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Year 5 Pathology > Haematology > Flashcards

Haematology Flashcards

1
Q

Which percentage of hospital deaths are due to pulmonary embolism?

A
  • PE is the cause of 5-10% of hospital deaths
  • 25000 deaths pa from hospital related VTE
  • Difficult to reverse and leads to morbidity
  • Preventable
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2
Q

What is Virchow’s triad?

A

Blood
Vessel wall
Blood flow

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3
Q

What affects the blood part of ‘Virchow’s triad’?

A
  • Viscosity
  • Haematocrit
  • Protein/paraprotein
  • Platelet count
  • Coagulation system
  • Net excess of procoagulant activity
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4
Q

Name some familial or genetic conditions which affect blood/hyper coagulation

A 
Elevated factor VIII
Elevated factor XI
Factor V Leiden
Protein S deficiency
Protein C deficiency
Antithrombin deficiency
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5
Q

Is the vessel wall normally thrombotic?

A

Yes

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6
Q

How does the vessel wall maintain its antithrombotic activities?

A
  • Expresses anticoagulant molecules
  • Thrombomodulin
  • Endothelial protein C receptor
  • Tissue factor pathway inhibitor
  • Heparans
  • Does not express tissue factor
  • Secretes antiplatelet factors Prostacyclin
    NO
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7
Q

Which factors can make the endothelial wall prothrombotic?

A

Inflammation/injury of the vessel wall:

  • Infection – including COVID-19
  • Malignancy
  • Vasculitis
  • Trauma
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8
Q

How does inflammation/infection make the endothelial wall prothrombotic?

A
  • Anticoagulant molecules (eg TM) are down regulated
  • TF may be expressed
  • Prostacyclin production decreased
  • Adhesion molecules upregulated
  • Von Willebrand factor release
  • Platelet and neutrophil capture
  • Neutrophil extracellular traps (NETS) form
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9
Q

How does stasis promote thrombosis?

A
  • Accumulation of activated factors
  • Promotes platelet adhesion
  • Promotes leukocyte adhesion and transmigration
  • Hypoxia produces inflammatory effect on endothelium
  • Adhesion, release of VWF
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10
Q

What are some of the causes of stasis?

A
  • Immobility: surgery, paraparesis, travel
  • Compression: tumour, pregnancy
  • Viscosity: polycythaemia, paraprotein
  • Congenital: vascular abnormalities
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11
Q

What are some immediate and delayed anticoagulant drugs?

A

Immediate

  • Heparin
  • Unfractionated heparin
  • Low molecular weight heparin
  • Direct acting anti-Xa and anti-IIa

Delayed

  • Vitamin K antagonists
  • Warfarin
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12
Q

What are the procoagulant factors which lead to fibrin formation?

A

V VIII IX X XI

II Fibrinogen Platelets

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13
Q

What are anticoagulant factors which lead to fibrinolysis?

A 
TFPI
Protein C 
Protein S 
Thrombomodulin 
EPCR 
Antithrombin
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14
Q

Draw out the coagulation cascade and where the anticoagulant factors act on

A

TF/FVIIa
Coagulation Regulation

FVIII
FIXa
\+
FVIIIa
TFPI
Protein C & S
FX
FXa
\+
    FV
FVa
 Prothrombin
Thrombin
Antithrombin
 Procoagulant
Fibrinogen
Fibrin
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15
Q

Which conditions target specific factors in the clotting pathway causing clotting disorders?

A

Soluble proteins
◼ Factor VIII > Haemophilia A> bleeding
◼ Protein C > pro-thrombotic

Cellular haematology
◼ Erythrocytes > polycythaemia or anaemia
◼ Leucocytes
Granulocytes > leukaemia(CML) or reactive eosinophilia Lymphocytes > leukaemia(CLL) or Lymphopenia (HIV)
◼ Platelets > essential thrombocythemia or ITP

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16
Q

What is meant by a primary disorder of the blood?

A

Primary –> due to the blood and arise from DNA mutations

  • germline/inherited - FIX, erythrocyte
  • somatic/acquied BM rapid turnover organ - erythrocytes, myeloid, soluble factors
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17
Q

What is meant by secondary disorder of the blood?

A

Changes in haematological parameters secondary to non-haematological disease

  • erythrocytes (e.g. hypoxia, heart disease)
  • factor VIII (inflammatory response, autoantibodies)
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18
Q

How may anaemia in malignancy initially present?

A

◼Fe deficiency
◼Leucoerythroblastic anaemia
◼Haemolytic anaemias

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19
Q

What would be the blood results in someone with iron-deficiency anaemia?

A

◼ Microcytic hypochromic anaemia
◼ Reduced ferritin, transferrin saturation
◼ Raised TIBC

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20
Q

What may be the cause of Fe deficiency in different patients?

A

Fe deficiency is bleeding until proven otherwise
◼ Often menorrhagia in pre menopausal women
◼ Blood loss in men and post menopausal women

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21
Q

What are cancers which cause occult blood loss?

A

◼ GI cancers - Gastric, Colonic/rectal

◼ Urinary tract cancers - Renal cell carcinoma, Bladder cancer

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22
Q

What is leuco-erythroblastic anaemia?

A

Leukoerythroblastic anemia describes the presence of nucleated erythrocytes and immature white cells of the neutrophilic myeloid series in the peripheral blood

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23
Q

What morphological features in the blood film would you see for leuco-erythroblastic anaemia?

A
  • Teardrop RBCs (+aniso and poikilocytosis)
  • Nucleated RBCs
  • Immature myeloid cells
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24
Q

What are the causes of leucoerythroblastic anaemia?

A
  • Malignant - haemopoietic or non-haemopoietic
  • Severe infection - military TB, severe fungal
  • Myelofibrosis - massive splenomegaly, dry tap on BM aspirate
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25
Q

What are common laboratory features of all haemolytic anaemias?

A
  • Anaemia (though may be compensated)
  • Reticulocytosis
  • Unconjugated bilirubin raised (pre-hepatic)
  • LDH raised
  • Haptoglobins reduced
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26
Q

What are the two groups haemolytic anaemias?

A

Inherited (primary): defects of RBC/germline DNA mutation

Acquired (secondary): defects of the environment (systemic disease)

  • non-immune: DAT -ve
  • immune-mediated: DAT/Coombs +ve
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27
Q

What are examples of systemic disease where can get acquired immune haemolysis?

A
  • Malignancy : eg. Lymphoma or CLL
  • Auto immune: eg. SLE
  • Infection: eg. mycoplasma
  • Idiopathic
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28
Q

What would you see on the film of someone with immune haemolytic anaemia?

A
  • Spherocytes

- DAT +ve

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29
Q

Give examples of causes of acquired haemolytic anaemia (DAT-negative/non-immune)

A

Infection - malaria

Micro-angiopathic haemolytic anaemia (MAHA)
◼ Underlying adenocarcinoma
◼ Haemolytic uraemic syndrome

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30
Q

What would you see on the film of someone with microangiopathic haemolytic anaemia?

A
  • RBC fragments

* Thrombocytopenia

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31
Q

Describe the stages which occur in micro-angiopathy in malignancy

A

Adenocarcinomas, low grade DIC

  • Platelet activation
  • Fibrin deposition and degradation
  • Red cell fragmentation (microangiopathy)
  • Bleeding (low platelets and coag factor deficiency)
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32
Q

Which white blood cells would you expect to see in the bone marrow?

A
  • Blasts (myeloid and lymphoid)
  • Promyelocytes
  • Myelocytes
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33
Q

Which white blood cells would you expect to feel in the peripheral blood?

A

Phagocytes –> granulocytes (neutrophils, eosinophils, basophils), monocytes

Immunocytes - T lymphocytes, B lymphocytes

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34
Q

What does this mean if there are:

  • Blasts (myeloid and lymphoid)
  • Promyelocytes
  • Myelocytes

in the peripheral blood?

A

In healthy adults these cells never seen in Peripheral blood. If present think leukaemia or metastatic cancer invading bone marrow.

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35
Q

What do you observe on the slide of someone with chronic lymphocytic leukaemia?

A

WBC increased mature cells

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36
Q

What do you observe on the slide of someone with acute myeloid leukaemia?

A

WBC increased immature cells

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37
Q

What are the causes of neutrophilia?

A
  • Corticosteroids
  • Underlying neoplasia
  • Tissue inflammation (e.g. colitis, pancreatitis)
  • Myeloproliferative/leukaemic disorders
  • Pyogenic infection
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38
Q

In neutrophilia, you would suspect either reactive/infection or malignancy as the underlying cause. How would you be able to differentiate between them?

A

Reactive/Infection: neutrophilia + toxic granulation no immature cells

Malignant: neutrophilia, basophilia, immature cells myelocytes. Suggest a myeloproliferative (CML).

Neutropenia plus myeloblasts suggests acute leukaemia (AML)

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39
Q

What are the two underlying causes of eosinophilia?

A
  • Reactive eosinophilia

- Chronic eosinophilic leukaemia

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40
Q

List examples of causes of reactive eosinophilia

A
  • Parasitic infestation
  • Allergic diseases e.g. asthma, rheumatoid, polyarteritis, pulmonary eosinophilia.
  • Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia)
  • Drugs (reaction erythema multiforme)
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41
Q

What are the underlying causes of chronic eosinophilic leukaemia?

A
  • Eosinophils part of the “clone”

- FIP1L1-PDGFRa fusion gene

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42
Q

When would you see monocytosis?

A
  • TB, brucella, typhoid
  • Viral; CMV, varicella zoster
  • Sarcoidosis
  • Chronic myelomonocytic leukaemia (MDS)
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43
Q

What are the underlying causes of lymphocytosis?

A
  • EBV, CMV, Toxoplasma
  • Infectious hepatitis, rubella, herpes infections
  • Autoimmune disorders
  • Sarcoidosis
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44
Q

What are the underlying causes of lymphopenia?

A
  • Infection HIV
  • Auto immune disorders
  • Inherited immune deficiency syndromes
  • Drugs (chemotherapy)
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45
Q

What would you suspect if you saw mature lymphocytes on the slide (PB) and lymphocytosis?

A
  • Reactive/atypical lymphocytes (IM)

- Small lymphocytes and smear cells (CLL/NHL)

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46
Q

What would you suspect if you saw immature lymphocytes on the slide (PB) and lymphocytosis?

A

lymphoblasts (Acute Lymphoblastic Leukaemia)

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47
Q

What technique do we use to determine if the B lymphocyte is monoclonal (malignant) or poly-clonal? What would be the results?

A

Light chain restriction

Polyclonal: kappa and lambda light chains (60:40)

Monoclonal: kappa only or lambda only (99:1)

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48
Q

What are examples of haemato-oncology diagnosis used to assess the morphology of the tumour?

A
  • Architecture of tumour
  • Cytology
  • Cytochemistry
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49
Q

What are examples of haemato-oncology diagnosis used to assess the cytogenetics of the tumour?

A
  • Conventional karyotyping
  • Fluorescent in-situ hybridisation
  • Interphase FISH
  • Metaphase FISH
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50
Q

What are examples of haemato-oncology diagnosis used to assess the immunophenotype of the tumour?

A
  • Flow cytometry

- Immunohistochemistry

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51
Q

What are examples of haemato-oncology diagnosis used to assess the molecular genetics of the tumour?

A
  • Mutation detection
  • Direct sequencing
  • Pyrosequencing
  • PCR analysis
  • Gene expression profiling
  • Whole genome sequencing
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52
Q

What are the examples of lymph-haemopoietic system cancers?

A
  • Bone marrow
  • Peripheral blood
  • Lymph nodes
  • Other sites {skin, gut, brain, eye, testes}
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53
Q

Primitive lymphoid blast cells expressing B cell marker. What is your diagnosis?

A

B cell acute lymphoid leukaemia

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54
Q

Mature lymphoid cells expressing T cell antigens and involving skin. What is your diagnosis?

A

Cutaneous T cell lymphoma

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55
Q

Mature erythrocytes with JAK2 mutation. What is your diagnosis?

A

Polycythaemia vera

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56
Q

Describe the stages in normal myeloid differentiation.

A

Myeloblast –> Myelocyte –> Neutrophil

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57
Q

What is the difference between chronic myeloproliferative neoplasm and acute myeloid leukaemia?

A

Chronic myeloproliferative neoplasm - differentiation of myeloid lineage normal, but the proliferation is increased

Acute myeloid leukaemia - differentiation is blocked and proliferation is increased

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58
Q

What types of mutations cause leukaemia and lymphoma?

A
  • Cellular proliferation (type 1) - BCR-ABL1 (CML), JAK2 (MPD)
  • Impair/block cellular differentiation (type 2) (PML -RARA in acute promyelocytic leukaemia
  • Prolong cell survival (anti-apoptosis) - BCL2 and follicular lymphoma
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59
Q

Give 3 examples of lymphoma and which part of B cell development it affects

A
  • B cell Acute lymphoblastic lymphoma
  • Mantle cell lymphoma
  • Multiple myeloma
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60
Q

What would you find after analysing the morphology and immunophenotype in B cell ALL?

A

TdT +ve
CD19 +ve
Surface Immunoglobulin -ve

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61
Q

What would you find after analysing the morphology and immunophenotype in multiple myeloma?

A

TdT negative

Surface Immunoglobulin +ve CD138 positive

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62
Q

What is the clinical course of these three types of lymphomas?

  • Burkitt Lymphoma
  • Chronic myeloid leukaemia
  • Polycythaemia vera
A
  • Burkitt Lymphoma highly aggressive needs urgent treatment
  • Chronic myeloid leukaemia has a chronic phase followed by a blast transformation
  • Polycythaemia vera is generally an indolent disorder
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63
Q

What are associated problems in leukaemia and lymphoma?

A
  • Lympho-haemopoietic failure
    Bone marrow : anaemia, infection (neutrophils) bleeding
    (platelets)
    Immune system: infection
  • Excess of malignant cells
    Erythrocytes (polycythemia): impair blood flow >stroke or TIA
    Massively enlarged lymph nodes (lymphoma)> compress structures, bowel, vena cava, ureters, bronchus.
  • Impair organ function - CNS lymphoma
    Skin lymphoma
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64
Q

How is leukaemia or lymphoma diagnosed according to the WHO histopathological diagnosis?

A

Lineage e.g. B or T lymphocyte:

  • Stage of maturation (immature or mature)
  • Normal cell counterpart
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65
Q

What is the use of histopathological diagnosis?

A
  • Predict clinical course (eg aggressive or indolent)

- Guide need for and choice of therapy

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66
Q

How does lymphoma typically present?

A
  • Painless progressive lymphadenopathy - palpable node, extrinsic compression of tubes in body
  • Infiltrate/impair organ system
  • Recurrent infections
  • Constitutional symptoms
  • Coincidental e.g. FBC, imaging
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67
Q

How does non-Hodgkin lymphoma often present? How would you confirm diagnosis?

A

Lymphadenopathy - mesenteric, axillae, cervical, spenlomegaly

Biopsy

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68
Q

After biopsy lymphoma is confirmed. What would you do to stage?

A
  • CT/PET scans
  • BM biopsy
  • +/- Lumbar puncture
  • Blood tests, HIV, hep B tests
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69
Q

What are the main two types of lymphoid malignancies?

A

Lymphoma/leukaemia - 15%

Non-Hodgkin lymphoma (NHL) - 85%

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70
Q

What are characteristic of Hodgkin’s lymphoma?

A

Reed-Sternberg cells

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71
Q

What are the types of non-hodgkin lymphomas?

A
  • B cell - precursor (B lymphoblastic leukaemia, B cell neoplasm, follicular NHL, CLL)
  • T cell - precursor T lymphoblastic leukaemia or lymphoma, T and NK neoplasm, anapaestic, cutaneous
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72
Q

Describe the epidemiology of Hodgkin lymphoma

A

M>F

Bimodal age - 20-29, >60

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73
Q

What are the typical presentations of Hodgkin lymphoma?

A
  • Painless enlargement of lymph node/nodes
  • May cause obstructive symptoms/signs
  • Constitutional symptoms - 1) fever, 2) nigh sweats, 3) weight loss

Rarely - pruritus, alcohol induced pain

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74
Q

What are the different classifications of Hodgkin lymphoma?

A
  • Nodular sclerosing - 80% - good prognosis
  • Mixed cellular - 17% - good prognosis
  • Lymphocyte rich - rare - good prognosis
  • Lymphocyte-depleted - rare - poor prognosis
  • Nodular lymphocyte predominant 5% (disorder of elderly which recurs)
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75
Q

How does Hodgkin lymphoma spread?

A

Lymphatic system

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76
Q

How is Hodgkin lymphoma staged?

A

I: one group of nodes
II: > 1 group of nodes, same side of diaphragm
III: nodes above and below diaphragm
IV: extra nodal spread

A: none of the symptoms in B
B: weight loss>10% in 6m, fever, night sweats

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77
Q

Describe the typical presentation of cHL nodular sclerosing subtype of Hodgkin’s lymphoma

A 
Young women > men
Neck nodes and mediastinal 
SVC or trachea
May have B symptoms
Needs tissue diagnosis
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78
Q

What does ABVD stand for in combination chemotherapy for cHL?

A

A - adriamycin
B - bleomycin
V - vinblastine
D - DTIC

4-weekly intervals (2-6 cycles)

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79
Q

What are the pros and cons of using ABVD combination chemotherapy?

A

Pros - perseveres fertility

Cons - long term can cause pulmonary fibrosis, cardiomyopathy

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80
Q

How would you treat relapse in Hodgkin’s lymphoma?

A

High dose chemotherapy + autologous PB stem cell transplant as support

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81
Q

What are the pros and cons of using radiotherapy for Hodgkin’s lymphoma?

A

Pros - low/negligible risk of relapse in that area
Cons - Ca breast (1:4), leukaemia, lung or skin cancer

Combined chemo + radio = used in greatest risk of second malignancy

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82
Q

What is the prognosis for Hodgkin’s lymphoma?

A

Stage I - 90% cured

Stage IV - 50% cured

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83
Q

What is non-Hodgkin’s lymphoma?

A

Neoplastic proliferation of lymphoid cells

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84
Q

Describe the epidemiology of non-Hodgkin’s lymphoma

A
  • Incidence rising 200/million population/year
  • Fastest proliferating malignancy (Burkitt)
  • Indolent diseases
  • Antibiotic responsive disease
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85
Q

When would you do a lumbar puncture in suspected non-Hodgkin lymphoma?

A

Risk of CNS involvement

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86
Q

What are some prognostic markers and important tests in managing non-Hodgkin lymphoma?

A
  • LDH
  • Performance status
  • HIV serology
  • Hep B serology
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87
Q

What are the common types of non-Hodgkin lymphoma?

A
  • Follicular

- Diffuse

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88
Q

Which types of lymphoma are aggressive and indolent?

A

Very aggressive (high grade) - Burkitt, T and B cell lymphoblastic leukaemia

Aggressive (high grade) - diffuse large B cell, mantle cell

Indolent (low grade) - follicular, small lymphocytic/CLL, mucosa associated (MALT)

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89
Q

How is diffuse large B cell NHL treated?

A

Immunotherapy - anti CD20 monoclonal antibodies

50% cure rate

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90
Q

How common is follicular NHL and how does it normally arise?

A

35% of NHL

Associated with t(14,18) which results in over-expression of bcl2 and anti-apoptosis protein

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91
Q

What is the prognosis and treatment of follicular NHL?

A

Incurable, median survival 12-15 years
May require 2-3 different chemotherapy schedules over the 12-15 year period
May use combination immunotherapy R-COP or R-CHOP

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92
Q

What is extra nodal marginal zone lymphoma of stomach (NHL)?

A

Chronic antigen stimulation - H pylori infection

H-pylori eradication cures 75% of patients

55-60yrs of age

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93
Q

What type of NHL are coeliac disease patients at high risk of?

A

Enteropathy associated T cell lymphoma – > mature T cells, involves jejunum and ileum, aggressive

Abdo pain, malabsorption, systemic, responds poorly to chemo

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94
Q

Describe what is meant by chronic lymphocytic leukaemia

A 
Proliferation of mature B cells
Most common leukaemia in western world 
Caucasian
72 yrs average
Relative 7x increased risk
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95
Q

What would be your laboratory findings for someone with CLL?

A
  • Lymphocytosis between 5-200 x109/L
  • Smear cells
  • Normocytic normochromic anaemia
  • Thrombocytopenia
  • Bone marrow lymphocytic replacement of normal marrow elements
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96
Q

What would you find when immunophenotyping peripheral blood by flow cytometry in normal vs CLL patient?

A

Normal B cells - CD5-ve, CD19+ve

CLL - CD5+ve, CD19+ve

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97
Q

What is the natural history of CLL?

A

5-10 years of good health until 2-3 years of terminal phase

1/3 never progress
1/3 respond to treatment and die from something other than CLL
1/3 require multiple treatment and die from CLL

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98
Q

What is the prognosis of CLL?

A

Cell-based prognostic factors: IgHV mutation status, CLL FISH cytogenic panel, TP53 mutation status (chromosome 17p del and/or TP53 point mutation)

Clinical staging systems: Binet or Rai (clinical staging), CLL IPI score

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99
Q

What would indicate bad prognosis of CLL?

A

Deletion of 17p (TP53)

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100
Q

What are the clinical issues with CLL?

A
  • Increased risk of infection
  • Bone marrow failure
  • Lymphadenopathy +/- splenomegaly, lymphocytosis
  • Transform into high grade lymphoma –> Richter transformation
  • Auto-immune complications - immune haemolytic anaemia
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101
Q

What supportive care would someone with CLL receive?

A
  • Sino-pulmonary infections: early treatment with antibiotics, recurrent infection + IgG < 5g/L = IVIG replacement therapy
  • Vaccinations: pneuomococcal, Covid-19, seasonal flu, avoid live vaccines
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102
Q

What are some treatment options in CLL?

A
  • BCR kinase inhibitors - Ibrutinib (BTK), idelalisib (PI3K)
  • BCL2 inhibitors - Venetoclax
  • Experimental cell-based therapies - chimeric antigen receptor T cells (CAR-T)
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103
Q

How does Venetoclax work in treating CLL?

A
  • BCL2 inhibitor - permits apoptosis of CLL cells
  • High risk CLL - p53 mutated 85% response and maintained at greater risk than 1 year
  • Main risk is tumour lysis syndrome
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104
Q

Is CD2 expressed on normal T cells?

A

Yes

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105
Q

What is your diagnosis?
Hb raised
Platelets raised
Haematocrit raised

A

Polycythaemia

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106
Q

How do you differentiate between relative and true polycythaemia?

A

Relative - plasma volume decreased, red cell mass the same

True - red cell mass increases

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107
Q

What are the causes of relative/pseudo polycythaemia?

A
  • Alcohol
  • Obesity
  • Diuretics
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108
Q

What are the causes of appropriate true secondary polycythaemia (non-malignant)?

A
  • High altitude
  • Hypoxic lung disease
  • Cyanotic heart disease
  • High affinity haemoglobin
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109
Q

What are the causes of inappropriate true secondary polycythaemia (non-malignant)?

A
  • Renal disease (cysts, tumours, inflammation)
  • Uterine myoma
  • Other tumours (liver, lung)
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110
Q

List all the haematological malignancies

A 
Myeloid
– Acute myeloid leukaemia (blasts >20%
– Myelodysplasia (blasts 5-19%)
– Myeloproliferative disorders
• Essential thrombocythaemia (megakaryocyte)
• Polycythemia vera (erythroid)
• Primary myeofibrosis
– Chronic myeloid leukaemia

Lymphoid
Precursor cell malignancy
• Acute lymphoblastic leukaemia (B & T)

Mature cell malignancy
• Chronic Lymphocytic leukaemia
• Multiple myeloma
• Lymphoma (Hodgkin & Non Hodgkin)

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111
Q

Describe normal haematopoiesis for each cell

A 
Pre-T --> T cell
Pre-B --> B-cell
BFU-E --> RBCs
Meg-CFC --> megakaryocytic/platelets
GM-CFC --> granulocytes, monocytes
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112
Q

How is tyrosine kinase activation impaired in malignancy?

A

Normal: transmit cell growth signals fro surface receptors to nucleus, activated by transferred phosphate groups to self and downstream proteins (JAK2 chime rises–>stat5,mapk,p13k/akt), tightly inactive state and they promote cell growth – do not block maturation

Activations: more mature cells
RBCs = polycythaemia
Platelets = thrombocytopenia
Granulocytes = CML

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113
Q

What’s the most common type of mutation associated with polycythaemia vera ~100%?

A

JAK2

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114
Q

How is the diagnosis of MPD Ph negative made?

A

– Clinical features - symptoms (see next slides), splenomegaly
– FBC +/- Bone marrow biopsy
– Erythropoietin level (epo)
– Mutation testing - phenotype linked to acquired mutation

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115
Q

What is the epidemiology of polycythaemia vera?

A
  • More males - 1.2:1

- Mean age - 60yrs

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116
Q

How does polycythaemia vera present?

A
  • Routine FBC
  • Symptoms of increased hyper-viscosity: headaches, light-headed, stroke, visual disturbance, fatigue, dyspnoea
  • Increased histamine release: aquagenic pruritus, peptic ulcer
  • Test for JAK2 V617F mutation
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117
Q

What are the treatment options of PCV?

A
  • Aim to reduce HCT <45%
  • Venesection
  • Cytoreductive therapy hydroxycarbamide
  • Reduce risks of thrombosis: control HCT, aspirin, keep platelets below 400x109/L
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118
Q

What is essential thrombocythaemia (ET)?

A

• Chronic MPN mainly involving megakaryocytic lineage
• Sustained thrombocytosis >600x109/L
• Incidence 1.5 per 100000
■ Mean age two peaks 55 years and minor peak 30 years
■ Females:males equal first peak but females predominate second peak

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119
Q

What is the typical presentation of essential thrombocytosis?

A

• Incidental finding on FBC (50% cases)
• Thrombosis: arterial or venous – CVA, gangrene, TIA
– DVT or PE
• Bleeding: mucous membrane and cutaneous
• Headaches, dizziness visual disturbances
• Splenomegaly (modest)

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120
Q

What is the treatment of essential thrombocytosis?

A
  • Aspirin: to prevent thrombosis
  • Hydroxycarbamide: antimetabolite. Suppression of other cells as well.
  • Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
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121
Q

What is the prognosis of essential thrombocytopenia?

A
  • Normal life span may not be changed in many patients
  • Leukaemic transformation in about 5% after >10 years
  • Myelofibrosis
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122
Q

What is primary myelofibrosis?

A
  • A clonal myeloproliferative disease associated with reactive bone marrow fibrosis
  • Extramedullary haematopoieisis

• Primary presentation:
– Incidence 0.5-1.5 /100000
– Males=females
– 7th decade. Less common in younger patients
• Other MPDs (ET & PV) may transform to PMF

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123
Q

What is the typical presentation of primary myelofibrosis?

A
  • Cytopenia: anaemia or thrombocytopenia
  • Thrombocytosis
  • Splenomegaly: may be massive (Budd-Chiari syndrome)
  • Hepatomegaly
  • Hypermetabolic state: weight loss, fatigue and dyspnoea, night sweats, hyperuricaemia
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124
Q

What would you see on the blood film of someone with primary myelofibrosis?

A
  • Leucoerythroblastic picture
  • Tear-drop poikilocytes
  • Extramedullary haemopoiesis in spleen and liver

DNA: JAK2 or CALR mutation

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125
Q

What would you find when taking a biopsy of someone with primary myelofibrosis?

A 
• ‘Dry tap’
• Trephine:
Increased reticulin or collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering with abnormalities
• New bone formation
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126
Q

What is the prognosis of someone with primary myelofibrosis?

A 
• Median 3-5 years but very variable
• Bad prognostic signs:
Severe anaemia <100g/L
Thrombocytopenia <100x109/l Massive splenomegaly
Prognostic scoring system (DIPPS) 
Score 0 -- median survival 15years
Score 4-6– median survival 1.3 years
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127
Q

What is the treatment of someone with primary myelofibrosis?

A

■ Supportive: RBC and platelet transfusion often ineffective because of splenomegaly
■ Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
■ Ruxolotinib: JAK2 inhibitor (high prognostic score cases)
■ Allogeneic SCT (potentially curative reserved for high risk eligible cases)

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128
Q

What is the typical presentation of chronic myeloid leukaemia (Ph positive)?

A

Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA, bruising bleeding

Massive splenomegaly +/- hepatomegaly

Hb and platelets well preserved or raised
Massive leucocytosis 50-200x109/L

Neutrophils and myelocytes (not blasts if chronic phase), basophilia

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129
Q

What are the laboratory features of someone with chronic myeloid leukaemia?

A
  • Leucocytosis between 50 – 500x109/l
  • Mature myeloid cells
  • Bi-phasic peak Neutrophils and myelocytes
  • Basophils
  • No excess (<5%) myeloblasts
  • Platelet count raised/upper normal (contrast acute leuk)
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130
Q

What is meant by the Philadelphia chromosome?

A

BCR-ABL (BCR from chromosome 22 and ABL from chromosome 9)

Fuse to make gene which expresses 210 KD protein –> oncoprotein with constitutive tyrosine kinase activity–> myeloid proliferation

Use PCR for detection

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131
Q

How do you treat CML?

A

1st line
Imatinib, dasatanib, bosutinib - oral active TKI
Monitor - FBC, cytogenetics, RQ-PCR

2nd line
No response after 1 year - 2Gen or 3G TKI

3rd line
Inadequate response or intolerant of 2G TKIs
Progression to accelerated or blast phase

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132
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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133
Q

What are features of myeloma plasma cells?

A
  • home and infiltrate the bone marrow
  • form bone expansile or soft tissue tumours: plasmacytomas
  • produce a serum monoclonal IgG or IgA: paraprotein or M-spike
  • produce excess of monoclonal (κorλ) serum free light chains
  • Bence Jones protein: urine monoclonal free light chains
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134
Q

What is Waldenstrom’s - Lymphoplacytic lymphoma?

A

Lymphoplasmacytic lymphoma, also known as Waldenstrom macroglobulinemia, is a low-grade B cell lymphoproliferative neoplasm characterized by small lymphocytes and monoclonal IgM monoclonal gammopathy.

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135
Q

What is the median age of myeloma and its prevalence?

A

Median age 67 years

The second most common haematological malignancy, 19th in all cancers

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136
Q

What is the aetiology of myeloma?

A

Aetiology is unknown …

Myeloma is always preceded by a premalignant condition:
Monoclonal Gammopathy of Uncertain Significance (MGUS)

Risk factors
• Obesity increases the risk for myeloma 
• Age
• Genetics
• Incidence in black population
• Sporadic cases of familiar myeloma
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137
Q

What is Monoclonal Gammopathy of Uncertain Significance (MGUS)?

A

Benign M protein levels are higher than normal:

  • the most common (known) premalignant condition
  • incidence increases with age
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138
Q

What is the average risk for progression of Monoclonal Gammopathy of Uncertain Significance (MGUS)?

A

Average risk for progression: 1% annually

IgG or IgA MGUS → myeloma
IgM → lymphoma

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139
Q

What is the diagnostic criteria for Monoclonal Gammopathy of Uncertain Significance (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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140
Q

What other risk factors are associated with Monoclonal Gammopathy of Uncertain Significance (MGUS)?

A

Higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population

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141
Q

What are the risk factors for Monoclonal Gammopathy of Uncertain Significance (MGUS)?

A
  • Non-IgG M-spike
  • M-spike >15g/L
  • Abnormal serum free light chain (FLC) ratio
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142
Q

What is the criteria for smouldering myeloma?

A

Serum monoclonal protein (IgG or IgA) ≥30g/L or urinary monoclonal protein ≥500mg per 24h and/or clinical bone marrow plasma cells 10-60%. Absence of myeloma defining events of amyloidosis.

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143
Q

What are the risk factors for smouldering myeloma (2019 IMWG Updated Risk Stratification model)?

A
  • Bone marrow myeloma cells ≥20%
  • M-spike ≥20g/L
  • Serum FLC ratio ≥20
144
Q

Describe the progression from MGUS to plasma cell leukaemia

A

MGUS –> smouldering myeloma –> symptomatic myeloma –> remitting relapsing –> refractory –> plasma cell leukaemia

145
Q

What are the primary and secondary genetic events of multiple myeloma?

A

Primary events
• 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

Common secondary events
• KRAS, NRAS
• t(8;14) IGH/MYC
• 1qgain/1pdel
• del 17p (TP53)
• 13- / del 13q
146
Q

What is the pathogenesis of multiple myeloma?

A

Myeloma cells interact with bone marrow microenvironment:

  • Bone destruction
  • Angiogenesis
  • Anaemia
  • Immunosuppression and infections
147
Q

What is the diagnostic criteria of multiple myeloma?

A

≥10% plasma cells in bone marrow or plasmacytoma + ≥1 CRAB or MDE

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

2014 Myeloma Defining Events (MDE)
• Bone marrow plasma cells ≥60%
• Involved : uninvolved FLC ratio >100
• > 1 focal lesion in MRI (>5mm)

148
Q

What is the most common clinical presentation of bone disease?

A

80% of myeloma patients present with bone disease

  • Proximal skeleton
  • Back (spine), chest wall and pelvic pain
  • Osteolytic lesions, never osteoblastic
  • Osteopenia
  • Pathological fractures
  • Hypercalcaemia
149
Q

What are the different imaging options for myeloma bone disease?

A

Plain XR films (skeletal surveys): are now obsolete – low sensitivity, require >30% bone mass loss

Whole-body diffusion-weighted MRI - bone marrow cellularity, active vs treated disease

150
Q

What are some emergencies in myeloma?

A
  • Cord compression

- Hypercalcaemia

151
Q

What is cord compression?

A

Spinal cord compression occurs when a mass places pressure on the cord. A mass can include a tumor or bone fragment. Symptoms include pain, numbness, stiffness, cramping, trouble with hand coordination.

152
Q

What is the management of cord compression?

A
  • Diagnosis & treatment within 24hrs
  • MRI scan
  • Ig and FLC studies +/- biopsy
  • Dexamethasone
  • Radiotherapy
  • Neurosurgery: rarely required
  • Stabilise unstable spine
  • MDT meeting
153
Q

What are some symptoms of hypercalcaemia?

A
  • Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
  • Fluids, steroids, zolendronic acid
154
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
155
Q

What is the cause of myeloma kidney disease?

A

Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria

Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics

156
Q

What is cast nephropathy in myeloma kidney disease?

A

The formation of plugs (urinary casts) in the kidney proximal tubule from free immunoglobulin light chains leading to kidney failure in the context of multiple myeloma. It is the most common cause of kidney injury in myeloma.

157
Q

What is the prognosis of those with kidney disease and myeloma?

A

Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome.

Early mortality in severe kidney disease is an area on unmet clinical need:
• 12% early death (<2 months)
• Prolonged hospital stay, lethal infections
• Nephrotoxic or renal excreted myeloma drugs: eg zoledronic acid, lenalidomide

158
Q

What is the cornerstone treatment of kidney disease in myeloma?

A

Bortezomib-based therapy

159
Q

What are the causes of complex humeral and cellular immunodeficiency in myeloma?

A

Immunoparesis: low serum normal Igs
Myeloid, T cells and NK cells impairment
Chemotherapy impairs immune response
Myeloma immune evasion

160
Q

What is the myeloma diagnostic workup?

A

1) Immunoglobulin studies: serum protein electrophoresis, serum free light chain levels, 24hr Bence Jones proteins
2) Bone marrow aspirate and biopsy: IHC for CD138
3) FISH analysis
4) Flow cytometry immunophenotyping: diagnosis, MRD

161
Q

How is myeloma staged and risk stratified?

A

1) International staging system: I, II, III (stage I: <3.5 mg/L beta-2-microglobulin, >3.5 g/dL serum albumin, stage II: serum beta-2-microglobuli >5.5 mg/L)
2) Revised international staging system: I, II, III (using cytogenic abnormalities, iFISH, LDH)

162
Q

What is amyloidosis?

A
  • Misfolded free light chains aggregate into amyloid fibrils in target organs
  • The amyloidogenic potential of light chains is more important than their amount
  • Amyloid fibrils stain with Congo Red, are solid, non- branching and randomly arranged with a diameter of 7 – 12 nm
163
Q

What are the chains commonly found in amyloidosis?

A

Lambda light chain is involved in 60%

  • IGLV6-57 in kidney
  • IGLV1-44 in cardiac
164
Q

What is the clinical presentation of amyloidosis?

A

• Nephrotic syndrome (70%)
– Proteinuria, peripheral oedema

• Unexplained heart failure → determinant of prognosis
– Raised NT-proBNP
– Abnormal echocardiography and cardiac MRI

  • Sensory neuropathy
  • Abnormal liver function tests
  • Macroglossia
165
Q

What is Monoclonal Gammopathy of Renal Significance (MGRS)?

A

MGRS applies specifically to any B-cell clonal lymphoproliferation where there are: one or more kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig) and the underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy

166
Q

What is the pathology of Monoclonal Gammopathy of Renal Significance (MGRS)?

A
  • Rare disease, several subtypes
  • Demonstration of the involved monoclonal Ig or light chain is possible in most cases
  • Work up similar to myeloma
  • Many patients will require myeloma-type treatment aiming to renal survival
167
Q

What are examples of alkylators and steroids used in the treatment of myeloma therapy?

A

1) Melphalan - nitrogen mustard derivate, high-dose melphalan 200 mg/m2 still in use in Autologous SCT
2) Cyclophosphamide - used in combination with steroids, immunomodulation and microenvironment
3) Dexamethasone and prednisolone - induce apoptosis in myeloma, strong synergy in all combinations

168
Q

Which combination of thalidomide with other drugs can be used in the treatment of myeloma?

A
  • Thalidomide in combination with cyclophosphamide and dexamethasone was established in the treatment of relapsed myeloma
  • It was later replaced older therapies as a front line treatment prior to autologous SCT
169
Q

What are different immunomodulatory drugs (IMiD) used in myeloma?

A
  • Lenalidomide - 2005: more potent, different toxicity profile, better tolerated
  • Pomalidomide – 2013 : even more potent than Lenalidomide
  • Iberdomide–awaits approval
170
Q

How do proteasome inhibitors in myeloma work?

A

Myeloma cells are protein production factories

Proteasome is crucial in removing misfolded protein

Accumulation of misfolded protein→endoplasmic reticulum stress and unfolded protein response → apoptosis

Alteration of NF-κB pathway

171
Q

What are proteasome inhibitors in myeloma?

A

1) Bortezomib - neuropathy is main toxicity, first line or relapse
2) Carfilzomib - more potent, only approved in relapse, thrombocytopenia, cardiotoxicity
3) Ixazomib - approved in relapse

172
Q

How do therapeutic moAbs in multiple myeloma

anti-CD38: Daratumumab and Isatuximab work?

A

Therapeutic moAbs in multiple myeloma:

1) Anti-CD38: Daratumumab and Isatuximab
2) Daratumumab is the first therapeutic moAb approved for multiple myeloma (2015)

3) CD38 is strongly expressed in normal and malignant plasma cells
Not a lineage specific marker

173
Q

What is the treatment algorithm in new diagnosis myeloma?

A

Transplant-eligible patients - fit and typically <65 years old

If fit: induction and then transplant - consolidation, the maintenance

If not fit: different combination therapies

174
Q

What is BiTE and CAR-BCMA in the context of myeloma treatment?

A

BiTE - Bispecific antibodies: CD3-BCMA and CD3-FcRL5 BiTE under development

BCMA: B cell maturing antigen, specific for plasma cells (normal and malignant)

175
Q

What is the definition of lymphoma?

A

The term ‘lymphoma’ means a neoplastic (malignant) tumour of lymphoid cells.

176
Q

Where are lymphomas normally found in?

A

Lymph nodes, bone marrow and/or blood (the lymphatic system
Lymphoid organs; spleen or the gut-associated lymphoid tissue
Skin (often T cell disease)
Rarely “anywhere” (breast kidney) {*Immune privilege sites CNS, occular, testes}

177
Q

List the different types of lymphoid malignancies

A

1) Precursor malignancies - B or T cell lineage
2) Mature B cell malignancies - Non-Hodgkin’s, Hodgkin’s lymphoma
3) Mature T cell malignancies - T cell or NK cell Non-Hodgkin’s lymphoma

178
Q

Where does B cell acute lymphoblastic leukaemia affect in B cell ontogeny?

A

B-precursor lymphoblastic leukaemia

179
Q

Where does mantle cell lymphoma affect on B cell ontogeny?

A

Large non-cleaved cell in mantle zone

180
Q

Where does multiple myeloma affect on B cell ontogeny?

A

Plasma cells

181
Q

How does DNA instability lead to malignancy?

A

Lymphocyte: DNA molecules are 1) cut and recombined 2) subjected to deliberate DNA mutagenesis (somatic hypermutation)

  • Generates immunoglobulin and T cell receptor diversity and Ig class switching
  • Potential for recombination errors and new point mutations

Rapid cell proliferation in the germinal centre

  • Allows rapid response to infection
  • Rapid cell division = increased risk of DNA replication errors

Dependent on apoptosis (90% of normal lymphocytes die in the Germinal centre!)
Exquisite antibody specificity & eliminates self reactive clones
Apoptosis is “switched off” in germinal centre
Consequences of mutation ins in apoptosis regulating genes

182
Q

What is the molecular basis of adaptive immune response?

A

VDJ recombination
Occurs in BM
Key enzymes: RAG1+2
TdT

Class switch recombination
Somatic hypermutation
Key enzyme: Adenosine induced
Deaminase

183
Q

What are some immune genes recombination errors and lymphoma-linked translocations?

A

Chr 14 –> instead of Ig heavy chain you can get C-MYC oncogene t(8;14)

Lymphoma/recombination associated translocations
Involves the Ig Locus (IgH, K or l loci)
Ig promoter highly active in B cells
Bring intact oncogenes close to the Ig promoter
Oncogenes may be anti apoptotic, proliferative.
bcl2
bcl6
Myc
cyclinD1

184
Q

What are the three main mechanisms of Non-Hodgkin’s lymphoma?

A

1) Constant antigenic stimulation
Bacteria infection (chronic)
Auto immune disorders

2) Viral Infection (direct viral integration of lymphocytes)

3) Loss of T cell function and EBV infection (EBV driven B cell lymphomas)
Loss of T cells (HIV)
Iatrogenic immunosuppression

185
Q

What are two examples of Non-Hodgkin’s lymphoma which have bacterial or autoimmune antigenic drive?

A

1) B cell Non Hodgkin Lymphoma Marginal zone sub type (MZL)

2) Enteropathy associated T-Cell Non Hodgkin lymphoma (EATL)

186
Q

What are the causes of B cell Non Hodgkin Lymphoma Marginal zone sub type (MZL)?

A

H.Pylori: Gastric MALT (mucosa associated lymphoid tissue) (MZL of stomach)
Sjogren syndrome: MZL (Low-grade marginal zone lymphomas) which causes joint pain, swelling and stiffness
Hashimoto’s: MZL of thyroid

187
Q

What is the main potential cause of enteropathy associated T-Cell Non Hodgkin lymphoma (EATL)?

A

Coeliac disease/Gluten: small intestine EATL

188
Q

What is the cause of direct viral integration and lymphomagenesis?

A

Direct Viral Integration

  • HTLV1 retrovirus infects T cells by vertical transmission
  • Caribbean, Japan (and world wide) endemic infection
  • Risk of Adult T cell leukaemia lymphoma is 2.5% at 70 years
  • ATLL is a subtype of T cell Non Hodgkin Lymphoma
189
Q

How can the following cause Non-Hodgkin’s lymphoma?

  • EBV
  • Loss of T cell function
  • Loss of cytotoxic T cell function can cause failure to eliminate EBW driven proliferation of B cells
A

1) EBV infection
EBV infects B lymphocytes, healthy carrier state post glandular fever.
EBV driven proliferation of B cells is associated with surface expression of EBV antigens. Proliferating B cells targeted and killed by EBV specific cytotoxic T cell response

2) Loss of T cell function
HIV (in uncontrolled infection there is x60 increased incidence of B NHL )
Iatrogenic (transplant immunosuppression)
PTLD (post transplant lympho-proliferative disorder)

3) Loss of cytotoxic T cell function can cause failure to eliminate EBV driven proliferation of B cells

190
Q

What would be the histological findings for classical Hodgkin’s lymphoma?

A

Reed Sternberg cells

191
Q

What are the B symptoms in Hodgkin’s lymphoma?

A

Fever
Night sweats
Weight loss

192
Q

What is the classification of Hodgkin’s lymphoma?

A

Nodular sclerosing 80%
Mixed cellularity 17% Good prognosis
Lymphocyte rich (rare) Good prognosis
Lymphocyte depleted (rare) Poor Prognosis

193
Q

What are the two most significant blood subtypes in blood transfusion?

A

ABO and Rh systems

194
Q

What are the ABO blood groups determined by?

A
  1. By the antigens (sugars) on the red cell membrane.

2. The naturally-occurring antibodies (IgM) in the plasma.

195
Q

What would happen if you give an ABO incompatible blood transfusion?

A

If you give an ABO incompatible blood

transfusion it will cause massive INTRAVASCULR haemolysis and this is potentially fatal

196
Q

Describe RhD+/- blood type

A

RhD positive (85% of population)
• Carry the RhD antigen
• Patients can receive RhD negative or RhD positive red cells

RhD negative (15% of population)
• Lack the RhD antigen
• Patients can make immune anti-D if exposed to RhD positive red cells

197
Q

A RhD- individual is exposed to RhD+ blood. What happens next?

A

Immune anti-D antibodies
• Are IgG (so cross the placenta)
• Do not cause direct agglutination of RBCs
• Cause delayed haemolytic transfusion reaction
There are some other Rh antigens e.g., C, c, E and e

198
Q

A RhD+ baby is exposed to RhD- blood from the mother which also has anti-RhD antibodies. What could be a complication of this?

A

Rh D negative women exposed to Rh D positive blood can produce immune anti D, which can cause haemolytic disease of the newborn or severe foetal anaemia and heart-failure (hydrops fetalis) in pregnancy.

199
Q

How is blood group tested for?

A

Column Agglutination Technology
• Automated
• Manual
• Room temp

Positive Agglutination (clumping)
Negative
Red cells stay suspended

200
Q

What is meant by group and screen when testing for blood type?

A

Use 2 or 3 reagent red cells containing all the important red cell antigens between them

Indirect anti-globulin technique: (bridges red cells coated by IgG, which can’t themselves bridge 2 red cells – to form a visible clump. Takes 30 mins’ incubation at 37°C)

201
Q

What is electronic crossmatch in blood group testing?

A

Electronic issue (EI) is the selection and issue of red cell units where compatibility is determined by IT system, without physical testing of donor cells against patient plasma

202
Q

What is serological crossmatching for blood groups?

A

FULL CROSSMATCH
INDIRECT ANTIGLOBULIN TECHNIQUE
Patient plasma incubated with donor red cells at 370C for 30-40 mins, will pick up antibody antigen reaction that could destroy the red cells and cause extravascular haemolysis
ADD ANTIGLOBULIN REAGENT (AHG)

IMMEDIATE SPIN (SALINE, ROOM TEMPERATURE)
Incubate patient plasma and donor red cells for 5 minutes only and spin, will detect ABO incompatibility only

IgG antibodies can AGGLUTINATION (OR bind to RBC antigens HAEMOLYSIS) = but do not crosslink so AHG reagent is INCOMPATIBLE added IgM anti-A and/or anti-B bind to RBCs, fix complement and lyse the cell

203
Q

How are blood bags labelled in the hospital?

A

Donor RBCs are labelled with:

  1. ABO & D TYPE
  2. Kell
  3. OTHER Rh ANTIGENS

Select the correct ABO and D type from stock fridge.
Select antigen negative blood if RBC antibody detected in antibody screen and ID panel
Select K negative blood for females of childbearing potential
All units have a traceability tag – 100% traceability is a legal requirement

204
Q

What are the pillars of patient blood management?

A

1) Optimise haemopoiesis
2) Minimise blood loss and bleeding
3) Harness and optimise physiological tolerance of anaemia

205
Q

How are red cells stored prior transfusion?

A

Stored at 40 C for 35 days.
Must be transfused within 4 hours of leaving fridge
Transfuse 1 unit RBC over 2-3 hours

206
Q

How are platelets stored and given in transfusion?

A

If group O given to A, B or AB patients select ‘high-titre’ negative (anti-A/B antibodies)
Stored at 20C for 7 days
Transfuse 1 unit of platelets over 20-30 minutes

207
Q

How is fresh frozen plasma stored and then transfused?

A

Once thawed can be kept at 4 0C for 24 hours

Transfuse 1 unit over 20-30 minutes

208
Q

How is cryoprecipitate stored and then transfused?

A

Once thawed has to kept at room temperature and use within 4 hours
Transfuse 1 unit over 20-30 minutes

209
Q

What is Maximum Surgical Blood Ordering Schedule (MSBOS)?

A

MSBOS is based agreement between surgeons and transfusion lab about predictable blood loss for ‘routine’ planned surgery

210
Q

What are some transfusion indications?

A

Major Blood Loss - if >30% Blood volume lost
Peri-Op, Critical Care - Hb <70g/L vs 80g/L
Post Chemo - Hb <80g/L

211
Q

What are the platelet transfusion indicators?

A 
Massive transfusion - Aim Plts >75 x109/L
Prevent bleeding (post chemo) - If < 10 x109/L (<20 if sepsis)
Prevent bleeding (surgery) - <50 x109/L (<100 if critical site: eye, CNS, polytrauma)

Platelet dysfunction or immune cause – only if active bleeding

212
Q

What are the indications of fresh frozen plasma and the dosage?

A
  • Replacement of single coagulation factor deficiency
  • DIC in the presence of bleeding and abnormal coagulation results
  • Thrombotic thrombocytopenic

Dosage: 15-20ml/kg

213
Q

What is cryoprecipitate?

A 
Fibrinogen
Factor VIII, vWF
Fibronectin
fXIII
Platelet microparticles
IgA
Albumin
214
Q

What is the difference between cryoprecipitate and FFP?

A

FFP contains coagulation factors at the same concentration present in plasma. Cryoprecipitate is a highly concentrated source of fibrinogen.

215
Q

What are the different autologous blood transfusion options?

A

Pre-operative autologous deposit - donate own blood before surgery

Intra-operative cell salvage - collect blood lost during surgery: centrifuge, filter, wash & re-infuse it - most UK surgical and obstetric units can do this

Post-operative cell salvage - collect blood lost post-op into wound drain – filter & re-infuse - mainly orthopaedic (knee surgery)

216
Q

What are some special requirements which must be undertaken in immunocompromised or pregnant individuals who need a transfusion?

A
  • CMV negative blood - only required for intra-uterine /neonatal transfusions and for elective transfusion in pregnant women (baby in-utero is exposed to maternal transfusion)
  • Irradiated blood - required for highly immunosuppressed patients, who cannot destroy incoming donor lymphocytes: which can cause (fatal) transfusion associated graft versus host disease (TA-GvHD)
  • Washed - red cells and platelets are only given to patients who have severe allergic reactions to some donors’ plasma proteins
217
Q

What is the most common blood type?

A

O+

218
Q

What is the acute reaction to blood transfusion in the case of mismatch?

A 
<24hrs
1. Acute haemolytic (ABO incompatible) 
2. Allergic/anaphylaxis
3. Infection (bacterial)
4. Febrile non-haemolytic
5. Respiratory
• Transfusion associated circulatory overload (TACO)
• Acute lung injury (TRALI)
219
Q

What is the delayed reaction to blood transfusion in the case of mismatch?

A

> 24hrs

  1. Delayed haemolytic transfusion reaction (antibodies)
  2. Infection - viral, malaria, vCJD
  3. TA-GvHD
  4. Post transfusion purpura
  5. Iron overload
220
Q

Describe the features of the febrile non-haemolytic transfusion reaction

A

‘MILD/ MODERATE’
During / soon after transfusion (blood or platelets), rise in temperature of 10C, chills, rigors
Common before blood was leucodepleted, now rarer Have to stop or slow transfusion; may need to treat with
paracetamol
Cause: White cells can release cytokines during storage

221
Q

Describe the features of incorrect blood transfusion

A

‘Severe or fatal’
Symptoms and signs of acute intravascular haemolysis- IgM
• Restless, chest/ loin pain, fever, vomiting, flushing, haemoglobinuria (later);
• ↓BP & ↑HR (shock), ↑Temp
Stop transfusion – check patient / component
Take samples for FBC, biochemistry, coagulation
Repeat x-match and Direct Antiglobulin Test (DAT)
Discuss with haematology doctor ASAP

221
Q

Describe the features of allergic transfusion reactions

A

‘MILD/ MODERATE’
Common especially with plasma
Mild urticarial or itchy rash sometimes with a wheeze
During or after transfusion
Usually have to stop or slow transfusion
IV antihistamines to treat (and prevent in future if recurrent)
Cause:
Allergy to a plasma protein in donor so may not recur again, depending on how common the allergen is
Commoner in recipients with other allergies and atopy

222
Q

Describe the features of bacterial contamination after blood transfusion

A

Restless, fever, vomiting, flushing, ↓BP & ↑HR (shock), ↑Temp, collapse, ‘severe or fatal’
•Bacterial growth can cause endotoxin production which causes immediate collapse
•From the donor (low grade GI, dental, skin infection) •Introduced during processing (environmental or skin) •Platelets >red cells > frozen components (storage temp)

223
Q

Why do platelet transfusions have a higher risk of bacterial contamination as oppose to red blood cell transfusion?

A

Red cells are stored at 4°C

Platelets are stored at room temperature – more likely to get bacterial growth

224
Q

What are some methods of bacterial contamination prevention?

A

Donor questioning
Arm cleaning
Diversion of first 20mL into a pouch (used for testing)
Look for abnormalities e.g. clumps of discoloured debris; brown plasma etc.

225
Q

How does anaphylaxis present after blood transfusion?

A 
Immediate and fatal reaction
• ↓BP & ↑HR (shock),
• very breathless with wheeze,
• often laryngeal &/or facial oedema
Mechanism:
IgE antibodies in patient cause mast cell release of granules & vasoactive substances Most allergic reactions are not severe, but few are e.g. in IgA deficiency
226
Q

In which patients is anaphylaxis more common in after blood transfusion?

A

IgA deficiency
• 1:300 - 1:700 (common); where in 25%, anti-IgA antibodies develop in response to exposure to IgA (transfusion – especially with plasma);
• But only minority ever have transfusion reactions- frequency is 1:20,000 - 1:47,000

227
Q

What are the respiratory complications of blood transfusion?

A

Transfusion Associated Circulatory Overload (TACO) Transfusion Related Acute Lung Injury (TRALI) Transfusion Associated Dyspnoea (TAD)

228
Q

Which is the most common pulmonary complication of blood transfusion?

A

TACO is the most common pulmonary complication

Majority present within 6 hours of transfusion

229
Q

What are the clinical features of transfusion associated circulatory overload (TACO)?

A

Often lack of attention to fluid balance, especially in cardiac failure, renal impairment, hypo-albuminaemia, those on fluid replacement, very young, very small and very old.

Clinical features: SOB, ↓SAO2 , ↑HR, ↑BP

CXR: fluid overload / cardiac failure

230
Q

What is transfusion related acute lung injury?

A

Acute lung injury/ARDS

  • SOB, ↓O2, ↑HR, ↑BP; (similar to TACO)
  • CXR: bilateral pulmonary infiltrates during/within 6 hr of transfusion

Mechanism
• Anti-wbc antibodies (HLA or neutrophil Abs) in donor
• Interact with corresponding ag on patient’s WBCs
• Aggregates of WBCs get stuck in pulmonary capillaries → release neutrophil proteolytic enzymes & toxic O2 metabolites → lung damage
• Prevention - male donors for plasma & platelets (no pregnancy or transfusion, so no HLA/HNA antibodies)

231
Q

What are some infections which occur post-blood transfusion?

A 
CMV
Very immunosuppressed (stem cell transplant) patients can get fatal CMV disease, but leucodepletion removes CMV (in wbc’s) Only give CMV- now for pregnant women (foetus) & neonates.

Parvovirus
Causes temporary red cell aplasia - affects foetuses and patients with haemolytic anaemias e.g. sickle cell; hereditary spherocytosis

232
Q

What is the delayed haemolytic transfusion reaction?

A

1-3% of all patients transfused develop an ‘immune’ antibody to a RBC antigen they lack ALLOMMUNISATION

If the patient has another transfusion with RBCs expressing the same antigen, antibodies cause RBC destruction EXTRAVASCULAR HAEMOLYSIS (as IgG) so
takes 5-10 days

233
Q

What are the test results for someone with delayed haemolytic transfusion reaction?

A 
Haemolysis screen:
High: bilirubin, LDH, retics
DAT positive
Haemoglobinuria over a few days
Test U&Es – as can cause renal failure
234
Q

What is the transfusion associated graft-versus-host disease (TaGVHD)?

A
  • Donor’s blood contains some lymphocytes (able to divide)
  • In ‘susceptible’ patients (e.g… very IS) - lymphocytes not destroyed
  • Lymphocytes recognise patient’s tissue HLA antigens as ‘foreign’ – so attack patient’s gut, liver, skin and bone marrow

Prevent: irradiate blood components for very immunosuppressed; or patients having HLA matched components

Clinical features - severe diarrhoea, liver failure, skin desquamation, bone marrow failure

235
Q

Describe the features of post transfusion purpura

A

Purpura appears 7-10 days after transfusion of blood or platelets and usually resolves in 1-4 weeks but can cause life threatening bleeding

Affects HPA -1a negative patients - previously immunised by pregnancy or transfusion (anti-HPA-1a antibody)

?exact mechanism of own platelet destruction, as HPA-1a negative!
?innocent bystander mechanism

236
Q

How is post-transfusion purpura treated?

A

Infusion of IVIG

237
Q

What is immune-modulation?

A

Possible
• Increased rate of infections post-op
• Increased recurrence of cancers in patients who have blood transfusion

238
Q

What is iron overload?

A

If lots of transfusion (e.g. >50) over time accumulate iron (not excreted); 200-250mg of iron per unit of blood
• Can cause organ damage - liver, heart, endocrine etc
• Prevent by iron chelation (Exjade) with transfusions once ferritin >1000 e.g. used in Thalassaemia / Sickle cell disease - regular transfusions

239
Q

What are the clinical features of haemolytic disease of the newborn?

A

Only IgG antibodies can cross the placenta

If mother has high levels of IgG antibody - it can destroy foetal red cells

Fetal anaemia (haemolytic)

Haemolytic disease of newborn (anaemia plus high bilirubin)

240
Q

How does prophylactic anti-D immunoglobulin work?

A

To be effective - must give anti-D injection within 72 hours of the ‘sensitising event’

It does not work if the mother has already been sensitised (developed anti-D) in the past

241
Q

What are sensitising events?

A
  1. Give anti-D at delivery if baby is RhD positive
  2. Give anti-D Ig for ‘sensitising events’ during pregnancy, where FMH is likely to occur
    - spontaneous miscarriages if surgical evacuation needed and therapeutic terminations
    - amniocentesis and chorionic villous sampling
    - abdominal trauma (falls and car accidents) - external cephalic version (turning the fetus)
    - stillbirth or intrauterine death
242
Q

What are the doses of anti-D?

A
  • At least 250 iu - for events before 20 weeks of pregnancy

- At least 500 iu - for events any time after 20 weeks of pregnancy (including delivery)

243
Q

What are other antibodies which can cause sensitisation reaction?

A

Anti-c and anti-Kell can cause severe HDN

  • usually less severe than anti-D
  • Kell causes reticulocytopenia in fetus as well as haemolysis

IgG anti-A and anti-B antibodies from Group O mothers can cause mild HDN
- usually not severe (phototherapy)

244
Q

What is non-invasive fatal genotyping for mother with antibodies?

A
  • A rapid, non-invasive, convenient and reliable service for prediction of fetal D, C, c, E and K status, using cell-free fetal DNA in maternal blood for women who have allo- antibodies.
  • Upon identification, mothers can then be informed and prepared for further careful monitoring during their pregnancy.
  • Also identifies pregnant women who have antigen-negative fetuses and who therefore are not at danger from HDFN
245
Q

What can predict the Rh D status of the foetus? how can this be managed?

A

The ffDNA technique can predict Rh D status of fetus from 11+2 weeks gestation.
• At 16 weeks women can be consented for sample for ffDNA testing
• Results available in 10 days
• If baby Rh D negative – no anti D needed

Currently anti-D (1500 IU) is administered at 28 weeks gestation as RADDP regime.

At birth: further dose of 1500 IU

246
Q

Which HLA molecules are relevant in transplant and which cells are they found on?

A

HLA-A, -B, -C, (class I), present peptide to CD8+ (cytotoxic T-cells)

HLA-DP,-DQ and -DR (class II), present peptide to CD4+ (helper T-cells)

Function – present foreign peptides to T cells

Routinely, HLA-A, -B and DR are typed for compatibility purposes

247
Q

Describe the stages involved in autologous transplantation

A

1) Grown factor given
2) Collect stem cells and freeze
3) Thaw and reinfuse
4) High dose chemotherapy

248
Q

What are autologous transplantations suitable for?

A 
Acute leukaemia
Solid tumours
Autoimmune disease
Myeloma
Lymphoma
Chronic lymphocytic leukaemia
249
Q

What is allogeneic transplantation?

A

Bone marrow or peripheral stem cells given by donor

250
Q

When is allogeneic transplantation suitable?

A 
Suitable for
Acute leukaemia
Chronic leukaemia
Myeloma
Lymphoma
BM failure
Congenital immune deficiencies
251
Q

How many human stem cells are needed for transplantation?

A

Need 2x106/kg CD34+ cells

252
Q

What is graft versus host disease (GvHD)?

A

An immune response when donor cells recognise the patient as ‘foreign’

Acute GvHD affects skin, gastrointestinal tract and liver. Chronic GvHD affects skin, mucosal membranes, lungs, liver, eyes, joints.

253
Q

What are risk factors for acute GvHD?

A 
Degree of HLA disparity
Recipient age
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase
Viral infections
254
Q

What is the treatment for acute GvHD?

A 
Corticosteroids
Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
Mycophenylate mofetil
Monoclonal antibodies
Photopheresis
Total lymphoid irradiation
Mesenchymal stromal cells
255
Q

How can GvHD be prevented?

A

Methotrexate
Corticosteroids
Calcineurin inhibitors: cyclosporin A, tacrolimus, sirolimus
CsA plus MTX

T-cell depletion
Post-transplant cyclophosphamide

256
Q

When does GvHD occur?

A

Diagnosis within 6 months of transplant, lasts 2-5 years
85% of survivors can discontinue treatment at that time
5-year survival is 70–80%, in persons with low risk cGVHD and those responding to corticosteroids.
Five-year survival is 30–40% for those with high-risk disease +/- failure of steroids

257
Q

What are the consequences of chronic GvHD?

A

Immune dysregulation
Immune deficiency,
Impaired end-organ function
Decreased survival.

258
Q

What are risk factors for chronic GvHD?

A

Affects 50% of patients who survive >1 year from transplant

Prior acute GvHD
Increased degree of HLA disparity
Male recipient: female donor
Stem cell source (PB>BM>UCB)
T-cell replete
Older donor age
Use of DLI
259
Q

What are the main sources of infection in neutropenic patients?

A

Gram positive - vascular access

Gram negative - gastrointestinal tract

260
Q

In how many neutropenic patients is the causative organism identified?

A

1/3

261
Q

What is the most common causative bacterial infection in neutropenic patients?

A

Gram positive e.g. staph epidermidis

262
Q

What is the most common bacterial infection which causes the most deaths due to sepsis in neutropenic patients?

A

Gram negative organisms eg e.coli, pseudomonas aeruginosa

263
Q

How can bacterial infections be reduced in neutropenic patients?

A

Reduced incidence of infection using isolation measures and broad spectrum oral antibiotics

264
Q

How is neutropenic sepsis treated?

A

Assess patient: temperature, pulse, oxygen saturation and blood pressure. History and examination for evidence of source

Blood cultures, MSU, CXR

Initiate empirical broad spectrum antibiotics and supportive care

265
Q

Define neutropenic sepsis

A

Defined as temperature >38 sustained for one hour, or single fever >39, in a patient with neutrophils <1.0 x 109/L

266
Q

How can fungal infections occur post-transplant?

A

Yeasts from translocation from the intestinal mucosa, or indwelling catheters

Moulds: inhalation, chronic sinusitis, skin, mucosa

267
Q

How can CMV be reactivated in immunosuppressed individuals and manifest?

A

Pneumonitis

Retinitis

Gastritis – colitis

Encephalitis

268
Q

How can CMV be treated in transplant patients?

A

Twice weekly quantitative monitoring of peripheral blood viraemia to day 100

Thresholds for treatment together with evidence of increasing viral load

Ganciclovir/valganciclovir: oral and IV preparations.

Minimum of 2/52 treatment with clear evidence of reduction in viral load

269
Q

Apart from CMV, what are other viral complications of post-transplant?

A

EBV: acute infection, PTLD

Respiratory viruses: influenza, parainfluenza, respiratory syncytial virus, rhino, metapneumovirus, COVID-19

PAPOVA viruses: BK and haemorrhagic cystitis

Adenovirus

270
Q

Which factors can affect the outcome of the transplant?

A
  • Age
  • Disease phase
  • Gender
  • Time to BMT
  • Donor
271
Q

Why are conditions like iron and folic acid deficiency more common in children?

A

The rapid growth of the child can predispose to deficiency of vitamins or minerals

272
Q

How are the neonatal blood ranges different to an adult’s?

A

A higher Hb

A lower WBC

Smaller red blood cells

The same percentage of haemoglobin F

Enzyme levels in red cell also differ, e.g. glucose-6-phosphate dehydrogenase (G6PD) concentration is about 50% higher than in adults

273
Q

What can polycythaemia in the foetus or neonate be caused by?

A

Twin-to-twin transfusion
Intrauterine hypoxia
Placental insufficiency

274
Q

What are the causes of anaemia in a foetus or neonate?

A

Twin-to-twin transfusion
Fetal-to-maternal transfusion
Parvovirus infection (virus not cleared by immature immune system)
Haemorrhage from the cord or placenta

275
Q

What happens if a lactating woman eats fava beans and breastfeeds her baby who is G6PD-deficient?

A

Haemolysis

276
Q

In which cases can congenital leukaemia occur?

A

Congenital leukaemia is particularly common in Down syndrome

This specific type of neonatal leukaemia (also sometimes called transient abnormal myelopoiesis or TAM) differs greatly from leukaemia in older infants or children

Can relapse after 1-2 years in 25% of cases

277
Q

What are the three normal forms of haemoglobin in the foetus, infant, child and adult?

A

A - 2 alpha, 2 beta - late foetus, infant, child and adult

A2 - 2 alpha, 2 delta - infant, child and adult

F - 2 alpha, 2 gamma - foetus and infant

278
Q

How does vascular obstruction in sickle cell anaemia occur?

A

Red cells elongate to pass through capillary bed to post-capillary venules

Red cells adhere to endothelium

Sickle cells obstruct venues and retrograde capillary obstruction occurs

279
Q

Why is sickle cell anaemia different in infants compared to adults?

A

The distribution of red bone marrow (susceptible to infarction) differs

The infant still has a functioning spleen—splenic sequestration can occur

The infant has an immature immune system and has not developed immunity to pneumococcus or parvovirus

280
Q

How do crises of sickle cell manifest in children and adults?

A

Infancy –> childhood –> adulthood manifestations in order

1) The hand/foot syndrome
2) Acute chest syndrome
3) Painful crisis
4) Stroke/cumulative incidence

281
Q

What is spenlic sequestration?

A

Splenic sequestration is the acute pooling of a large percentage of circulating red cells in the spleen

The spleen enlarges acutely

The Hb falls acutely and death can occur

This doesn’t happen in older children and adults because recurrent infarction has left the spleen small and fibrotic

282
Q

Why do infants with sickle cell have higher folic acid requirements?

A

Hyperplastic erythropoiesis requires folic acid

Growth spurts require folic acid

Red cell life span is shorter so anaemia can rapidly worsen

283
Q

How can sickle cell be managed in infants?

A

Accurate diagnosis

Educate parents

Vaccinate

Prescribe folic acid and penicillin

284
Q

Define beta-thalassaemia

A

Beta thalassaemia is a condition resulting from reduced synthesis of beta globin chain and therefore haemoglobin A. Manifests in the first 3-6 months.

285
Q

What are the clinical effects of poorly treated thalassaemia major?

A

Anaemia - heart failure, growth retardation

Erythropoietic drive - bone expansion, hepatomegaly, splenomegaly

Iron overload - heart failure, gonadal failure

286
Q

What are the two types of haemolytic anaemia?

A

Inherited

Acquired

287
Q

What can inherited haemolytic anaemias be caused by?

A

Red cell membrane

Haemoglobin molecule

Red cell enzymes—glycolytic pathway

Red cell enzymes—pentose shunt

288
Q

What are the haemolytic anaemias according to which part of erythrocyte synthesis they affect?

A

Red cell membrane defects
Hereditary spherocytosis
Hereditary elliptocytosis

Haemoglobin defects
Sickle cell anaemia

Glycolytic pathway defects
Pyruvate kinase deficiency

Pentose shunt defects
G6PD deficiency

289
Q

What are the two acquired haemolytic anaemias in children?

A

Autoimmune haemolytic anaemia

Haemolytic uraemic syndrome

290
Q

What is autoimmune haemolytic anaemia characterised by on blood film?

A

Spherocytosis

Positive direct antiglobulin test (Coombs’ test)

291
Q

What is microangiopathic haemolytic anaemia?

A

The red cells are damaged in capillaries and are fragmented by the process. Small angular fragments and microspherocytes are formed.

292
Q

What is the typical presentation of haemophilia A and B?

A

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

293
Q

What is the typical presentation of von Willebrand disease?

A

Mucosal bleeding
Bruises
Post-traumatic bleeding

294
Q

What is the mode of inheritance of VWD?

A

Mostly autosomal dominant

295
Q

Prolonged aPTT but all other variables normal. Joint bleeding was first presentation. What is your diagnosis?

A

Haemophilia A

296
Q

What is the typical presentation of autoimmune thrombocytopenia purpura?

A

Petechiae
Bruises
Blood blisters in mouth

297
Q

How is autoimmune thrombocytopenia purpura treated?

A

Observation

Corticosteroids

High dose intravenous immunoglobulin

Intravenous anti-Rh D (if Rh positive)

298
Q

What are some chromosomal abnormalities which can occur in AML?

A

Duplication (usually trisomy)
Loss
Translocation t(15;17), t(5;8)
Inversion (16)
Deletion - loss of 5/5q & 7/7q, tumour suppression gene loss
Altered DNA sequence - creation of new fusion genes, abnormal regulation of genes

299
Q

What are some risk factors of AML?

A

Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking

300
Q

What are the two types of abnormalities which occur in leukaemogenesis in AML?

A

Type 1 abnormalities - promote proliferation & survival

Type 2 abnormalities - block differentiation (which would normally be followed by apoptosis)

301
Q

What is an example of a chromosome with fusion gene in a core binding factor AML?

A

t(8;21)

RUNX1 gene chromosome 21: red probe
RUNX1T1 gene chromosome 8: green probe

302
Q

What is core binding factor in the context of haematopoeisis?

A
  • Dimeric transcription factor

- Master controller of haematopoiesis

303
Q

What is acute promyelocytic leukaemia caused by and the clinical manifestations?

A

t(15;17)

An excess of abnormal promyelocytes
Disseminated intravascular coagulation (DIC)
Two morphological variants but the same disease (classical and variant)
The great majority of patients can now be cured

304
Q

How can you differentiate between AML and ALL?

A

Cytological features
Cytochemistry
Immunophenotyping

305
Q

What are the three types of immunophenotyping?

A

Flow cytometry

Immunocytochemistry - binds to monoclonal antibody

Immunohistochemistry

306
Q

What are the clinical features of AML?

A

Bone marrow failure
Anaemia
Neutropenia - infection e.g. necrotising fasciitis
Thrombocytopenia - bleeding, DIC (also promyelocytic)

Local infiltration
Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy (only occasionally)
Skin, CNS or other sites
Retinal haemorrhages/exudates
307
Q

How is AML diagnosed?

A 
Blood film
Usually diagnostic: circulating blasts
Auer rods (proves myeloid)
ALL versus AML -Immunophenotyping
“Aleukaemic” leukaemia If                            there are no leukaemic cells                in in the blood you need a bone                marrow aspirate
308
Q

What can be used to determine prognosis of AML?

A

Cytogenic studies

Molecular studies and FISH

309
Q

How can AML be treated?

A

Supportive care
Red cells
Platelets
Fresh frozen plasma/ cryoprecipitate if DIC
Antibiotics
Long line
Allopurinol, fluid and electrolyte balance

Chemotherapy
4-5 courses - 6 months each
x2 remission, x2-3 consolidation

Targeted molecular therapy

Transplantation

310
Q

Give some examples of molecularly targeted therapy in AML

A

All-trans-retinoic acid (ATRA) and A2O3 for acute promyelocytic leukaemia

Tyrosine kinase inhibitors for the rare Ph-positive cases

Drugs targeting the products of other mutated genes

Antibody treatment, e.g. gemtuzumab ozogamicin, a cytotoxic antibiotic linked to an anti-CD33 antibody

311
Q

Name some clinical features of ALL

A

Bone marrow failure
Anaemia
Neutropenia
Thrombocytopenia

Local infiltration
Lymphadenopathy (± thymic enlargement)
Splenomegaly
Hepatomegaly
Testes, CNS, kidneys or other sites
Bone (causing pain)
312
Q

What are the pathological features of ALL?

A 
Peripheral blood
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts

Bone marrow and other tissues
Lymphoblast infiltration
Lymphoblasts may be B-lineage or T-lineage

313
Q

What changes could result in photo-oncogene dysregulation?

A
  • Fusion genes
  • Wrong gene promoter
  • Dysregulation by proximity to T-cell receptor (TCR) or immunoglobulin heavy chain loci
314
Q

What is the Philadelphia chromosome?

A

t(9;22)(q34;q11.2)

Predisposes to CML and ALL

315
Q

Why does immunophenotype matter for ALL and AML?

A

AML and ALL are treated very differently

T-lineage (15%) and B-lineage (85%) ALL may be treated differently

316
Q

How are Philadelphia positive ALL patients treated?

A

Imatinib

317
Q

How is ALL treated?

A

Tyrosine kinase inhibitors for Ph-positive cases e.g. imantinib

Rituximab – monoclonal antibody directed at CD20 (applicable to CD20-positive cases)

318
Q

What is the most common cause of osteomyelitis?

A

Staphylococcus aureus

319
Q

What is the pentad of clinical features of thrombotic thrombocytopenic purpura?

A 
Microangiopathic haemolytic anaemia
Thrombocytopenia
Fever
Neurological abnormalities
Renal impairment
320
Q

What is microangiopathic haemolytic anaemia?

A

Microangiopathic haemolytic anaemia is a term that is used to describe the anaemia that results from physical damage to the red cells following the occlusion of arterioles and capillaries as a result of fibrin deposition or platelet aggregation

321
Q

What is the pathophysiology of anaemia of chronic disease?

A

Reduction in red cell lifespan
Cytokine release
IFNg, IL1 and TNF
Reduced proliferation of erythroid precursors
Suppression of endogenous erythropoietin production
Impaired iron utilisation

322
Q

What are some of the associations of Hodgkin lymphoma?

A

Increased risk in families of affected patients
Association with HLA DPB1
Epstein‒Barr virus found in >79% of over 50s

323
Q

What can be used to predict prognosis and monitor Hodgkin patients?

A

ESR

324
Q

How can you distinguish between anaemia of chronic disease (inflammation) or Fe deficiency?

A

Low ferritin confirms Fe deficiency

Normal or high ferritin can be ACD {or Fe deficiency in a case with inflammation and iron deficiency}

The iron transporting protein transferrin is the key
Low/normal&raquo_space; ACD
High» Fe deficiency

325
Q

Why are iron stores sequestered in inflammation?

A

Hepcidin is master regulator of Iron - elevated hepcidin inhibits GI absorption of Iron and sequesters Fe in macrophage and Kupffer cells

Hepcidin is an anti bacterial/ inflammatory response protein. Removing available iron from the blood circulation deprives invading bacteria of iron required for rapid bacterial proliferation

326
Q

What would you see on the blood film of someone with chronic myeloid leukaemia?

A

Neutrophils and myelocytes (not blasts if chronic phase)

Basophilia

327
Q

What are the different treatment options in CLL?

A

BCR Kinase Inhibitors: Ibrutinib (BTK), Idelalisib (PI3K

BCL2 inhibitors: Venetoclax

Experimental Cell Based Therapies: Chimaeric Antigen Receptor T cells (CAR-T)

328
Q

What does CRAB stand for in multiple myeloma?

A

Calcium elevation
Renal dysfunction
Anemia
Bone disease

329
Q

What happens to the FBC in pregnancy?

A 
Mild anaemia
Red cell mass rises (120 -130%)
Plasma volume rises (150%)
Macrocytosis
Normal
Folate or B12 deficiency
Neutrophilia
Thrombocytopenia
increased platelet size
330
Q

What are the nutritional demands of pregnancy?

A

Iron requirement
300mg for fetus
500mg for maternal increased red cell mass
RDA 30mg;
Increase in daily iron absorption:1-2mg to 6mg

Folate requirements increase
Growth and cell division
Additional 200mcg/day required

331
Q

What are the causes of thrombocytopenia in pregnancy?

A

Physiological: ‘gestational’/incidental thrombocytopenia

Pre-eclampsia - associated with coagulation activation

Immune thrombocytopenia (ITP)

Microangiopathic syndromes

All other causes: bone marrow failure, leukaemia, hypersplenism, DIC etc.

332
Q

How may ITP be treated for delivery or in PPH?

A

IV immunoglobulin

Steroids etc.

333
Q

Describe the coagulation changes in pregnancy

A

Increase in: factor VIII, vWF, fibrinogen, factor VII

Decrease in: protein S

PAI-1 and PAI-2 increase

  • Increased thrombin generation
  • Increased fibrin cleavage
  • Reduced fibrinolysis
  • Interact with other maternal factors
334
Q

What are some risk factors of VTE during and following pregnancy?

A
  • BMI > 25
  • Personal/family Hx
  • Air travel
  • Hyperemesis gravidarum
  • OHSS
  • Unrelated surgery
  • Age
335
Q

What are some issues with using Warfarin in the first trimester?

A

Chondrodysplasia Punctata:

Abnormal cartilage and bone formation
Early fusion of epiphyses
Nasal hypoplasia
Short stature
Asplenia
Deafness
Seizures
336
Q

What is the typical triad in antiphospholipid syndrome?

A

Antiphospholipid Syndrome (APLS): Recurrent miscarriage + persistent Lupus anticoagulant (LA) and/or antiphospholipid antibodies

Adverse pregnancy outcome: three or more consecutive miscarriages before 10 weeks of gestation

337
Q

Define what is meant by postpartum haemorrhage

A

> 500 mL blood loss

5% of pregnancies have blood loss >1 litre at delivery

338
Q

What is disseminated intravascular coagulation (DIC)?

A 
Amniotic fluid embolism
Abruptio placentae
Retained dead fetus
Preeclampsia (severe) 
Sepsis
339
Q

What is myelodysplasia?

A

Disorder of the elderly.
Symptoms/signs are those of general marrow failure
Develops over weeks & months

340
Q

List the different myelodysplasia disorders

A

Pelger-Huet anomaly (bilobed neutrophils)

Dysganulopoieses of
neutrophils

Dyserythropoiesis of red cells

Dysplastic megakaryocytes – e.g. micro-megakaryocytes

Increased proportion of blast cells in marrow (normal < 5%)

341
Q

What are some of the driver mutations in myelodysplasia?

A

TP53, EZH2, ETV6, RUNX1, ASXL1

Others: SF3B1, TET2, DNMT3A

342
Q

What is the prognosis of myelodysplasia?

A
  1. Deterioration of blood counts
    • Worsening consequences of marrow failure
  2. Development of 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. As a rule of thumb
    • 1/3 die from infection
    • 1/3 die from bleeding
    • 1/3 die from acute leukaemia
343
Q

What are the two treatment options of myelodysplasia?

A
  1. Allogeneic stem cell transplantation (SCT)

2. Intensive chemotherapy

344
Q

What are all the treatment options of myelodysplasia?

A

1) Supportive care
Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF, TPO-Receptor Agonist)

2) Biological Modifiers Immunosuppressive therapy Azacytidine, Decitabine, Lenalidomide (del5q variant)
3) Chemotherapy - Hydroxyurea
4) Low dose chemotherapy SC low dose cytarabine

5) Intensive Chemotherapy/SCT (for high risk MDS) AML type regimens
Allo/VUD standard/ reduced intensity

345
Q

What are some primary and secondary disorders of bone marrow failure?

A
  1. PRIMARY
  2. Congenital: Fanconi’s anaemia (multipotent stem cell)
  3. Diamond-Blackfan anaemia (red cell progenitors)
  4. Kostmann’s syndrome (neutrophil progenitors)
  5. Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
  6. SECONDARY
  7. Marrow infiltration:
  8. Haematological (leukaemia, lymphoma, myelofibrosis) 3. Non-haematological (Solid tumours)
  9. Radiation
  10. Drugs
  11. Chemicals (benzene)
  12. Autoimmune
  13. Infection (Parvovirus, Viral hepatitis)
346
Q

Which drugs can cause bone marrow failure?

A
  1. PREDICTABLE (dose-dependent, common)
  2. Cytotoxic drugs
  3. IDIOSYNCRATIC (NOT dose-dependent, rare)
  4. Phenylbutazone
  5. Gold salts
  6. ANTIBIOTICS
  7. Chloramphenicol
  8. Sulphonamide
  9. DIURETICS
  10. Thiazides
  11. ANTITHYROID DRUGS
  12. Carbimazole
347
Q

What are the different types of aplastic anaemia?

A
  • Idiopathic
  • Inherited - Dyskeratosis congenita, Fanconi anaemia, Shwachman-Diamond
  • Secondary - drugs (chloramphenicol, NSAIDs), viruses, immune
  • Miscellaneous (thymoma, paroxysmal nocturnal haemoglobinuria)
348
Q

What is the pathophysiology of aplastic anaemia?

A

Failure of BM to produce blood cells

“Stem cell” problem (CD34, LTC-IC) [Long-Term Culture-Initiating Cells]

Immune attack:
Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell

349
Q

What is the triad of bone marrow failure?

A

1) Anaemia - fatigue, breathlessness
2) Leucopenia - infections
3) Platelets - easy bruising/bleeding

350
Q

What are the two types of aplastic anaemia?

A
  1. Severe aplastic anaemia (SAA)

2. Non-severe aplastic anaemia (NSAA)

351
Q

What is the Camitta criteria for severe aplastic anaemia?

A

2 out of 3 features:

  1. Reticulocytes < 1% (<20 x 109/L)
  2. Neutrophils (< 0.5 x 109/L)
  3. Platelets (< 20 x 109/L)

Bone marrow <25% cellularity

352
Q

How can bone marrow failure be managed?

A
  1. Seek and remove a cause (detailed drug & occupational exposure history)
  2. Supportive: Blood/platelet transfusions (leucodepleted, CMV neg, irradiated) Antibiotics
    Iron Chelation Therapy
  3. Immunosuppressive therapy (anti-thymocyte globulin, steroids, eltrombopag, cyclosporine A)
  4. Drugs to promote marrow recovery - Oxymethone, TPO receptor agonists (eltrombopag)
  5. Stem cell transplantation
  6. Other treatments in refractory cases – e.g. alemtuzumab (anti-CD52, high dose cyclophosphamide)
353
Q

What is the treatment of aplastic anaemia?

A

Blood products
Leucodepleted (CMV negative)
(Irradiated)

Antimicrobials

Iron Chelation Therapy (when ferritin > 1000 μg/L)

354
Q

What is Fanconi anaemia?

A
  1. The most common form of inherited aplastic anaemia
  2. Autosomal recessive or X-linked inheritance
  3. Heterozygote frequency may be 1:300
  4. Multiple mutated genes are responsible
  5. When these genes become mutated, this results in:
    • Abnormalities in DNA repair
    • Chromosomal fragility (breakage in the presence of in-vitro mitomycin or diepoxybutane)

Congenital malformations may occur in 60-70% of children with FA

355
Q

What is dyskeratosis congenita characterised by?

A

Marrow failure
Cancer predisposition
Somatic abnormalities

Classical Triad:

1) Skin pigmentation
2) Nail dystrophy
3) Leukoplakia

356
Q

What are the different inheritance patterns of dyskeratosis congenita?

A

X-linked recessive trait — the most common inherited pattern (mutated DKC1 gene - defective telomerase function)

Autosomal dominant trait — (mutated TERC gene - encodes the RNA component of telomerase)

Autosomal recessive trait — The gene for this form of DC has not yet been identified

Year 5 Pathology (5 decks)

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