Haem Flashcards
symptoms of anaemia?
fatigue
SOB
faintness
palpitations
headache
tinnitus
signs of anaemia
pallor
hyperdynamic circulation: tachycardia, flow murmur (apical ESM), cardiac enlargement
ankle swelling w heart failure
types of microcytic anaemia?
Haem defect:
IDA
Anaemia of chronic disease
Sideroblastic/ Lead poisoning
Globin defect:
thalassaemia
causes of normocytic anaemia?
recent blood loss
bone marrow failure
renal failure
early anaemia of chronic disease
pregnancy (raised plasma volume)
causes of macrocytic anaemia?
megaloblastic:
folate/ B12 deficiency
anti folate drugs: methotrexate, phenytoin
cytotoxics: hydroxycarbamide
non-megaloblastic:
reticulocytosis
alcohol or liver disease
hypothyroidism
myelodysplasia
Causes of IDA?
increased loss:
GI bleeding, menorrhagia, hookworms
decreased intake:
poor diet
malabsorption: coeliac, crohns
Ix of Iron deficiency anaemia?
haematinics: low ferritin, high TIBC, low transferrin saturation, low Fe
Blood film: anisocytosis, poikilocytosis, pencil cells
OGD + Colonoscopy
Mx of Iron deficiency anaemia?
Ferrous Sulphate 200mg PO TDS
(se: GI upset)
what is sideroblastic anaemia?
ineffective erythropoiesis
- increased iron absorption
- iron loading in bone marrow -> ringed sideroblasts
- haemosiderosis: endo, liver and cardiac damage
causes of sideroblastic anaemia?
congenital
acquired: myelodysplasia/ myeloproliferative disease
drugs: chemo, anti-TB, lead
Ix of sideroblastic anaemia?
microcytic anaemia and not responsive to iron
high ferritin, high serum Fe, normal TIBC
mx of sideroblastic anaemia?
tx underlying cause
pyridoxine may help
featuers of Beta thalassaemia trait?
mild anaemia - usually harmless
low MCV
high HbA2 (a2d2) and high HbF (a2y2)
Features of Beta thal major?
features develop from 3-6mo
- severe anaemia, jaundice (haemolysis), FTT
extramedullary erythropoiesis: frontal bossing, maxillary overgrowth, hepatosplenomegaly
Hameochromatosis after 10 yrs (transfusions)
Ix of Beta thal major?
low Hb, low MCV, high HbF, high HbA2
Blood film: target cells and nucleated RBCs
Mx of Beta thal major?
lifelong transfusions
+ desferrioxamine for iron chelation
BM transplant may be curative
features of alpha thal trait?
asymptomatic
hypochromic microcytes
HbH disease?
type of alpha thal
moderate anaemia: may need transfusions
haemolysis: jaundice, hepatosplenomegaly
Hb Barts?
Fatal
hydrops fetalis -> death in utero
Blood film findings of B12/ Folate deficiency?
Hypersegmented PMN -> megaloblastic
oval macrocytes
Mx of Folate deficiency?
assess for underlying cause
give B12 first! (unless B12 level known to be normal)
-> may precipitate or worsen SACD if folate prescribed when b12 is low
Folate 5mg/d PO
Sources of Folate?
Diet: Green veg, nuts, liver
stores for 4mo in the body
absorption: proximal jejunum
Causes of Folate deficiency anaemia?
low intake: poor intake
increased demand: pregnancy, haemolysis, malignancy
malabsorption: coeliac, crohns
Drugs: anti folates e.g. phenytoin, methotrexate, alcohol
Bloods to Ix macrocytic anaemia?
LFTs: mild raised Br in folate/ B12 deficiency
TFT
Serum B12
Red cell folate: reflects body stores over 2-3 mo
Source of Vit B12?
meat fish and dairy (vegans likely deficient)
stores for 4 yrs
absorbed in terminal ileum bound to intrinsic factor (released from gastric parietal cells)
role: DNA and myelin synthesis
Causes of B12 deficiency?
low intake: vegans
low intrinsic factor: post gastrectomy, pernicious anaemia
terminal ileum: crohns, ileal resection, bacterial overgrowth
features of B12 deficiency?
general: symptoms of anaemia
lemon tinge- pallor + mild jaundice
glossitis (beefy, red tongue)
Neuro:
parasthesia
peripheral neuropathy
SACD
optic atrophy
what is subacute combined degeneration of the cord?
usually only caused by pernicious anaemia
combined symmetrical dorsal column loss and corticospinal tract loss
- > distal sensory loss: esp joint position and vibration
- > ataxia w wide gait and Rombergs +ve
Mixed UMN and LMN signs
- spastic paraparesis
- brisk knee jerks, absent ankle jerks
upgoing plantars
pain and temp remain intact
Ix of Vit B12 deficiency?
low Hb, high MCV
low WCC and platelets if severe
intrinsic factor Abs: specific
Parietal cell Abs: sensitive
Mx of Vit B12 deficiency?
Malabsorption: Parenteral B12 (hydroxycobalamin)
Dietary -> oral B12 (cyanocobalamin)
Parenteral B12 reverses neuropathy but not SACD
What is pernicious anaemia?
autoimmune atrophic gastritis caused by autoabs vs parietal cells or IF
-> low IF and low H+
assoc w other AI disease and Ca: 3x risk of gastric adenoca
myositis
interstitial lung disease
thickened and cracked skin of the hands (mechanic’s hands)
Raynaud’s phenomenon
Antisynthetase syndrome
subtype of dermatomyositis
anti Jo1 +ve
Causes of cold AIHA?
Mycoplasma/ EBV, CLL
idiopathic
Mx of cold AIHA?
avoid cold
Rituximab (anti-CD20) to deplete B cells
Ix of Cold AIHA?
Direct antiglobulin test +ve
Features of cold AIHA?
igM-mediated, bind @<4 degrees
often fix complement -> intravascular haemolysis
may cause agglutination -> acrocynanosis or Raynauds
Features of warm AIHA?
IgG mediated, bind @37 degrees
extravasc haemolysis and spherocytes
Ix of warm AIHA?
Direct antiglobulin test +ve
Causes of warm AIHA?
idiopathic
SLE
RA
CLL
Medications: NSAIDs
Mx of Warm AIHA?
immunosuppression
splenectomy
IgG Donath-Landsteiner Abs
Paroxysmal Cold Haemoglobinuria
rare
assoc w measles, mumps, chicken pox
IgG Donath-Landsteiner Abs bind RBCs in the cold and
-> complement mediated lysis on rewarming
Paroxysmal Cold Haemoglobinuria
?
assoc w measles, mumps, chicken pox
IgG Donath-Landsteiner Abs bind RBCs in the cold and
-> complement mediated lysis on rewarming
Features of Paroxysmal nocturnal haemoglobinuria?
Visceral viscous thrombosis (hepatic, mesenteric, CNS)
haemolysis and haemoglobinuria
Visceral viscous thrombosis (hepatic, mesenteric, CNS)
haemolysis and haemoglobinuria
absence of RBC anchor molecule -> lysis of RBCs
may also cause low Platelets + PMN
Paroxysmal nocturnal haemoglobinuria
Ix of Paroxysmal nocturnal haemoglobinuria?
Anaemia +/- thrombocytopenia +/- neutropenia
FACS: low CD55 and CD59
Mx of Paroxysmal nocturnal haemoglobinuria
Chronic disorder -> long term anticoagulation
Eculizumab (prevents complement MAC formation)
what organism is most assoc w HUS?
E coli O157:H7
features of Haemolytic Uraemic Syndrome?
Bloody diarrhoea and abdo pain precedes:
- MAHA
- Thrombocytopenia
- Renal failure
Ix of HUS?
schistocytes (MAHA)
low Platelets
normal clotting
U+E, Ur/Cr deranged (renal impairment)
Mx of HUS?
usually resolves spontaneously
Exchange transfusion and dialysis may be needed
Deficiency of what causes TTP?
Genetic/ acquired deficiency of ADAMTS13
Pentad of Thrombotic Thrombocytopenic Purpura?
Fever
CNS signs: confusion, seizures
MAHA
thrombocytopenia
renal failure
Ix of TTP?
schistocytes
low PL
normal clotting
U+E/ UR/Cr deranged: renal impairment
Mx of Thrombotic Thrombocytopenic Purpura?
Plasmapheresis
Immunosuppression
Splenectomy
What is Pyruvate Kinase deficiency?
autosomal recessive defect in ATP synthesis
- > rigid red cells phagocytosed in spleen
features: splenomegaly, anaemia +/- jaundice
Ix of pyruvate kinase deficiency?
Pyruvate kinase enzyme assay
Mx of Pyruvate Kinase deficiency?
not needed
or transfusion +/- splenectomy
Pathology of G6PD deficiency?
X linked disorder
g6PD in pentose phosphate pathway -> low NADPH production -> low glutathione which is used to mop up free radicals that cause oxidative damage
-> increased RBC oxidative damage
Triggers of haemolysis in G6PD deficiency?
Fava beans
Mothballs (naphthalene)
infection
Drugs: antimalarials, henna, dapsone, sulphonamides
ix of G6Pd deficiency?
blood film: irregularly contracted cells, bite cells, Heinz bodies
G6PD assay after 8 wks of acute haemolysis
mx of G6PD deficiency?
treat underlying infection
stop and avoid precipitants
transfusion may be needed
mx of hereditary elliptocytosis?
most pts asymptomatic
auto dom defect-> elliptical RBCs
Folate (increased utilisation), rarely splenectomy
pathophysiology of hereditary spherocytosis?
auto dom defect in RBC membrane
spherocytes trapped in spleen -> extravasc haemolysis
features of hereditary spherocytosis?
Splenomegaly
Pigment gallstones
Jaundice
complications of hereditary spherocytosis?
aplastic crisis
megaloblastic crisis
Ix of hereditary spherocytosis?
Blood film: spherocytes
DAT -ve
increased osmotic fragility
Mx of hereditary spherocytosis?
folate
rarely -> splenectomy
pathogenesis of sickle cell?
point mutation in B globin gene: glu -> val
SCA: HbSS
Trait: HbAS
HbSS insoluble when deoxygenated -> sickling
sickle cells have lower life span -> haemolysis
sickle cells get trapped in microvasc -> thrombosis
Ix of sickle cell?
Hb 6-9, high reticulocytes/ Br
Blood film: sickle cells and target cells
Hb electrophoresis
Neonatal screening at birth: Guthrie Heel prick
presentation of sickle cell anaemia?
clinical features manifest 3-6 mo due to drop in HbF
triggers: infection, cold, hypoxia, dehydration
Splenomegaly -> may get sequestration crisis
Infarction: Stroke, spleen
Crises: pain, pulmonary
Kidney, Liver, Lung disease
Erection
Dactylitis
Complications of Sickle Cell Disease?
Sequestration crisis:
splenic pooling -> shock + severe anaemia
Splenic infarction: atrophy and hyposplenism
increased risk of infection: e.g. osteomyelitis
Aplastic crisis: parvovirus B19
Gallstones
Mx of chronic Sickle cell disease?
Folate
Pen V + immunisations if no spleen (pneumococcal, meningococcus, Hib)
hydroxycarbamide if freq crises
Mx of Acute Sickle cell crises?
A->E, call for senior help
Analgesia: Opioids IV
Good hydration
Give O2
keep warm
Ix for cause: e.g infection
Abx if suspect infection
Transfusion: exchange if severe
Features of DIC?
thrombosis and bleeding
increased APTT/PT/TT
low Platelets/ fibrinogen
high fibrin degradation products
Causes of DIC?
sepsis
malignancy esp APML
trauma
obstetric complications
Mx of DIC?
FFP
Platelets
Heparin
Haemophilia A vs B?
A: fVIII
B: fIX deficiency
Haemophilia features?
X-linked
affects males
present w haemarthroses, bleeding after surgery/ extraction
Ix of Haemophilia?
low fVIII: A, fIX: B assay
prolonged APTT, normal PT
Mx of Haemophilia A?
avoid IM Injections and NSAIDs
minor bleeds: desmopressin + tranexamic acid
Major bleeds: fVIII
von willebrands disorder features?
vWF: stabilises fVIII
binds platelets via Gp1b to damaged epithelium
if mild, APTT and bleeding time normal
if not: high APTT, bleeding time, normal Pl and decreased vWF
Mx of Von Willebrands Disease?
Desmopressin: raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
tranexamic acid for mild bleeding
fVIII concentrates
Causes of thrombocytopenia?
decreased production:
BM failure: aplastic, infiltration, drugs
Megaloblastic anaemia
increased destruction:
immune - ITP, SLE, CLL, Heparin, viruses
non immune: DIC, TTP, HUS, PNH, anti-phospholipid
Splenic pooling:
portal HTN, sickle cell
features of idiopathic thrombocytopenic purpura?
children commonly post URTI
self limiting
in adults: F>M, long term
Anti-platelet abs present
mx of ITP?
conservative
steroids
IVIg
splenectomy
Causes of Functional platelet defects?
drugs: aspirin, clopidogrel
secondary to: uraemia, paraproteinaemias
Hereditary: bernard-soulier (Gp1b deficiency), Glanzmanns (GpIIb/IIIa deficiency)
features of coagulation disorders e.g. haemophilia/ VWD?
deep bleeding: muscles, joints, tissues
delayed but severe bleeding after injury
features of vascular or platelet disorder?
Bleeding into skin: purpura, petechiae, ecchymoses
Bleeding into mucous membranes: epistaxis, menorrhagia, gums
Immediate, prolonged bleeding from cuts
Thrombin time tests?
Fibrinogen function
Increased w Heparin, DIC
What does bleeding time test?
platelet function
increased if decreased pl number/ function, VWD, aspirin, DIC
What does APTT test?
intrinsic pathway: 12, 11, 9, 8
+ common: 10, 5, 2, 1
Increased:
haemophilia, VWD, unfractionated heparin, DIC, hepatic failure, antiphospholipid
What does PT test?
extrinsic pathway: 7
+ common: 10, 5, 2, 1
increased:
warfarin/ Vit K deficiency, hepatic failure, DIC
Types of thrombophilia?
- predisposing to thrombosis
Inherited:
Factor V Leiden
Prothrombin Gene mutation
Protein C and S deficiency
Antithrombin III deficiency
Acquired:
Antiphospholipid syndrome
OCP
Pathophysiology of Factor V Leiden -> thrombosis?
Factor V Leiden is resistant to protein C
Protein C normally deactivates fV and fVIII w protein S and thrombomodulin cofactors
-> increased risk of VTE
indications for thrombophilia screen?
arterial thrombosis < 50
venous thrombosis < 40 w no RFs
familial VTE
unexplained recurrent VTE
unusual site: portal, mesenteric
recurrent foetal loss
neonatal
Ix of thrombophilia?
FBC, clotting, [fibrinogen]
Factor V Leiden/ APC resistance
Lupus anticoagulant and anti-cardiolipin Abs
Assays for ATIII, Protein C and S
PCR for prothrombin gene mutation
Mx of thrombophilias?
tx acute thrombosis as normal
anticoagulate to INR 2-3
consider lifelong warfarin
if recurrence occurs on warfarin -> INR 3-4
prevention of thrombosis in pts w thrombophilia?
lifelong anticoagulation may be needed
avoid OCP/HRT
prophylaxis in high risk situations e.g. surgery, pregnancy
ix of Aplastic Anaemia?
Bone marrow biopsy: Hypocellular marrow
Mx of aplastic anaemia?
supportive; transfusion
immunosuppression: anti-thymocyte globulin
Allogeneic Bone marrow transplant: may be curative
Causes of pancytopenia?
congenital: fanconis anaemia
acquired:
idiopathic
BM infiltration
Haemotological: Leukaemia, Lymphoma, Myelofibrosis, Myelodysplasia, Megaloblastic anaemia
infection: HIV
Radiation
Drugs: e.g. cyclophosphamide cytotoxics, chloramphenicol, thiazide, carbimazole, clozapine, phenytoin
what drugs may cause pancytopenia?
cytotoxic: cyclophosphamide, methotrexate, azathioprine
chloramphenicol
thiazides
carbimazole
clozapine
phenytoin
features of myelodysplastic syndromes?
cytopenias
hypercellular BM
defective cells e.g. ringed sideroblasts
30% -> AML
usually in elderly
BM failure: infection, bleeding, bruising, anaemia
splenomegaly
Pelger Huet Anomaly?
AML/ CML
myelodysplastic syndrome
Mx of myelodysplastic syndrome?
supportive: transfusions, EPO, G-CSF
Immunosuppression
Allogeneic BMT: may be curative
features of essential thrombocythaemia?
Thrombosis:
arterial- TIA, strokes, peripheral emboli
venous- DVT, PE, Budd Chiari
bleeding: (abnormal pl fn)
e. g. mucous membranes
erythromelalgia: episodes of burning pain and redness in the feet
Ix of essential thromboythaemia?
platelets > 600 (often >1000)
BM: increased megakaryocytes
50% JAK2 +ve
mx of essential thrombocythaemia?
Platelets 400-1000: aspirin alone
Platelets > 1000 or thrombosis: hydroxycarbamide
Anagralide: inhibits pl maturation
Essential thrombocythaemia assoc w?
progression to AML/ Myelofibrosis
Features of polycythaemia vera?
hyperviscosity:
headaches, visual disturbances, tinnitus, thrombosis (arterial/ venous)
histamine release:
aquagenic pruritus
erythromelalgia:
sudden severe burning in hands and feet w redness of skin
splenomegaly, hepatomegaly
gout
Ix of Polycythaemia vera?
99% JAK2 +ve
high RBC, Hb, Hct
high WCC/ Pl
BM: hypercellular w erythroid marrow
low EPO
Mx of polycythaemia vera?
Aim to keep Hct <0.45 to reduce thrombosis risk
Aspirin 75mg OD
Venesection if young
Hydroxycarbamide if older/ higher risk
prognosis of polycythaemia vera?
thrombosis and haemorrhage
30% -> myelofibrosis
5% -> AML
Differential of polycythaemia?
true polycythaemia:
Polycythaemia vera
secondary to hypoxia (smoking, altitude, COPD) or high EPO (renal cyst/ tumour)
Pseudopolycythaemia: low plasma vol
Acute- dehydration, shock, burns
chronic- smoking, diuretics
differential for thrombocythaemia?
primary: essential thrombocythaemia
secondary to
- bleeding, infection, chronic inflammation (RA, IBD)
trauma/ surgery, hyposplenism/ splenectomy
Features of primary myelofibrosis?
elderly
massive hepatosplenomegaly
due to extramedullary haemotopoiesis in liver and spleen
Hypermetabolism: FLAWS
BM Failure: anamia, infection, bleeding
Ix of Myelofibrosis?
Film: leukoerythroblastic w tear drop poikilocytes
cytopenias
BM: dry tap (neep trephine biopsy)
50% JAK2+ve
Mx of primary myelofibrosis?
supportive: blood products
Splenectomy
Allogeneic BMT may be curative
What Drugs increase risk of VTE?
COCP
HRT
Antipsychotics esp olanzapine
Risk factors for developing ALL/AML
ionising radiation- radiotx
chemotx
benzene
MDS/ myeloproliferative disorders
Downs: signficantly increased risk of AML
t(15;17)
excess of abnormal promyelocytes
DIC
PML-RARA fusion protein
Acute promyelocytic leukaemia
ALL
- peak age incidence
- clinical features
peak incidence in childhood
BM failure - pancytopenia
hepatosplenomegaly
lymphadenopathy
thymic enlargement
testicular enlargement
bone pain
ALL Ix
Blood count and film, bone marrow aspirate (>20% blasts)
high WCC (lymphoblasts). low RBC/platelets/ neutrophils
· Immunophenotyping – matters as T (15%) and B-lineage (85%) ALL may be treated differently
· Cytogenetic/molecular genetic analysis - Ph positive need imatinib, treatment must be tailored to the prognosis
· Blood group, LFTs, creatinine, electrolytes, calcium, phosphate, uric acid, coagulation screen
CXR + CT: mediastinal + abdominal LNs
LP: CNS involvement
Mx of ALL
· Specific therapy – systemic or CNS-directed chemotherapy
· Supportive care – blood products, abx, general medical care, prophylaxis for Pneumocystis jirovecii infection (co trimoxazole)
· Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase
· Hyperphosphataemia; Al(OH)3, calcium
· Hyperkalemia: fluids, diuretics
· Extreme leukocytosis (WBC > 200 × 109/l): leukapheresis, sometimes haemodialysis
BMT: best option for younger adults
AML
- typical features
- more specific features
- Blood film features
BM failure- effects of pancytopenia
Splenomegaly, hepatomegaly
Gum infiltration if monoblasts/ monocytic
Skin infiltration/ CNS involvement + hypoK
Blood film: circulating blasts (>20%) with granules. auer rods.
if unclear- immunophenotyping
AML
- age of incidence
- mutations seen
- pathognomonic features
bimodal incidence: peak in under 2s and in 65-70yos
many mutations assoc with AML
t(5;8), inv(16), t(8;21), trisomy 8, trisomy 21
>20% myeloblasts on BM + Auer Rods
treatment of AML
Supportive care:
blood products, abx, FFP/Cryoprecipitate if DIC, allopurinol, fluid and electrolytes to prevent tumour lysis syndrome
Chemotherapy
Consider Allo BMT in young / autologous HSCs
Specific for acute promyelocytic leukaemia: ATRA
Ix in CML?
PCR for BCR-ABL (philadelphia chr) fusion gene
Ph Chr +ve in 80%
t(9;22)
high WCC, FBC: low Pl, Hb
Blood film: neutrophils, myelocytes, basophilia
Can monitor disease and treatment response with FBC, BCR-ABL:ABL ratio
Treatment of CML
Imatinib*
a BCR-ABL tyrosine kinase inhibitor
or
if resistant -2nd line: Dasatinib/ Nilotinib
young patients- possible allogeneic SCT
how to monitor disease and response to therapy in CML
FBC and WCC count
cytogenetics and detection of Ph chr - reduction in % of Ph Chr expressed
RT-PCR of BCR-ABL fusion transcript. can calculate BCR-ABL: ABL ratio
successful therapy means this will drop
e.g. complete response: 0% Ph +ve
partial response 1-35% Ph +ve
BCR-ABL transcripts reduce from 100% to the best - 0.001%
chronic phase vs accelerated phase vs blast phase of CML?
no of blasts in BM/blood
chronic (80% of pts): <5% blasts
indolent
Accelerated: 10%-19% blasts
increasing manifestations e.g. splenomegaly
Blast crisis: >20% blasts
median survival 3-6 months
resembles acute leukaemia
what translocation is assoc w CML?
t (9;22)
Philadelphia chr
- > formation of BCR-ABL fusion gene
- > constitutive tyrosine kinase activity
Blood film- tear drop poikilocytes (dacrocytes) and leukoerythroblasts
Dry tap on BM biopsy
extramedullary haemopoiesis - massive splenomegaly (budd chiari syndrome may present), hepatomegaly
pancytopenia: anaemia, thrombocytopenia, neutropenia
hypermetabolic state: weight loss, fatigue, night sweats, hyperuricaemia
myelofibrosis
t(9;22)
produces philadelphia chrosome (BCR-ABL gene)
seen in CML
expresses a fusion oncogene with tyrosine kinase activity
can be detected using FISH
features of CML?
Systemic: FLAWS
massive HSM -> abdo discomfort
Bruising/ bleeding
Gout
Hyperviscosity
treatment of CLL
many patients undergo watchful waiting if asymptomatic with slowly progressive disease
1st line: alemtuzumab anti-CD52 (depletes lymphocytes)
Ibrutinib - Brutons Tyrosine kinase inhibitor
supportive: abx, vaccination, e.g. aciclovir, PCP prophylaxis, IVIG, pneumovax
young patients: allogeneic SCT
Autoimmune phenomena: 1st line steroids. 2nd line Rituximab
Radiotx - debulking LNs/ splenomegaly
Chemotx: fludarabine, cyclophosphamide, Rituximab
what may undergo richter transformation to DLBCL?
CLL
hairy cell leukaemia
CLL prophylaxis and treatment of infections
Aciclovir
PCP prophylaxis for those receiving fludarabine or alemtuzumab
IVIG for those w hypogammaglobulinaemia and recurrent bacterial infections
Immunisation against pneumococcus and seasonal flu
CLL autoimmune phenomena e.g. AIHA
mx?
1st line steroids
2nd line rituximab
Features of CLL?
often asymptomatic incidental finding
symmetrical painless Lymphadenopathy
HSM
Anaemia
B symptoms: FLAWS
complications of CLL?
AIHA, ITP
Infection: bacterial, zoster
Marrow failure/ infiltration
Smear cells seen in?
CLL
(most often assoc w abnormally fragile lymphocytes)
ix of CLL?
high WCC, lymphocytes
Smear cells
low serum Ig
+ve DAT: if AIHA
Rai or Binet staging
Diagnosis via immunophenotyping to distinguish from NHL
Hodgkins Lymphoma
- how does it present
- associated with which virus
- affects which age groups
presents as asymmetrical painless lymphadenopathy.
most often single node and spreads contiguously to adjacent LNs
+/- obstructive/mass effect symptoms -> SVC/ bronchial obstruction
B symptoms may be present: fever>38, night sweats, weight loss (>10% over 6mo)
pain in affected nodes after alcohol
assoc w EBV
bimodal age incidence - 20-30 and >60
itch, Pel Ebstein fever, hepato/splenomegaly
Reed sternberg cell
binucleate/ owl eyed cell on a background of lymphocytes and reactive cells
LN/ BM biopsy - cells stain with CD15 and CD30
Hodgkins Lymphoma
Staging of Hodgkins Lymphoma
I; one group of nodes
· II; >1 group of nodes same side of the diaphragm
· III; nodes above and below the diaphragm
· IV; extra nodal spread (other organs)
· Suffix A if none of below, B if any of below
o Fever, night sweats
o Unexplained Weight loss >10% in 6 months
**RMB that spleen is considered a LN
Pel Ebstein fever assoc w?
fevers which cyclically increase then decrease over an average period of one or two weeks.
Hodgkins lymphoma
Ix of Hodgkins Lymphoma
FBC, film, ESR, LFT, LDH, Ca
- high ESR or low Hb = worse prognosis
LN excision biopsy or FNA
- Reed sternberg cells (Owls eyes nuclei)
Staging: CT/MRI Chest, Abdo, pelvis
BM biopsy if B symptoms of stage 3/4 disease
treatment of Hodgkins Lymphoma
Chemotherapy
Radiotherapy
Chemotherapy:
ABVD: adriamycin, bleomycin, vinblastine, dacarbazine
2-4 cycles in stage 1/2, 6-8 in stage 3
given at 4 wkly intervals
prognosis excellant esp in the young. preserves fertility but can cause long term pulmonary fibrosis, cardiomyopathy
Radiotherapy:
HL is highly responsive to radiotx
usually given at the end of chemo to small area of diseased nodes
risk of collateral damage: BrCa, Leukaemia/ MDS, lung/skin Ca
what are the chemotherapy drugs used in hodgkins lymphoma tx?
ABVD
Adriamycin, Bleomycin, Vinblastine, Dacarbazine/DTIC
cycles given at 4 wkly intervals
SE: Adriamycin- cardiomyopathy
Bleomycin- Pulm fibrosis
Tx of Hogdkins Lymphoma in relapse patients
Autologous SCT
+ Intensive chemo
Of the common B cell non-hodgkin lymphomas,
which are high grade?
which are low grade?
High Grade:
V aggressive: Burkitt’s
Aggressive: Diffuse Large B cell, Mantle Cell
Low Grade:
Indolent-
Follicular, small lymphocytic/ CLL, marginal zone lymphoma, mantle zone lymphoma
affects middle aged/ elderly
*Large T cell lymphocytes
Aggressive
Often with associated reactive cell population esp eosinophils
Lymphadenopathy and extranodal sites
Peripheral T Cell lymphoma
what lymphoma is associated with longstanding coeliac disease?
EATL
Enteropathy Associated T cell lymphoma
what lymphoma is associated with mycosis fungoides?
Cutaneous T cell lymphoma
Affects mainly children/ young adults
Histology shows large ‘epitheliod’ lymphocytes
t(2;5) and Alk-1 protein expression
Aggressive.
Anaplastic large cell lymphoma
What immunodeficiency is associated with burkitts lymphoma?
HIV / post transplant patients
MALT (mucosal associated lymphoid tissue) lymphoma / Marginal zone NHL
- what sites are normally affected?
- treatment?
mainly at extranodal sites. e.g. gut, lung, spleen, thyroid, parotid
arise in response to chronic antigen stimulation
treatment involves removing the antigenic stimulation e.g. H pylori eradication
what is the H pylori triple therapy for eradication?
omeprazole, clarithromycin and amoxicillin
what causes constant antigenic stimulation, predisposing the patient to small bowel T cell lymphoma?
Coeliac disease
-> enteropathy associated T-cell Non-Hodgkins Lymphoma (EATL)
a lymphoma caused by HTLV-1 infection
HTLV-1 infects T cells
common in the Carribean and Japanese population
what lymphoma is associated?
Adult T cell leukaemia/ lymphoma
*nuclei of ATL cells have characteristic cloverleaf appearance
what virus is associated with Adult T cell leukaemia/ lymphoma?
HTLV-1
Known risk factors of lymphoma:
constant antigenic stimulation (will increase risk of DNA replication error)
infection (direct viral infection of lymphocytes e.g. EBV)
loss of T cell function (e.g. HIV)
Gastric MALToma
what causes the chronic antigenic stimulation that may lead to gastric MALToma
Helicobacter pylori
-> marginal zone non-hodgkins lymphoma of the stomach
Lymphoma
- what is it?
- where may it be found?
Lymphomas are neoplastic tumours of lymphoid cells.
usually found in lymph nodes, bone marrow and or blood (via the lymphatic system)
and in lymphoid organs such as the spleen, MALT
why are lymphocytes particularly at risk of neoplasm/ malignancy?
rapid cell proliferation in immune response risks DNA replication error
dependent on apoptosis (in the germinal centre) -> apoptosis may get switched off in the germinal centre, there may be acquire DNA mutations in the pro apoptotic genes
DNA molecules are cut and rejoined and undergo deliberate point mutation to generate immunoglobulin and T cell receptor diversity -> potential for recombination errors and new point mutations
what causes constant antigenic stimulation that may result in marginal zone lymphoma of the thyroid gland?
Hashimoto’s Disease
What causes chronic antigenic stimulation that may predispose to developing parotid lymphoma?
Sjogren’s syndrome
-> marginal zone non-hodgkins lymphoma of the parotids
Spread of neoplasia in Hodgkins vs Non Hodgkins Lymphoma?
Hodgkins: spreads contiguously to adjacent LNs
Non Hodgkins: spreads discontinuously
Treatment for DLBCL
6-8 cycles of Rituximab-CHOP
aim of therapy is curative
if relapse-> 2nd line tx: autologous SCT
-> same regimen for other high grade non hodgkin lymphomas
what drugs does R-CHOP consist of?
Rituximab (anti CD20)
Cyclophosphamide
Adriamycin
Oncovin aka Vincristine
Prednisolone
features of multiple myeloma
CRAB
hypercalcaemia - stones, bones, groans, moans
renal impairment
anaemia
bone pain, osteolytic lesions, fractures, osteoporosis
Ix of Multiple myeloma
serum Ca, high ESR, high Urea/Cr
*NORMAL ALP
MRI whole body
blood film shows Rouleaux formation
Urine electrophoresis: bence-jones protein
serum protein electrophoresis: dense narrow band
BM aspirate: >10% plasma cells
Xray: Punched out lytic lesions, Pepper pot skull, vertebral collapse, fractures
Diagnosis of Multiple Myeloma?
1 major and 1 minor criteria or 3 minor criteria + signs or symptoms
Major criteria
Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
Minor criteria
10% to 30% plasma cells in a bone marrow sample.
Minor elevations in the level of M protein in the blood or urine.
Osteolytic lesions (as demonstrated on imaging studies).
Low levels of antibodies (not produced by the cancer cells) in the blood.
what is the first investigation you want to do when you suspect Multiple myeloma?
serum protein electrophoresis
- paraprotein detected
myeloma bone disease: possible complications
80-90% have lytic lesions
pathological fractures
spinal cord compression leading to paralysis
hypercalcaemia
bone pain -> affecting QOL, independence, mobility
too many osteoclasts (from increased IL6) and not enough active osteoblasts
what investigations for myeloma bone disease
X ray - for lytic lesions
MRI- High sensitivity for marrow infiltration, response monitoring possible, expensive & limited availability
CT – full body CT is the standard used in Imperial to diagnose as it detects very small lesions (high sensitivity). Good for radiotherapy planning but higher radiation dose
PET - detects active disease
why does multiple myeloma cause renal failure?
free light chains cause injury to kidneys - active inflammatory mediators in the proximal tubule epithelium
-> leads to amyloidosis (AL chains)
cast nephropathy
treatment of multiple myeloma
supportive for CRAB symptoms including bisphosphonates
Auto-SCT - curative, best for younger patients
steroids
Classical cytostatic drugs (relatively low dose) eg. melphalan
Proteasome inhibitors – prevent misfolded proteins from being degraded, which accumulates in myeloma cells (esp effective as myeloma produces a lot of proteins)
e.g. bortezomib
IMIDs – thalidomide, lenalidomide, pomalidomide (also used in MDS). Reduces cell turnover by affecting transcription factor relevant for plasma cells
mx of AKI due to Myeloma?
rehydration +/- dialysis
Mx of hypeviscosity due to myeloma?
Plasmapheresis (remove light chains)
Poor prognostic indicators of multiple myeloma?
high B2-microglobulin
low albumin
mx of cord compression secondary to myeloma?
Radiotx
+ dexamethasone
Mx of high calcium in myeloma?
hydration, frusemide, bisphosphonates
mx of infections secondary to multiple myeloma?
broad spec abx +/- IVIg if recurrent
Diagnosis of Multiple Myeloma?
Clonal BM plasma cells ≥ 10%
presence of serum and or urinary monoclonal protein
end organ damage: CRAB (1 or more)
Ca high (>2.6 mM)
Renal insufficiency
Anaemia (<10g/dL)
Bone lesions
what amyloid is assoc w Multiple Myeloma?
AL Amyloid
Echo findings of AL amyloidosis?
Sparkling appearance on echo
Diagnosis of Amyloidosis?
Biopsy of affected tissue ->
Apple green birefringence w Congo Red stain under polarized light
indications for splenectomy?
trauma
rupture e.g. EBV
AIHA
ITP
Hereditary spherocytosis
hypersplenism
complications of splenectomy?
redistributive thrombocytosis -> early VTE
Gastric dilatation (ileus)
left lower lobe collapse: v common
increased susceptibility to infections:
encapsulated bacteria meningococcus, pneumo, Hib
Blood film after splenectomy?
Howell-Jolly bodies
Pappenheimer bodies
Target cells
Mx of Splenectomy/ hyposplenism?
Immunisation: pneumovax, HiB, Men C, yrly flu
Daily Abx: pen V or erythromycin
Warning: Alert card and/or bracelet
Causes of hyposplenism?
post splenectomy
SCD
coeliac
IBD
Haematological causes of Splenomegaly?
Haemolysis: HS
Myeloproliferative disease: CML, PV, MF
Lymphoproliferative disease: lymphoma, leukaemia
infective causes of splenomegaly?
malaria, leishmaniasis, hydatid disease
EBV, CMV
TB, infectious endocarditis
Connective tissue causes of splenomegaly?
rheumatoid arthritis
SLE
Sjogrens
Causes of splenomegaly?
Haematological: haemolysis, myeloproliferative, lymphoproliferative
Infection: EBV, malaria, leishmaniasis
Portal HTN: cirrhosis, Budd-Chiari
Connective tissue: RA, SLE, sjogrens
Other: Sarcoid, Amyloid,
Causes of massive splenomegaly (>20cm)?
CML
Myelofibrosis
Malaria
leishmaniasis
Gauchers (AR, glucocerebrosidase deficiency)
Features of the spleen?
LUQ
lies anterior to ribs 9-11
Dull to percussion
enlarges to RIF
moves inferiorly on resp
cant get above it
medial notch
Function of the spleen?
phagocytosis of the old RBCs, WBCs, opsonised bugs
antibody production
haematopoiesis
sequestration of formed blood elements
Normal ESR?
20 mm/hr
what causes raised ESR?
plasma factors:
- increased fibrinogen: inflammation
- increased globulins: e.g. myeloma
red cell factors:
anaemia
differentials for ESR >100?
Multiple myeloma
SLE
GCA
AAA
Ca prostate
differential for basophilia?
parasitic infection
IgE-mediated hypersensitivity: urticarial, asthma
CML
Differential for eosinophilia?
parasitic infection
drug reactions
allergies: asthma, atopy, churg-strauss
Skin disease, psoriasis, eczema, pemphigus
differential of high monocyte count?
Chronic infection: TB, Brucella, Typhoid
AML
Differential of low lymphoctes?
Drugs: steroids, chemo
HIV
differential for lymphocytosis?
Leukaemia, lymphoma esp CLL
Viral infections eg. CMV, EBV
Chronic infections TB, Brucella, hepatitis, toxo
Differential for neutrophilia?
bacterial infection: left shift, toxic granulation, vacuolation
stress: trauma, burns, surgery, haemorrhage
steroids
inflammation: MI, polyarteritis nodosa
Myeloproliferative disorders e.g. CML
differential of neutropenia?
viral infection
Severe sepsis
Drugs: chemo, cytotoxics, carbimazole, sulphonamides
Feltys
tartrate resistant acid phosphatase +ve
Hairy cell leukaemia
Sudan Black B, MPO +ve
AML
Blood film showing target cells?
hyposplenism
thalassaemia
liver disease
Heinz bodies?
G6Pd deficiency
Acanthocytes?
LAB
Liver disease
Abetalipoproteinaemia
Basophilic stippling
Lead poisoning
thalassaemia
Burr cells?
Uraemia
Howell Jolly bodies?
hyposplenism
leukoerythoblastic film?
BM infiltration
Pappenheimer bodies?
hyposplenism
Pencil cells?
IDA
What is the most common inherited bleeding disorder?
Von Willebrand’s disease
Types of Von Willebrand’s disease?
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
Investigation of Von Willebrands disease?
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
Tx for post-thrombotic syndrome?
Compression stockings
painful, heavy calves
pruritus
swelling
varicose veins
venous ulceration
following previous DVT
Post-thrombotic syndrome
What is cryoprecipitate used for?
contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin
Clinically it is most commonly used to replace fibrinogen
e.g. DIC, liver failure
universal donor of FFP?
AB -ve blood
lacks anti-A or anti-B antibodies
What is Prothrombin complex concentrate used for?
used for the emergency reversal of anticoagulation in patients with either severe bleeding or a head injury with suspected intracerebral haemorrhage
Critical bleeding e.g. CNS
+ Pl < 100
Mx
immediate platelet transfusion
normally if other bleeding e.g haematemesis, melaena -> only transfuse if Pl < 30
An 88-year-old male has been formally diagnosed with anorectal cancer. Imaging confirms the cancer is localised to a region inferior to the pectinate line.
If untreated which group of lymph nodes will this cancer likely metastasize to?
Below the pectinate line cancer spreads to the superficial inguinal lymph nodes.
stomach cancer drains to which LN first?
Coeliac lymph nodes
Ca in the anal canal above pectinate line drains into which LNs?
Internal iliac lymph nodes
Ca of glans penis drains into which LNs?
Deep inguinal lymph nodes
Ca of testes/ ovaries/ kidney/ adrenal glands drain into which LNs?
Para-aortic lymph nodes
Ca of Lateral breast
Upper limb drain into which LNs?
Axillary lymph nodes
Ca in
Duodenum
Jejunum drains into which LNs?
Superior mesenteric lymph nodes
ca in Descending colon
Sigmoid colon
Upper part of rectum will drain into which LNs?
Inferior mesenteric lymph nodes
diagnosis of Hodgkins lymphoma?
This is made by excision of a complete lymph node that is then submitted for detailed histological evaluation.
poor prognostic markers of Hodgkins lymphoma?
Lymphocyte depleted Hodgkins lymphoma, advancing age, male sex and stage IV disease
Normal blood transfusion threshold?
Transfusion threshold in pts wihth ACS?
Normal: 70g/L
ACS: 80g/L
Electrolyte abnormalities in Tumour Lysis syndrome?
High K and PO4
and low Ca
+ high uric acid
Which one of the types of Hodgkin’s lymphoma carries the best prognosis?
Lymphocyte predominant
What is the most common type of Hodgkins Lymphoma?
Nodular sclerosing
What drug class is known to precipitate renal failure in patients with multiple myeloma (MM)?
NSAIDs
t(11;14)
deregulation of the cyclin D1 (BCL-1) gene
Mantle cell lymphoma
t(15;17)
fusion of PML and RAR-alpha genes
seen in acute promyelocytic leukaemia (M3)
t(8;14)
MYC oncogene is translocated to an immunoglobulin gene
Burkitt’s lymphoma
most common type of Hodgkin’s lymphoma?
nodular sclerosing
platelet transfusions should not be performed in which conditions?
Chronic bone marrow failure
Autoimmune thrombocytopenia
Heparin-induced thrombocytopenia, or
Thrombotic thrombocytopenic purpura.
reversal agent for dabigatran?
Idarucizumab
- humanised monoclonal antibody that directly inhibits dabigatran.
How to investigate patients w unprovoked clots?
Investigate for underlying malignancy:
- physical exam guided by full hx
- CXR
- Blood tests and urinalysis
Consider CT abdo-pelvis in all >40 w unprovoked DVT/ PE
Thrombophilia screening:
consider test for antiphospholipid abs
consider testing for hereditary thrombophilia in pts who have first degree relative who have had DVT/PE
