Haematoogy Flashcards
1
Q
RBC with a purple spot in it
Name
Conditions that cause it
A
Howell-Jolly bodies
- nuclear remnants
1) Post splenectomy
2) Hyposplenism
(E.g. sickle cell disease, coeliac, IBD, myeloproliferative, amyloid)
3) Megaloblastic anaemia
2
Q
Anaemia cut off men and women
A
<135g/L men
<115g/L women
3
Q
Anaemia causes
A
Reduced production
Increased loss of RBC (haemolytic anaemia)
Increased plasma volume (pregnancy)
4
Q
Signs of anaemia
A
Pallor
If <80 - tachycardia, flow murmurs —> HF
5
Q
Anaemia associated with cancer/systemic disease
A
Fe deficiency
Anaemia of inflammation
Leucoerythroblastic anaemia
Haemolytic anaemia
NB: renal cell cancer and liver cancer can cause secondary polycythaemia
6
Q
Causes of iron deficiency anaemia
A
Blood loss until proven otherwise
- GI - ulcers, gastritis, polyps, colorectal cancer
- Menorrhagia
- Hookworm
- increased utilisation - pregnancy/lactation/children
- Decreased intake (premature, child)
- Decreased absorption (coeliac, post gastric surg
- Intravascular haemolysis (Microangiopathic, haemolytic anaemia, PNH)
7
Q
Teardrop RBCs, nucleated RBCs, immature myeloid cells
Condition
Causes
A
Leuco-erythroblastic anaemia
- red and white cell precursor anaemia
Malignancies
Infection
Myelofibrosis
8
Q
Causes of hereditary anaemia
A
1) Membrane defects
- Hereditary spherocytosis
2) Red cell metabolism
- G6PD deficiency
3) Hb
- Thalassaemias
- Sickle cell disease
9
Q
Consequences of haemolytic anaemias
A
Normocytic Anaemia (+/-) Increased reticulocytes/erythroid hyperplasia
Increased folate demand
Susceptibility to parvovirus B19
Gallstones
Risk of iron overload and osteoporosis in chronic haemolytic anaemias
10
Q
Bone marrow film showing erythroid progenitors, all look the same.
Low reticulocytes in blood
A
Parvovirus B19
11
Q
What is Gilbert syndrome
Genotype
A
Bilirubin conjugation impaired = High uncojugated billirubin
Autosomal recessive
UGT 1A1 TA7/TA7 genotype
12
Q
Clinical features of haemolytic anaemia
A
Pallor Jaundice Splenomegaly (if spleen destroying RBCs) Pigmenturia FH
13
Q
Anaemia
Increased reticulocytes
Polychromasia
A
Haemolytic anaemia
14
Q
Specific lab changes in intravascular haemolytic anaemia
A
All:
Reticulocytes, polychromasia
Intravascular: Hyperbillibrubinaemia LDH high Absent haptoglobins Haemoglobinuria Haemosiderinuria (brown urine)
15
Q
Inheritance of hereditary spherocytosis
type of haemolysis
Blood film
A
AD in 75%
De novo/AR mutations in 25%
Extravascular - splenomegaly
Blood film showing RBC lacking central pallor, small and round, Mean cell Hb increased, polychromatic cells
16
Q
Osmotic fragility test used for
More up to date test for this condition
A
Hereditary spherocytosis
Eosin 5 malamide (EMA) Die binding test - reduced binding
17
Q
Blood film showing RBC lacking central pallor, small and round, Mean cell Hb increased, polychromatic cells
What test can be done to confirm condition
A
Hereditary spherocytosis
Osmotic fragility test
Die binding test - reduced binding
18
Q
G6PD deficiency inheritance
G6PD function
A
X-linked - severe disease in hemizygous boys and homozygous girls
G6PD catalyses 1st step in pentose phosphate pathway - generates NADPH to maintain glutathione - needed to protect RBC against oxidative stress
19
Q
Acute episodic haemolysis
Methyviolet stain of blood shows - heinz bodies - what are these
A
G6PD deficiency
Peripheral inclusions formed of denatured Hb - characteristic of oxidative haemolysis
20
Q
Blood film in G6PD deficiency
Other test
What stain and what does it show
A
Contracted cells
Nucleated RBcs
Bite cells
Hemighosts
Enzyme assay 2-3 months after crisis
Methyviolet - Heinz bodies
21
Q
Agents that provoke haemolysis in G6PD deficiency
A
Antimalarials - primaquine Antibiotics - Sulphonamides, Ciprofloxacin, Nitrofurantoin Dapsone, Vit K, Fava beans Moth balls
22
Q
Blood film showing RBC with spiky projections
- what are these called
- In what condition do they occur
- symptoms of this condition
A
Echinocytes
Pyruvate kinase deficiency - autosomal recessive
Haemolytic anaemia. Hereditary enzyme defect
Severe neonatal jaundice, splenomegaly, haemolytic anaemia
23
Q
Blood film shows basophilic stippling -
What is it
Causes
A
Accelerated erythropoeisis or defective Hb synthesis, small dots in the periphery are seen
Lead poisoning Megaloblastic anaemia Myelodysplasia Liver disease Haemoglobinopathy e.g. thalassaemia
24
Q
Principles of management for haemolytic anaemias
A
Folic acid supplementation
Avoid precipitating factors
RBC transfusion/exchange
Immune against hepA/B
Monitor for gall stones, iron overload, osteoporiss
Cholestectomy for symptomatic gall stones
Splenectomy if indicated
25
What is Virchow's triad
Blood
Flow
Vessel wall
26
Factors in blood that predispose to thrombosis
1) High platelets
2) Coagulation system (triggered by TF, generates thrombin, thrombin converts fibrinogen to fibrin aka the clot)
3) Viscosity (haematocrit, protein/paraprotein)
27
Physiological anti-coagulant
TFPI
- neutralises TF and VIIa complex
Protein C and S
- Thrombin activates TM
- TM opens receptor to bind + activate protein C
- In presence of protein S, APC inactivates FV and FVIII
Antithrombin
- Binds thrombin 1:1 and stops it's generation
(NB: heparin acts by augmenting antithrombin effect)
28
Vessel wall - normal state with regards to thrombosis
Anti-thrombotic
- Expresses anticoagulant molecules (Thrombomodulin, Protein C receptor, TF pathway inhibitor, Heparens)
- Doens't express TF
- Secretes antiplatelet factors (Prostacyclin, NO)
29
Vessel wall pro-thrombotic state
Due to injury/inflammation
- Anticoagulant molecules downregulated
- Adhesion molecules upregulated
- TF expression
- Prostacyclin production decreased
30
Blood flow promoting thrombosis
Stasis
- Accumulation of activated factors
- Promotes platelet adhesion
- Promotes leukocyte adhesion and transmigratuon
31
Causes of blood stasis that may promote thrombosis
- Surgery, travel, paraparesis
- Tumour, pregnancy
- Polycthaemia, paraprotein
- Vascular abnormalities
32
Dose of anticoagulant therapy principles
High dose - therapeutic
| Low dose - prophylaxis
33
Immediate acting anticoagluants
- Heparin(IV,SC) - unfractionated or LMWH
Promotes antithrombin III which inactivates thrombin and factors 9, 10, 11
- Direct acting (oral) - anti-Xa (rivaroxiban) and anti-IIa
34
Delayed acting anticoagulants
Vit K antagonists - Warfarin
35
Heparin use
Positives
Negatives
Antidote
Immediate anticoagulant - potentiates anti-thrombin
+ve: Immediate use and easy administration
-ve: Not long term because injections and risk of osteoporosis, bleeding and heparin induced thrombocytopenia (HIT) --> osteoporosis
Use LMWH over unfractionated because needs monitoring
Antidote: Protamine sulphate
36
Rivaroxiban use
Anti-Xa direct acting anticoagulant
+ve: Fast on and off effect, oral, useful in long term, short half life, no monitoring
37
Warfarin use
| Factors affects
Vit K antagonist - delayed anticoagulant - Factor II, VII, IX and X fall but so do protein C and S, Z
-ve: delayed - a week before stable, NEEDs monitoring with INR, interaction with other drugs, teratogenic
+ve: reversed with vitamin K
38
Warfarin monitoring
INR - derived from prothrombin time
39
Reversal of heparin
Protamine
40
ThromboProphylaxis for patients art risk
```
Options
LMWH e.g. tinzaparin low dose
Rivaroxiban
TED stockings (ONLY IF surgery of if heparin CI)
Intermittent compression (to increase flow)
```
41
Treatment of DVT/PE
Options
1) LMWH (tinzaparin 175) + warfarin
- stop LMWH once INR >2 for 2 days
- Continue for 3-6 months
2) Start DOAC and continue for 3-6 months
If cancer pt, continue LMWH not warfarin
42
Risk of recurrence of thrombosis
```
High risk - idiopathic VTE
- consider long term anticoagulation
Low risk - surgery
- No need for long term
Minor precipitants - COCP, flights, trauma
- 3 months usually adequate
```
43
Classification of Fe deficiency anaemia causes
Blood loss - main
Increased use - pregnancy/lactation, children
Decreased intake - premature, children, elderly
Decreased absorption - coeliac, post gastric surgery
Intravascular haemolysis - MAHA, haemolytic anaemia, PNH
44
Sickle cell disease define
Inheritance
Pathological effects of sickling
Autosomal recessive
Single base mutation GAG -GTG Glut-Val at codon 6 on beta chain
45
Sickle cell disease key features
```
Anaemia 60-80g/
Splenomegaly
Folate deficiency
Gall stones
Aplastic crisis (parvovirus B19)
```
46
Vado-occlusive and infarction symptoms of sickle cell disease
```
Stroke
Infections (hyposplenism, CKD)
Crises (splenic, sequestration, chest and pain)
Kidney
Liver (gall stones)
Eyes (retinopathy)
Dactylitis
Mesenteric ischaemia
Priapism
```
47
Acute sickle cell treatment
Opioid analgesia for painful crises
| Exchange transfusion in severe crises
48
Chronic tx for sickle cell anaemia
All should be on penicillin, pneumococcal vax, HIB vac
Some benefit from
Folic acid and hydroxycarbamide
Regular exchange transfusions
Doppler monitoring in early childhood for prophylactic exchange if turbulent flow
49
4-6months old severe anaemia, failure to thrive, hepatosplenomegaly, bony deformity, severe anaemia, heart failure
Diagnosis and treatment
Dx by Hb electrophoresis (Guthrie test at birth)
Beta thalassaemia major (B0/B0)
Blood transfusions with desferrioxamine to stop iron loading plus folic acid
50
Morning haemoglobunuria, thrombosis
Test to do
Ham’s test or immuno phenotype shows altered GPI on RBC - complement mediated lysis - Intravascular haemolysis
= Paroxysmal nocturnal haemoglobinuria
NON IMMUNE
51
1st line investigations in a haemolytic anaemia picture
```
DAT (for autoimmune haemolysis)
Urinary haemosiderin/Hb
Osmotic fragility/dye binding test
G6PD +/- PK activity
Hb separation A and F %
Heinz body stain
Hams test/FACs of GPI linked proteins
Thick and think blood film
```
52
Malaria associated with haemolytic anaemia
Plasmodium falciparum
53
Neutrophilia causes
```
Corticosteroids
Underlying neoplasia
Tissue inflamation e.g. colitis, pancreatitis
Myeloproliferative/leukaemic disorders
Infection (most common)
```
54
True polycythaemia causes
= Raised red cell mass
1) Secondary
- Appropriate - high altitude, hypoxic lung disease, cyanotic heart disease
- Inappropriate - HCC, Renal cancer, bronchial cancer
2) PV
- Clonal myeloproliferative disorder (acquired mutation in JAK2 V617F)
55
Types of WBC
Mature:
Phagocytes: Granulocytes (neut, eos, baso), monocytes
Immunocytes: T lymphocytes, B lymphocytes, NK cells
Immature:
Blasts, promyelocytes, myelocytes
56
Investigating a high WBC count
Hb and MCV: Are RBC and platelets abnormal too
WBC and automated differential: 1 lineage only raised = BM healthy
Blood film: Morphology, how mature cells in PB are
(If grossly immature cells in blood - AML
57
Causes of eosinophilia
Reactive
- Parasitic
- Allergic (asthma, rheumatoid etc.)
- Underlying neoplasm esp Hodgkin, T-cell NHL
- Drugs (reaction erythema multiforme)
Chronic eosinophilic leukaemia
58
Monocytosis causes
TB, brucella, typhoid
Viral: CMV, VZV
Sarcoidosis
Chronic myelomonocytic leukaemia (MDS)
59
What are myelodysplastic syndromes (MDS)
Heterogeneous group of acquired haemopoietic stem cell disorders
- -> clone of marrow stem cells with abnormal maturation = numeric and functional reduction in blood cells =
1) Cytopenia(s)
2) Qualitative (functional) abnormalities of erythyroid, myeloid and megakaryocyte maturation
3) Increased transformation to leukaemia (chance depend on type of MDS)
60
MDS epidemiology
Blood and BM morphological features
Elderly usually
Develops over weeks + months
Signs and symptoms of general marrow failure
Pegler Huet anomaly - bilobed neutrophils
Dygranulopoeisis
Dyseryrthropoiesis of RBC
Micro-megakaryocytes
Increased proportion of blast cells in BM
61
MDS classification
Dependent on proportion of blast cells in BM
- 5-9% = refractory anaemia with excess blasts 1
- 10-19% = refractory anaemia with blasts 2
Generally, the greater the BM blasts, more likely to get a cytogenic abnormality
- exception is 5q syndrome - by definition is a cytogenic abnormality
nb: AML = BM >/= 20% blast cells
62
Evolution of MDS
Treatment
1) Deterioration of blood counts
2) AML development
3) As a rule of thumb: 1/3 die from infection, 1/3 die from bleeding, 1/3 die from acute leukaemia
```
Only 2 tx to prolong survival
1) Allogenic stem cell transplant
2) Intensive chemotherapy
But only a minority of MDS benefit from them. Give:
- Supportive care
- Biological modifiers
- Oral chemo
- Low dose chemo
- Intensive chemo/SCT (for high risk MDS) - AML type regimens
```
63
Bone marrow failure
Causes
Damage or suppression of stem or progenitor cell
1) Primary BM failure
- Congenital: Fanconi anaemia (multipotent stem cell)
- Diamond-Blackfan anaemia (red cell progenitor)
- Kostmann's syndrome (neutrophil progenitors)
- Acquired: Idiopathic aplastic anaeia (multipotent stem cell)
2) Secondary BM failure - far more common, due to infiltration/damage of BM
- Haematological (leukaemia, lymphoma, myelofibrosis)
- Non haematological (solid tumours)
- Radiation
- Drugs
- Chemicals
- Autoimmune
- Infection (parvovirus, viral hepatitis)
64
Drugs related to BM failure
Predictable (dose dependent) - cytotoxic drugs
Idiosyncratic (not dose dependent) - Phenylbutazone, Gold salts
Antibiotics - Chloramphenicol, sulphonamide
Diuretics - Thiazides
Antithyroid drugs - carbimazole
65
Aplastic anaemia diagnosis
Classification
1) Blood - pancytopenia
2) Marrow - hypocelullar
- Idiopathic - majority (70-80%)
- Inherited: DC, Fanconia anaemia, Schwachman-Diamond syndrome
- Secondary: Radiation, drugs, Viruses, Immune (sle)
```
Also classified as severe aplastic anaemia or non-severe aplastic anaemia
- severe = 2 PB features
1) Reticulocytes <1%
2) Neutrophils <0.5
3) Platelets <20
+ BM <25% cellularity
```
66
Differential diagnosis for pancytopenia and hypocellular BM
1) Hyoplastic MDS/AML
2) Hypocellular ALL
3) Hairy cell leukaemia
4) Mycobacterial
5) Anorexia nervosa
1st thought should be aplastic anaemia but these are differentials
67
Management of BM failure
1. Seek and remove cause
2. Supportive: Blood/platelet transfuson, antibiotics, iron chelation
3. Immunosuppressive therapy (anti-thyomcyte globulin, steroid, cyclosporine)
4. Drugs to promote BM recivery: Oxymethone
5. SCT
6. Other treatments if refractory
68
Treatment of aplastic anaemia
1) Supportive
- Blood products
- Antimicrobials
- Iron chelation when ferritin >1000mcg/l
2) Specific treatment based on age/severity
- Immunosuppressive therapy - ALG, ciclosporin - older pt
- Androgens - oxymethalone
- SCT - younger pt with doner (80% cure), VUD/MUD for >40yrs (50% survival)
69
Complications following immunosuppresive therapy for aplastic anaemia
1. Relapse (35% over 15yrs)
2. Clonal haemotological disorders - MDS, leukaemia
- 20% risk over 10 yrs
3. Solid tumours - 3% risk
70
Fanconi anaemia
Most common inherited aplastic anaemia
X-linked or AR
Abnormalities in DNA repair --> chromosomal fragility
- Short stature
- Hypo pigmented spots and cafe-ai-lait
- Abnormality of thumbs
- Microcephaly/hydrocephaly
- Hypogonadism
- Developmental delay
30% have no abnormalities
Complications: AA (90%) , Leukaemia (10%) , Liver disease, MDS (32%), Cancer (5%)
71
Dyskeratosis congenita
```
Genetic basis - telomere shortening - can be x-linked, AR or AD
Inherited disorder characterised by:
- Marrow failure
- Cancer predisposition
- Somatic abnormalities
```
Classic triad of: Skin pigmentation, leukoplakia, nail dystrophy
Somatic abnormaliyies/complications: Skin pigmentation (89%), Nail dystrophy (88%), BM failure (85.5%), Leucoplacia (78%)
72
AML chromosomal abnormalities
```
t(15;17) - acute promyelocytic leukaemia
t(5;8)
t(8;21)
Trisomy 8, trisomy 21
Inv(17)
Deletion (5/5q or 7/7q)
```
Remember there are also molecular abnormalities - look for using PCR
73
Myeloblast appearance on blood film
AML causes
V fine granules
Cytoplasm
```
Unknown = 90%
Familial, Down's
Irradiation
Anti-cancer drugs
Cigarrete smoking
```
74
Leukamogenesis in AML
2 genetic hits requires
Type 1: proliferative and survival
Type 2: blocks differentiation
75
Acute promyelocytic leukaemia
T (15;17) - fusion PML, RARA gene. Type 2 abnormality
Block in maturation later than other AML - promyelocytes with lots of Auer rods
DIC - low platelets, low fibrinogen, d dimer +ve = bleeding/haemorrhage
Responds to all-trans retinoic acid
76
T (8;21)
AML - most common karyotypic abnormality in AML
Fusion of RUNX1 (encoding CBFalpha) with RUNX1T1
Relatively good prognosis
- not all blast cells, some maturation
77
AML vs ALL diagnosis
20% BLAST BM cells
Cytology: AML have auer rods
Cytochemistry: AML +ve staining for myeloperoxidase, sudan black, non-specific esterase
Immunophenotyping:
AML
- MPO, CD13, CD33, CD14, CD15, glycophorin
ALL
- Precursor B cell - CD19, CD20, TdT, CD10 +/-ve
- B cell - CD19, CD20, sIg
- T-cell: CD2, CD3, CD4, CD8, TdT
Both AML and ALL have CD-34, CD45, HLA-DR
78
AML clinical features
AML diagnosis
BM failure: Anaemia, thrombocytopenia, neutropenia
Local infiltration: Hepatosplenomagaly, gum infiltration, lymphadenopathy (much less than ALL), Skin or other sites
```
Blood count and film
BM morphology
Immunophenotyping - more so to follow up disease
Cytogenic analysis on BM
Molecular studies (when needed)
```
79
AML treatment
Supportive
- Red cells (in anaemia), platelets (if <10 or bleeding), FFP (if DIC), Antibiotics, Long line, Allopurinol (prevent breakdown of blood products leading to renal failure), fluid and electrolyte balance
Chemo - damages DNA of leukaemic cells as they are continuously dividing and lack cell cycle checkpoint control
- usually combination chemo 4-5 courses ~ 6 months
Consider transplant if poor prognosis
Nb: ATRA for promyelocytic leukaemia
TK inhibitors for rare PH +ve
80
ALL features
PB: anaemia, thrombocytopenia, neutropenia
| BM and other organs - lymphadenopathy (v often), Hepatosplenomegaly, Tests, CNS, kidneys, Bone (pain in long bones)
81
t (9;22) in which conditions and prognosis
ALL and CML
| Poor prognosis but better now because TK inhibitors e.g. imatinib
82
ALL diagnosis
treatment
```
Blood count and film
- Anaemia, Neutropenia, Thrombocytopenia
BM aspirate
- 20% blasts
Immunophenotyping
Cytogenetic/molecular analysis
Blood group, LFTs, urea, Cr, electrolytes, uric acid, coagulation screen
```
Supportive: blood products, antibiotics
Specific: Systemic chemo, CNS directed for all, Molecular targeted tx, transplantation
~2yrs for girls
3 yrs for boys
5 yr disease free survival 80% children
5yr disease free survival 30-40% adults
83
What is lymphoma
Where found
Types
Neoplastic tumour of lymphoid cells
Lymph nodes, BM, blood
Lymphoid organs: spleen or gut associated lymphoid tissue
Skin (often T cell disease)
Rarely anywhere
NHL - 80% - B cell or T cell - precursor or peripheral of each - more widespread at presentation than HL
HL - 20% - classical or lymphocyte predominant. Spreads continuously to adjacent lymph nodes. Often localised to one lymph node
84
3 reasons why lymphoma risk is present
Risk factors
1) Rapid cell proliferation - risk DNA replication error
2) Depend on apoptosis (90% normally die in germinal centre) - apoptosis switched off, acquired DNA mutation in pro-apoptotic genes
3) DNA molecules 1. cut and rejoined plus 2. undergo deliberate mutations for Ig and T cell receptor diversity - Recombination errors and new point mutations
Constant antigenic stimulation
Infection
Loss of T cell function
85
Lymphomas due to chronic antigenic stimulation
Gastric MALT: H.pylori. Mariginal zone NHL of stomach - B cell - tx with omep 20mg, Clarith 500mg, amox 1gm bd
Sjogren syndrome Marginal zone NHL of parotid lymphoma = B cell
Coeliac - small bowel enteropathy associated T-cell NHL
- responds poorly to chemo generally fatal - aim to prevent
Hashimoto's thyroid
86
Lymphomas due to infectious agents
HTLV1 infects T cells by vertical transmission - Japanese and Caribbean - may develop Adult T cell leukaemia lymphoma
EBV infects B lymphocytes . Usually maintained by T cells. But if immumosuppression/loss of normal T cells, increased risk of B cell lymphomas
- HIV
- Iatrogenic (renal, heart, pancreas transplant immunosuppression)
- Post transplant lymphoproliferative disorder
87
Mantle cell lymphoma buzzwords
Pre-greminal centre cell. Mantle zone expands and then spreads thoughout node.
```
11;14
Aberrant CD5 and Cyclin D1 expression = dx
Low grade (slowly progressing)
```
Median survival 3-5yrs
88
Follicular lymphoma buzzwords
Treatment
Prognosis
Lymphadenopathy of middle ages/elderly. Indolent
CD10, bcl6+,
14;18 involving bcl-2 gene
Microscopy: Node effaced by round structures (neoplastic follicles)
Indolent but can transform to high grade lymphoma (composed of large rapidly proliferating cells)
Incurable, median survival 12-15yrs
Wait and watch and treat only if nodes compressing bowel, ureter, vena cava, massive painful nodes
- R-CVP
- Maintenance rituximab delays next progression
89
CLL/Small lymphocytic lymphoma buzzwords
Prognosis
From naive or post-germinal centre memory B cells
CD5 (not on mature B cells normally), CD23 +
Lymphocytosis, smear cells, thrombocytopenia
Microscopy: lymph node has no germinal centre, just sheets of small lymphocytes
Indolent. Median survival ~10-15yrs. Can transform to high grade lymphoma where sheets of large cells would be seen (Richter transformation)
IgH mutated survival ~25yrs
IgH unmutated survival ~8yrs
Do FISH as 17p deletion (p53 deleted) = poor prognosis
90
Burkitt's Lymphoma buzzwords
Jaw of abdo mass childre/young adults
EBV associated
Germinal centre origin
Starry sky appearance
C-myc translocation - removes break on cycle
91
Diffuse large B cell lymphoma buzzwords
Treatment
Lymphadenopathy in middle aged/elderly -
30-40% of NHL
Germinal centre or post-germinal centre B cell
Sheets of large lymphoid cells
Germinal centre phenotype DC10 +ve = good prognosis
p53 +be, high proliferative fraction = poor prognosis
R-CHOP: Rituximab, Cyclophoshamid, Adriamycin, Vincristine, Prednisolone
x 6-8 cycles
Aim is curative ~ 50%
Relapse - Autologous SCT saves 25%
92
T cell lymphomas buzzwords
Eosinophils aggressive
Adult T cell leukaemia/lymphoma - Carribean/Japan, HTLV1 associated
Enteropathy associated T cell lymphoma - Coeliac
Cutaneous T cell lymphomas - e.g. mycosis fungoides
Anaplastic large cell lymphoma - children/young
- ALk-1 protein staining
- 2;5
- Sheets of anaplastic (nuclei wide), large lymphocytes
93
Classical Hodgkin lymphoma buzzwords
Owls eye appearance cells with prominent nuceloli - Reed steinberg cells
CD15 + CD30
CD20 - originate from B cells - germinal/post-germinal centre
EBV associated
Young and middle aged
Types: Nodular sclerosis, Mixed cellularity, lymphocyte rich/delepted
94
Non classical hodgkin lymphoma buzzword
No EBV association
Negative for CD15, CD30, +ve for CD20
Called nodular lymphocyte predominant hodgkin lymphoma
95
Hodgkin lymphoma staging
Treatment
Prognosis
```
Ann Arbour staging
I; one group of nodes
II: >1 group nodes same side diaphragm
III; nodes above and below diaphragm
IV: extra-nodal spread
B if fever, night sweats, unexplained weight loss
```
```
Chemo - preserves fertility. 2-6 cycles
Adriamycin (se cardiomyopathy)
Bleomycin (se pulmonary fibrosis)
Vinblastine
DTIC
```
+/-
Radiotherapy: field only
(risk of breast Ca after 25y, Leukaemia 3% after 10yrs, lung/skin cancer)
PET-CT after 2 cycle ABVD to assess response and guide radiotherapy need at end of chemo
Prognosis ~ 50-90% cure
Stage I or II: 80% cured
IV: Only 50% cured
96
Staging of non-hodgkin lymphoma
As for hodgkin lymphoma - ann arbour staging:
I; one group of nodes
II: >1 group nodes same side diaphragm
III; nodes above and below diaphragm
IV: extra-nodal spread
B if fever, night sweats, unexplained weight loss
Use CT or PET
+ BM biopsy
+ /- LP
```
Prognostic markers
LDH
Performance status
HIV serology
Hep B serology
```
97
CLL treatment principles
Supportive and prophylaxis and tx of infections
Prophylactic aciclovir, immunisation against pneumococcus and seasonal flu, IVIG if hypogammaglobulinemia and recurrent bacterial infection
Autoimmune phenomena
1st line steroids. 2nd line rituximab
Irridaed blood products if risk of TA GVHD
If Richter transformation
R-CHOP
Leukaemia directed treatment
Wait and watch. Don't tx stage A
Tx only if:
- progressive lymphcytois >50% increase in 2 months or doubles in <6months
- progressive BM failure: Plt <100, Hb <100, neutrophils <1
- progressve lymphadenopathy/splenoegaly
- systemic symptoms
```
1st line (Tpp53 intact)
Chemo immunotherapy
```
Tp53/17p deleted CLL/ refractory disease
- Imbrutinib (Bruton tyrosine kinase inhibitor)
- Venetoclax (anti Bcl-2 oral agent)
98
Multiple myeloma key features
```
Monoclonal plasma cells - have expanded ER and golgi
- nucleus pushed to 1 side
Paraprotein
Anaemia
End stage renal failure
Infection
Osteolytic lesions
```
Normal PC suffers chromosome incident --> incorrect translocation of genetic material --> limited acccumulation of some monoclonal PCs = MGUS (harmless)
1% with MGUS pick up more mutations (e.g KRAS) --> MM
99
Multiple myeloma diagnosis
MGUS characteristics
Calcium elevated
Renal impairment
Anaemia
Bone lesions
+ monoclonal protein (on serum electrophoresis)
X-ray of spine if back pain
Lab tests (Ca, renal impairment, anaemia)
Immunophenotype: CD138, CD38, monotypic cytoplasmic Ig.
- ve CD19, CD20 and sIg
BM: 40-90% plasma cells (all either kappa or lambda +)
MGUS
1. monoclonal serum protein <30g/l
2. BM plasma cells <10%
3. Annual risk of progression to MM ~1-2%
4. Rare in young
100
Multiple myeloma treatment approaches
Steroids
Immunomodulatory drugs
Classic chemo agents - mephalan, cyclophosphamide
Proteasome inhibitors - bortezomib; carfilxomib
101
RBC transfusion indications
Aim of transfusion
Special requirements for RBC transfusion
1) Major blood loss >30% volume
2) Perio-op/critical care if Hb <70/80g/L
3) Post chemo or ACS threshold is Hb <80g/L
4) Symptomatic anaemia
Aim for Hb 70-90g/L
Unless CVS and then aim for 100g/L
Transfuse only 1 unit at a time
Ensure fe/folate/b12 deficiency treated first
- CMV negative blood for intra-uterine and neonatal transfusions
- Irradiated blood for immunosuppressed
- Washed if concern of severe allergic reaction
102
FFP transfusion indication
1) Massve transfusion if blood los >150ml/min
2) DIC ONLY IF BLEEDING
3) Liver disease and risk if PT 1.5x normal
Really only for bleeds
Use vit K first
1 unit = 250ml - adult dose is 4-6 units
103
Platelet transfusion indications
1) Platelets <10 with no bleeding
2) Bleeding and platelets <30
3) Massive transfusion aiming for plt >75
4) Prevent bleeding in surgery if <50 (<100 in eye/CNS)
5) Prevent bleeding post chemo if <10 (<20 if sepsis)
One unit raises platelets by 30-40
Contraindications to prophylaxis (even if above)
- HIT
- TTP
- ITP
- Chronic BM failure
104
Monitoring blood transfusion reactions
Signs to look out for
Baseline temp, BP, HR, RR
Repeat after 15 mins
Repeat hourly and at end of transfusion
Symptoms: Fevers, rigors, flushing, vomiting, dyspnoea, tachycardia, pain at transfusion site, loin/chest pain, urticaria, itching, headache, collapse
105
Acute transfusion reactions
Stop transfusion and call a doctor
MIld fever or urticarial only = Febrile non-haemolytic transfusion or mld allergic reaction]
Significant changes in observations with shock/collapse
- Bleeding, dark urine = ABO incompatability
- Swelling, wheezing = severe allergic reaction/anaphylaxis
- High fever - bacterial contamination
Significant breathlessness
- Raised CVP - TACO
- Normal CVP - TRALI - due to anti-WBC antibodies (HLA or neutrophil Abs) in dono - reacts with patient's WBC and aggregates stuck in pulmonary capillaries --> lung damage
106
GVHD symptoms
Treatment
Donor lymphocytes attack patients gut, liver, skin and BM --> severe diarrhoea, liver failure, skin desquamation, BM failure + death weeks to months post transfusion
Prevent - irradiate blood components for immunosuppressed or HLA matched
107
Delayed transfusion reactions
```
Delayed haemolytic transfusion reaction
GVHD
Post transplantation purpura
Viral infections
Iron overload
```
108
Thalassaemia
vs
Haemoglobinopathy
What is Hb molecule made up off
Thalassaemia = Genetic disorder of globin chain synthesis
Haemoglobinopahy = Any disorder of globin chain synthesis
Haemoglobin molecule made up of 4 globin chains, each with a haem group in the middle
```
Alpha gne on chr 16
Beta, gamma, delta globin genes on chr 11
HbF = 2 alpha, 2 gamma
HbA2 = 2 alpha, 2 delta
HbA = 2 alpha, 2 beta
```
109
SCD symptoms in child
Dactylitis
Splenic sequestration - severe anaemia, shock, death
Immature immune systems - pneumococcus, parvovirus B19, HI and meningococcus
Folic acid need greater
110
betha thalassaemia major clinical picture
Anaemia - HF, growth retardation
Erythropoietic drive --> bone expansion and extramedullary haematopeisis - hepatosplenomegaly
Iron overload - HF, gonadal failure
111
Fragmented red cells, microspherocytes, had a GI infection recently
HUS
112
TTP classical signs
```
MAHA
Thrombocytopenia
Fever
Neurological abnormalities
Renal impairment
```
Is autoimmune
Underlying defect is deficiency of vWF cleaving protease (ADAMTS13) --> large vWF multimers form --> widespread platelet thrombi
Tx is plasma exchange (gets rid of Ab and replaces deficient protein.
113
Microcytic anaemia causes
Fe-deficiency anaemia
Anaemia of chronic disease
Sideroblastic anaemia
Thalassaemia (in absence of anaemia)
114
Causes of normocytic anaemia
```
BM failure
Blood loss (acutely)
Hypothyroid
Haemolytic anaemia
Pregnancy
Anaemia of chronic disease
Renal failure
```
115
Causes of macrocytic anaemia
Megaloblastic: folate deficiency + B12 deficiency
Non megaloblastic:
- Reticulocytosis
- Alcohol (macrocytosis without anaemia)
- Liver disease
- Pregnancy
- Hypothyroid
Haem:
- Myelodysplasia
- Myeloproliferative
- Myeloma
- Aplastic anaemia
116
Megaloblastic anaemia blood film
Hypersegmented polymorphs
Leucopenia
Thrombocytopenia
Macrocytosis (oval)
117
Anaemia of chronic disease
Causes
Normocytic or Microcytic
Chronic infection
Vasculitis
Rheumatoid arthritis
Malignancy
118
Low Fe, High TIBC(Transferrin), low ferritin
Fe deficiency anaemia
119
Low Fe, Low TIBC (transferrin), high ferritin
Anaemia of chronic disease
120
Causes of sideroblastic anaemia
```
MPD
MDS
Lead
Alcohol
B6 deficiency (Tb drugs)
Chemo/radio
```
121
High Fe, normal TIBC, high ferritin
Sideroblastic anaemia
Chronic haemolysis or Haemochromatosis
Same or low TIBC
122
What are ringed sideroblasts
Erythroid precursors with iron deposited in mitochondira in a ring around nucleus
123
Plummer vinson syndrome
Fe deficiency - also koilonychia (spoon nails), brittle hair/nails
Difficulty swallowing
Cheilosis (cracking of mouth corners)
Glossitis
124
What is pernicious anaemia
Management
Macrocytic megaloblastic anaemia
B12 deficiency
Autoimmune atrophic gastritis
Parietal cell antibodies (90%), Intrinsic factor antibodies (50%), Schilling test (outdated)
Replenish B12 with IM hydroxocobalamin
125
B12 deficiency features
Intake of B12
Pernicious anaemia
Mouth: glossitis, angular cheilosis
Neuropsych: Irritable, depression, psychosis, dementia
Neuro: Paraesthesia, peripheral neuropathy
Meat and dairy (b12 deficiency = vegan)
126
Folate deficiency features
Management
Macrocytic, megaloblastic anaemia
Malabsorption: Coeliac
Drugs: Alcohol, methotrexate, trimethoprim, phenytoin
Give folic acid if you know it is the cause
DO NOT GIVE IF YOU DON'T as exacerbates B12 deficiency neuropathy
127
Cold agglutin disease
Mediated by what
Causes
Management
IgM. Intravascular haemolysis
DAT (direct antiglobulin test) +ve
Primary idiopathic
Lymphoma
Infections: EBV, mycoplasma
Avoid underlying condition
Avoid cold
Chlorambucil (chemo)
128
Warm agglutin disease
DAT result
Mediated by what
Causes
Management
IgG. Extravascular haemolysis.
DAT (direct antiglobulin test) +ve
```
Primary idiopathic (mostly)
CLL
Methyldopa
```
Steroids
Splenectomy
Immunosuppression
129
Paroxysmal cold haemoglobinuria
DAT result
Causes
Specific blood test marker
Management
DAT (direct antiglobulin test) +ve
Viral infection: Measles, syphilis, VZV
Donath-Landsteiner antibodies
- stick to RBCs in cold --> complement mediated haemolysis on warming
No management needed as self-limiting
130
Paroxysmal nocturnal haemoglobinuria
DAT result
Mediated by what
Causes
Management
DAT -VE
Acquired loss of GPI surface marker on RBC (Ham's test) --> complement mediated lysis = intravascular haemolysis
- Morning haemoglobinuria
- Thrombosis
- Budd chiari syndrome
Folate, iron. Prophylactic vaccination
Eculizumab prevents complement binding to RBCs
131
Budd chiari syndrome
Hepatomegaly
Ascites
Abdo pain
132
MAHA
DAT result
Mediated by what
Causes
Management
DAT -ve
RBC damage --> schistocytes due to mechanical forces
HUS
TTP (Antibodies against ADAMTS13)
DIC
Pre-eclampsia
Plasma exchange
Supportive
133
Primary haemostasis
Platelet aggregation
Vessel injury
Platelt bind via Gp1b (vWF)
Thromboxane + ADP release -->
Platelet aggregation vi Gp2b/3a (fibrinogen receptor)
134
Secondary haemostasis
Exrinsic pathway (PT)
- TF-VII
- X--> Xa
- Xa-5a --> generates thrombin but mainly activates intrinsic pathway
```
Intrinsic pathway (aPTT)
- Starts with 12
- 11
- 9
- 8
--> Xa
Xa-5a --> Thrombin burst
```
Common:
Thrombin converts fibrinogen to fibrin - Stable clot
Fibrinolysis = breaks down fibrin into fibrin degradation products
- TPA (tissue plasminogen activator) and urikinase convert plasminogen to plasmin
- plasmin degrades fibrin
135
What is factor V Leiden
APC resistance so Factor V not broken down
136
Most thrombogenic condition
Lack of antithrombin
137
ITP treatment
> 50,000
- No symptoms, no treatment
20,000-50,000
- Only treat if bleeding -> steroids, IVIG
<20,000
- No symptoms - Steroids
- Bleeding - Steroids, IVIG, Hospital
138
Thrombocytopenia causes
Reduced production
- EXCLUDE AML + Myeloblastic anaemia!!!
- BM failure
Destruction
- AITP
- Drugs e.g. heparin, DIC, TTP, HUS
139
Haemophilia diagnosis
Severity
Treatment
X-linked recessive. Deep bleeding
A more common.
High aPTT, normal PT, low VIIIa or IXa
Bleeding time normal
Severity depends on factor level
- Sev: <1%
- Mod: 1-5%
- Mild: 5-25%
A Rx: Desmopressin, FVIII concentrates
B Rx: FIX concentrates
140
vWF diagnosis
High aPTT, normal PT, low FVIII, low vWF
Increased bleeding time (normal TT)
Autosomal dominant
141
DIC diagnosis
Causes
High PT, high aPTT, high TT, low platelets, low fibrinogen, high D-dimer
Malignancy, Sepsis, Toxins, Trauma
142
Liver clotting factors synthesis
Liver disease picture
Fibinogen
2, 7, 9, 10 + 5, 11
Low synthesis of above factors, less vit K absorption, abnormalities of platelet function
High PT, high aPTT, norm or high TT
AST high
143
Vit K deficiency
high aPTT, high PT, rest norm
Warfarin, Antibiotics, malabsorption, biliary obstruction
IV vit K or FFP in acute haemorrhage
144
Managing high INR in warfarin patients
therapeutic - 5:
- low/omit next dose and resume when normal
5-9, no bleeding
- low/omit next dose and resume when normal
- Omit dose and give vit K
>9
- omit dose and vit K 3-5mg, repeat if need
- resume therapy at lower dose when INR normal
>20; serious bleed
- OMIT
- Vit K 10mg slow IV infusion
- FFP or PCC
- Repeat vit K every 12 hrs as needed
NB: Prothrombin complex concentrate is for emergency reversal of warfarin in either
- severe bleeding or
- head injury with suspected intracerebral haemorrhage
145
Target INR for warfarin patients
2. 5
- Everything else aka 1st episode DTV/PE, AF, cardioversion
3. 5
- Recurrent DVT/PE
- Mechanical prosthetic valve
- Antiphospholipid syndrome
146
Cyclin D1 over expression
Mantle cell lymphoma
Pre-greminal centre cell. Mantle zone expands and then spreads thoughout node.
```
11;14
Aberrant CD5 and Cyclin D1 expression = dx
Low grade (slowly progressing)
```
Median survival 3-5yrs
147
- ALk-1 protein staining
- 2;5
- Sheets of anaplastic (nuclei wide), large lymphocytes
Anaplastic T cell lymphoma
Children/adults. Lymphadenopathy.
Aggressive
Alk-1 = better prognosis
148
ABVD therapy for what?
Side effects
Hodgkin lymphoma
```
Chemo - preserves fertility. 2-6 cycles
Adriamycin (se cardiomyopathy)
Bleomycin (se pulmonary fibrosis)
Vinblastine
DTIC
```
+/-
Radiotherapy: field only
(risk of breast Ca after 25y, Leukaemia 3% after 10yrs, lung/skin cancer)
149
Obstetric haematology
Macrocytic anaemia, thrombocytopenia, neutrophilia
Pro coagulant state, hypofibrinolytic
150
Platelets >600 x 10^9
Thrombosis/bleeding, headaches
ET
Mutations in JAK2, calreticulin and MPL
Rx: Aspirin
Hydroxycarbamide
Anagrelide (not commonly)
151
Leukoerythroblastic picture
JAK2/Calreticulin +ve
Management
PMF
Supportive
Hydroxycarbamide (try but can worsen anaemia)
Ruxolotinib (JAK2 inhibitor)
Allogenic SCT
152
Massive leucocytosis 50-200
Neutrophils and myelocytes
Basophils
Hepatosplenomegaly
CML
9;22
Chronic phase --> Advanced phase -->Blast crisis
