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Medicine Year 3 > Week 4 - Haematology > Flashcards

Week 4 - Haematology Flashcards

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1
Q

Describe the action of hydroxycarbamide in the treatment of essential thrombocytopenia

A

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

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2
Q

Describe the pharmacological characteristics of warfarin

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

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

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

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

A

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

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5
Q

Describe the mechanism of action of tPA derivatives

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

Describe the survival rates of ALL

A

5 year survival rate for children - 90%

5 year survival rate for adults - 40%

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7
Q

What are the indications for anti-platelet drugs?

A

Cardiovascular disease

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

Cerebrovascular disease (without AF)

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

Peripheral vascular disease

  • Clopidogrel
  • Aspirin if clopidogrel not well tolerated
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8
Q

List the causes of warm type autoimmune haemolytic anaemia

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

How is acute myeloid leukaemia managed?

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

What is required for blood coagulation?

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

Define thrombocytosis

A

Too many platelets

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12
Q

How is myeloma treated?

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

How has the prognosis of chronic myeloid leukaemia been improved?

A

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

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14
Q

How is Fanconi’s anaemia treated?

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

Where is red bone marrow found?

A

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

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16
Q

When is streptokinase ineffective?

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

How is intermediate essential thrombocytopenia treated?

A

Aspirin +/- hydroxycarbamide (cytoreductive agent)

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18
Q

List the risks of splenectomy

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

How can secondary haemostasis be assessed?

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

List the signs/symptoms of iron deficiency anaemia

A

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

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

Describe the principles of coagulation testing

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

How are autograft stem cells usually harvested?

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

Describe the pharmacological characteristics of heparins

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

How is the thrombin clotting time measured?

A
  • Add at 37 degrees - patient’s plasma, bovine thrombin
  • Less calcium or phospholipid dependent
  • Time to clot
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25
Describe the pattern of inheritance of hereditary spherocytosis
Autosomal dominant
26
Describe the pathogenesis of sickle cell disease
Mutation in beta globin gene on chromosome 11 - single amino acid substitution at position 6: * Glutamine swapped for valine = Hb S * Glutamine swapped for lysine = Hb C
27
What tools can be used to assess co-morbidities in lymphoma?
* CGA (comprehensive geriatric assessment) * CIRS (cumulative illness rating scale) * Haemato-oncology elderly care liaison service
28
How is folate absorbed?
Mostly in small bowel, 200-400ug, no carrier molecule required
29
What is thrombophilia?
* Deficiencies of natural anticoagulants * Antithrombin * Protein C * Protein S * Specific genetic mutations * Factor V Leiden (resistance to APC) * Prothrombin gene mutation (increased prothrombin)
30
How does graft vs host disease usually present?
* Most commonly manifests as a skin rash, jaundice or diarrhoea (skin, liver and gut are organs most commonly affected) * Can also have dry mouth, dry eyes and breathlessness (due to pulmonary fibrosis)
31
When does functional IDA with epo therapy occur?
Renal disease
32
Describe the role of RES macrophages in iron metabolism
* At end of lifespan (120 days) RBC phagocytosed by macrophages of the RES * Iron released from Haem, stored in macrophages as ferritin (when there is little iron, soluble) or haemosiderin (when there is lots of iron, insoluble aggregates)
33
How does clonal haemopoiesis occur?
Progenitor acquires somatic mutation or through neutral drift in HSC population
34
Define myelodysplastic syndromes
* Characterised by dysplasia (abnormal cells) and ineffective haemopoiesis in \>1 of the myeloid series * May have increased myeloblasts * Multiple sub-types based on morphology and % blasts
35
Describe the pharmacological treatment of chronic lymphoblastic leukaemia
Chemoimmunotherapy - new combination treatments available have increased cases of complete remission
36
What can cause a purpuric rash?
* Platelet problem, usually thrombocytopenia - spontaneous purpura seldom occurs with platelet count \>20 x 109/l * Vasculitis i.e. Henoch Schonlein syndrome * Haemophilia doesn’t affect platelets so doesn’t cause purpuric rash
37
What is thromboplastin?
Mixture of phospholipids and tissue factor found in plasma, catalyses conversion of prothrombin to thrombin
38
Describe the structure of RBC and the functional relevance of this structure
Biconcave disc - squeeze in/out of small blood vessels, maximum surface area for gas transfer
39
Why is haemoglobin used by RBC to carry oxygen?
Able to reversibly bind O2 without undergoing oxidation or reduction
40
What influences prothrombin time?
* PT depends on * Factors in extrinsic and common pathways * Factors VII * And Factors X, V, II and Fibrinogen
41
How are Hickman lines used in stem cell transplants?
Central line which goes into chest, over clavicle and feeds into the subclavian vein which is used to take samples, do reinfusions of cells, monitor patient and give antibiotics
42
What are the clinical consequences of folate deficiency?
* Blood abnormalities - megaloblastic anaemia (leucopenia, thrombocytopenia), RBCs macrocytic (raised MCV) + anisopoiklocytosis * Growing foetus - 1st 12 weeks deficiency can cause neural tube defect (every woman pregnant/planning pregnancy needs folate supplement)
43
Describe haemoglobinopathies
Inherited conditions - two types: 1) Relative lack off normal globin chains due to absent genes (thalassaemias) 2) Variant (abnormal) globin chain e.g. sickle cell disease
44
Describe the side effects of chemotherapy used in AML
* High morbidity - bleeding and infection * Hair loss, sterility, mucositis, prolonged inpatient stays, psychological element
45
Describe the clinical staging of chronic lymphoblastic leukaemia
* Stage A * Features - \<3 involved nodes * Survival 10 years * Stage B * Features - \>3 involved nodes, liver, spleen * Survival 7 years * Stage C * Features - anaemia of thrombocytopaenia * Survival 2 years
46
List the types of division which haematopoietic stem cells can undergo and the consequences of this
1. Symmetrical division - both daughter cells become mature RBC, contraction of stem cell numbers 2. Asymmetrical division - one daughter cell is a self-renewing stem cell, one becomes a mature RBC, maintenance of stem cell numbers 3. Symmetrical division - both daughter cells become self-renewing stem cells, expansion in stem cell numbers
47
Describe the markers and phenotype of plasma cells in plasma cell myeloma
* Express plasma cell markers e.g. CD138 * Show aberrant phenotype e.g. * CD19 negative * CD56 positive * Cyclin D1 positive * Light chain restriction
48
Describe the classification of leukaemia
Leukaemia * Acute * Myelodysplastic syndrome/myeloproliferative disease can progress to acute leukaemia * Myeloid - acute myeloid leukaemia * Lymphoid - acute lymphoblastic leukaemia * Chronic * Chronic lymphoblastic leukaemia (can progress to high grade non-Hodgkin's lymphoma) * Chronic myeloid leukaemia (can progress to acute myeloid leukaemia/acute lymphoblastic leukaemia)
49
Describe the mechanism of action of clopidogrel/ticlidipine (irreversible blockers of ADP receptor)
* Decreases expression of GPIIb/IIIa * Reduced binding of fibrinogen
50
At which age is acute lymphoblastic vs myeloid leukaemia most prevalent?
* Acute lymphoblastic leukaemia more prevalent in 0-20 y/o (especially 0-4) * Acute myeloid leukaemia more prevalent in 40-85 y/o, prevalence increases with age * Approx. equal incidence in 20-35 y/o - low prevalence compared to young and old age groups
51
List causes of folate deficiency
* Dietary * Extensive small bowel disease - coeliac/severe Crohn's * Increased cell turnover - haemolysis, severe skin disorders, pregnancy
52
Describe the management of a major haemorrhage
* 2222 - major haemorrhage call * State major haemorrhage * State location and extension number * Haematologist, lab staff and porter alerted * Request major haemorrhage pack * 6U PRC * 4U FFP * 1 pooled platelets * IV access - wide bore x 2 * Grey/brown cannulae * Level one device - allows rapidly infusion of blood, can hang two units at same time (rate limiting step is size of cannula and vein) * Can also use dialysis catheter, pulmonary artery catheter sheaths or a rapid infusion catheter * Bloods - FBC, coagulation screen, fibrinogen, U+Es, LFT, calcium - near patient testing if available * Tranexamic acid (if trauma \<3 hours ago) * KEEP PATIENT WARM
53
What is the 1st line treatment for myeloma? What are the side effects?
* 1st line treatment - chemotherapy, MPT (melphalan, prednisolone and thalidomide) in elderly * Side effects - neuropathy, constipation, increased thrombosis --\> LMW heparin
54
What are clonal haematological malignancies/pre-malignant conditions?
Haematological conditions arising from a single ancestral cell
55
How does the structure of foetal haemoglobin differ from adult haemoglobin?
Hb F (foetal) - 2 x alpha, 2 x gamma Hb A (adult) - 2 x alpha, 2 x beta Hb A2 (more rare adult) - 2 x alpha, 2 x delta
56
What is the purpose of investigations done in lymphoma?
1. Staging - what areas are affected 2. Help decide fitness for treatment - renal/liver/ bone marrow function, cardiac/respiratory disease
57
Describe the chemotherapy treatment used in acute myeloid leukaemia
* Anthracycline and cytarabine based - heavy myelotoxicity * Most young patients entered into trials * MRC AML 17, UKALL14, UKALL2011 * Aim to eradicate abnormal clone
58
Describe the half life, minimum creatinine clearance and side effects vs warfarin of dabigatran
* Half life - 12 hours * Cmax - 2-3 hours * Minimum creatinine clearance * 30 (reduce dose if 30-50ml/min) * Side effects vs warfarin * Fewer ICH, possibly more GI bleeds
59
How is the risk of progression in myelodysplastic diseases determined?
Low risk vs high risk disease established by proportion of blast cells in marrow and cytogenetic profile (MDS vs AML, blast % cut-off is 20%)
60
Give examples of other myeloproliferative disorders
Mastocytosis Clonal hypereosinophilic syndromes Chronic neutrophilic leukaemia
61
List the causes of anaemia of chronic disease
Infection Inflammation Neoplasia
62
Where is transferrin synthesised?
Synthesised in hepatocytes - less iron more Tf made, more iron less Tf made
63
What is the function of the bone marrow stroma?
Provides requirements of the stem cell to enable it to grow and divide. Cells e.g. macrophages, fibroblasts and fat cells secrete growth factors and adhesion molecules, released by cells into the bone marrow sinus in close proximity to stem cells.
64
Describe dietary sources of B12
* Synthesised solely by microorganisms * Meat (esp. liver and kidney), small amount in dairy products * Normal western diet - 5-30ug/day * Strict vegan diet is B12 deficient
65
Give examples of classical myeloproliferative disorders
Polycythaemia rubra vera Essential thrombocytosis Myelofibrosis
66
Describe the risk of thrombosis in antithrombin deficiency
* Antithrombin deficiency - 20-50% risk of thrombosis in Type 1 AT deficiency by age 50
67
Describe the absorption of iron in the GI tract
Iron absorbed by mature enterocytes in the small bowel Haem iron (red meat) readily absorbed, non-haem iron (white meat, green vegetables, cereals) more difficult to absorb
68
Is the spleen enlarged in immune thrombocytopaenic purpura?
No
69
What new therapies are available for chronic lymphoblastic leukaemia?
* New therapies for p53 mutation/deletion, 11q22 (ATM) mutation
70
What part of the coagulation cascade is tested by the activated partial thromboplastin time?
Stimulates activation via the intrinsic pathway
71
List the advantages and disadvantages of umbilical cord blood stem cell transplants
* Advantages - more rapidly available than VUD, less rigorous matching to patient type as immune system naive * Disadvantages - small amount (adults will often require double cord transplant), slower engraftment, if relapse can't go back for DLI, expensive (single cord transplant costs £30,000)
72
Describe the prevalence of chronic lymphocytic leukaemia
* Commonest leukaemia * Incidence rises with age - median 67yrs * M:F ratio 2:1
73
Describe the types of sickle cell disease
Hb SS - more severe, two copies of sickle cell gene Hb SC - less severe
74
Describe the development of haemolytic disease of the newborn
Usually occurs in 2nd/3rd pregnancy Mother Rh-, father Rh +, baby Rh + Foetal and maternal circulations mix - Rh+ from foetus to maternal circulation Antibodies from mother against foetus
75
Define leukocytosis
Too many WBC
76
List rare bleeding disorders
* Fibrinogen deficiency * FXIII deficiency * FX deficiency * FV deficiency * FII deficiency * FVII deficiency * FXI deficiency
77
How can primary haemostasis by analysed?
* In vivo - bleeding time * Ex vivo - FBC (platelet count), platelet function
78
How does diffuse large B-cell lymphoma present?
Wide variation in presentation - * Lymphadenopathy - usually rapidly enlarging LN mass * Extra-nodal presentation common (30-40%) - * Waldeyer's ring (tonsils) * GI tract * Skin * Bone * CNS PUO - pyrexia of unknown origin * Night sweats and weight loss
79
What causes diffuse large B-cell lymphoma?
High grade lymphoma associated with various translocations and genetic abnormalities, complex karyotype - heterogeneous entity (variable phenotype)
80
What does a positive direct Coombs test indicate?
AIHA or haemolytic disease of the newborn
81
What are the contraindications for all DOACs?
* Pregnancy and breast feeding * Liver disease with cirrhosis +/- coagulopathy * Some drugs (mostly strong Pgp or CYP3A4 inhibitors or inducers)
82
What are the main indications for autologous stem cell transplant?
Relapsed Hodgkin's disease, non-Hodgkin's lymphoma and myeloma
83
What are the main indications for allogeneic stem cell transplants?
* Half of all transplants done are for AML * Acute and chronic leukaemias, reduced lymphoma, aplastic anaemia, hereditary disorders
84
How is chronic myeloid leukaemia diagnosed?
* Blood film and clinical features * Molecular test on blood (BCR-ABL PCR/FISH) * Cytogenetic analysis ('karyotype') * If BCR-ABL negative - not CML
85
Which patients are treated with transplants in ALL?
* Relapsed patients * Refractory patients * Poor risk disease in first complete remission * Age less than 60 years * Good performance
86
What proportion of adult bone marrow is haemopoietically active?
30%
87
What are the complications of chronic myeloid leukaemia?
* With modern therapy - very few * Imatinib resistance * Imatinib intolerance * Need for 2nd/3rd line TKI inhibitors * Accelerated phase/blast crisis
88
How is the prothrombin time tested?
1. Add patient's plasma, thromboplastin (tissue factor and phospholipids) 2. Warm to 37 degrees 3. Add calcium 4. Time to form clot
89
How prevalent are bleeding complications with warfarin?
* Bleeding complications with Warfarin: * Fatal haemorrhage - 0.25-0.64% per year * Major haemorrhage - 1.1-2.7% per year * Risk increases as achieved INR increases
90
How does B12/folate deficiency cause red cell abnormalities?
Disparity in rate of synthesis of precursors of DNA, abnormality of cell division, dissociation between nuclear and cytoplasmic development Ineffective erythropoiesis - death of mature cells whilst still in marrow
91
List the absolute and relative contraindications to thrombolysis
* Absolute - * Haemorrhagic stroke or stroke of unknown origin at any time * Ischaemic stroke in preceding 6 months * Central nervous system damage/neoplasms * Major trauma, surgery, head injury within preceding 3 weeks * GI bleeding within the last month * Known bleeding disorder * Aortic dissection * Relative (discuss with senior staff before withholding) - * Transient ischaemic attack in preceding 6 months * Oral anticoagulant therapy * Pregnancy or within 1 month postpartum * Non-compressible punctures \<24 hours * Traumatic resuscitation * Refractory hypertension (systolic BP \> 180mmHg) * Advanced liver disease * Infective endocarditis * Active peptic ulcer * Terminal illness
92
How is GvHD prevented?
Conditioning therapy before transplant includes drugs to prevent GvHD - usually immunosuppressive agents
93
What is the treatment for IDA?
* Investigate cause * Iron replacement (not blood transfusion) * Ferrous sulphate/fumarate 200mg tabs ( = 60mg elemental iron) * Ferrous gluconate 300mg tabs ( = 36mg elemental iron) * IV iron - can give 1g over 2-3 hours, Hb rises no quicker than oral replacement
94
What influences the thrombin clotting time?
* Depends on * How much fibrinogen present in plasma * How well that fibrinogen functions * Will also be prolonged by * Inhibitors of thrombin e.g. heparin, dabigatran * FDPs (fibrin degradation products) * Inhibitors of fibrin polymerisation (paraproteins)
95
Compare the severity of alpha and beta thalassaemia
Missing beta globin genes has more of an impact than missing alpha genes - only have two beta genes
96
What are the management options in splenic injury?
* Conservative - if stable, watch and wait * Interventional radiology - block off bleeding vessel * Surgery - tie off bleeding vessel, splenectomy
97
List the complications of a major haemorrhage
* Hypothermia * Exposure to elements during trauma (?) + transfusion with clear fluid = dilatational coagulopathy * Aggressively warmed - blood warmer, patient warmer, foil hat, monitor temperature, otherwise won’t clot * Acidosis * Blood loss means lower oxygen perfusion, tissue becomes hypoxic, more anaerobic respiration so more lactic acid production = lactic acidosis * Monitor with blood gases * Coagulopathy * FFP, platelets, cryoprecipitate - liaise with blood bank * Hypocalcaemia * Blood loss = calcium loss * Check ionised calcium on blood gas * Replace - need calcium to clot
98
Explain latent iron deficiency
If the RES iron store is slightly low, the serum ferritin will fall but the Hb is initially maintained (not anaemic) Present in 20% of pre-menopausal women
99
What is the major role of RBC?
Gas transfer - CO2 removal from tissues to lungs, O2 delivery from lungs to tissues
100
Describe the use of imaging in the diagnosis of myeloma
* Historically plain X-rays used but may miss early lytic changes * MRI is better at identification of lytic lesions * May indicate incipient risk of fracture * Skeletal survey of all long bones done * Affects bones with active BM * Plasma cells produce OAF --\> alters bone turnover * Multiple lytic lesions in skull and humerus * Osteolytic lesions, fractures, pain and hypercalcaemia * Pepper pot skull typical finding * Spinal MRI * Deformity more clear on MRI * Flattened vertebrae, bulging backwards towards disc * May present with spinal cord compression
101
Describe the phases which occur when you cut yourself
1. Blood vessel damage 2. Disruption of endothelium 3. Exposure of * Tissue factor * Collagen 4. Primary haemostasis 5. Recruitment of platelets 6. Secondary haemostasis 7. Activation of coagulation factors Occur simultaneously
102
Describe haemoglobin in sickle cell disease
HbS = 2 x alpha chains, 2 x beta chains (sickle) Continuously polymerised/depolymerised, rate of polymerisation depends on: * Deoxygenation rate - low oxygen = polymerisation (cells sickle) * HbF - high levels of HbF protect against sickling Hb concentration
103
Describe the immune complications associated with chronic lymphoblastic anaemia
* Autoimmune haemolytic anaemia - 5-10% * Autoimmune thrombocytopenia - \<5% * At presentation, precipitated by treatment * Treat with steroids, treat CLL * Infection due to: * Hypogammaglobulinaemia - not enough gamma globulins produced, low antibodies * Cell mediated immunity impaired * T lymphopenia * Neutropenia * Defects in complement activation * Pulmonary infection common * Bacteria, encapsulated organisms * Viral * Pneumocytosis * Fungi * As likely to die from infection as from CLL
104
How is the indirect Coombs test carried out?
Plasma mixed with red cells from unit of blood to be transfused, if antibodies are present they will bind to red cells in transfused blood - look for antibodies in plasma/on RBC
105
Compare LMWH and UFH
* LMWH have superior pharmacokinetic profile allowing predictable dose response * LMWH have safer side effect profile * LMWH clinical efficacy at least equal to UFH * LMWH have higher drug costs but lower consumable costs and do not require monitoring * LMWH can be used in out-patients
106
How are lymphomas staged?
Ann-Arbor classification system * Stage I: single lymph node group * Stage II: More than one lymph node group same side of the diaphragm * Stage III: lymph node groups both sides of the diaphragm (includes spleen) * Stage IV: extranodal involvement e.g. liver, bone marrow (spread via blood) A or B added after to signify absence or presence of B symptoms Early stage: 1 or 2A (no B symptoms) Advanced stage: 2B or 3/4
107
Describe the mechanism of action of GPIIb/IIIa antagonsits
* Monoclonal antibodies antagonise IIb/IIIa receptor * Reduced platelet aggregation * Reduced binding of fibrinogen
108
How is classic Hodgkin's lymphoma treated?
* Very effective * High cure rates (\>90% in early stage, 75-85% in advanced stages) * Early stage - usually combined modality Rx i.e. chemotherapy followed by radiotherapy * Advanced stage - chemotherapy * Late effects important e.g. malignancy, cardiac, pulmonary, fertility, endocrine * Balance between effective treatment of disease against risk of effects for given individual * Chemotherapy = ABVD
109
What can cause B12 deficiency?
* Pernicious anaemia * Low B12 in plasma (normal in tissues) - pregnancy, hormonal contraceptives, metformin, PPIs * Gastrectomy/achlorhydria - no parietal cells * Dietary * Terminal ileum problem - Crohn's, resection
110
Describe immunochemotherapy used to treat advanced stage follicular lymphoma
Rituximab (anti-CD20 monoclonal Ab) + chemotherapy (CVP or CHOP or bendamustine)
111
Describe the grading of splenic injuries
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112
List the types of stem cell transplant
1. Autologous transplant (autograft) - patients own blood cells 2. Allogenic transplant ('allograft') - any transplant in which stem cells come from a donor
113
To what extent can bone marrow compensate for reduced RBC lifespan in haemolytic conditions?
* Normal lifespan is 120 days * If reduced down to 20 days can compensate by producing more RBC, any less and anaemia will develop * Lifespan 120 days - Hb normal * Lifespan 20-100 days - Hb normal, raised reticulocytes, raised unconjugated bilirubin = compensated haemolytic state * Lifespan \<20 days - reduced Hb, raised reticulocytes, raised bilirubin, hypersplenism = haemolytic anaemia
114
Describe the AVBD chemotherapy regimen
A - Adriamycin (doxorubicin) B - Bleomycin V - Vinblastine D - Dacarbazine Given on days 1 and 15 of 28 day cycle
115
What is the treatment for hereditary spherocytosis?
If required - splenectomy * Destroys RBC so removal restores RBC lifespan to normal but at increased risk of infection from encapsulated organisms
116
How does leukaemogenesis occur?
* Normal HCS (or myeloid/lymphoid cell) acquires changes through a multistep process to become leukaemic cell - requires 2 genetic hits to develop leukaemia * Dysregulation of cell growth and differentiation - associations with mutations * Proliferation of the leukaemic clone, differentiation blocked at an early stage (immature leukaemic blast cell population)
117
Give examples of causes of DIC
* Sepsis * Malignancy * Massive haemorrhage * Severe trauma * Pregnancy complications e.g. pre-eclampsia, placental abruption, amniotic fluid embolism
118
How is the fate of a haematopoietic controlled?
Complex interaction between micro-environment signals (the niche) and internal cues - Wnt, notch and hedgehog signalling are important for controlling
119
List the different forms of graft vs host disease
Acute GvHD - within first 100 days of transplant Chronic GvHD - after first 100 days of transplant
120
How much dietary iron is required daily?
* 1-2mg/day * Western diet - 15-20mg/day so nutritional IDA in adults v rare
121
What causes haemophilia A?
* Classical haemophilia * Factor VIII deficiency * Severe \<1iu/dl (spontaneous bleeds) * Moderate 2-5iu/dl (minor trauma bleeds) * Mild 6-40iu/dl (surgical bleeding) * X-linked inheritance
122
List the abnormalities seen in Fanconi anaemia
* Microphthalmia * GU malformations * GI malformations * Mental retardation * Hearing loss * CNS e.g. hydrocephalus * Short stature * Digit abnormalities e.g. absent thumbs * Cafe au lait macules
123
Define thrombocytopenia
Reduction in the number of platelets
124
Describe the mechanism of action of kinases
* Bind to plasminogen - releases plasmin, enhanced breakdown of fibrin * Activity on both clot bound and free plasminogen * Causes both fibrinolysis and systemic fibrinogenolysis * Significant bleeding risk
125
Describe menorrhagia
\>80ml blood/period 20ml blood/period normal
126
What is the disadvantage of donor lymphocyte infusion?
1/3 of DLI recipients will develop graft vs host disease (donor cells attack the host tissue), unless measures are taken to reduce the risk
127
What are the requirements for samples used for coagulation tests?
* Pre-analytical * Citrate sample (9:1 ratio) * Chelates all calcium * Centrifugation * Separates cellular component * Platelet poor plasma (PPP)
128
What is the effect of B12/folate deficiency on blood cells?
* Macrocytic anaemia * Many large immature and dysfunctional red cells seen in bone marrow = megaloblasts * Hypersegmented neutrophils - 5-7 lobes * Erythroblasts destroyed in BM, v few reticulocytes but BM hypercellular
129
List the pros and cons of DOACS vs warfarin
Warfarin * Slow onset slow offset - results in smooth anticoagulation DOACs * Rapid onset and offset - anti-coagulated within 3h of 1st dose Warfarin * Requires very individualised dosing DOACs * May require dose adjustment based on CrCl Warfarin * Requires INR monitoring DOACs * Requires annual review Warfarin * Many drug, food and alcohol interactions DOACs * Few drug and no food/alcohol interactions Warfarin * Renal impairment may increase bleed risk DOACs * Renal impairment may be a contra-indication Warfarin * Rare side effects other than bleeding DOACs * More minor side effects Warfarin * Rapid reversal with PCC and Vitamin K DOACs * Currently no rapid reversing agent
130
Describe the mechanism of action of dipyridamole
* Increased platelet concentration of cAMP * Increased cAMP leads to decreased platelet responsiveness to ADP * Reduced platelet aggregation
131
List the types of antithrombotic agents
* Anticoagulants * Inhibit one or several components of coagulation cascade * Fibrinolytic agents * Enhance lysis (breakdown) of fibrin clot * Anti-platelet agent * Inhibit platelet activation or aggregation
132
Describe the management of acquired warm type haemolytic anaemia
* Corticosteroids * Mainstay of management * Usually Prednisolone, initially high dosage range of 60-100mg per day, subsequently reduced * Haemolysis should be dramatically reduced in 80% of patients within 3 weeks * Blood transfusion * Transfusion of packed red cells may be required dependent on patients symptoms * Folic acid * Demand for RBC so high that folic acid may be compromised and supplementation may be required in severe cases * Splenectomy * Treatment of choice in patients whose anaemia is refractory to prednisolone, or those who require long term high dose therapy to suppress the haemolytic state * Such patients liable to develop the serious complications of steroid therapy
133
Describe the typical natural history of multiple myeloma
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134
Define pernicious anaemia
Autoimmune disease of gastric parietal cells - gastric parietal cell autoantibodies in 95%, intrinsic factor autoantibodies in 50% Associated w/ other autoimmune diseases e.g. hypothyroidism
135
How is the coagulation cascade regulated?
* ![]()​Antithrombin inhibits VIIa, XIa, IXa, Xa, IIa * Tissue factor pathway inhibitor inhibits VII + TF --\> VIIa * Protein S and APC (activated protein C) inhibit Va and VIII
136
Define a major haemorrhage
* Loss of more than one blood volume within 24 hours (around 70mL/kg, \>5 litres in a 70kg adult) * 50% of total blood volume lost in less than 3 hours * Bleeding in excess of 150mL/minute
137
How is cold AIHA treated?
Self limiting mycoplasma, idiopathic - keep warm
138
Describe the normal saturation of transferrin with iron
Normally 30% iron saturated with iron
139
What can cause intravascular haemolysis?
* Can occur by mechanical trauma to red cell - red cell fragmentation syndromes i.e. RBC breakdown by defective mechanical heart valves (RBC fragmentation also seen in haemolytic uraemic syndrome and microangiopathic haemolytic anaemia * Can follow ABO incompatible blood transfusion (anti-A and anti-B are IgM antibodies) * Can also be due to malaria, cold (IgM) autoantibodies - cause RBC to agglutinate on blood film * Difficult to treat - advised to keep warm (antibody only fixes to RBCs in colder parts of the body i.e. cold hands etc.)
140
Define beta thalassaemia
Missing Beta globin genes - should have two
141
How does plasma cell myeloma present?
* Majority of new cases have non-specific symptoms * Backache or rib pain (60%) * Fatigue * Symptoms of hypercalcaemia (30%) * Recurrent infections - chest * Renal impairment (25-30%) * Average GP will only see 1-2 cases in whole career * Diagnosis often unavoidably delayed with patients being referred via a variety of specialists
142
List the types of alpha thalassaemia
* Normally 4 alpha globin genes - 2 from mother, 2 from father * Can be missing - * One alpha gene from one parent = alpha+ thalassaemia trait * One alpha gene from each parent = homozygous alpha+ thalassaemia trait * Two alpha genes from one parent = alpha0 thalassaemia trait * Two alpha genes from one parent, one from the other = HbH disease * Two alpha genes missing from each parent (no remaining genes) = alpha thalassaemia major
143
How can disorders of RBC enzymes cause haemolytic anaemia?
* Pyruvate kinase (glycolysis) deficiency anaemia - chronic extravascular haemolytic anemia due to ATP depletion, autosomal recessive * Glucose-6-phosphate dehydrogenase (pentose phosphate pathway) deficiency - acute episodic intravascular haemolysis, X-linked recessive, acute haemolysis from oxidative stress (Favism, drugs e.g. anti-malarials, sulphonamides)
144
What evidence is there to support the concept of clonality in haematological conditions?
* Almost all lymphoproliferative disorders and some AMLs carry a unique rearrangement of either an immunoglobulin or TcR gene (whereas non-malignant lymphoid proliferations are polyclonal) * X chromosome inactivation studies in women with leukaemia show the clonal proliferation carrier either an active maternal or paternal X chromosome (limited utility - many women develop skewed X inactivation with age) * Acquired cytogenic or molecular changes that arise during development of a malignancy e.g. Philadelphia translocation in CML
145
How do erythroblasts use iron?
Iron converted to haem in erythroblast mitochondria using enzyme ALA-S2, extra stored as ferritin
146
How is iron transported in plasma?
Transferrin - glycoprotein molecule with 2 iron binding domains Travels and binds to cells with transferrin receptors, delivers iron to all tissues, erythroblasts, hepatocytes, muscle etc
147
Define thalassaemia
Haemoglobinopathy due to relative lack of globin genes - alpha or beta
148
List the types of congenital haemolytic anaemias
1. Abnormalities of RBC membrane 2. Haemoglobinopathies 3. Abnormalities of RBC enzymes
149
List the characteristics of myeloproliferative diseases
* Clonal blood disorders * JAK2 mutation prevalent * Characterised by 'effective' haemopoiesis * Too many platelets - essential thrombocytopaenia * Too many red cells (+ platelets + WC) - polycythaemia vera or primary polycythaemia (same thing) * Too much fibrous tissue (+ platelets + WC) - myelofibrosis
150
What are the requirements for normal erythropoiesis?
* Drive for erythropoiesis - erythropoietin produced by interstitial cells of kidney in response to tissue hypoxia * Genes required for erythropoiesis * Haematinics - iron, B12, folate, minerals * Functioning bone marrow - no increased loss/destruction of red cells
151
What effect does G-CSF have on haematopoietic stem cells?
Mobilises stem cells peripherally using growth factors - used for stem cell transplant
152
Compare myeloma and monoclonal gammopathy of undetermined significance (MGUS)
* Difficult to differentiate * MGUS = common age related condition, plasma cell dyscrasia * Plasma cells or other antibody producing cells secrete a myeloma protein (abnormal antibody) into the blood/urine * Accumulation of bone marrow plasma cells derived from a single abnormal clone * Resembles multiple myeloma and similar diseases but lower levels of antibodies and lower levels of plasma cells in bone marrow * MGUS can lead to myeloma - monitoring needed * MGUS don’t experience any signs or symptoms usually ![]()
153
Which blood cells are derived from lymphoid stem cells?
B/T lymphocytes, NK cells
154
Who is the ideal VUD and why?
Young male donors are preferred - less exposure to antigens compared with women due to childbirth
155
Describe the molecular biology of Fanconi anaemia
* Fanconi anaemia mutations cause * Up-regulation of pathways e.g. MAPKs --\> TNF-alpha (inflammatory cytokine) * Altered DNA damage responses (FA-BRCA pathway) * Abnormal oxidative stress response * Other aberrations e.g. defective telomere maintenance * + environmental factors (e.g. sunlight, smoking, infections, chemotherapy) = Genomic instability, altered cell checkpoints and survival - cells survive damage and go on to become malignant
156
What usually causes IDA in males/post-menopausal women?
Due to GI blood loss until proven otherwise
157
List the presenting features of chronic lymphocytic leukaemia
* None * Lethargy, night sweats, weight loss * Symptoms of anaemia * Lymphadenopathy * Infection
158
List causes of macrocytosis other than folate/B12 deficiency
* Reticulocytosis - 20% bigger than average mature red cell * Cell wall abnormality (lipids) - alcohol, liver disease, hypothyroidism (poorly understood) * With anaemia - bone marrow failure syndromes e.g. myelodysplastic syndromes
159
What is expressed by B cells in B cell lymphoma that can be the target for treatment?
B cells express CD20 antigen, target for treatment of B cell lymphoma with the monoclonal antibody Rituximab
160
Describe the process of a splenectomy
* Trauma laparotomy for bleed into abdomen - * Incision from xiphoid sternum --\> pubic symphysis * Usually find several litres of blood + clots - remove * Blood/clots have been acting as tamponade stopping blood flow, need to pack abdomen with highly absorbent swabs to create tamponade * Swabs into paracolic gutters, pelvis, above spleen and liver * Remove packs from area of least concern to area of most concern to find source of bleeding, full laparotomy circuit to find injuries that the CT may have missed * Spleen is end on organ - on a single vascular pedicle - so is relatively easy to detach and remove * Splenic artery from coeliac plexus, passes behind pancreas * Splenic vein back to join with the SMV forming the HPV * Endoscopic stapling gun can be used
161
Define haemolytic anaemia
Anaemia related to reduced RBC lifespan, no blood loss, no haematinic deficiency
162
Why is there often a small residual mass after diffuse B-cell lymphoma treatment?
Fibrosis
163
Describe the treatment of sickle cell disease
* Prevent crises - hydration, analgesia, early intervention, prophylactic vaccination and antibiotics (hyposplenic infections), folic acid (BM inactive/ineffective) * Prompt management of crises - oxygen, fluids, analgesia, antibiotics, specialist care, transfusion/red cell exchange - reduce amount of HbS * Bone marrow transplantation
164
How can bone marrow be collected for investigation?
Aspiration - sample of bone marrow taken from back of iliac crest using hollow needle, under local anaesthetic - liquid component of bone marrow Trephine - solid core of bone
165
Describe the presentation of Burkitt lymphoma
* Usually short history, marked B symptoms, rapidly growing tumours with massive tumour bulk * Most cases present with extra-nodal disease * Jaws and facial bone (endemic BL in African children) * Ileocaecal region of GIT - often primary site * Ovaries * Kidneys * Breast * Lymph nodes and bone marrow more frequently affected in immunosuppression-associated BL * CNS involvement at presentation or relapse is common in all types - brain, meninges or both
166
What is alcohol induced pain in lymph nodes a symptom of?
Rare feature of Hodgkin's lymphoma
167
How are PET/CT scans used in the staging of lymphoma?
PET/CT scan with FDG tracer - taken up in areas that are metabolically active e.g. brain, heart, bladder
168
What is clonal haemopoiesis?
Common age related phenomenon in which HSC or other early blood progenitors contribute to the formation of genetically distinct subpopulations of blood cells (derived from single founding cell)
169
What causes warm AIHA?
Idiopathic in 30%, other autoimmune disease, lymphoproliferative disorder (NHL, CLL), drug induced
170
Where are haematopoietic stem cells found?
Bone marrow, peripheral blood after treatment with G-CSF, umbilical cord blood
171
How much iron is usually lost in pregnancy?
500mg/baby
172
How is myelodysplastic disorder managed?
Incurable (other than with SCT, \<65 years), for rest supportive care, consider drug therapy e.g. azacitidine
173
Describe the process of an umbilical cord blood stem cell transplant
Blood stem cells collected from umbilical cord and placenta Cells tissue typed and frozen and liquid nitrogen in cord blood banks for future use
174
Where are most transferrin receptors found?
80% on developing RBCs - erythroblasts
175
Define anaemia
Reduction in the number of RBC
176
How do patients with B12/folate present?
* Symptoms of anaemia/cytopenia - tired (macrocytic RBCs/megaloblastic marrow), easy bruising (thrombocytopenia - rare), beefy red tongue (B12 deficiency) * Mild jaundice - lemon yellow tint, due to ineffective erythropoiesis in marrow * Neurological problems - nerve disturbance as a result of B12 deficiency (subacute combined degeneration of cord)
177
List the causes of IDA
* Dietary - premature neonates, adolescent females, v uncommon in adults * Malabsorption * Blood loss
178
Describe beta thalassaemia major
* Missing both beta globin genes - unable to make adult haemoglobin * Autosomal recessive condition * Causes bone changes as bone marrow expands to try to compensate for missing beta globin
179
Describe the stratification of essential thrombocytopenia into risk groups for treatment
* Low risk = age \<40 with no risk features * Intermediate risk = aged 40-60 with no high risk features * High risk = aged \>60, one or more high risk features - platelets \>1500, previous thrombosis or thrombotic risk factors e.g. diabetes or hypertension
180
What is seen on electrophoresis in myeloma?
Monoclonal band
181
Describe abnormal destruction of red cells in haemolytic anaemia
* Haemolysis = increased in RBC destruction * Bone marrow has ability to increase red cell production 6-8 x - RBC lifespan has to be reduced to \<15-20 days before anaemia develops * Mechanism of destruction in haemolytic anaemia by two pathways: * Intravascular - destruction of red cells directly in the circulation * Extravascular - destruction of red cells in the RES of the spleen, liver and bone marrow
182
What are the indications for heparins?
* Provides immediate but short acting anticoagulant effect * Acute DVT or PE (subcutaneous LMWH) * During cardiac bypass surgery (IV UFH) * Acute coronary syndromes (along with anti-platelet agents) * Medium term after VTE in cancer patients * Prophylaxis against VTE * Medical and post-op patients (low dose LMWH) * Obstetric patients
183
Describe the abnormalities in coagulation screen and clotting factors seen in Von Willebrand's disease
* Prolonged APTT * (Blood loss) * Haemolglobin low * MCV low * F VIII deficiency * VWF:RCo low * VWF:Ag low
184
Describe the treatment of Burkitt lymphoma
* Short survival unless treated but responds well to chemotherapy * Requires intensive chemotherapy (CODOX-M/IVAC) * Aim of treatment is to cure - 70-90% long term survival * Elderly unable to tolerate intensive therapy - poorer outcomes
185
What are the clinical effects of Von Willebrand disease?
* Mucosal type bleeding pattern * Reduced VWF +/- reduced platelet aggregation +/- reduced FVIII
186
Describe the histological appearance of diffuse large B-cell lymphoma
Resemblance to activated B-cells (immunoblasts, centroblasts) High proliferation fraction, variable rate of cell death
187
What is the purpose of the direct Coombs test?
To detect autoimmune haemolytic anaemia (detect antibodies on RBC surface) Cold AIHA easy to detect (IgM big), warm AIHA harder to detect (IgG small)
188
List the characteristics of haematopoietic stem cells
Self renewal capacity, unspecialised, ability to differentiate into mature cells, rare (1 in 10,000 to 1 in 1 million in bone marrow), usually quiescent (only undergo occasional cell division, usually in G0)
189
How prevalent is Fanconi anaemia?
10-20% of aplastic anaemia case
190
Why is the use of ferritin as a measure of stored iron potentially problematic?
Serum ferritin is an acute phase protein (volume changes in response to inflammation)
191
Which population are predominantly affected by myelodysplastic disorders?
The elderly
192
Define leukopenia
Reduction in the number of WBC, or leukocytes
193
How are bone marrow aspirates taken?
Posterior superior iliac spine can be easily palpated as a bony prominence at the posterior end of the iliac crest. Bone marrow needle should be inserted at the top of this prominence. It should be angled in the direction of the anterior superior iliac spine, a prominence found at the anterior end of the iliac crest.
194
What is the effect of raised unconjugated bilirubin in chronic haemolytic states?
Can cause pigment gallstones
195
Which part of the coagulation cascade is tested using prothrombin time (PT)?
Extrinsic pathway
196
Describe the side effects of heparins
* Heparin induced thrombocytopaenia * UFH - 4% * LMWH - \<1% * Osteoporosis (3m use) * UFH - 17% * LMWH - 2.6% * Hyperkalaemia - rare with UFH/LMWH
197
Describe the role of Von Willebrand factor
1. Facilitates platelet adhesion and aggregation in primary haemostasis 2. Binds FVIII and prolongs its half-life in plasma (influences secondary haemostasis)
198
Describe secondary haemostasis
* Activation of coagulation factors * Cascade of events * Initiation - extrinsic pathway * Propagation - intrinsic pathway * Thrombin generation * Fibrin production - the 'clot'
199
What is pancytopaenia and what can cause it?
* Pancytopenia = reduced WBCs, Hb and platelets * Caused by variety of bone marrow diseases, hypersplenism and peripheral consumption of blood cells
200
How is beta thalassaemia major treated?
Transfusion dependent from early life (first couple years) Iron overload has major effect on life expectancy - may need iron chelators (with each unit of blood receive 200-250ml of chelators, iron excreted in urine)
201
Describe the process of fibrinolysis
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202
How is DIC treated?
* Treat underlying cause * FFP +/- platelets if bleeding or high risk for bleeding * ? * Heparin 300-500u/h if thrombotic phenotype * AT concentrate (reduces mortality 56% --\> 44%) * Protein C concentrate (meningococcal sepsis) * Activated protein C
203
How is high risk essential thrombocytopenia treated?
* First line therapy - hydroxycarbamide + aspirin * Second line therapy - anagrelide (inhibits megakaryocyte differentiation so doesn't affect all blood lines) + aspirin * INF-alpha - used in pregnancy (don't know teratogenicity of other drugs) * Busulphan, phosphorus-32 - associated with increased risk of leukaemogenesis, used in older patients who can't tolerate other treatments * May need to consider combination therapy * JAK2 inhibitors e.g. Ruxolitinib
204
List the most common lymphoma types
1. Diffuse large B cell lymphoma (38%) 2. Follicular lymphoma (19%) 3. Classical Hodgkin's lymphoma (10%) 4. Marginal zone lymphoma (7%)
205
How are cytogenetics used in the diagnosis of acute myeloid leukaemia?
* Essential to determine prognosis * Abnormalities correlate with response to treatment and survival * Allows decisions on management
206
What usually causes IDA in young women?
Menstrual blood loss +/- pregnancy GI investigations only for GI symptoms or blood in stools
207
How is the IPSS risk score for myelodysplastic disorders calculated?
Based on - BM blast %, karyotype, cytopenias
208
What is the lupus anticoagulant and what clinical effects does it have?
* Phospholipid dependent antibody * Interferes with phospholipid dependent tests i.e. APTT * APTT prolonged * If persistent, may be associated with prothrombotic state * Persisting lupus anticoagulant + thrombosis (or recurrent foetal loss) = antiphospholipid syndrome
209
Describe the aetiology of acute myeloid leukaemia
* Largely unknown * Chemicals * Chemotherapy * Radiotherapy * Genetic - Down's syndrome, Fanconi Syndrome * Antecedent blood disorders (MDS, MPD) * Viruses?
210
Describe the treatment of coagulation factor deficiency
* Education - patients and doctor * Desmopressin (DDAVP) - causes release of Von Willebrand's factor * Replacement therapy * FFP/cryoprecipitate * Plasma derived factor concentrate * Recombinant produced factor concentrate * Gene therapy
211
What is the pathological result of sickled RBCs?
Reduced red cell survival - haemolysis Vaso-occlusion - tissue hypoxia/infarction (sickled rec cells occlude BVs)
212
How is low risk essential thrombocytopenia treated?
Aspirin or anti-platelet agent
213
How does the grade of splenic injury guide treatment?
* Increasing grade = worsening splenic injury * Trauma doesn’t always require splenectomy - try to avoid if possible because asplenism causes higher risk of infection from encapsulated organisms * If grade IV/V will most likely require splenectomy, lower grades can also require depending on how the patient is clinically
214
When in RBC development is haem synthesised?
Haem synthesis occurs from proerythroblast --\> reticulocyte stage of RBC development
215
Describe the features of Fanconi anaemia
* Bone marrow failure (may present from birth into adulthood) * Somatic abnormalities * Short telomeres * Malignancy * Chromosome instability Currently 7 genetic sub-types FANC A-G
216
How is the activated partial thromboplastin time tested?
* Add patients plasma, contact factor e.g. (Kaolin or Silica) and phospholipid ('partial thromboplastin' * Warm to 37 degrees * Add calcium * Time taken to clot
217
Describe the autologous transplant process
1. Collection - stem cells collected from patient's blood or bone marrow 2. Processing - blood or bone marrow processed in the lab to purify and concentrate stem cells 3. Cyropreservation - blood or bone marrow frozen to preserve it 4. Chemotherapy - high dose chemotherapy and/or radiation therapy given to the patient 5. Reinfusion - thawed stem cells are reinfused into the patient
218
How does follicular lymphoma usually present?
* Incidence increases with age, median age at diagnosis is 65 y/o * Often present w/ stage 4 disease (marrow involvement) * B symptoms less common, indolent clinical course * Usually incurable
219
Describe the natural history of acute leukaemias
* Clonal disorders * Blastic proliferation in bone marrow ('maturation arrest') * Rapid onset * Serious compromise of normal marrow elements (so normal counts fall) * Death within days or weeks if untreated
220
Describe the prognosis of classic Hodgkin's lymphoma
Dependent on stage of disease
221
What is the mechanism of action of hepcidin?
* Reduces the levels of iron in plasma * Binds ferroportin and degrades it, reducing iron absorption by enterocytes and decreasing iron release from the RES
222
Describe the structure of adult haemoglobin
4 globin chains (2 alpha, 2 beta), 4 haem groups (1 iron per haem group, 1 per globin chain)
223
How common is Von Willebrand disease?
Most common mild bleeding disorder - 1/1000
224
What are the benefits/drawbacks of allogeneic stem cell transplants in malignant disorders?
Benefit of graft vs leukaemia effect in addition to the effect of high dose chemotherapy, but at the expense of graft vs host disease (donor cells attack host tissue)
225
Describe the maturation of macrophages
Myeloid stem cell --\> monoblast --\> monocyte (in blood) --\> macrophage (in tissues)
226
How do the cells seen on a bone marrow aspirate differ from peripheral blood cells?
More immature cells seen in bone marrow aspirate
227
What balance is required in coagulation? What are the consequences of imbalance?
* Balance * Coagulant vs. anticoagulant factors * Imbalance --\> thrombosis, bleeding
228
What are the treatment options for acute lymphoblastic leukaemia?
* Chemotherapy * Supportive treatment * Blood transfusion * Fresh frozen plasma * Platelet transfusion * Antibiotics/antifungals * Growth factors (G-CSF) * Granulocytes * Transplant procedures
229
Describe the natural history of follicular lymphoma
Very responsive to treatment Tendency to relapse - become more frequent and eventually resistant to treatment, will die of lymphoma May transform to diffuse large cell B-lymphoma Rituximab has increased average survival
230
What are the clinical consequences of B12 deficiency?
* Blood abnormalities - megaloblastic anaemia (leucopenia, thrombocytopenia), RBCs macrocytic (raised MCV) and anispoiklocytosis (variance in size/shape of RBCs) * Neurological manifestations - bilateral peripheral neuropathy or demyelination of posterior and pyramidal tracts of spinal cord (biochemical basis unclear)
231
What are the disadvantages of VUDs?
Increased risk of GvHD compared to family donor, majority of VUDs are caucasian - shortage of donors from other ethnic groups
232
How is warm AIHA treated?
Stop any drugs, steroids, immunosuppression, splenectomy
233
What mutations cause essential thrombocytosis?
50% carry JAK2V617F, 50% carry calreticulin mutation
234
What is HbH disease?
* Missing 3 alpha genes, lack of alpha chains and excess beta chains * Beta chains join together * Blood transfusion required during periods of stress * Hb variable - 65-75g/l
235
Describe the mechanism of action of warfarin
* Inhibits VKOR - vitamin K oxide reductase * Needed for oxidation of vitamin K for conversion of prothrombin precursor to prothrombin
236
Describe the half life, minimum creatinine clearance and side effects vs warfarin of apixaban
* Half life - 12 hours * Cmax 2-3 hours * Minimum creatinine clearance * 15 (for AF reduce rose if 15-29ml/min) * Side effects vs warfarin * Fewer ICH
237
List the types of classical Hodgkin's lymphoma
Nodular sclerosing, mixed cellularity, lymphocyte rich and lymphocyte depleted
238
How prevalent is haemophilia A?
Incidence - 1/20,000 (1/10,000 males)
239
What causes graft vs host disease?
Can happen in patients who have received allogeneic transplant - new donor's immune system recognises the host's body as foreign and starts to attack it
240
Describe RBCs in hereditary spherocytosis
RBCs spherocytic and polychromatic - reticulocyte count increased (appears blue colour under stain)
241
How are abnormal RBC in IDA described?
Hypochromic (pale, MCH low), microcytic (small, MCV low)
242
What common patterns of abnormalities are seen in coagulation screens?
* PT only abnormal (prolonged) - low factor II * APTT only abnormal (prolonged) - low factor VIII, IX, XI or XII, lupus anticoagulant * PT and APTT abnormal (prolonged) - common pathway factor low or multiple factors low
243
How do RBC appear in warm AIHA?
Spherocytic and polychromatic - same on blood film as hereditary spherocytosis Small and dark
244
Describe life expectancy in those with sickle cell disease
Reduced Longer life expectancy in those with high HbF (foetal haemoglobin)
245
What platelet count indicates essential thrombocytosis?
Platelets \>600 x 10(9)/L persistently (upper limit of 400 is normal)
246
Describe the histological appearance of Burkitt lymphoma
* Resemblance to proliferating germinal centre cells * Very high rate of proliferation (nearly all cells in cell cycle) * Due to MYC translocation and over-expression * High rate of cell death (apoptosis) * Tumour lysis syndrome an issue
247
Describe the typical presentation of acute lymphoblastic leukaemia
* Limping child * Purpuric rash * Unexplained, sometimes severe bone pains not uncommon * 'Lumps' vs 'liquid presentation' (i.e. lymphoblastic lymphoma vs true ALL)
248
Define polycythaemia/erythrocytosis
Too many RBC
249
What imaging should be done in a suspected major bleed?
* CT chest/abdomen/pelvis * Need to CT all cavities that they could be bleeding into - abdomen, chest , pelvis, femurs/long bones
250
Define myeloproliferative disorders
Clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny - disorders of bone marrow in which excess cells are produced
251
Name a haemolytic anaemia which is due to abnormalities of RBC membranes
Hereditary spherocytosis
252
When could normal serum ferritin levels be seen in IDA?
Ferritin is an acute phase protein - in presence of tissue inflammation IDA can occur with normal serum ferritin (rheumatoid arthritis and inflammatory bowel disease)
253
How is anaemia of chronic disease treated?
Treat underlying cause
254
What is done on arrival to A&E in a major bleed?
* Primary survey done again (ABCD) * Worry about DIC - consumptive coagulopathy * Initial investigations - FBC, coagulopathy screen, ROTEM (guides how to replace blood for individual patient), type and match for blood type (takes approx. 45 minutes) * Management
255
What is the main function of anticoagulant drugs? Give examples
* Main function - inhibit formation of fibrin clot * Heparins and Fondaparinux - injection, act via antithrombin, antagonise Factor Xa (+/- thrombin) * Oral warfarin - vitamin K antagonist (lowers Factors II, VII, IX and X) * Newer direct oral anticoagulants (DOACs) - dabigatran (thrombin), apixaban, rivaroxaban, edoxaban (Xa)
256
How much B12 is lost per day?
1-2ug/day in urine/faeces
257
At what stage are HL and NHL usually diagnosed?
Most HL diagnosed at early stage Most NHL diagnosed at advanced stage
258
What does the thrombin clotting time measure?
* Measurement of conversino of fibrinogen to fibrin clot ![]()
259
Define plasma cell myeloma
Neoplasm of mature plasma cells with varied clinical course
260
List the causes of cold autoimmune haemolytic anaemia
* Usually IgM antibodies * Primary (idiopathic) * Secondary including * Infection - mycoplasma pneumoniae * Infections mononucleosis * Lymphoproliferative disorders
261
Describe the microenvironment of bone marrow
Ideal environment for growth and development of stem cells, composed of stromal cells and a microvascular network
262
Define B symptoms in lymphoma
Systemic symptoms e.g. fever, weight loss, night sweats Itch (pruritis) is not a B symptom - can occur in NHL and HL
263
What is the main action of fibrinolytic drugs?
* Main action - enhancement of fibrinolysis * Breakdown of a fibrin thrombosis
264
Describe the typical presentation of acute myeloid leukaemia
* Rapid onset of symptoms * Lethargy * Infection * Bleeding and bruising * Bone pain * Gum swelling * Lymphadenopathy, skin rash
265
How can a patient with lymphoma present?
* Lymphadenopathy - painless, rubbery (hard and craggy suggests carcinoma, pain suggests infection) * Splenomegaly * B symptoms - night sweats, weight loss (10% of body weight in last 6 months), unexplained fever 38/9, recurrent, doesn't respond to antibiotics * Anaemia - several causes
266
What is the clinical significance of alpha thalassaemia?
* Missing one gene - mild microcytosis, no anaemia * Missing two genes - microcytosis, increased red cell count and sometimes v mild (asymptomatic) anaemia * Missing three genes - significant anaemia (Hb approx. 75g/L) and bizarre shaped small RBC, HbH disease (beta globins bind together) * Missing four genes - incompatible with life, hydrops foetalis (heart failure from severe anaemia foetally)
267
Describe causes of acquired thrombophilia
* Antiphospholipid syndrome * Presence of antiphospholipid antibodies * Lupus anticoagulant - actually a prothrombotic agent * Anti-cardiolipin antibodies * Beta-2 glycoprotein-1 antibodies * Mechanism * Disrupt Annexin V shield, expose excess phospholipid * Clinical scenario * Venous/arterial thrombosis * Recurrent miscarriage
268
How can CML progress?
Have potential to transform into AML
269
What is the most common cause of death in Fanconi anaemia?
Premature bone marrow failure, AML
270
What is seen histologically in acute myeloid leukaemia?
* Peripheral blood * Blasts * Anaemia, neutropaenia, thrombocytopaenia * Bone marrow * Blast cells \>20% * Morphology important
271
Describe the epidemiology of beta thalassaemia
1 in 7 Greek Cypriots 1 in 12 Turks 1 in 20 Asians 1 in 20-50 Africans/Afro-Caribbeans 1 in 1000 white English
272
Define classic Hodgkin's lymphoma
High grade lymphoma with prominent component of reactive cells
273
What can be done when the INR is too high in Warfarin therapy?
* Stop Warfarin or reduce dose * Give Vitamin K1 (oral or IV) * Give coagulation factors (II, VII, IX, X) * Prothrombin complex concentrates e.g. Beriplex, Octaplex
274
What is disseminated intravascular coagulation?
* Acquired, consumptive process * Activation of coagulation cascade - microthrombi * Exhaustion of coagulation cascade - bleeding * Systemic activation of coagulation * Depletion of platelets and coagulation factors - bleeding * Intravascular deposition of fibrin - thrombosis of small and midsize vessels and organ failure
275
What causes cold AIHA?
Idiopathic in most patients, can develop after mycoplasma infection or in patients with lymphoproliferative diseases e.g. lymphoma
276
How are normal RBC described?
Normochromic (normal colour, mean corpuscular haemoglobin normal) and normocytic (normal size, mean corpuscular volume normal)
277
What investigations are done in the staging of lymphoma?
* CT scan - neck, chest, abdomen and pelvis * PET/CT scan - HL, most DLBCL, FL/NLPHL (to confirm early stage) * Bone marrow aspirate and biopsy - no longer required in HL and many DLBCL
278
What are the consequences of bone marrow failure?
* Neutropenia - infections * Anaemia * Thrombocytopenia - bleeding
279
How do myelodysplastic disorders present?
* 20% incidental finding on FBC * 20% present with infections or bleeding e.g. ophthalmic herpes zoster, fungal infections in lungs * Majority (70-80%) present with fatigue due to anaemia
280
How is follicular lymphoma treated?
* Treatment aimed at alleviating symptoms * 1/3 of patients don't require treatment at diagnosis * Early stage (1A, some 2A) - localised radiotherapy (curable?) * Advanced stage - * Asymptomatic, no bulk, no end organ compromise (porta hepatis impairing liver function, spinal cord, kidneys) - watch and wait * Symptomatic and/or organ compromise - treatment with immunochemotherapy
281
Describe the characteristics of severe rare platelet disorders
* Rare * Autosomal recessive * Mucosal type bleeding pattern
282
List the types of NOACs
* Factor IIa inhibitor - dabigatran etexilate (Pradaxa) * Factor Xa inhibitors * Rivaroxaban (Xarelto) * Apixaban (Eliquis) * Edoxaban (Lixiana)
283
Where are the globin gene clusters found?
Alpha 1/2 - chromosome 16 Beta, delta, gamma - chromosome 11
284
What are the two types of bone marrow?
Red - due to erythrocytes Yellow - due to fat cells Conversion of red to yellow with age but can interconvert (e.g. yellow --\> red with blood loss)
285
Define cytosis/cythaemia
Too many mature blood cells
286
Describe myeloablative regimens
1. Conditioning Eliminate host haematopoietic system and immune system - high dose chemotherapy and total body irradiation 1440cGy 2. Bone marrow transplantation
287
What causes anaemia of chronic renal failure?
Combination of effects of ACD and reduced Epo production
288
What are the important stages in management of a major haemorrhage?
* Early recognition important * Remember estimated blood volume varies dependent on patient weight * Transfusion usually necessary after 30-40% loss * Hb not a reliable indicator in acute situation * Get help - need lots of people to keep up with rate of blood loss * Control bleeding * Surgery * Interventional radiology * Transfuse early - need to think about future blood loss and potential for deterioration
289
Describe the natural history of chronic myeloid leukaemia
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290
What abnormalities are seen on the coagulation screen with lupus anticoagulant?
* APTT - often prolonged * APTT 50:50 dilution - only partially corrects (inhibitor present) * DRVVT ratio prolonged * DRVVT ratio corrects with excess phospholipid
291
Describe the clinical consequences of sickle cell anaemia
Multisystem disease: * Brain - stroke, Moya Moya (degeneration in and around basal ganglia) * Lungs - acute chest syndrome, pulmonary hypertension * Bones - dactylitis (swelling, pain), osteonecrosis * Spleen - hyposplenic * Kidneys - loss of concentration, infarction * Urogenital - priapism (acute/chronic) * Eyes - vascular retinopathy * Placenta - IUGR (intrauterine growth retardation), foetal loss
292
Why are the number of stem cell transplants being carried out increasing?
Transplanting older patients and for more conditions
293
What laboratory investigations should be done in DIC?
* Look for underlying cause * Sepsis, trauma, cancer, obstetric disease * Coagulation - PT, APTT, fibrinogen * D-Dimers * FBC + film - platelets, RBC fragments
294
Describe the possible pathogeneses of drug induced AIHA
1. Hapten - drug binds to RBC and acts as antigen hapten, antibodies which destroy RBC raised in response 2. Immune complex (innocent bystander) - antibodies raised against drug not RBCs, interaction of antibody with drug causes complement fixation = severe haemolysis e.g. cephalosporins 3. Autoimmune - drug is introduced, antibodies against RBC develop (not sure why), rare + mild
295
Describe the stages involved in the coagulation cascade
* Initiation - extrinsic pathway ![]() * Propagation - intrinsic pathway ![]() The coagulation system, is triggered by the tissue factor (TF)/factor VIIa complex, which activates FIX and FX. Activated FIX converts small amounts of prothrombin to thrombin, which is sufficient to amplify coagulation by activating factors V and VIII, platelets, and platelet-bound factor XI. Coagulation is propagated when FIXa binds to FVIIIa on the surface of activated platelets, forming intrinsic tenase, which, in turn, activates FX. Activated FX binds to activated factor V to form prothrombinase, which converts prothrombin (Factor II) to thrombin (Factor IIa). In the final step, thrombin converts fibrinogen to fibrin.
296
Describe the histological appearance of chronic lymphocytic leukaemia
* Peripheral blood - blasts * Bone marrow * Nodular infiltrate * Diffuse infiltrate * Diagnosis * Clonal population of B lymphocytes 9 (\>5 x 109/L) * CD5, 19, 20, 23 positive, weak surface Ig * Unique immunophenotype * Co-expression CD5, CD19, CD23
297
Describe the platelet receptors
* VWF and collagen facilitate platelet adhesion to subendothelium * Fibrinogen (and VWF) facilitate crosslinking of activated platelets
298
Describe the use of catheter directed thrombolysis
* All fibrinolytic drug types effective * Pros * Smaller doses * Administered directly into vessel containing thrombosis * Less systemic effect * Paradoxically not necessarily less bleeding * Uses * Acute limb ischaemia * Massive CVT * Blocked CVC (central venous catheter)
299
What are the triggers for treatment in chronic lymphoblastic leukaemia?
* Symptoms * Sweats, weight loss, symptomatic nodes * Bone marrow failure * Anaemia, thrombocytopenia * Do not treat asymptomatic patients
300
Where does haemopoiesis occur in infants?
Bone marrow (all bones) - during childhood there is a progressive replacement of marrow by fat in the long bones (conversion from red --\> yellow marrow)
301
Describe the incidence of lymphoma
5th most common cancer, commonest blood cancer Can occur at any age - commonest cancer in \<30 y/o, accounts for 1 in 10 cancers in children
302
What is the effect of beta thalassaemia major on RBCs?
Significant dyserythropoiesis, RBC are small and misshapen
303
What causes myelodysplastic syndromes?
May be secondary to previous chemotherapy or radiotherapy - 3-10 years after initial treatment Can occur without clear underlying cause
304
Describe the use of JAK2 inhibitors in the treatment of essential thrombocytopenia
* JAK2 mutations result in continuous activation of JAK receptor regardless of ligand binding * JAK inhibitor Ruxolitinib approved for use in myelofibrosis with trials ongoing in ET and PRV - inhibits JAK1/2, no reduction in allelic burden, main side effect is thrombocytopenia * Responses seen in JAK2 positive and negative patients
305
How is myeloma diagnosed?
* Blood tests * FBC, ESR, U&Es, Calcium - serum protein electrophoresis, SFLC (serum free light chain) quantity * Can be anaemic - microcytic, hypochromic * ESR can be over 100 * Urine tests (GP) - to look for Light chains in urine (Bence-Jones protein) * Bone marrow aspirate * Imaging
306
Define neutropenia
Reduction in the number of neutrophils
307
Describe the clinical presentation of chronic myeloid leukaemia
* May be asymptomatic (20-50%) * Symptoms * Fatigue * Weight loss * Night sweats * Abdominal discomfort * Splenomegaly in 50-75%
308
How are donor lymphocyte infusions given?
Following bone marrow transplant and subsequent relapse, give incremental increasing concentrations of donor lymphocytes
309
Describe the clinical features of essential thrombocythaemia
* Continuum with polycythaemia rubra vera * Thrombotic complications * Haemorrhagic complications - abnormal platelets also produced = abnormal clotting (can also develop Von Willebrand's disease) * Splenomegaly * Transformation to PRV or myelofibrosis (fibrotic tissue replacing marrow, become pancytopaenic) * Leukaemic transformation in 3%
310
Describe the graft vs leukaemia effect
Same cells which cause GvHD also attack remaining leukaemia cells - minimising GvHD carries an increased risk of relapse GvL is very effective, esp. in patients where a good remission has been difficult to maintain with chemotherapy alone Can work in other cancers e.g. lymphoma, myeloma Challenge is to minimise GvHD and maximise GvL
311
Which blood cells are derived from myeloid stem cells?
RBC, platelets, monocytes, neutrophils, eosinophils and basophils
312
Describe R-CHOP chemotherapy
* R - Rituximab (monoclonal antibody) * C - Cyclophosphamide * H - Adriamycin (Doxorubicin) * O - Vincristine * P - Prednisolone (steroid for 5 days) Given on day 1 of a 21 day cycle
313
What causes symptoms in chronic and acute leukaemia?
* Chronic - accumulation of cells * Acute - marrow failure
314
Describe the role of ferroportin
Transmembrane protein for the exportation of iron, hepcidin blocks its activity
315
What are the clinical consequences of myelodysplastic syndromes?
Majority characterised by progressive bone marrow failure, some progress to AML
316
Describe the onset of acquired warm type haemolytic anaemia
Onset of warm antibody autoimmune haemolytic anaemia may be insidious or explosive
317
What are the indications for DOACs?
* Total hip replacement or total knee replacement * Atrial fibrillation * DVT and PE prophylaxis
318
What is leukaemia?
* Blood cancer * Accumulation of abnormal leucocytes in marrow +/- blood +/- other tissues
319
Which cell is the precursor to mature platelets?
Megakaryocyte
320
How much iron is released from stores per day?
30-40mg released from stores per day but only 4mg in plasma at any one time
321
List the major classes of fibrinolytics
* Kinases - streptokinase, urokinase * Tissue plasminogen activators (tPA) - alteplase, tenecteplase, reteplase
322
What are blast cells?
* Primitive cells * Can be malignant or normal primitive cells * Myeloid and erythroblasts in leucoerythroblastic blood sample are normal primitive cells, pushed out of bone marrow by fibrotic tissue (myelofibrosis) or malignant infiltration by carcinomas
323
How is acute lymphoblastic leukaemia diagnosed?
* Histology of bone marrow * Cytogenetics * T(9:22) * T(4:11)
324
What measures are taken in those who have had a splenectomy to prevent further morbidity?
Hyposplenic prophylaxis - immunisations and long term penicillin V
325
Describe the supportive management of ALL
* Blood transfusion * Symptomatic patients * Improve QOL * Fresh frozen plasma * For coagulopathy/DIC (disseminated intravascular coagulopathy) * Platelet transfusion * Purpura and bleeding - e.g. retinal haemorrhage * During fever, sepsis, DIC * Antibiotics/antifungals - bacterial and fungal infections e.g. chest infections * Growth factors (G-CSF) * Granulocytes * Refractory infections
326
Describe the histological features of classic Hodgkin lymphoma
* Rees Sternberg cells - distinct, giant cells seen in Hodgkin's lymphoma * Neoplastic cell resembles atypical activated B-cell as seen in some viral infections (e.g. EBV - approx. 40% of cases associated with EBV infection) * Characterised by strong expression of CD30 and loss of some B-cell antigens
327
How does classic Hodgkin's lymphoma present?
* Bimodal age incidence - peak in 20-30s then later peak \>50 yrs * Usually presents with painless lymphadenopathy (\>70%) * Neck lump * Cough, shortness of breath * May present with CXR mass * Spreads from one nodal group to immediately adjacent nodes * Later, haematogenous spread to liver, lungs, BM * May have B symptoms * Itch may precede diagnosis for many months * Alcohol related pain - very rare
328
What causes extravascular haemolysis?
* More common than intravascular haemolysis, occurs in RES, particularly spleen * Often related to production of 'warm' (incomplete) antibodies, usually IgG * IgG attaches to red cell antigen and damages the RBC membrane, damaged RBCs become spherocytic and are phagocytosed by the RES, particularly the spleen - hypersplenism
329
How is warfarin monitored?
* By INR * INR = (PT patient/mean normal PT)^ISI * Normal INR = 1/0 (not on Warfarin) * Target INR on Warfarin = 2.0 - 3.0
330
What is the most significant disorder of haemoglobin variance?
Sickle cell disease
331
Why are volunteer unrelated donor transplants needed?
Majority of patients (70%) do not have a family donor
332
Why do men and women require different amounts of iron?
Men need 1mg/day, women need 2mg/day due to loss in menstruation/pregnancy
333
Describe the pattern of inheritance of Fanconi anaemia
Autosomal recessive inheritance
334
Why does anaemia of chronic disease occur?
Failure of iron utilisation, iron trapped in RES - cause not clear
335
How long does blood type matching take?
Group specific takes 10-20 minutes, full cross matching takes 30-40 minutes
336
What influences the activated partial thromboplastin time?
* Depends on * Factors in intrinsic and common pathways * Factors VIII, IX, XI and XII, X, V, II and fibrinogen
337
Describe blood cell production in adults
Red blood cells produced in the red bone marrow throughout adult life, process is continuous. Specialist cells called haematopoietic stem cells are responsible for making all the different types of blood cells. Many blood cells die and are replaced every day.
338
Describe the inheritance pattern of Von Willebrand disease
Mostly autosomal dominant with variable penetrance
339
Define pancytopenia
Reduction in all types of blood cells - WBC, RBC, platelets
340
Give an example of a classic GI cause of IDA without GI symptoms
Adenocarcinoma of the colon
341
What is Burkitt lymphoma?
* High grade lymphoma * Characterised by translocations involving MYC gene (but simple karyotype)
342
Describe the normal body stores of iron
Total body - 4g Bone marrow and RBCs - 3g RES macrophages - 200-500mg Myoglobin - 200-300mg Essential enzymes - 100mg
343
What chance is there that siblings are HLA matched?
Each sibling has a 1 in 4 chance of being a HLA match
344
Describe the classifications of lymphoma
Hodgkin's (15%) - classical (90%) or nodular lymphocyte predominant Non-Hodgkin's - B cell (\>90%) or T cell, indolent or aggressive
345
How effective is chemotherapy in acute myeloid leukaemia?
* Cures in 15-90% according to risk group * Some patients refractory, some only curable using allogenic transplant
346
Which mutations are associated with myeloproliferative disorders?
JAK2V617F and calreticulin mutation
347
How can allogeneic transplants be modified for older/less fit patients?
Can have full intensity 'myeloablative' (host bone marrow completely destroyed) or reduced intensity 'mini' transplant (usually for older patients)
348
What is seen histologically in plasma cell myeloma?
* Peripheral blood - Rouleaux * Stacks/aggregations of red blood cells * Bone marrow - excess plasma cells, pleomorphic * Eccentric nucleus, basophilic cytoplasm * The neoplastic plasma cells are monoclonal and therefore produce only produce one type of immunoglobulin light chain (kappa or lambda)
349
List the uses of autologous stem cell transplants
Plasma cell dyscrasias Non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukaemia Solid tumours - used for breast cancer commonly in the 90s, not shown to increase survival Leukaemia
350
How is the direct Coombs test carrier out
Add antibodies e.g. to IgG on red cell surface, immunological lattice forms, red cell agglutination
351
Describe the folate stores
Require a lot, stored poorly, if stop folate takes 4-6 weeks to run out (process quickened by alcohol)
352
Describe the, dose, half life, minimum creatinine clearance and side effects vs warfarin of edoxaban
* Dose * 60mg od * 5d LWMH 60mg od (or 30mg od) * Half life - 12 hours * Cmax - 1-2 hours * Minimum creatinine clearance * 15 (reduce dose if 15-50 ml/min, \<60Kg or interacting drugs) * Side effects vs warfarin * Fewer ICH
353
What are the consequences of BM failure?
Risk of bleeding, anaemia, infections
354
How is chronic lymphocytic leukaemia often diagnosed?
Incidental Diagnosis: * Common - 50% cases * FBC - lymphocytosis * GP samples * Hospital patients - medical or surgical * Pre-symptomatic diagnosis
355
Explain the terms responder and non-responder in reference to resuscitation of a major bleed
* Responder vs. non-responder * Responder - bleeding stops, stabilises following transfusion of blood products and fluid * Non-responder - stays stable while blood is being replaced but when transfusion stops they deteriorate quickly as the bleeding continues * Stable enough for investigation? Or do they need intervention immediately? * Secondary survey
356
What is the role of nursing in the management of ALL?
* Key component to success * Need specialised experienced staff * Nursing bond important to patients * Demanding both physically and psychologically * Rewarding specialty
357
What determines the severity of haemoglobinopathies?
Amount of abnormal haemoglobin Type of abnormal haemoglobin Ameliorating factors
358
Describe the histological appearance of essential thrombocytopenia
Peripheral blood - platelets clumped together, different sizes Bone marrow - lots of megakaryocytes Myelofibrosis
359
Describe the stores of B12
Absorb small amount per day but is stored well, if stop absorbing B12 will take 5 years to be deficient
360
Describe the chemotherapy used to treat ALL
* Complex, specialist units * Prednisolone, cyclophosphamide, anthracycline, asparaginase, vincristine, etoposide, cytarabine based * CNS directed treatment essential * Initial aggressive therapy, then oral maintenance (1-2 years)
361
Describe primary haemostasis
* Vasoconstriction * Reduces blood flow and limits blood loss * Collagen exposed at site of injury promotes platelet adhesion to the injury site * Platelets release cytoplasmic granules containing serotonin, ADP and thromboxane A2 - increase vasoconstriction * Platelet plug formation * Activated by von Willebrand factor, found in plasma * Platelets release cytoplasmic granules which creates positive feedback loop to continue the process of platelet aggregation
362
Describe the mutation responsible for CML
Reciprocal translocation from long arm of chromosome 9 --\> 22 BCR-ABL fusion gene (Philadelphia) produced is responsible for CML - ABL1 gene on chromosome 9 joined to a part of BCR (breakpoint cluster region) gene on chromosome 22 BCR-ABL causes permanent activation of tyrosine kinase - impaired DNA binding and unregulated cell division --\> cancer
363
Describe the uses of fibrinolytic drugs
* Breakdown pathological thrombosis * Systemically * Locally - catheter directed
364
What abnormalities are seen in the coagulation screen in haemophilia A?
Prolonged APTT
365
From which cells are chronic leukaemias derived?
* B lymphocytes - chronic lymphoblastic leukaemia * Neutrophils, eosinophils, basophils - chronic myeloid leukaemia
366
What are the potential options for the fate of a haematopoietic stem cell?
Self-renewal to produce an identical copy, apoptosis, differentiation (maturation and specialisation)
367
What is the purpose of the indirect Coombs test?
To detect RBC antibodies in plasma for screening/cross-matching (transfusion)
368
Describe the coagulopathy in liver disease
* Poor coagulation factor synthesis in liver * Vit K deficient (poor diet +/- obstructive component to jaundice) * Poor clearance of activated coagulation factors * DIC * Hypersplenism (--\> low WBC and platelets) * Reduced thrombopoietin synthesis (--\> low platelets)
369
Why would IV iron replacement be used rather than oral tablets?
Iron intolerance (GI upset) - before starting IV try reducing elemental iron dose (use gluconate instead of sulphate/fumarate) Compliance e.g. psychiatric patients Renal anaemia + Epo replacement
370
Compare warm and cold AIHA
Cold - IgM + complement, rarer, harder to treat Warm - IgG +/- complement, more common, easier to treat
371
What causes follicular lymphoma?
Translocations involving BCL2 gene (18 --\> 14 translocations) Slow growth but reduced apoptosis
372
What is the internationalised normalised ratio? What is it used for?
* Standardised form of prothrombin time * Monitoring of oral coumarins e.g. Warfarin * Vit K dependent coagulation factors - II, VII, IX and X * Patient's INR identical in any laboratory * Patient's PT/average of 20 normal PTs * Result factored by International Sensitivity Index * Every thromboplastin has its own ISI * Calculated form international standard thromboplastin * Should be close to 1.0
373
How can the reason for a prolonged APTT be determined?
* If reason for prolonged APTT is factor deficiency, 50:50 dilution will show full correction (factors replaced with those in normal plasma). * If reason for prolonged APTT is inhibitor, 50:50 dilution will show partial correction (inhibitor still present).
374
How are myelodysplastic disorders managed?
* Supportive care - blood and platelet transfusion (may need iron chelation in younger patients) * Growth factors - erythropoietin +/- granulocyte colony stimulating factor (G-CSF), reduce anaemia, improve quality of life * Immunosuppression - some success in treating low-risk MDS with anti-thymocyte globulin * Low dose chemotherapy if high blast counts - e.g. hydroxycarbamide, low dose cytarabine * Demethylating agents e.g. azacytidine, an epigenetic therapy * Intensive chemotherapy (BM transplant) - only in patients who can tolerate, AML type chemotherapy * Allogenic stem cell transplantation - only in selected patients (suitable donor, well enough to tolerate)
375
Describe the genetics of chronic myeloid leukaemia
* Philadelphia chromosome, t(9:22) * BCR-ABL gene produced
376
List the potential problems with stem cell transplant
* Limited donor availability, upper age limit \<65 years * Mortality 10-50% depending on risk factors * Graft vs host disease - chronic GvHD has 30% mortality * Immunosuppression * Infertility in both sexes * Risk of cataract formation * Hypothyroidism, dry eyes and mouth * Risk of secondary malignancy * Risk of osteoporosis/avascular necrosis - reduction in androgens and steroids needed for GvHD
377
How are volunteer unrelated donors identified?
Anthony Nolan Trust donor registry within the UK, several million volunteers worldwide 70% chance of finding a VUD for each patient
378
What are the clinical consequences of hereditary spherocytosis?
Splenomegaly Jaundice (neonatal and adult)
379
Give examples of organisms asplenic patients have a greater risk of infection from
Encapsulated organisms - pneumococcus, meningococcus, haemophilus
380
Describe the types of acute leukaemia classified by the cells from which they originate
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381
What laboratory findings are seen in extravascular haemolysis?
* Positive direct antiglobulin test indicates the presence of antibodies (or complement) on RBC surface * Serum bilirubin usually elevated and is unconjugated (hence acholuric jaundice)
382
Describe the mechanism of action of heparins
* Mixture of glycosaminoglycans of differing polysaccharide chain length * Augment activity of endogenous antithrombin (1000-2000 fold) * Particularly anti-IIa and anti-Xa activity * Anti-Iia effect influenced by longer saccharide chains * Do not cross placenta * Short half-life * Administered parenterally
383
How is non-haem iron absorbed?
Converted from ferric to ferrous iron requiring cytochrome b, then absorbed through the divalent metal transporter DMT1
384
List the types of Von Willebrand disease
* Type 1 - partial quantitative deficiency of VWF * Type 2 - qualitative deficiency of VWF * 2A - qualitative variants with decrease platelet dependent function associated w/ absence of HMW VWF multimers * 2B - all qualitative variants with increased affinity for platelet glycoprotein 1b * 2M - qualitative variants with decreased platelet dependent function NOT caused by absence of HMW VWF multimers * 2N - qualitative variants with markedly decreased affinity for factor VIII * Type 3 - virtually complete deficiency of VWF
385
What can cause hypochromic, microcytic RBCs?
Iron deficiency anaemia - not enough haem Thalassaemia - not enough globin Anaemia of chronic disease Sideroblastic anaemia (esp. congenital SA) - enough iron but not converted to haem
386
Describe the pathogenesis of cold AIHA
Autoantibody IgM + complement IgM antibodies cause red cells to aggregate
387
Describe the potency of haematopoietic stem cells
Multipotent - can produce several different cell types
388
What are the retrieval team?
* Team of emergency medicine, anaesthetic and ITU consultants * Attend serious emergencies * 999 call responder triages patient to decide if retrieval team are needed * Use helicopter, can go to rural areas * Carry lots of kit and blood products * Pass information to hospital * Code red - phone ahead from ambulance to have blood products waiting, can add FFP, platelets, cryoprecipitate (rich source of fibrinogen)
389
What investigations should be done in patients with lymphoma?
* History - symptoms, duration of symptoms (needs to be persistent lymphadenopathy), B symptoms (fever, night sweats, weight loss) * Clinical examination - lymph nodes, splenomegaly * Blood tests - FBC, U&Es, LFTs, Ca (can be high), ESR (HL), LDH * Imaging tests - CT scan, PET/CT scan - lessens need for biopsy, can show marrow infiltration * Bone marrow - aspirate and trephine * Additional tests (may be required pre-treatment) - echocardiogram, pulmonary function tests
390
How is B12 absorbed?
Binds to intrinsic factor (made by gastric parietal cells in fundus/body of stomach) Absorbed in ileum Binds to transcobalamin in plasma
391
What is the disadvantage of syngeneic stem cell transplants?
Doesn't give desired graft vs leukaemia effect
392
How much B12 is required daily?
1ug/day
393
How is iron recycled by the RES?
Effete RBC removed by the macrophages of the RES RES stored around 500mg of iron as ferritin/haemosiderin RES releases iron to transferrin in plasma when required Tf-iron complex taken up via Tf receptors on erythroblasts, hepatocytes etc.
394
Describe the appearance of bone marrow in aplastic anaemia
Normal haematopoietic tissue replaced by fat spaces Fat spaces increase with age - 70y/o have 70% replaced w/ fat spaces
395
List the pre-leukaemic conditions
1. Myelodysplastic disorder 2. Myeloproliferative diseases
396
How does the appearance of bone marrow aspirate differ from a trephine sample?
Trephine is solid rather than liquid so shows the architecture more clearly
397
How does haemoglobin production change throughout life?
Foetal haemoglobin produced during gestation, gamma chain production switched off just before birth - replace foetal haemoglobin with adult haemoglobin
398
Describe the normal mechanism of red cell destruction
* Senescent red cells (100 days+ old) are destroyed by the cells of the reticuloendothelial system particularly in the spleen * Intravascular haemolysis (breakdown of RBC in the general circulation) normally has little or no role in RBC destruction
399
What does Moya Moya appear as on imaging?
'Puff of smoke'
400
Describe the stroma of bone marrow
Stromal cells include macrophages, fibroblasts, endothelial cells, fat cells and reticulum cells. They secrete extracellular molecules such as collagen, fibronectin, haemonectin, laminin and proteoglycans including growth factors and adhesion molecules - essential for growth, division and differentiation into mature blood cells.
401
Give an example of a relatively benign myelodysplastic disorder
Refractory anaemia with ring sideroblasts Patients can live for years but are transfusion dependent - iron overload is problem
402
Describe the prevalence and features of factor deficiencies (other than Haemophilia A)
* Rare bleeding disorders * Represent 3-5% of all congenital bleeding disorders * Often manifest clinically in autosomal recessive form only * Prevalence of homozygous or double heterozygous cases - 1/500,000 - 1/2,000,000 * Lower factor levels doesn’t necessarily mean higher bleeding severity
403
Describe non-myeloablative stem cell transplants
Low-dose, less toxic preparative regimens Provides immune suppression to allow donor cells to engraft, while graft vs leukaemia effect eradicates tumour Permits SCT use in patients not eligible for conventional SCT
404
What is leukaemogenesis?
The development of leukaemia cells from normal haematopoietic stem cells
405
Describe the treatment of bleeding in inherited platelet disorders
* Pressure * Tranexamic acid/Desmopressin * Platelet transfusion (HLA matched) * rFVIIa
406
Describe the synthesis of haem in RBC development
Globin genes contain 3 coding sequences (exons) and 2 intervening sequences (introns) Transcription of genes controlled by promoter genes at 5' end, influenced by upstream locus elements (LCR regions) After translation introns excised Globin chains produced on ribosomes Control of production mainly at transcription level and depends on availability of haem
407
What are the consequences of clonal haemopoiesis?
Linked to increased risk of haematological disease
408
Give examples of hereditary conditions which impair bone marrow function
Thalassaemia Sickle cell anaemia Fanconi anaemia Dyskeratosis congentia Schwann-Diamond syndrome Diamond Blackfan anaemia Thrombocytopenia with absent radii Hereditary leukaemia (rare)
409
What is the best lab test to confirm iron deficiency anaemia?
Serum ferritin - low serum ferritin always indicates low RES iron stores
410
List the characteristics of myelodysplastic disorder
* Clonal blood disorder * Characterised by * Failure of effective haemopoiesis (low blood counts) * Most common in elderly * 'Dysplastic' blood and marrow appearances * Approx. 25% rate of transformation to AML * Consequences of marrow failure
411
Describe the use of allogenic transplants in ALL
* HLA matched stem cells * Sibling or unrelated donor * Procedure more complex * GVHD but GVL * Higher early mortality * Less risk of relapse
412
Describe the main laboratory findings in intravascular haemolysis and the pathological mechanisms which lead to this
* After intravascular haemolysis, free haemoglobin saturates plasma haptoglobin (binding protein), resulting in disappearance of plasma haptoglobin * Excess free haemoglobin in plasma filtered at the glomerulus leading to haemoglobinuria, tubules reabsorb some haemoglobin from urine, broken down to form haemosiderin (can also appear in urine) Main laboratory findings in intravascular haemolysis are: * Anaemia, reticulocytosis and raised unconjugated bilirubin * Haemoglobinaemia and haemoglobinuria * Haemosiderinuria
413
Give an example of a myelodysplastic disorder which has a high chance of progressing to AML
Refractory anaemia with excess blasts - increased number of blast cells with expanded chromatin and prominent nucleoli
414
How is diffuse B cell lymphoma treated?
Requires aggressive chemotherapy with intention to cure Response is variable, subset of tumours resistant to conventional treatments Early stage (1A) - R-CHOP x 3 + radiotherapy All other stages - R-CHOP x 6 Elderly/unfit patients - need assessment of general frailty and co-morbidities
415
Where can stem cells used for allogeneic transplants come from?
Can use peripheral blood stem cells, bone marrow or umbilical cord blood
416
Which tissues are commonly invaded in ALL?
CSF and testicular infiltration
417
Describe the, dose, half life, minimum creatinine clearance and side effects vs warfarin of rivaroxaban
* Dose * 10mg od, 20mg od (15mg bd d21) * Half life - 12 hours * Cmax 2-4 hours * Minimum creatinine clearance * 15 (for AF reduce dose if 15-49 ml/min) * Side effects vs warfarin * Fewer ICH, possibly more GI bleeds
418
Define follicular lymphoma
Indolent type of B cell lymphoma, low grade Accounts for 20-25% of lymphomas, 2nd commonest subtype of lymphoma, commonest subtype of low grade lymphoma
419
Describe the prognosis of myeloma
* Incurable * Variable - median 5.5 years (\<6 months to \>10 years) * Overall 5 year survival approaching 50% * Females survive longer
420
Describe the mechanism of action of aspirin
* Blocks conversion arachidonic acid --\> thromboxane A2 * Decreased platelet activation
421
Describe the process of reduced intensity SCT (mini-transplant)
1. Conditioning - low dose chemo, total body irradiation 200cGy 2. Bone marrow transplant - patient mixed chimera (mixture of own cells and donor cells in haematopoietic system)
422
Describe the indications for tPA derivatives and which would be used in each
* Acute MI (alteplase, tenecteplase, reteplase) for patients not suitable for PCI * Within 12 hours of onset of symptoms * 30 day mortality reduced compared to streptokinase or placebo * Ischaemic stroke (alteplase) * Within 4.5 hours of onset of symptoms * Reduced disability at 90 days * Massive pulmonary embolism with haemodynamic instability (alteplase) * Reduced thrombus size and cardiac strain * Effect on overall mortality unknown
423
List the possible mechanisms of action of antiplatelet drugs
* Irreversible blockage of ADP receptor (P2Y12) - clopidogrel, ticlidipine * GPIIb/IIIa antagonists - abciximab, tirofiban * Irreversible inhibition of cyclooxygenase - aspirin * Phosphodiesterase III inhibitor - dipyridamole * Thromboxane synthetase inhibitors and thromboxane receptor blockers - picotamide (combined), ifetroban (receptor blocker)
424
Describe the lab values seen in anaemia of chronic disease
MCV/MCH - normal/reduced (RBCs can be normochromic and normocytic or hypochromic and microcytic) ESR - raised (inflammation) Ferritin - normal/high (iron stores not affected, just can't utilise iron) Iron - low TIBC (measure of transferrin) - low (not normal for anaemia)
425
What typifies myeloma?
* Increased plasma cells in bone marrow * Clonal immunoglobulin or paraprotein * Lytic bone lesions
426
How are iron levels regulated?
No regulatory excretory mechanism for iron, regulated by amount of absorption from GI tract, controlled by hormone hepcidin (decreases amount absorbed)
427
Where does haemopoiesis occur in the foetus?
0-2 months - yolk sac 2-7 months - liver, spleen 5-9 months - bone marrow
428
What is the aim of investigations in plasma cell myeloma?
* Diagnosis * Extent of organ damage * Prognosis (Beta 2 microglobulin is important prognosis indicator - raised in myeloma)
429
Describe the epidemiology of alpha thalassaemia
Alpha+ thalassaemia trait - Southern Europe, Middle East, Africa, South East Asia Alpha0 thalassaemia trait - South East Asia, Greece, Turkey
430
Why is serum ferritin important?
Small amount of total body ferritin in serum but amount of serum ferritin directly related to how much iron is stored - important clinical marker 1mmol/l serum ferritin = 8mg RE iron
431
Describe dietary sources of folate
Colourful foods e.g. green vegetables (destroyed by cooking), orange juice
432
How is CO2 removed from the body?
Involves the renal tubules, lungs and RBCs Chloride shift and carbonic anhydrase reaction important for CO2 removal
433
Describe the transferrin iron saturation in iron deficiency anaemia and hereditary haemochromatosis compared with normal transferrin iron saturation
Normal - 30% Iron deficiency anaemia - liver senses low iron, makes more transferrin, transferrin saturation can be \<15% HH - liver senses high iron, makes less transferrin, transferrin saturation can be up to 100%
434
Describe the survival rate of acute myeloid leukaemia
* Childhood AML - 5 year survival rate approx. 60-70% * Adult AML (\<60 years) - 5 year survival rate approx. 50% * Adult AML (\>60 years) - 5 year survival rate approx. 10-20%
435
What is the genetic cause of leukaemia?
* Acquired genetic abnormalities * 1 gene vs 2 genes or more? * Cell type in which mutation arises likely to be crucial - allow diagnostic testing, monitoring, research, pharmaceutical targeting
436
Describe the hierarchy of normal haemopoiesis
Pluripotent haematopoietic stem cell --\> lymphoid or myeloid stem cell --\> maturation --\> mature cells
437
Give examples of acquired conditions which impair bone marrow function
Aplastic anaemia Leukaemia Myelodysplasia Myeloproliferative disorders Lymphoproliferative disorders Myelofibrosis Metastatic malignancy e.g. breast, prostate Infections e.g. TB/HIV Drugs and toxins Chemotherapy Haematinic deficiencies
438
Give an example of a cause of mechanical fragmentation haemolysis
Ventricular assist device for heart failure, forces blood out of heart, causes mechanical damage to RBC and fragmentation
439
Describe pre-hospital resuscitation for a major bleed
* Need to replace blood lost and maintain intravascular volume * Access * Replace blood lost w/ fluid + blood products * O negative blood used - universal donor * Also give tranexamic acid - fibrinolytic inhibitor * Binds to plasminogen, prevents conversion of plasminogen to plasmin, preventing fibrin breakdown
440
List the types of donor in allogenic stem cell transplants
Syngeneic transplant - between identical twins Allogeneic sibling - HLA identical (match HLA A, B, C, DR, DQ) Haplotype identical - half matched family member, usually patent or half matched sibling Volunteer unrelated/match unrelated donor
441
Mutation of what gene causes hereditary haemochromatosis? What is the effect?
HFE gene mutation - causes iron overload Liver cirrhosis, skin bronzing, arthritis, diabetes
442
List the essential enzymes which contain iron
Cytochromes Perioxidases Xanthine oxidase Catalases RNA reductase
443
Why are B12 and folate relevant to haematological disorders?
Haematinics - required for RBC production Required for DNA synthesis
444
How can platelet function be assessed?
Light transmission aggregometry to assess platelet function
445
What is the purpose of donor lymphocyte infusion?
T-cells obtained by leukapharesis from the original bone marrow donor have an anti-tumour effect Used to prevent/treat relapse after allogeneic SCT - can induce a graft vs leukaemia effect with complete cytogenetic and haematological remission in 2/3 patients
446
Describe the diagnostic criteria for myeloma
* Clinical spectrum of disease * Asymptomatic to highly aggressive disease * Diagnosis based on combination of features * Neoplastic plasma cells in bone marrow, \>10% of total cells plus at least one of the following: * Evidence of end-organ damage attributable to the plasma cell proliferation (CRAB criteria) * Hypercalcaemia * Renal insufficiency * Anaemia * Bone lesions - \>1 lytic lesion on skeletal X-ray, CT or PET/CT * Biomarkers of malignancy * Clonal plasma cell percentage \>=60% * Serum free light chain ratio \>=100 * \>1 focal lesion on MRI
447
Define cytopenia
Reduction in the number of mature blood cells
448
Which tissues are affected by macrocytic anaemia?
All rapidly growing, DNA synthesising cells - bone marrow, epithelial surface (painful red glossitis), stomach, small intestine, urinary, female genital tracts
449
List the types of acquired haemolytic anaemia
Autoimmune - warm type (IgG) and cold type (IgM) Isoimmune - haemolytic disease of the newborn (HDN) Non-immune - mechanical fragmentation haemolysis
450
Describe the progression and management of myeloproliferative disorders
* Essential thrombocytopaenia and polycythaemia rubra vera - good outcome, risk of vascular events (prescribe aspirin), cytoreduction (hydroxycarbamide, venesection or interferon), 5-10% risk of AML, 10% progress to myelofibrosis * Myelofibrosis - difficult, large spleen, systemic symptoms, blood counts high or low, incurable other than with SCT. New class of drugs = JAK2 inhibitors
451
What are the side effects of tPA derivatives?
* Significant risk of haemorrhage * Any organs, particularly intracerebral * Stroke - large ischaemic or small stroke * Risk of bleeds increased in * Elderly * Later administration * Uncontrolled diabetes
452
Describe the actions of antiplatelet drugs
* Actions * Inhibit platelet activation * Inhibit platelet aggregation * Achieved via * Platelet receptor inhibition * Platelet signalling pathway inhibition
453
Compare the pharmacological properties of tPA derivatives
* Alteplase/Tenecteplase * Very short half life (4-5 mins) * Given as bolus, then infusion * Reteplase * Longer half life * Bolus only
454
What factors affect choice of treatment in lymphoma?
Type of lymphoma Stage of lymphoma Age Performance status Co-morbidities Support e.g. family circumstances Patient's preference
455
Give examples of severe inherited platelet disorders
* Glansmanns thrombasthenia * Absent/defective GP IIb/IIIa (alpha-IIb-beta3) * Normal platelet count * Bernard Soulier syndrome * Absent/defective GP Ib/V/IX * Macrothrombocytopenia
456
Describe the morphology of RBC when ESR is raised?
RBC rouleaux form - 'stack of coins' RBC

Medicine Year 3 (15 decks)

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