Haematology Flashcards
(178 cards)
1
Q
Describe the changes to the FBC in pregnancy
A
Mild anaemia (dilutional)
Neutrophilic leucocytosis
Thrombocytopenia with increase in size
2
Q
What is the recommended pregnancy Fe and folate intake?
A
Folate: 400ug/day
Fe: 30mg/day
3
Q
Describe several reasons for platelet levels falling in pregnancy
A
Gestational thrombocytopenia: normal, not well understood. Increases in the days following delivery
Pre-eclampsia: increased platelet activation and consumption due to inflammation. Associated with DIC. Improves after delivery
Immune thrombocytopenic purpura: may precede pregnancy, or pregnancy can uncover. Very low levels.
Microangiopathic syndromes: eg HELLP, SLE, APS, HUS. Deposits of 0latelet rich thrombi and fragmented RBCs, causing organ damage.
4
Q
Describe the management of ITP in pregnancy
A
Management includes IV Ig, steroids and azathioprine.
May affect the fetus, so important to check cord blood and monitor for falling platelets.
5
Q
Describe the changes to the maternal clotting pathways in pregnancy
A
Increased clotting factors (vWF, FVIII, fibrinogen)
Decreased fibrinolytic factors (protein S)
Placenta produces PAI 1 and 2, which are hypofibrinolytic
6
Q
T/F. D dimer remains unchanged in pregnancy.
A
False. Ddimer is increased and therefore should not be used to assess for VTE
7
Q
What is antiphospholipid syndrome? What are the indications for testing?
A
APS: recurrent miscarriages or mid trimester loss and persistence of antibodies
Indications:
-3+ consecutive miscarriages before 10 weeks
-1+ mid trimester loss of normal fetus
-1+ preterm birth with abnormal placenta
8
Q
Describe some haematological conditions that affect the fetus
A
- Twin-twin transfusion syndrome/TAPS: polycythaemia in one, anaemia in the other twin. Due to imbalance of AV anastomoses
- Parvovirus infection: anaemia/hydrops
- Rhesus disease: anaemia/hydrops
- Polycythaemia due to placental insufficiency
9
Q
Which disorder is associated with congenital leukemia? Describe this condition.
A
Downs syndrome.
Transient disease, often remits in several months but may relapse after several years
10
Q
Which chromosomes contain the globin genes?
A
Chromosome 11: beta cluster
Chromosome 16: alpha cluster
11
Q
What are the types of haemoglobin? When are they present?
A
Foetal Hbs: 1st trimester
HbF (2 alpha, 2 gamma): during most of fetal life, and first few months of life
HbA (2 alpha, 2 beta): increases during 1st year of life. Main adult Hb
HbA2 (2 alpha, 2 delta): develops during 1st year of life. Makes up <3.5% of adult Hb
12
Q
Describe the spectrum of sickle cell disease
A
Sickle cell disease: describes a spectrum of AR conditions including sickle cell anaemia + other heterozygous states
- SCA: HbSS. Homozygous for HbS
- HbSC: heterozygous for HbS and HbC (similar)
- Sickle beta thalassaemia: heterozygous for HbS and beta thalassaemia
- Sickle cell trait: HbAS. Heterozygous for HbS
13
Q
What is the cause of sickle cell anaemia?
A
Point mutation of GAG -> GUG on codon 6 of beta globin
Causes amino acid switch from glutamine -> valine
Results in abnormal polymerisation of Hb when deoxygenated
Sickling of RBCs
14
Q
Describe the complications of sickle cell anaemia
A
SICKLED Splenomegaly + sequestration crises -> hyposplenism Infarction: stroke, splenic Crises: painful, acute chest, aplastic Kidney disease Liver + lung disease Erections (priapism) Dactylitis
+gallstones
15
Q
Describe the blood results of a person with sickle cell anaemia
A
- FBC: low, microcytic
- Film: sickle cells, boat cells, Howell-Jolly bodies (hyposplenism)
- Sickle solubility test
- Hb electrophoresis/HPLC: low HbA, higher HbA2
16
Q
Which complications of sickle cell anaemia are specific to children?
A
- Splenic sequestration
- Hand-foot syndrome (painful crises)
- Increased susceptibility to infections
17
Q
Strokes in children should make you think of ___
A
Sickle cell anaemia
18
Q
Describe the pathophysiology of beta thalassaemia
A
- Defect in the beta globin gene on Chromosome 11
- Low levels of HbA, increased HbA2. Presents in infancy
- Trait: asymp/mild anaemia mimics Fe deficiency
- Intermedia: mild-mod anaemia
- Major: severe anaemia, extramedullary haematopoiesis, requires transfusions and chelation with desferrioxamine
19
Q
Name some consequences of blood transfusion for beta thalassaemia
A
Iron overload causing:
- Cardiomyopathy
- Diabetes
- Hyperpigmentation
- Infertility
20
Q
Describe the pathophysiology of alpha thalassaemia
A
- Defect in the alpha globin gene on Chr 16
- Low/absent HbF, HbA, HbA2
- Trait: only 2-3 functioning genes
- HbH: only 1 functioning gene
- HbBarts: no functioning genes. Incompatible with life. Severe hydrops.
21
Q
Name some causes of haemolysis in neonates
A
- Haemolytic disease of the newborn: eg Rh disease
- ABO incompatibility
- Hereditary spherocytosis
- G6PD deficiency
- Pyruvate kinase deficiency
22
Q
Describe the presentation (clinical and biochemical) of haemolytic anaemia
A
-Anaemia: conjunctival pallor, fatigue, SOB
-Jaundice
-Splenomegaly
-Low Hb
-Film: schistocytes, spherocytes, etc.
-High unconjugated bilirubin and urobilinogen (+ dark urine)
-High reticulocyte count (polychromasia)
-High LDH
-Low haptoglobins
+/- DAT test
23
Q
What are some types of acquired haemolytic disease?
A
- Autoimmune haemolytic anaemia
- MAHA: HUS, DIC, TTP
- Malaria
24
Q
What are some characteristics of AIHA?
A
Spherocytes, DAT +ve
Can be associated with infections (eg hepatitis, mycoplasma), malignancy, connective tissue D (RA, SLE)
25
What is HUS?
Haemolytic uraemic syndrome:
- Microangiopathic haemolytic anaemia
- AKI
- Thrombocytopenia
26
What is the pathophysiology of haemophilia? How does it present?
Deficiency in FVIII (A) or FIX (B). A > B incidence
- > abnormal secondary haemostasis
- Bleeding, bruising, haemarthrosis
27
Define anaemia + ranges
Low RBCs or haemoglobin in the blood.
Men: <135 g/L
Women: <115 g/L
28
Name some broad mechanisms of anaemia
Reduced production of RBCs: aplastic anaemia
Increased breakdown of RBCs: haemolytic anaemia
Decreased haemoglobin: Fe/B12/folate deficiency
Increased plasma volume: pregnancy
29
What are the different types of anaemia? What are some causes of each
Microcytic: Fe deficiency, anaemia of chronic disease, sideroblastic anaemia, thalassaemia
Normocytic: blood loss, pregnancy, anaemia of chronic disease, bone marrow failure, haemolysis, renal disease
Macrocytic: B12/folate deficiency, alcoholism/liver disease, hypothyroidism, reticulocytosis
30
Name some signs/symptoms of anaemia
Pallor, SOB, dizziness, fatigue, palpitations, headache
31
Name some signs/symptoms of iron deficiency. What is the syndrome associated with iron deficiency and what are the features?
-General anaemia: pallor, SOB, dizziness, fatigue
-Koilonychia
-Atrophic glossitis
-Angular cheilosis
-Brittle hair and nails
Plummer Vinson syndrome: oesophageal webs, iron deficiency anaemia, dysphagia
32
Describe the FBC + blood film in iron deficiency anaemia
- Anaemia (low Hb)
- Microcytic (low MCV)
- Hypochromic
- Anisocytosis, poikilocytosis
33
What are some causes of iron deficiency anaemia? What are some red flags?
- Chronic blood loss: GI (ulcers, cancer), HMB, urine
- Increased use: growth/pregnancy/lactation
- Decreased intake: poor diet, malabsorption
**Worried if male, post-menopausal, weight loss -> ?malignancy
34
How is iron deficiency anaemia treated?
Treat cause
Conservative:
-Diet modification
Medical:
- Ferrous sulphate 200mg PO BD
- > ferrous fumarate
- > IV
* Co-prescribe with laxatives, warn about GI upset
35
Describe the pathophysiology of anaemia of chronic disease. What are some common causes?
Cytokines cause inhibition of RBC production thru affecting EPO synthesis and iron metabolism
- Inflammatory conditons eg. IBD, RA
- Chronic infection eg. TB
- Malignancy
36
Describe the haem picture in ACD
- Anaemia
- Micro/normocytic
- High ferritin
37
What is sideroblastic anaemia? What are some causes?
A condition of ineffective erythropoiesis causing iron loading in the bone marrow -> ringed sideroblasts
-Myelodysplastic disorders, chemorad, alcohol, anti-TB drugs, porphyrias
38
Describe the iron studies in iron deficiency anaemia
LOW iron
HIGH total iron binding capacity
LOW ferritin
39
Describe the iron studies in ACD
LOW iron
LOW TIBC
HIGH ferritin
40
Describe the iron studies in chronic haemolysis
HIGH iron
LOW TIBC
HIGH ferritin
41
What is ferritin? What is it affected by?
Ferritin is an acute phase protein that stores iron in cells.
It can be increased in inflammation, infection, malignancy -> always do a CRP with ferritin
42
If a patient has an inflammatory condition, what is the best way to estimate iron?
Transferrin saturation (serum iron/TIBC)
43
Name some causes of macrocytosis
- Megaloblastic: B12 deficiency, folate deficiency
- Non-megaloblastic: alcohol, reticulocytosis (from haemolysis), liver disease, hypothyroidism, pregnancy
- Other: myelodysplasia, myeloma, etc
44
What are 4 characteristics of a megaloblastic blood film?
- Macrocytic anaemia: nucleated RBCs, Howell-Jolly bodies
- Leukopenia
- Thrombocytopenia
- Hypersegmented neutrophils
45
What are some causes of B12 deficiency? How can it present?
-Dietary insufficiency eg. vegan
-Malabsorption: pernicious anaemia, Crohn's, infestation
Presents with peripheral neuropathy (tingling, numbness), glossitis, angular cheilosis, neuropsych (irritable, depression, dementia)
46
Describe the pathophysiology of pernicious anaemia
- Antibodies to gastric parietal cells + intrinsic factor
| - Decreased absorption of B12
47
What is the treatment for B12 deficiency?
IM hydroxycobalamin
48
Where is folate found? What are some causes of deficiency?
- Leafy greens, nuts, yeast
- Causes: poor diet, pregnancy, increased cell turnover (malignancy, haemolysis), malabsorption, alcohol, anti-epileptics, methotrexate
49
How is folate deficiency treated? What is the important caution?
- Give folate supplements
| - Be careful not to give randomly as can exacerbate B12 neuropathy
50
What are the haem features of haemolytic anaemia?
- Low Hb, normocytic or macrocytic if reticulocytosis
- High reticulocytes, polychromasia
- High LDH
- High bilirubin (unconjugated)
- Low haptoglobins
- Blood film: specific depending on type eg spherocytes, Heinz bodies, bite cells, schistocytes
51
Describe the classification of haemolytic anaemia and name some causes
- Inherited (hereditary spherocytosis, SCA, G6PD deficiency)
| - Acquired can be immune (AIHA, HDFN) vs non-immune (MAHA, malaria, ADENOCARCINOMA)
52
Describe the pathophysiology of hereditary spherocytosis and elliptocytosis
HS: AD mutation in the B spectrin, ankyrin, band 3
HE: usually AD mutation in A/B spectrin
-Leads to membrane structure changes -> haemolysis in the spleen
53
A 35 year old man comes to A&E with severe breathlessness and extreme fatigue for the past 2 days after developing a mild cold. He has a PMH of hereditary spherocytosis. What investigation will indicate the most likely diagnosis?
Reticulocyte count- this man may have parvovirus B19 infection that has caused aplastic crisis. Therefore, a reticulocyte count would be low.
54
Which stain shows iron deposition in the liver? What is the name for this state?
Perl's stain. Hepatic siderosis
55
Which tests are diagnostic for hereditary spherocytosis?
Osmotic fragility and dye binding tests
56
What is the pathology in paroxysmal nocturnal haemoglobinuria
Mutation in GPI protein (on outside of membrane), important for preventing immune-mediated destruction
57
What is the pathophysiology of G6PD deficiency?
- X linked mutation causing decreased G6PD enzyme activity
- Protects against oxidative damage thru glutathione
- When ox. damage occurs -> intravascular haemolysis
58
Describe the haematological features of G6PD deficiency
- Haemolytic anaemia picture (low Hb, high reticulocytes, high bilirubin, high LDH etc)
- Blood film: bite cells, Heinz bodies, abnormally contracted cells
59
Name some triggers of haemolysis in G6PD deficiency
- Fava beans
- Moth balls
- Infection
- Drugs: sulfonamides, primaquine
60
What are the classic cells seen in pyruvate kinase deficiency?
Echinocytes - spiky cells
61
What are the types of autoimmune haemolytic anaemia? Describe.
- Warm AIHA: IgG. Associated with blood cancers, SLE
| - Cold agglutinin disease: IgM. Assoc with EBV, mycoplasma
62
What is Ham's test used for?
To diagnosis paroxysmal nocturnal haemolgobinuria
63
Name some types of MAHA.
- HUS
- TTP
- HELLP
64
What are the features of HUS? TTP?
HUS: MAHA, AKI, thrombocytopenia
TTP: MAHA, AKI, thrombocytopenia, fever, neurological dysfunction
65
Describe the pathophysiology of TTP
ADAMTS13 antibodies -> abnormal vWF that cause RBC destruction
66
Heinz bodies suggest ____
Oxidative damage eg. G6PD deficiency
67
Describe the principles of haemostasis
- Primary haemostasis: formation of the platelet plug. Involves platelet activation and recruitment, binding.
- Secondary haemostasis: formation of a fibrin clot. Involves clotting cascade forming crosslinking fibrin
- Fibrinolysis
68
Describe the clotting cascade
- Intrinsic pathway: includes FXII -> FXI - FIX - FVIII - FX
- Extrinsic pathway: involves TF activating FVII
- Common pathway: FV - Prothrombin - Fibrin
69
What is the role of FVIII in the clotting cascade?
Supports the conversion of FIX to FX
70
How is clotting assessed?
- APTT: intrinsic pathway
- PT: extrinsic pathway
- TT: common pathway
71
What is Virchow's triad? Name some factors that affect each.
- Vessel wall injury: atherosclerosis, infection, malignancy, vasculitis
- Hypercoagulability: pregnancy, COCP, dehydration, multiple myeloma
- Stasis: flights, surgery, casts, bed rest
72
Describe the process of primary haemostasis
- Vessel wall injury causes exposure of collagen + vWF to the blood
- Attracts platelets -> binding directly or via vWF with Glp1 -> release CKs/thromboxane
- Platelet activation + recruitment -> crosslinking with GlpII and fibrinogen
73
What is the mechanism of action of aspirin? Other NSAIDs?
Aspirin is an irreversible inhibitor of COX1 enzymes -> inhibits production of thromboxane A2 -> decreased platelet aggregation
NSAIDs are reversible inhibitors.
74
What is the function of thrombin?
- Activates platelets
- Activates the clotting cascade
- Converts fibrinogen -> fibrin
75
What is the complex that is needed to activate thrombin the most efficiently?
- FXa
- FVa
- Ca
76
Why is vitamin K needed?
Important in the activation of factors:
| -2, 7, 9, 10
77
Describe the process of fibrinolysis
- Tissue plasminogen activator activates plasminogen to plasmin
- Plasmin cuts fibrin into fibrin degradation products
78
What are the physiological anticoagulants? How do they work?
- Protein C and S: protein S supports activation of protein C to inactivate FV and FVIII
- Antithrombin: binds to thrombin, allows excretion
79
What is the pathophysiology of FV Leiden?
Resistant to breakdown by protein C -> leads to hypercoagulable state
80
What is the mechanism of action of heparin? Warfarin? How are they monitored?
Heparin: potentiates the action of antithrombin. Measured with APTT
Warfarin: Vit K antagonist, prevents activation of Factors 2,7,9,10. Monitored with INR/PT. Narrow therapeutic window
81
What is the mechanism of action of DOACs? What are their advantages?
- Anti Xa: rivaroxaban, apixaban
- Anti IIa: dabigatran
- Better bc less risk of bleeding
82
Name some causes of bleeding disorders
- Inherited: platelet disorders, haemophilias, vWD
| - Acquired: liver disease, Vit K deficiency, thrombocytopenias (ITP, TTP, pre-eclampsia, HUS), DIC
83
Describe the pattern of bleeding in platelet disorders and clotting factor deficiencies
- Platelet: superficial bleeding, petechiae/purpura, mucous membrane bleeding, prolonged bleeding
- Clotting factors: deep bruising, haemarthrosis, delayed bleeding
84
When is treatment required for thrombocytopenia?
When Plt <30 X 10^9. Risk of spontaneous haemorrhage
85
What are the treatment options for ITP?
- Steroids
| - IVIG (to bind antibodies and prevent destruction)
86
What are some causes of thrombocytopenia?
- Immune: MAHA, HUS, ITP, SLE, RA
| - Non-immune: B12 deficiency, bone marrow failure, DIC
87
What are the types of haemophilia? What is the treatment?
A: FVIII deficiency
B: FIX deficiency
Haem: prolonged APTT, normal PT, low FVIII/IX
Management: transfusion of factor VIII/IX concentrate when bleeding occurs, may need prophylactic transfusions
88
What are the types of vWD? What is the haematological/clotting picture?
Type 1: partial decreased vWF
Type 2: poor vWF function
Type 3: no vWF -> low FVIII. Similar to haemophilia
-Prolonged APTT and bleeding time, normal PT, normal Plts, low/normal vWF antigen, low vWF function
89
What are some causes of DIC?
- Sepsis
- Burns
- Trauma
- Malignancy
90
Describe the pathophysiology of DIC
Activation of coagulation pathways:
1) Deposition of fibrin clots in small vessels -> organ damage
2) Consumption of clotting factors, Plts -> bleeding
91
A 78 year old man with urosepsis is in ICU due to DIC. What do you expect to see on the clotting screen?
- Prolonged APTT
- Prolonged PT
- Low Plts
- Low fibrinogen
- High FDPs
- +/- haemolytic anaemia
92
Why is liver disease associated with increased bleeding?
Decreased synthesis of clotting factors: 2, 7, 9, 10, 11, fibrinogen
93
What is the therapeutic window for warfarin? How is warfarin OD managed?
Around 2.0-3.0
| -Depending on the INR and bleeding, may hold next dose/give PO Vit K/give Vit K infusion/give FFP or PCC
94
How is heparin OD managed? What are the complications of heparin use?
Protamine
| Bleeding, heparin induced thrombocytopenia, osteoporosis
95
Name some ways in which cancer can cause anaemia
- Chronic blood loss-> Fe deficiency (colon)
- Anaemia of chronic disease
- Haemolytic anaemia (thru immune + non-immune)
- Infiltration of bone marrow
96
What is leucoerythroblastic anaemia?
Red and white cell precursor anaemia. Occurs due to bone marrow infiltration eg. mets, lymphoma, myelofibrosis.
Findings include: teardrop RBCs, nucleated RBCs, immature myeloid cells
97
What do nucleated RBCs indicate?
Bone marrow stress - eg. infiltration by malignancy, myelofibrosis
98
What do spherocytes in the blood film indicate?
Hereditary spherocytosis, autoimmune haemolytic anaemia
99
Define polycythaemia. Name some causes
Polycythaemia: increase in Hb and haematocrit
Relative: due to decreased plasma eg alcohol, obesity
1˚: polycythaemia rubra vera (increased JAK2)
2˚: high altitude, chronic hypoxia, renal cancer
100
What are immature white cells in the blood film called? What do they suggest?
Blasts eg. myeloblasts, lymphoblasts.
| Bone marrow problem eg leukemia
101
Name some causes of neutrophilia. What do you look for on a film?
Neutrophilia: infection (bacterial), inflammation, leukemia, steroids
Film can show if they are reactive (eg. toxic granulation) in infection/inflammation or malignant (eg. presence of blasts)
102
What can cause eosinophilia?
Parasitic infection, allergic disease, malignancy (Hodgkins)
103
What are some causes of lymphocytosis and lymphopenia? How do you interpret a lymphocytosis?
Lymphocytosis: viral infection (EBV), malignancy (CLL)
-Reactive will have polyclonal expansion, malignant will have monoclonal
-Film: atypical lymphocytes in infection eg. mono, smear cells in CLL, immature in ALL
Lymphopenia: HIV, autoimmune disease
104
What is immunophenotyping used for?
Determining the stages of maturation
| Determining clonality eg. light chain restriction
105
Describe the clinical features of acute leukemias. What are the distinguishing features?
Rapidly worsening
- Anaemia: fatigue, pallor, SOB, dizziness
- Thrombocytopenia: petechiae, bruising, mucosal bleeding
- Neutropenia: infections
- Weight loss, fever, night sweats, hepatosplenomegaly
Specific to AML: gum hypertrophy, skin infiltration, hyperviscosity and retinal haemorrhages
Specific to ALL: lymphadenopathy, CNS involvement, testicular and thymic enlargement
106
Which groups are primarily affected by acute leukemias? What are some risk factors?
ALL: children. Down's.
AML: older adults + infants. RFs: radiation, chemo, smoking, trisomy
107
Describe the pathogenesis of AML
Genetic changes: duplications esp Chr 8 and 21, t15;17 translocation to form the APML gene, deletion of 5/5q or 7/7q, changes to core binding factor (CBF) action
-> inability to mature -> proliferation of immature myeloblasts
108
What is APML?
Acute promyelocytic leukemia. A form of AML caused by the formation of a fusion gene at t15;17 -> PML-RARA
-Characteristically causes haemorrhage and DIC
109
What is the classic finding on blood film in AML?
Auer rods
110
What investigations are used for diagnosing AML and ALL? What will they show? What is the importance of each?
- FBC: low Hb, low Plt, high WCC (suggests malignancy)
- Film: blasts, Auer rods (diagnostic of leukemia)
- Cytochemistry: for AML- myeloperoxidase, Sudan black
- Immunophenotyping: MPO, different CDs (diagnostic for type: AML, B-ALL, T-ALL)
- Cytogenetics: very important. (aids in treatment decision-making)
111
Describe the treatment of acute leukemias
Chemotherapy is mainstay. 6 mos AML, 2 yrs F/3 yr M in ALL
1) Induce remission -> 2) consolidation -> 3) maintenance
+ Intrathecal chemo in ALL
Also important to give allopurinol, antibiotics, etc
Last line: BMT
112
Describe the pathogenesis of ALL
Genetic changes in the B/T cell lineages: translocations, duplications etc. Usually first hit happens in utero
-> oncogene dysregulation and proliferation of blasts
113
What percentage of blasts in peripheral blood is normal? What level is too high?
Normal is <5%
5-19% suggests myelodysplasia
>20% suggests AML
114
What type of mutations typically leads to cell proliferation in haem malignancies?
Tyrosine kinase mutations -> increased mature cells
115
What is a myeloproliferative disorder? What does this include? What are the common mutations associated with these?
Increase in myeloid cells with normal differentiation. Includes PV, CML, essential thrombocytopenia, PMF
Common mutations: JAK2, philadelphia chr (9:22), calreticulin
116
What are some signs and symptoms of PV, management
- Hyperviscosity: thrombosis, plethoric, retinal haemorrhage, blurred vision, headache,
- Splenomegaly
- Aquagenic pruritus
- Erythromelalgia
Mx:
- Aspirin
- Venesection (remove RBCs)
- Hydroxycarbamide
117
What is primary myelofibrosis? What are the signs/symptoms? How is it diagnosed? What is the prognosis?
A type of MPD, caused by replacement of BM with collagen (reactive fibrosis) and extramedullary haematopoeisis.
-Anaemia, thrombocytopenia
-Massive splenomegaly + hepatomegaly (EMHP)
-Hypermetabolic state
Dx: clinical, BM biopsy is key (dry tap)
Very poor prognosis
118
What are the haem findings in PV, PMF, ET?
- PV: high Hb/Hct/RCV, high Plt
- PMF: low Hb, low Plt (leucoerythroblastic anaemia). Tear drop RBCs, nucleated RBCs, circulating megakaryocytes
- ET: very high Plts
119
What is essential thrombocytosis? How does it present?
Increase in platelets (abnormal functioning)
- Can have either increased thrombus formation OR bleeding
- Erythromelalgia
- Splenomegaly, headache, dizziness, blurred vision
120
What is the classic genetic mutation in CML? What is the presentation?
```
Philadelphia chromosome (9:22 translocation, formation of the fusion protein BCR-ABL, abnormally active tyrosine kinase) detected with FISH/PCR
Hypermetabolism, MASSIVE hepatosplenomegaly, bleeding/bruising
```
121
Describe the haem findings in CML
- N/High Hb, Plts
- Massively high WCC (neutrophils, basophils)
- Ph +ve on FISH
122
What is the course of CML? What is the treatment?
1. Chronic phase: asymptomatic, slow increase in WCC. Increased proliferation but normal differentiation
2. Accelerated phase: increase in WCC + symptoms
3. Blast phase: increase in blasts, becomes like AML with hypermetabolic symptoms
- During the chronic phase, can use Imatinib/newer
123
What is lymphoma? Describe the classification
Lymphoma is a malignant tumour of lymphoid cells. Can occur in the lymph nodes, spleen, skin, gut- any organ with lymphoid tissue.
Many types!!!
-Hodgkins (20%)
-Non-Hodgkins (80%): B cell, T cell
124
How does the physiology of lymphocyte production create the environment for lymphoma?
- Recombination means genetic instability: VDJ recom, class switching, somatic hypermutation contribute
- Reliance on apoptosis to regulate -> if mutated, prolif
- Rapid proliferation -> increased error
125
What are some risk factors for lymphoma?
- Constant antigen stimulation eg. inflammation -> H pylori and gastric MALT, coeliac and EATL
- Infection: HTLV1 and ATLL, EBV
- Loss of T cell function: HIV (fails to stop EBV lymphomas eg Burkitts, Hodgkins)
126
Describe the anatomy of the lymph nodes
B cell follicles surrounded by T cell zones
Centre is the medulla where B cells end up
Within the B cell follicles: mantle zone -> germinal centre where the naive cells undergo maturation when meeting presented Ag
127
Name the common CD markers that differentiate lymphocytes
CD20: B cells, not plasma B cells (differentiated)
CD19: B cells
CD10: germinal centre B cells
CD 3, 4, 5: T cells
128
Describe the different investigations used in diagnosis of lymphoma
- Cytology and histology: eg follicular, diffuse
- Immunophenotyping: clonality, CD markers, etc
- Molecular tools: FISH/PCR for chromosomal translocations etc
129
Name some types of NH B cell lymphoma and briefly describe
- Follicular: lymphadenopathy in older adults. Low grade, 14;18 translocation of bcl-2 gene. Germinal centre.
- Marginal zone/MALT: post-GC memory B cells. Usually extranodal eg. GI, thyroid. Chronic Ag stimulation. May reverse with removal of stimulus in early stage
- Diffuse large B cell: sheets of large cells, destroy node structure. Aggressive.
- Burkitts: presents as jaw/abdo mass, rapidly growing. Assoc w/ EBV, HIV. c-myc oncogene. Starry sky appearance. Germinal centre cells.
- Mantle cell: pre-GC cells. CD5 and cyclin D1. 11;14 translocation. Aggressive.
130
Name some types of NH T cell lymphoma and briefly describe
- Anaplastic large cell: young. Large cells. Alk-1 protein.
- Adult T cell leukemia/lymphoma (ATLL): HTLV1 infection. Caribbean and Japan.
- EATL: assoc w/ coeliac
131
What are the main differences between Hodgkins and non-Hodgkins lymphoma?
Hodgkins: spreads contiguously to nearby nodes, more localised, germinal/post-germinal B cells only
132
What are the types of Hodgkins lymphoma? Briefly describe
Classical- nodular sclerosing/lymphocyte rich or depleted/mixed: single nodal group. Young + middle aged. Large cells w/ pink nucleoli- owl's eyes, Reed Sternberg cells, eosinophils. CD30+ 15+ 20-.
Non-classical/lymphocyte predominant: B cell rich nodules, no eosinophils, CD 30/15 -ve, CD 20+ve.
133
How does Hodgkins lymphoma present? How is it staged?
Presents with painless enlarging LNs +/- obstructive symptoms, B symptoms
Staged with Ann Arbor staging:
1: 1 group of nodes affected (spleen counts)
2: multiple groups affected, same side of diaphragm
3: multiple groups affected, two sides of diaphragm
4: other sites eg. liver, BM
A/B: if B symptoms present eg. fever >38, night sweats, weight loss (>10% in <6 mos).
134
Describe the management of Hodgkins lymphoma. What is the prognosis?
Intensive chemotherapy ABVD: adriamycin, bleomycin, vinblastine, dacarbazine
+/- radiotherapy: if bulky area
Stem cell transplant
Prognosis is very good!! Treatment is balance of risk of recurrence and risk of chemo-related complications (2˚ malignancy, etc)
135
How are lymphomas staged/graded?
- Biopsy: cytology, histology, immunophenotyping, cytogenetics, molecular genetics
- Imaging: PET-CT, MRI
- Bloods: kidney function, LDH, BBVs, albumin
136
What is the standard treatment for NHL? What is the prognosis?
```
For DLBC: chemotherapy with R-CHOP
-Rituximab
-Cyclophosphamide
-Doxorubicin
-Vincristine
-Prednisolone
For indolent eg. follicular: watch and wait
The higher the grade (based on histological subtype), the better the outcome eg. DLBCL better, follicular worse
```
137
Which group is CLL commonly found? What are the signs/symptoms?
Old white people. Most common leukemia in West
- Usually asymp/picked up on routine testing
- Anaemia, thrombocytopenia, neutropenia
- Smear cells on blood film
138
Which cells are affected in CLL? What are the CD markers?
- Mature B cells
| - Express CD-19 (normal for B cells) but also abnormally express CD 5 (normal for T cells)
139
What is Richter transformation?
Transformation of CLL into a high grade leukemia (ALL) or aggressive large cell lymphoma
140
What is the treatment for CLL?
Usually watch and wait due to indolent course
| Can use new agents eg Ibrutinib (BCR kinase inhibitor), Venetoclax or CAR-T cell therapy
141
What is multiple myeloma? Describe the pathophysiology and precursor syndrome. Which type is most common?
Malignancy of plasma cells. Lead to proliferation of monoclonal B cells that produce immunoglobulins (paraproteins). IgG most common
-Preceded by monoclonal gammopathy of uncertain significance (MGUS)
142
Describe the clinical features of multiple myeloma
Signs/symptoms due to BM infiltration and Ig secretion
Calcium high (>2.75)
Renal failure: raised Cr (>177) or GFR (<40)
Anaemia (<100)
Bone pain, osteoporosis
-Infections due to low range of Igs
-Monoclonal paraprotein, Bence Jones proteins in urine
-High ESR
143
What CD markers are found on myeloma plasma cells?
CD 138, CD 38, CD 56. NO CD 19/20
144
Describe the diagnostic tests for multiple myeloma
- FBC and film: low Hb, lots of plasma cells, rouleaux
- U+Es: renal failure
- Bone profile: high Ca
- BM biopsy: high blasts (>10%), Immunohistochemistry
- Serum protein electrophoresis: monoclonal gammopathy, high M spike (>30g/l). IgG/A
- 24 hr urine collection/urine protein electrophoresis: Bence Jones proteins
145
What is Waldenstrom's macroglobinaemia?
A type of low grade NHL, producing monoclonal IgM. Similar to MM
146
Describe the management of multiple myeloma
- Symptomatic: bisphosphonates
1. Chemo: melphalan, cyclophosphamide
2. Steroids: dex/pred
3. Proteasome inhibitors: Bortezumib
4. Immunomodulatory drugs: Lenalidomide, thalidomide
- Stem cell transplant
147
What are myelodysplastic syndromes? How do they present?
A group of disorders of myeloid stem cells characterised by ineffective proliferation and differentiation
-Present with signs of pancytopenia in the elderly with defective cells (on film/BM biopsy)
148
Name some different types of MDS
-Refractory anaemia (RA): anaemia no blasts.
-Refractory anaemia with ringed sideroblasts (RARS):
-Refractory cytopenia with multilineage dysplasia (RCMD): cytopenia, dysplasia in BM
-RCMD + RS:
etc etc
149
Name some cells/findings in blood film and BM biopsy in MDS
- Hypercellular and dysplastic BM with peripheral cytopenias
- Ringed sideroblasts
- Hypogranulated white cells, bilobed neutrophils (Pelger-Huet)
- Small platelets
- <20% blasts
150
Describe the treatment of MDS
- Supportive: eg transfusions, antibiotics/vaccines
- Modifiers: azacytidine, lenalidomide
- Chemo
- Stem cell transplant
151
Name some causes of BM failure
1˚: Fanconi anaemia, Diamond-Blackfan anaemia, Kostmanns
| 2˚: mets, haem malignancy, drugs, radiation, autoimmune, infection
152
What is aplastic anaemia? What are some causes?
AA is the inability of BM to produce blood cells. Usually refers to RBCs but can be all cells
- Idiopathic (80%)
- Inherited: Fanconi (all cells), dyskeratosis congenita
- Infection: parvovirus
- Infiltration (all cells)
153
How is aplastic anaemia assessed?
Camitta criteria
154
Describe the differences between aplastic anaemia, MDS, and MPD.
- AA: hypocellular BM and cytopenias
- MDS: hypercellular BM and cytopenias, blasts in BM
- MPD: fibrotic/hypercellular BM, cythaemias
155
What type of reaction occurs if someone is transfused with the wrong blood group (ABO)? What about the wrong blood group (Rh)?
- ABO incompatibility: immediate massive intravascular haemolysis (IgM mediated)
- Rh incompatibility: delayed haemolytic transfusion reaction (IgG mediated)
156
What are some RBC antigens that can cause transfusion reactions?
- ABO
- Rh C, D, E
- Duffy
- Kell
- Kidd
157
What is a group and screen and how is it done?
Checks for reaction between patient plasma and donor RBCs. Detects significant ABs in patient plasma
-Isolate recipient plasma, add donor blood -> add Coombs antibodies -> reaction occurs if Coombs ABs cause linking of the RBCs -> clumping
158
What is a full crossmatch and how is it done? When is it needed?
- Incubate recipient plasma with donor RBCs for 30-40 mins
- Or can be electronic CM system without testing. But needs a valid G&S
- If there are antibodies found on G&S, ALWAYS do a crossmatch
159
When is a RBC transfusion reasonable? Platelets? FFP?
- RBC: If symptomatic <80 or asymp <70
- Plts: <10 or <20 in sepsis. <50 before surgery. In DIC only if actively bleeding
- FFP: if patient bleeding/before surgery, severe liver disease
160
How are RBCs stored and how should they be used? Platelets? FFP? Which need to be crossmatched?
-RBCs: 4˚ for 35 days. Use within 4 hours. Transfuse over 2-3 hours.
-Plts: 22˚ for 7 days. Transfuse over 20-30 mins
-FFP: transfuse over 20-30 mins.
RBCs and plasma must be crossmatched (recipient plasma may interact) eg. give O blood or AB plasma to anyone. Platelets should be D compatible.
161
What blood should be given to immunosuppressed patients?
Irradiated (gets rid of donor lymphocytes)
162
Name some immediate transfusion reactions
- Acute haemolytic reaction: ABO incompatibility, IgM mediated
- Febrile non-haemolytic: cytokine release
- Allergy: anaphylaxis, itching
- Bacterial contamination: esp platelet transfusion
- Circulatory overload (TACO)
- Acute lung injury (TRALI)
163
How does ABO incompatibility present? How should it be managed?
- Immediate (mins-hours)
- Chest pain, fever, vomiting, flushing, collapse
- STOP transfusion. Check blood products. Do blood tests: FBC, U+Es, LFTs, CM, DAT
164
How does febrile non-haemolytic transfusion reaction present? How should it be managed?
- During/soon after transfusion
- Increase in temp <1, chills, rigors
- Stop or slow transfusion
- Paracetamol
165
How does transfusion related allergy present? How should it be managed?
- Itching, wheezing +/- anaphylaxis (BP, HR)
- Stop/slow infusion
- Give antihistamines or IM adrenaline etc
166
How does bacterial contamination of blood products present?
Very similarly to ABO incompability. But more common with platelets (ABO rare).
167
How does transfusion associated circulatory overload present? How is it managed?
- Presents within 6 hours
- Pulmonary oedema/fluid overload, heart failure, raised JVP
- Responsive to diuretics
168
How does transfusion related acute lung injury present? How is it managed?
- Similar to TACO but less common. Due to anti-WBC antibodies in donor blood
- eg SOB, low sats, increased HR
- NO response to diuretics
169
Name some types of delayed transfusion reactions.
- Delayed haemolytic transfusion reaction: extravascular haemolysis-IgG mediated. Due to other ABs eg. Kell Usually occurs in patients with multiple transfusions
- Infections: HIV, HCV (rare). CMV, parvovirus.
- Transfusion associated graft-vs-host disease: fatal but rare. Lymphocytes in donor blood evade host defence and destroy host tissues. If immunosuppressed.
- Iron overload: if lots of tranfusions. Chelators.
170
Describe the process of bone marrow transplantation
- Remove bone marrow cells -> isolate CD 34+ve (stem cells) -> freeze
- Eradicate BM with chemo
- Reinfuse stem cells -> find way to BM and multiply
171
Name some indications for BM transplant
- Haem malignancy eg. MM, leukemia
| - Haemoglobinopathy eg. SCA, B thal major
172
What are the different types of BM transplant?
Autologous: patient-patient
Allogeneic: donor-patient
173
How are BM transplant donors identified?
HLA matching. Best are siblings/parents
174
Name some complications of BM transplantation
- Infection
- Graft failure
- Graft vs host disease: donor lymphocytes attack patient causing multiorgan system damage -> give immunosuppression.
- Relapse
175
What causes basophilic stippling?
Beta-thal trait
Lead poisoning
Alcoholism
Sideroblastic anaemia
176
What causes target cells?
Iron deficiency
Thalassaemia
Hyposplenism
Liver disease
177
Describe the management of sickle cell crises
A to E approach
- Analgesia!! Opioids
- Hydration, warmth
- High flow O2
Septic screen + treat
178
What is subacute combined degeneration of the spinal cord?
Irreversible complication of B12 deficiency (usually pernicious an.)
- Combined symmetrical dorsal column sensory loss + corticospinal loss
- > distal sensory loss (esp proprioception + vibration) + ataxia + UMN/LMN signs
