have not developed fully yet
223
Q

How are column agglutination results interpreted?

A
  • A positive result causes agglutination at the top
  • A negative result will mean that the red cells stay suspended at the bottom of the vial
224
Q

Describe the antibody screen that occurs during a group and screen.

A
  • Uses 2 or 3 reagent RBCs containing all important RBC antigens between them
  • Incubate patient’s plasma and screening cells using the Indirect Antiglobulin Technique (IAT)
    • Patient serum containing specific antibody added to reagent RBCs →
    • Add Anti-Human Globulin (AHG) to promote agglutination →
    • If +ve, reaction creates bridges between RBCs coated in IgG antibodies → visible clumps
225
Q

What is the purpose of an antibody screen within a group and screen?

A

Avoid a delayed transfusion reaction with IgG antibodies

226
Q

What are donor RBCs labelled with?

A
  • ABO and RhD-type - always select correct type
  • Kell - select K -ve in females of child-bearing age
  • Other Rh antigens - patient-dependant selection
227
Q

Describe serological cross-matching.

A
  • Full Crossmatch (uses IAT):
    • Patient’s plasma is incubated with donor red cells at 37 degrees for 30-40 mins
    • Detects antibody-antigen reaction that destroys the RBCs leading to extravascular haemolysis
    • Add antiglobulin reagent to cause cross-linking
    • IgG antibodies bind to RBCs but do not crosslinking
  • Immediate Spin (EMERGENCY Only):
    • Incubate patient’s plasma and donor red cells for 5 minutes only and spin
    • Will only detect ABO incompatibility
    • IgM anti-A and/or anti-B bind to RBCs, fix complement and lyse the cell
228
Q

Describe electronic cross-matching.

A
  • Compatibility is determined by an IT system without physical testing of donor cells against plasma
  • This is a quick process, requiring fewer staff which allows better stock management
229
Q

What are the kinds of cross-matching?

A
  • Serological
    • Full cross-match
    • Immediate Spin - emergency only
  • Electronic
230
Q

How are blood components stored?

A
  • RBCs = 4° for 35 days
  • Platelets = 22° for 7 days
  • Plasma = Frozen
  • Cryorecipitate = Frozen
231
Q

What is the infusion time of 1 unit of blood components?

A
  • RBCs = 2-3 hrs
  • Platelets = 20-30 mins
  • Plasma = 20-30 mins
  • Cryorecipitate = 20-30 mins
232
Q

What are the indications for a transfusion?

A
  • Major blood loss - >30% of blood volume
  • Peri-op or Critical care - Hb <70g/L
  • Post-chemo - Hb <80g/L
  • Symptomatic anaemia
    • IHD
    • Breathless
    • ECG changes
233
Q

Describe Autologous blood transfusion.

A
  • Pre-operative autologous deposit
    • Patient’s own blood is donated before a planned operation
    • Not done in the UK
  • Intra-operative cell salvage
    • Blood is collected during surgery
    • It is then centrifuged, filtered and washed before being reinfused
  • Post-operative cell salvage
    • Collect blood that is lost post-operatively into a wound drain
    • This is filtered and re-infused
    • Mainly done for orthopaedic operations
  • NOTE: all the coagulation factors and platelets are removed from cell salvage blood
  • Cell salvage is useful in people with rare blood groups and Jehovah’s witnesses
234
Q

In which patients is autologous blood transfusion particularly useful?

A
  • Rare blood groups
  • Jehovah’s witnesses
235
Q

When is CMV negative blood required?

A
  • Pregnancy
    • Required for intra-uterine and neonatal transfusions
    • Also used for elective transfusion in pregnant women
236
Q

When is irradiated blood required?

A
  • Highly immunosuppressed patients
    • Patients cannot destroy incoming donor lymphocytes
    • Presence of these lymphocytes → fatal transfusion-associated graft-versus-host disease (TA-GvHD)
237
Q

When is washed blood required?

A
  • IgA-deficient patients
    • RBCs/platelets given to patients who had severe allergic reactions to some donors’ plasma proteins
    • This takes 4 hours to happen so needs to be pre-planned
238
Q

What are the indications for platelet infusion?

A
  • Massive transfusion
  • Prevent bleeding post-chemo = <10x109/L
  • Prevent bleeding in surgery = 50x109/L (100 if at critical site - eye, CNS etc)
  • Platelet dysfunction or immune cause - only if active bleeding
239
Q

What is the target Hb after transfusion?

How much does 1 unit of RBCs increase a persons Hb?

A
  • 100g/L
  • 10g/L
240
Q

What are the contraindications for platelet infusion?

A
  • Heparin-induced thrombocytopaenia and thrombosis
  • Thrombotic thrombocytopenic purpura (TTP)
241
Q

How much does 1 unit of platelets increase a persons platelet count?

A
  • 30-40 x 109/L
242
Q

What are the indications for FFP?

A
  • Massive transfusion - Blood loss >150ml/min
  • DIC with bleeding
  • Liver disease + Risk - PT ratio >1.5x normal
  • Coagulation factor replacement where factor concentrate isn’t available
243
Q

What is contained in FFP?

A
  • All clotting factors
244
Q

Describe the dosing and unit size of FFP.

A
  • Adult dose = 15 mL/kg
  • 1 unit of FFP contains 250 mL → enough for 16.6kg
    • 75kg (or so) = 5 doses needed
245
Q

When is FFP not the treatment of choice for active bleeding?

A

Reverse warfarin

  • Better treatment is PCC (prothrombin complex concentrate)
    • Contains factors 2, 7, 9 and 10
246
Q

What are the acute adverse reactions to transfusions?

A

<24hrs from transfusion

  • Acute haemolytic (ABO incompatible)
  • Allergic/anaphylaxis
  • Infection (bacterial)
  • Febrile non-haemolytic
  • Respiratory
    • Transfusion associated circulatory overload (TACO) - most common
    • Acute lung injury (TRALI)
247
Q

What are the delayed adverse reactions to transfusions?

A

>24hrs from transfusion

  • Delayed haemolytic transfusion reaction (antibodies) - Duffy and Kidd
  • Infection (viral, malaria, vCJD)
  • TA-GvHD (week or 2 after transfusion)
  • Post transfusion purpura
  • Iron overload
248
Q

What monitoring should be done post-transfusion?

A
  • 1st signs (potentially, before the patient experiences any symptoms):
    • Increased­ temperature or pulse
    • Decreased BP
  • Monitoring may be the only way to detect a reaction if the patient is unconscious
    • Baseline temperature, pulse, RR, BP before transfusion
    • 0m → 15m → 1hr → 1hr… → end - most reactions start within 15 mins
    • Repeat hourly and at the end of the transfusion
  • Monitor for general symptoms
    • Fever
    • Rigors
    • Flushing
    • Vomiting
    • Dyspnoea
    • Pain at transfusion site
    • Loin pain/chest pain
    • Urticaria
    • Itching
    • Headache
    • Collapse
249
Q

Describe Febrile Non-haemolytic Transfusion Reaction (FNHTR).

A
  • Mild/Moderate
  • Occurs during/soon after transfusion → blood or platelets
  • May cause a rise in temperature by around 1 degree
  • Patient may have chills and rigors
  • Common before blood was leucodepleted
  • Caused by the release of cytokines from white cells during storage
250
Q

What is the management of Febrile Non-haemolytic Transfusion Reaction (FNHTR)?

A
  • Transfusion stopped or slowed
  • May need paracetamol
251
Q

Describe Allergic Transfusion Reactions.

A
  • Mild/Moderate
  • Common, especially with plasma - proteins in plasma
  • Causes a mild urticarial or itchy rash sometimes with a wheeze
  • Caused by allergy to donor plasma proteins
    • Recipients have a history of atopy
  • Can occur during or after transfusion
252
Q

What is the management of Allergic Transfusion Reactions?

A
  • Stopping/slowing of transfusion if still ongoing
  • IV antihistamines
253
Q

What are the signs and symptoms of ABO Incompatibility?

A
  • Severe/Fatal
  • Symptoms and signs of acute intravascular haemolysis (IgM-mediated)
    • General
      • Restless
      • Chest/loin pain
      • Fever
      • Vomiting
      • Flushing
      • Collapse
      • Haemoglobinuria (later)
    • Monitoring
      • Low BP
      • High HR
      • High Temperature
254
Q

What are the causes of ABO Incompatibility?

A
  • Failure of bedside check/Human error - By far the most common
  • Wrongly labelled blood sample
  • Laboratory error
255
Q

What are the appropriate investigations for suspected ABO Incompatibility?

A
  • FBC
  • Biochemistry
  • Coagulation
  • Repeat X-match
  • Direct antiglobulin test (DAT)
256
Q

What are the signs and symptoms of Bacterial Contamination of Blood Components?

A
  • Severe/Fatal
  • General
    • Restless
    • Fever
    • Vomiting
    • Flushing
    • Collapse
  • Monitoring
    • Low BP
    • High HR
    • High Temperature
257
Q

What are the sources of bacterial contamination to blood components?

A
  • From the donor → e.g. from low grade GI, dental or skin infection
  • Introduced during processing → environmental or skin
258
Q

Which blood components are most likely to be contaminated?

A

Platelets (stored at room temperature) > RBCs > FFP

259
Q

in place to prevent bacterial contamination of blood components?

A
  • Donor questioning + Arm cleaning + Diversion of first 20 mL into a pouch for testing
  • Red Blood Cells
    • Store in a controlled fridge at 4 degrees
    • Shelf-life: 35 days
    • If it is kept out for >30 mins it needs to go back in the fridge for 6 hours
    • Complete transfusion should take place within 4 hours of leaving the fridge
  • Platelets:
    • Stored at 22 degrees
    • Shelf-life: 7 days
    • Screened for bacteria before release
    • Transfused over 20-30 mins
260
Q

What are the signs and symptoms of blood component anaphylaxis?

A
  • Severe/Fatal
  • Soon after the start of transfusion
    • Shock = Drop in BP + Rise in HR
    • Very breathless with wheeze
    • Often laryngeal and/or facial oedema
261
Q

What is the mechanism of severe anaphylaxis from blood componenets?

A
  • Mechanism = IgE antibodies in the patient cause mast cell degranulation
  • Most allergic reactions are not severe, but some can be in the case of IgA deficiency
    • IgA deficiency = 1: 600
    • In 25% of these, anti-IgA antibodies develop in response to exposure to IgA in the donor blood
    • Only a minority go on to have a severe transfusion reaction
262
Q

What is Transfusion Associated Circulatory Overload (TACO)?

A
  • Pulmonary oedema/fluid overload as a consequence of transfusion
  • Often caused by lack of attention to fluid balance
  • More common in
    • Cardiac failure
    • Renal impairment
    • Hypoalbuminaemia
    • Extremities of age
263
Q

What are the signs and symptoms of TACO?

A
  • Severe/Fatal
  • SoB
  • Low O2 saturations
  • High HR
  • High BP
  • CXR
    • Fluid overloaded
    • Cardiac failure
264
Q

What is the management of TACO?

A
  • Diuretics - TRALI does NOT respond to diuretics
  • Reduced fluid intake
  • Carefully urine monitoring
265
Q

What is the mechanism of Transfusion Related Acute Lung Injury (TRALI)?

A
  • Anti-WBC antibodies in donor blood
  • These interact with WBCs in the patient
  • Aggregates WBCs stick to pulmonary capillaries → release neutrophil proteolytic enzymes and toxic O2 metabolites → lung damage
266
Q

What are the signs and symptoms of TRALI?

A
  • Looks at bit like ARDS - more common in FFP or platelet transfusion
  • Clinical features:
    • SoB
    • Low O2 saturations
    • Fever
    • High HR
    • High BP
    • No clinical fluid overload
267
Q

How is TRALI prevented?

A
  • Use male donors for plasma and platelets who haven’t had transfusions
    • No pregnancy or previous transfusions → no HLA/HNA Abs
268
Q

What is the mechanism of Delayed Haemolytic Transfusion Reaction?

A
  • 1-3% of all patients transfused will develop an antibody against and RBC antigen that they lack = alloimmunisation
  • Further transfusions with RBCs expressing same antigens → antibodies will lyse RBCs → extravascular haemolysis
    • This is IgG-mediated so takes 5-10 days
269
Q

What are the appropriate investigations for suspected Delayed Haemolytic Transfusion Reaction?

A
  • Haemolysis Tests:
    • High bilirubin
    • Low Hb
    • High reticulocytes
    • Haemoglobinuria over a few days
  • U&Es = can cause renal failure
  • Repeat the group and screen → look for new antibodies
270
Q

What are the consequences of tranfusing someone with Parvovirus +ve blood?

A
  • Causes temporary red cell aplasia – so affects those with RBCs of a shortened life span
  • Affects foetuses and patients with haemolytic anaemias - e.g. sickle cell, hereditary spherocytosis
271
Q

What is the pathophysiology of Transfusion Associated Graft-Versus-Host Disease?

A
  1. Donor’s blood will contain some lymphocytes that are able to divide
  2. Normally, the patient’s immune system will recognises these donor lymphocytes as foreign and destroy them
  3. In susceptible/very immunosuppressed patients these lymphocytes are NOT destroyed
  4. Lymphocytes recognise patient’s tissue HLA antigens as foreign and attack → gut, liver, skin and bone marrow
272
Q

What are the consequences of Transfusion Associated Graft-Versus-Host Disease?

A
  • ALWAYS FATAL – can take weeks to months post transfusion
  • Diarrhoea
  • Liver failure
  • Skin desquamation
  • Bone marrow failure
273
Q

How is Transfusion Associated Graft-Versus-Host Disease prevented?

A
  • Irradiation of blood components for very immunocompromised patients

OR

  • HLA-matched components
274
Q

Describe Post-transfusion Purpura.

A
  • Appears 7-10 days after transfusion of blood or platelets
  • Usually resolves in 1-4 weeks but can cause life-threatening bleeding
  • Affects Human Platelet Antigen (HPA) 1a -ve patients previously immunised via pregnancy or transfusion (HPA-1a AB)
  • Treatment: IVIG
275
Q

Describe Immune Modulation following a Transfusion?

A
  • Possible increased rate of infections post-operatively and increased recurrence of cancer in patients who have blood transfusions
    • Evidence is conflicting
276
Q

Describe Iron Overload following a Transfusion?

A
  • If someone has lots of transfusions (thalassaemia patients/sickle cell) iron will accumulate in their body
  • There is about 200-250 mg of iron per unit of blood
  • This can damage the liver, heart and endocrine organs
  • Requires chelation
277
Q

What is the mechanism of Haemolytic Disease of the Newborn?

A
  • People lacking an RBC antigen (RhD) can form corresponding antibodies if exposed to the antigen
  • This can happen:
    • By receiving blood transfusions
    • In pregnancy → foetal red cells enter the mother’s circulation during pregnancy or at delivery
  1. The first RhD-positive foetus will not experience any issues, however, they will stimulate the development of anti-D antibodies in the mother
  2. In a subsequent pregnancy, if the mother has another RhD-positive foetus, the antibodies will destroy foetal red cells leading to severe anaemia ± HDN
278
Q

Which antibody class can cross the placenta?

279
Q

What are the haematological differences between neonates and adults

A
  • High WCC
  • High neutrophils
  • High lymphocytes
  • High Hb
  • High MCV
  • Higher percentage of HbF
  • 50% the G6PD concentration of an adult
280
Q

What are the causes of foetal polycythaemia?

A
  • Twin-to-twin transfusion
  • Intrauterine hypoxia
  • Placental insufficiency
281
Q

What are the causes of foetal anaemia?

A
  • Twin-to-twin
  • Foetal-to-maternal transfusion (rare)
  • Parvovirus infection
  • Haemorrhage from cord or placenta
282
Q

Describe leukaemia in utero?

A
  • The first mutation that subsequently leads to childhood leukaemia often occurs in utero
    • Pre-leukaemic cells carrying this mutation can even spread to a twin
  • Congenital leukaemia is particularly common in Down syndrome = Transient Abnormal Myelopoiesis (TAM)
    • This is different from leukaemia in older children
    • Disease tends to remit spontaneously within the first 2 months of life → tends to relapse 1-2 years later in 25%
      • Capacity for spontaneous remission is similar to neuroblastoma
283
Q

Define Thalassaemia and Haemoglobinopathy.

A

Defects in the globin chain

  • Thalassaemia = reduced rate of synthesis of ≥1 globin chain as a result of a genetic defect
  • Haemoglobinopathy = structurally abnormal Hb - some think thalassemia a form of haemoglobinopathy
284
Q

Where are the genes for globin chains found?

A

Chromosome 11 and Chromosome 16

  • Chromosome 11 (beta cluster) = deletion of LCRB → reduced downstream globin expression
    • Beta, delta, gamma gene
    • Epsilon is an embryonic globin gene
  • Chromosome 16 (alpha cluster)
    • Alpha 1 and alpha 2 gene
      • HbA2 = <3.5% of total adult Hb
    • Zeta is an embryonic globin gene
285
Q

How do Hb chains change throughout pregnancy and childhood?

A
  • Specific foetal haemoglobins are present in the first 16 weeks - HbF predominates
  • After around 32 weeks you get a rapid increase in HbA production
  • At birth → 1/3rd of haemoglobin is HbA → rapidly increases after birth
286
Q

What is the pathophysiology of SCD?

A
  1. Hypoxia → polymerisation of haemoglobin S → crescent shaped RBCs and blocked blood vessels (occurs in post-capillary venules - reversible if the hypoxic state is resolved)
  2. If circulation slows, cells sickle and become adherent to the endothelium which causes obstruction
  3. Retrograde capillary obstruction → arterial obstruction
287
Q

What are the types of SCD?

A
  • bb = Normal
  • bbS / AS = Sickle cell trait (not SCD) → totally asymptomatic
  • bSbS / SS = Sickle cell anaemia
  • bSbC / SC = Sickle cell / haemoglobin C → milder than HbSS
  • bSbThal = Sickle cell / beta thalassaemia
  • bbThal = Beta thalassaemia
288
Q

What affects the severity of SCA?

A
  • Depends on whether it is a:
    • Beta-0 gene (no beta globin production)
    • Beta+ gene (a little bit of beta globin production)
289
Q

At what age does SCA present?

A
  • 3-6 months of age
    • Gamma chain production and HbF synthesis decreases
    • HbS production increases
290
Q

When is SCA diagnosed?

A
  • UK = birth → Guthrie spot test
    • Antenatal screening is based on risk → Family Origins Questionnaire
      • Neonate diagnosis allows prevention and anticipation of some of the complications
291
Q

What are the differences in symptoms of SCA in a child?

A
  • Red bone marrow:
    • Adult haematopoietic BM = restricted to axial skeleton
    • Child haematopoietic BM = axial skeleton + extends to bones of hands and feet
      • Hand-foot syndrome – from infarction
        • Developing RBCs and white cell need vascular, glucose and requires an oxygen supply = susceptible to infarction
    • Different spleen types:
      • Adult / older-child spleen – spleen is small and fibrotic from recurrent infarction
        • Suffer from sequalae of hyposplenism (i.e. pneumococcal infection)
      • Child spleen – still has a functioning spleen
        • Splenic sequestration → acute pooling of a large % of circulating RBCs in spleen (Splenomegaly) → severe anaemia, shock and death
          • Parents should be taught how to palpate the spleen and to seek medical attention if needed
          • Blood transfusion required
    • Acute chest syndrome
    • Painful crisis
    • Stroke - most common cause of stroke in childhood
    • Bacteraemia
    • Parvovrius
292
Q

What is the folic acid requirement of a child with SCA?

A
  • Increased folic acid demands due to:
    • Hyperplastic erythropoiesis
    • Growth spurts - have an additive effect
    • Red cell lifespan is shorted so anaemia can rapidly worsen
293
Q

What is the management of SCA in childhood?

A
  • Educate parents – splenomegaly, pale pallor, breathlessness, fever
  • Vaccinate
  • Folic acid
  • Penicillin
294
Q

Which complication of SCA is more common in adults than children?

  • Hand-foot syndrome
  • Hyposplenism
  • Red cell aplasia
  • Splenic sequestration
  • Stroke
A

Hyposplenism

295
Q

Siblings with SCA present simultaneously with severe anaemia and a low reticulocyte count - which is the most likely?

  • Splenic sequestration
  • Parvovirus B19 infection
  • Folic acid deficiency
  • Haemolytic crisis
  • Vitamin B12 deficiency
A

Parvovirus B19 infection

296
Q

A 6-year-old Afro-Caribbean boy presents with chest and abdominal pain.
- Hb = 63 g/L
- MCV = 85 fl
- Blood film = sickle cells present
Which is the most likely

  • Sickle cell trait
  • SCA
  • Sickle cell / beta thalassaemia
297
Q

Define beta thalassaemia.

A

Condition resulting from reduced synthesis of beta globin chain - and so, HbA

  • No HbA = major
  • Some HbA = intermedia
298
Q

When does beta thalassaemia present?

A
  • 3-6m of life because of decline of synthesis of HbF and the increased production of HbA
    • Can be suspected at birth through the Guthrie spot test
299
Q

What are the types of beta thalassaemia?

A
  • bb = Normal
  • bthalb = trait - harmless but genetically important
  • bthalbthal = major - severe anaemia → fatal without transfusions
  • bthalbthal = intermediate - ‘+’ forms of beta (instead of ‘0’)
300
Q

What are the clinical features of thalassaemia major?

A
  • Anaemia
    • Heart failure
    • Growth retardation
  • Erythropoietic drive
    • Bone expansion
    • Hepatomegaly
    • Splenomegaly
  • Iron overload
    • Heart failure
    • Gonadal failure
301
Q

What is the treatment of bet thalassaemia major?

A
  • Accurate diagnosis
  • Family counselling
  • Blood transfusion ± Iron chelation (desferrioxamine, deferiprone)
302
Q

What are the causes of inherited haemolytic anaemia in children?

A
  • Red cell membrane - hereditary spherocytosis/eliptocytosis
  • Haemoglobin molecule - sickle cell anaemia
  • Glycolytic pathway enzymes (rare) - pyruvate kinase deficiency
  • Pentose-phosphate shunt - G6PD deficiency
    • G6PDD = X-linked (recessive) → more common in males
303
Q

What are the two main causes of autoimmune haemolytic anaemia in children?

A
  • Autoimmune haemolytic anaemia
    • Spherocytosis
    • Positive DAT (Coombs’ test)
  • Haemolytic uraemic syndrome:
    • Haemolysis
    • Uraemia
304
Q

What are the triggers for haemolysis in G6PDD?

A
  • Infections
  • Drugs
  • Naphthalene – moth balls (banned in EU)
  • Fava beans (broad beans)
305
Q

What is MAHA?

A
  • Red cells are damaged in capillaries forming small angular fragments and micro-spherocytes
306
Q

What is the presentation of haemophilia A/B?

A
  • Bleeding following circumcision
  • Haemarthroses when starting to walk
  • Bruises
  • Post-traumatic bleeding
  • Family history
307
Q

What are the possible diagnose for bleeding, haemarthroses and post-traumatic bleeding?

A
  • Inherited thrombocytopaenia or platelet functional defect
  • Acquired defects of coagulation (e.g. ITP, acute leukaemia)
  • Non-accidental injury
  • Henoch-Schönlein purpura
308
Q

What clotting studies would be expected in haemophilia A/B?

A
  • Platelet count = normal
  • aPTT = prolonged
  • PT = normal
  • Bleeding time = normal
309
Q

What is the treatment of haemophilia A/B?

A
  • Treatment of bleeding episodes
  • Use of prophylactic coagulation factors
  • Counselling the family
310
Q

Define Myelodysplasia.

A

Biologically heterogenous group of acquired haematopoietic stem cell disorders.

311
Q

What are the characteristics of myelodysplasia?

A
  • Development of a clone of marrow stem cells with abnormal maturation resulting in:
    • Functionally defective blood cells
    • Numerical reduction
  • Leads on to:
    • Cytopaenia
    • Functional abnormalities of erythroid, myeloid and megakaryocyte maturation
    • Increased risk of transformation to leukaemia
312
Q

What are the signs and symptoms of MDS?

A
  • Elderly
  • Signs of BM failure developing over weeks-months
    • Weight loss
    • Fatigue
    • Infections
    • Bleeding
313
Q

What are the morphological features of MDS?

A
  • Pelger-Huet - bilobed neutrophils
  • Dysgranulopoiesis of neutrophils - low granule number
  • Dyserythropoiesis of red cells
    • Lack of separation between red cell precursors → abnormal ring of cytoplasm around the nucleus
  • Dysplastic megakaryocytes
  • Increased proportion of blast cells in marrow - normal < 5%
  • Ringed sideroblasts - iron granules in red cell precursors
314
Q

What type of cell is this?

A

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

315
Q

What type of cell is this?

A

Myeloblasts + Auer rods → classical in AML

316
Q

What type of cell is this?

A

Myelokathexis → fragmented neutrophil nucleus

317
Q

What type of cell is this?

A

Normal neutrophil

318
Q

What type of cell is this?

A

Pelger-Heut → bilobed neutrophil (MDS)

319
Q

What type of cell is this?

A

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

320
Q

What is the disease process of MDS?

A
  • 1. Deterioration of blood count
    • Worsening consequences of marrow failure
  • 2. Development of acute myeloid leukaemia (AML)
    • Develops in 5-50% <1 year (depends on subtype)
    • Some cases of MDS are much slower to evolve
    • AML from MDS has an extremely poor prognosis and is usually not curable
  • 3. Death
    • 1/3 die from infection
    • 1/3 die from bleeding
    • 1/3 die from acute leukaemia
321
Q

What is the management of MDS?

A
  • Treatments to prolong survival - only benefit a small minority → that vast majority of which are young:
    • Allogenic Stem Cell Transplant (A-SCT)
    • Intensive chemotherapy
  • Supportive care
    • Blood products
    • Antimicrobial therapy
    • Growth factors (EPO, G-CSF)
  • Biological modifiers
    • Immunosuppressive therapy
    • Hypomethylating agents (Azacytidine, Decitabine)
    • Lenalidomide – in del(5q) variant
  • Chemotherapy
    • Oral = hydroxyurea
    • Low dose = SC low dose cytarabine
322
Q

Which of the following is true about MDS?

  • (a) Myelodysplasia has a bi-modal age distribution
  • (b) The primary modality of treatment of MDS is by intensive chemotherapy
  • (c) One third of MDS patients can be expected to die from leukaemic transformation
  • (d) There is no good correlation between the severity of the cytopenia and the overall life expectancy
  • (e) White cell function is frequently well preserved in MDS
A

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

323
Q

What cells are affected in aplastic anaemia?

A

All blood cell types - pluripotent HSC is affected

324
Q

What are the causes of aplastic anaemia?

A
  • Primary
    • Congenital: Fanconi’s anaemia (multipotent stem cell), Dyskeratosis congenita
    • Acquired: Idiopathic aplastic anaemia (multipotent stem cell) → VAST MAJORITY (70-80%)
    • Diamond-Blackfan anaemia (red cell progenitors)
    • Kostmann’s syndrome (a form of SCID; neutrophil progenitors)
  • Secondary
    • Marrow infiltration
    • Leukaemia / Lymphoma / Myelofibrosis
    • Non-haematological / Solid tumours
    • Radiation
    • Drugs
      • Cytotoxic drugs
      • Phenylbutazone
      • Gold salts
      • Chloramphenicol
      • Sulphonamide
      • Thiazides
      • Carbimazole
    • Chemicals (benzene)
    • Autoimmune
    • Infection (Parvovirus, Viral hepatitis)
325
Q

What is the pathophysiology of idiopathic aplastic anaemia?

A
  • Failure of BM to produce blood cells because of:
    • “Stem cell” problem - CD34, LTC-IC (long-term culture-initiating cells)
    • Immune attack - humoral or T cell attack against multipotent haematopoietic stem cell
326
Q

What is the clinical presentation of aplastic anaemia?

A
  • Classic triad of BM failure:
    • Anaemia – fatigue, breathlessness
    • Leucopaenia – infections
    • Thrombocytopaenia – bleeding/bruising
  • Bimodal age distribution – 15-25 and >60
327
Q

What are the investigations of suspected aplastic anaemia?

A
  • Peripheral blood → cytopaenia
  • Bone marrow → hypocellular + fat
328
Q

What is the classification of severe aplastic anaemia?

A

Camitta criteria → 2 out of 3 peripheral blood features + Bone marrow of <25% cellularity

  • Reticulocytes = < 1% (<20 x 109/L)
  • Neutrophils = < 0.5 x 109 /L
  • Platelets = < 20 x 109 /L
329
Q

What are the differential diagnoses of pancytopaenia?

A
  • Hypoplastic MDS/AML
  • Hypocellular ALL
  • Hairy cell leukaemia
  • Mycobacterial (usually atypical) infection
  • Anorexia nervosa
  • Idiopathic thrombocytopenic purpura (ITP)
    • Unlikely to confuse aplastic anaemia with ITP
      • ITP = normal Hb and RBC
330
Q

What is the management of aplastic anaemia?

A
  • Seek and remove a cause - requires a detailed drug and occupational exposure history
  • Supportive:
    • Blood/platelet transfusions
    • Antibiotics
    • Iron chelation therapy
  • Immunosuppressive therapy - anti-thymocyte globulin, steroids, Eltrombopag, cyclosporine A
    • Tend to be used in older patients
    • Late complications following immunosuppressive therapy for AA
      • Relapse - 35% over 15 years
      • Blood disorders - 20% risk over 10 years
      • Solid tumours - 3% risk
    • Drugs for marrow recovery (androgens (oxymetholone), thrombopoietin receptor agonists (Eltrombopag))
    • Stem cell transplantation
      • Young (<40yo) + Sibling donor → 80% cure rate
    • Other treatments in refractory cases (e.g. alemtuzumab)
331
Q

What factors affect a patients management for aplastic anaemia?

A
  • Severity of illness
  • Age of patient
    • Stem cell transplantation tends to be used in younger patients (80% cure rate if a sibling donor)
  • Immunosuppressive therapy used in older patients (e.g. anti-lymphocyte globulin, ciclosporin)
  • Potential sibling donor
  • Androgens (oxymetholone) can also promote bone marrow recovery
332
Q

Which of the following is true about Aplastic Anaemia?

  • (a) Immunosuppressive therapy is only used to treat a minority of patients with aplastic anaemia
  • (b) If treated with immunosuppression, then relapse of Aplastic Anaemia occurs in less than 15% of cases
  • (c) Cure rate of AA treated by sibling related allogeneic SCT in a patient under 40 years old is > 70%
  • (d) Severe aplastic anaemia is differentiated from non-severe aplastic anaemia on the basis of the acquired cytogenetic abnormalities in the bone marrow
  • (e) Leucodepletion of cellular blood products is only exceptionally undertaken for patients with aplastic anaemia
A

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

333
Q

What is Fanconi Anaemia?

A
  • Most common form of inherited aplastic anaemia
  • Autosomal recessive or X-linked
  • Heterozygote frequency = 1:300
  • Multiple mutated genes are involved which result in:
    • Abnormalities in DNA repair
    • Chromosomal fragility
  • Genes responsible → act through a final common pathway involved with DNA repair mechanisms:
    • FA-A
    • -B
    • -C
    • -D
334
Q

What are the signs and symptoms of Fanconi anaemia?

A
  • 60-70%
    • Short Stature
    • Hypopigmented spots and café-au-lait spots
    • Abnormality of thumbs
    • Microcephaly or hydrocephaly
    • Hypogonadism
    • Developmental delay
  • 30-40%
    • No abnormalities
335
Q

What are the complication of Fanconi anaemia?

336
Q

What is Dyskeratosis congenita?

A
  • An inherited disorder characterised by
    • Marrow failure
    • Cancer predisposition
    • Somatic abnormalities
      • Leukoplakia
      • Nail dystrophy
      • Skin pigmentation
337
Q

What are the signs and symptoms of Dyskeratosis congenita?

A
  • Leukoplakia
  • Nail dystrophy
  • Skin pigmentation
338
Q

What are the complications of dyskeratosis congenita?

339
Q

Name 2 inherited causes of aplastic anaemia?

A
  • Fanconi anaemia
  • Dyskeratosis congenita
340
Q

What is the genetic basis of dyskeratosis congenita?

A

Telomere shortening

  • 3 patterns of inheritance
    • X-linked recessive = most common
      • Mutant DKC1 gene leads to defective telomere functioning
    • Autosomal dominant
      • Mutant TERC gene encodes the RNA component of telomerase
    • Autosomal recessive
      • Mutant gene has NOT been identified
341
Q

IN which causes of aplastic anaemia is telomere shortening found?

A
  • Dyskeratosis congenita
  • Idiopathic
342
Q

Which of the following is true?

  • (a) Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita
  • (b) Development of malignancy is an uncommon complication of Fanconi Anaemia
  • (c) A single genetic defect has been identified as the underlying cause for Fanconi Anaemia
  • (d) Fanconi Anaemia is usually inherited in an autosomal dominant fashion
  • (e) Telomeric function is considered to be unimportant in the pathophysiology of Dyskeratosis Congenita
A

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

343
Q

What is the treatment algorithm for severe aplastic anaemia?

344
Q

What are the normal blood changes in pregnancy?

A
  • Mild anaemia
    • Red cell mass rises (120-130%)
    • Plasma volume rises (150%)
    • Both due to net dilution
  • Macrocytosis
    • Normal
    • Folate or B12 deficiency
  • Neutrophilia
  • Thrombocytopenia
    • Increased platelet size from increase in turnover of platelets
345
Q

What is the iron requirements in pregnancy?

A
  • 300mg (foetus); 500mg (maternal RBC mass)
    • Required Daily Average = 30mg
    • Increase in daily iron absorption 1-2mg to 6mg
    • Iron deficiency → IUGR, prematurity, PPH
346
Q

What is the folate requirements in pregnancy?

A
  • Folate requirement increase = +200mcg/day
    • Growth and cell division
347
Q

What are the recommended dose of iron and folate supplements in pregnancy?

A
  • WHO = 60mg iron and 400ug folic acid daily
  • RCOG = 400ug folic acid (and no iron)
    • Supplement before conception and for more than 12-weeks’ gestation
    • High-dose folic acid = 5mg / 5000ug folic acid
348
Q

What is the definition of anaemia in pregnancy?

A
  • <110 g/l in 1st trimester
  • <105 in 2nd and 3rd trimester
  • <100 g/l postpartum
349
Q

What are the causes of thrombocytopaenia in pregnancy?

A
  • Physiological / Gestational
  • Pre-eclampsia → HELLP – Haemolysis, Elevated Liver enzymes, Low Platelets
  • Immune thrombocytopenia (ITP) – BM creates lots of platelets but there is peripheral destruction
  • MAHA syndromes – TTP, anti-phospholipid
  • All other causes – BM failure, hypersplenism, DIC, leukaemia
350
Q

What is the most likely cause of thrombocytopaenia in pregnancy with levels of:

  • >70 x 109/L
  • <70 x 109/L
A

Lower platelets = more likely it is pathological

  • >70 x 109/L = gestational thrombocytopenia
  • <70 x 109/L = Pre-eclampsia / HELLP or ITP
351
Q

Describe gestational thrombocytopaenia.

A

Physiological decrease in platelets affecting around 10%

  • Mechanism is poorly defined (dilution and increased consumption potentially)
  • Baby is not affected
  • Platelet count rises 2-5 days post-delivery
352
Q

What platelet counts are enough for delivery and an epidural?

A
  • >50x109/L = delivery
  • >70x109/L = epidural
353
Q

What is the link between pre-eclampsia and thrombocytopaenia?

A
  • 50% get thrombocytopenia (proportionate to severity) → some of these suffer from HELLP
  • Association with increased activation and consumption - incipient DIC (normal PT, APTT)
  • Platelet count remits following delivery
354
Q

What are the treatment options for immune thrombocytopaenia in pregnancy?

355
Q

How might a baby be affected if their mum suffers from immune thrombocytopaenia in pregnancy?

A

Unpredictable → platelets <20 in 5%

  • Avoid ventose and forceps if baby platelet count is unknown / low
  • Check cord blood and then daily → may fall for 5 days after delivery
  • Bleeding in 25% of severely affected – IVIG if low
  • Usually normal delivery
356
Q

What are the causes of microangiopathic haemolytic anaemia (MAHA)?

A
  • TTP
  • HUS
  • AFLP
  • SLE
  • APLS
357
Q

What is the pathophysiology of HUS?

358
Q

What are the cardinal signs of MAHA?

A

Fragmentation (shistocytes) and Destruction of RBC within vasculature

  • Thrombocytopenia, schistocytes
  • Organ damage – kidney, CNS, placenta (in pregnancy)
359
Q

How does delivery alter the course of TTP or HUS in pregnancy?

360
Q

What are the signs and symptoms of TTP?

A
  • MAHA
  • Fever
  • Renal impairment
  • Neurological impairment
  • Thrombocytopenia
361
Q

What changes occur that lead to a pro-thrombotic environment in pregnancy?

A
  • Pro-thrombotic
    • Factor 8 and VWF = Increases 3-5x
    • Fibrinogen = Increases 2x
    • Factor 7 and 10 = Increases 0.5x
  • Less fibrinolysis
    • Protein S = Falls to half basal
    • PAI-1 (plasminogen activator inhibitor) = Increases 5x
    • PAI-2 = Produced by placenta
362
Q

Why is there an increased risk of thrombosis in pregnancy?

A
  • Procoagulant state
    • Increased thrombin generation
    • Increased fibrin cleavage
    • Reduced fibrinolysis
    • Interact with other maternal factors
363
Q

What is the most high risk times for PE in pregnancy?

A
  • Biggest maternal killer in UK
    • Highest risk time = post-partum and 1st trimester
    • High BMI is the largest predictor of incidence of PE
      • High risk patients need to be on heparin from the first trimester
364
Q

What are the appropriate investigations for DVT and/or PE in pregnancy?

A
  • Doppler and V/Q
    • D-dimer is elevated in pregnancy → not useful for exclusion of thrombosis
365
Q

What factors change in pregnancy that lead to increasing risk of thrombosis?

A
  • All patients = Virchow’s triad
    • Changes in blood coagulation
    • Reduced venous return → 85-95% in left leg
    • Vessel wall
  • Variable numbers of patients:
    • Hyperemesis or dehydration
    • Bed rest
    • BMI >29 = 3x risk of PE
    • Pre-eclampsia
    • Operative/emergency delivery
    • Previous thrombosis or thrombophilia
    • Age (increases dramatically over 35)
    • Multiparity (>4 = increased risk)
    • Multiple pregnancy
    • PMHx – HbSS, nephrotic syndrome
366
Q

What is the management of thromboembolic disease in pregnancy?

A
  • Prevention:
    • Women with RFs = prophylactic heparin and TED stockings
    • Mobilise early
    • Maintain hydration
  • Treatment:
    • LMWH (OD or BD) - does not cross placenta
      • No Warfarin - DOES CROSS PLACENTA (teratogenic), avoid weeks 6-12
    • After 1st trimester monitor anti-Xa
  • Stop medications for labour or planned delivery
    • Especially if a women wishes for an epidural
      • Wait 24 hours after treatment dose
      • 12 hours after prophylactic dose
367
Q

Describe anti-phospholipid syndrome.

A

≥3 Miscarriages + lupus anticoagulant or anticardiolipin antibodies

  • Adverse pregnancy outcomes → 3+ consecutive miscarriages before 10 weeks of gestation
  • 1 or more morphologically normal foetal losses after 10w of gestation
  • 1 or more preterm birth before 34-weeks of gestation
  • Treatment = unfractionated heparin and aspirin
    • Dramatically improved outcomes
368
Q

Is thrombophilia associated with pregnancy complications

A
  • May or may not be associated with pregnancy complications
    • RCTs fail to demonstrate improvement in pregnancy outcome in unselected women with idiopathic recurrent pregnancy loss
369
Q

Define PPH.

A
  • >500ml blood loss (SVD)
    • 5% pregnancies have blood loss more than 1L
    • Requiring transfusion post-partum
      • 1% after vaginal delivery
      • 1-7% after C-section
370
Q

What are the mechanism / causes of PPH?

A
  • Major factors
    • Uterine atony
    • Trauma
    • Tissue
    • Thrombin
  • Haematological factors minor except
    • Dilutional coagulopathy after resuscitation
    • DIC in abruption, amniotic fluid embolism
371
Q

What are the triggers for decompensation leading to DIC in pregnancy?

A
  • Amniotic fluid embolism
  • Pre-eclampsia (severe/HELLP)
  • Placental abruption
  • Sepsis
  • Retained dead foetus
372
Q

Describe amniotic fluid embolisms.

A

S/S’s = sudden onset shivers, vomiting, shock, DIC

  • Presumed due to tissue factor in amniotic fluid entering maternal bloodstream
  • Almost all 25yo+
  • Usually in the 3rd trimester
  • Drugs used to induce labour – misoprostol increase risk
  • Most catastrophic event in obstetrics
    • 86% mortality
    • 1 in 20,000-30,000 births
373
Q

What haematological screening programmes exist in the UK?

A
  • Thalassaemia
  • Sickle cell disease
374
Q

What is the aim of the thalassaemia and sickle cell disease screen programmes?

A

Avoid /counselling parents about birth of children with:

  • Alpha 0 thalassaemia / Hb Barts (4 gamma chains) - death in utero, hydrops fetalis
  • Beta 0 thalassemia - transfusion dependent
  • HbSS / SCD - life expectancy 43yo
  • Other compound HbS syndromes - symptomatic, stroke
  • Some compound thalassaemia’s - transfusion dependent, iron overload
375
Q

Who is screened in pregnancy for thalassaemia or SCD of the foetus and what options are available to parents?

A
  • All disorders are recessive
  • If mother is heterozygous = Partner tested
  • Combinations important as homozygous states
  • Options:
    • Proceed
    • Prenatal dx
      • CVS sampling (10-12 weeks)
      • Amniocentesis (15-17 weeks)
      • cffDNA testing (NEW)
    • US screening for hydrops
376
Q

Which of the following statements is correct?

  • In gestational thrombocytopenia, the baby’s platelet count is usually affected
  • Thrombocytopenia is rarely found in association with pre-eclampsia
  • Thrombotic thrombocytopenic purpura remits spontaneously following delivery
  • Platelet count may fall following delivery in babies born to mothers with ITP
A

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

377
Q

A reduction in pregnancy-associated thrombosis mortality rate can be attributed to

  • Lower obesity rates
  • Improved targeted thromboprophylaxis
  • Rising maternal age
  • Increase in prevalence of gestational thrombocytopenia
A

Improved targeted thromboprophylaxis

378
Q

Which of the following statements is correct?

  • 1 litre of blood loss is considered normal in a vaginal delivery
  • Uterine atony is a common cause of post-partum haemorrhage
  • Post-partum haemorrhage is often caused by changes in the coagulation factors in pregnancy
A

Uterine atony is a common cause of post-partum haemorrhage

Y5 Pathology (5 decks)

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