Haem/Onc Flashcards
causes of neutropenia
viral HIV Epstein-Barr virus hepatitis drugs cytotoxics carbimazole clozapine benign ethnic neutropaenia common in people of black African and Afro-Caribbean ethnicity requires no treatment haematological malignancy myelodysplastic malignancies aplastic anemia rheumatological conditions systemic lupus erythematosus: mechanisms include circulating antineutrophil antibodies rheumatoid arthritis: e.g. hypersplenism as in Felty's syndrome severe sepsis haemodialysis
indication for treatment in CLL
progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
autoimmune cytopaenias e.g. ITP
CLL management
patients who have no indications for treatment are monitored with regular blood counts
fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority of patients
ibrutinib may be used in patients who have failed a previous therapy
methaemoglobinaemia causes
Congenital causes
haemoglobin chain variants: HbM, HbH
NADH methaemoglobin reductase deficiency
Acquired causes
drugs: sulphonamides, nitrates (including recreational nitrates e.g. amyl nitrite ‘poppers’), dapsone, sodium nitroprusside, primaquine
chemicals: aniline dyes
methaemoglobinuria management
NADH - methaemoglobinaemia reductase deficiency: ascorbic acid
IV methylthioninium chloride (methylene blue) if acquired
most common cause of thrombophilia
factor V Leiden (activated protein C resistance)
prothrombin gene mutation (second most cause)
deficiencies of naturally occuring anticoagulants
antithrombin III deficiency
protein C deficiency
protein S deficiency
examples of sickle cell crisis
thrombotic, 'painful crises' sequestration acute chest syndrome aplastic haemolytic
what is thrombotic crisis?
also known as painful crises or vaso-occlusive crises
precipitated by infection, dehydration, deoxygenation
painful vaso-occlusive crises should be diagnosed clinically - there isn’t one test that can confirm them although tests may be done to exclude other complications
infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain
what is sequestration crisis?
sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
what is acute chest syndrome?
dyspnoea, chest pain, pulmonary infiltrates, low pO2
the most common cause of death after childhood
what is aplastic crisis?
caused by infection with parvovirus
sudden fall in haemoglobin
what is haemolytic crisis?
rare
fall in haemoglobin due an increased rate of haemolysis
CLL features
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
CLL pathophysiology
a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%). It is the most common form of leukaemia seen in adults.
CLL investigations
full blood count:
lymphocytosis
anaemia
blood film: smudge cells (also known as smear cells)
immunophenotyping is the key investigation
ITP management
Emergency treatment: life-threatening or organ threatening bleeding Platelet transfusion, IV methylprednisolone and intravenous immunoglobulin
Platelet count >30*109/L Observation
Platelet count <30*109/L Oral prednisolone
ITP pathophysiology
Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex.
Children with ITP usually have an acute thrombocytopenia that may follow infection or vaccination. In contract, adults tend to have a more chronic condition.
ITP presentation
may be detected incidentally following routine bloods
symptomatic patients may present with
petichae, purpura
bleeding (e.g. epistaxis)
catastrophic bleeding (e.g. intracranial) is not a common presentation
what is Evan’s syndrome>
ITP in association with autoimmune haemolytic anaemia (AIHA)
paroxysmal nocturnal haemoglobinuria pathophysiology
an acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
Pathophysiology
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
paroxysmal nocturnal haemoglobinuria features
haemolytic anaemia
red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
thrombosis e.g. Budd-Chiari syndrome
aplastic anaemia may develop in some patients
paroxysmal nocturnal haemoglobinuria diagnosis
flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
Ham’s test: acid-induced haemolysis (normal red cells would not)
paroxysmal nocturnal haemoglobinuria management
blood product replacement
anticoagulation
eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
stem cell transplantation
hyposplenism on blood film
target cells Howell-Jolly bodies Pappenheimer bodies siderotic granules acanthocytes
IDA blood film
target cells
‘pencil’ poikilocytes
if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
myelofibrosis blood film
‘tear-drop’ poikilocytes
intravascular haemolysis on blood film
schistocytes
megaloblastic anaemia on blood film
hypersegmented neutrophils
what are the porphyrias?
abnormality in enzymes responsible for the biosynthesis of haem
results in overproduction of intermediate compounds (porphyrins)
may be acute or non-acute
Acute intermittent porphyria
autosomal dominant
defect in porphobilinogen deaminase
female and 20-40 year olds more likely to be affected
typically present with abdominal symptoms, neuropsychiatric symptoms
hypertension and tachycardia common
urine turns deep red on standing
porphyria cutanea tarda
most common hepatic porphyria
defect in uroporphyrinogen decarboxylase
may be caused by hepatocyte damage e.g. alcohol, oestrogens
classically photosensitive rash with bullae, skin fragility on face and dorsal aspect of hands
urine: elevated uroporphyrinogen and pink fluorescence of urine under Wood’s lamp
manage with chloroquine
variegate porphyria
autosomal dominant defect in protoporphyrinogen oxidase photosensitive blistering rash abdominal and neurological symptoms more common in South Africans
categories of tumor markers
monoclonal antibodies against carbohydrate or glycoprotein tumour antigens
tumour antigens
enzymes (alkaline phosphatase, neurone specific enolase)
hormones (e.g. calcitonin, ADH)
monoclonal antibody tumor markers
CA 125 Ovarian cancer
CA 19-9 Pancreatic cancer
CA 15-3 Breast cancer
tumor antigen markers
Prostate specific antigen (PSA) Prostatic carcinoma
Alpha-feto protein (AFP) Hepatocellular carcinoma, teratoma
Carcinoembryonic antigen (CEA) Colorectal cancer
S-100 Melanoma, schwannomas
Bombesin Small cell lung carcinoma, gastric cancer, neuroblastoma
ECOG score
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5 Dead
common neutrophil disorders
- chronic granulomatous disease
- chediak-higashi syndrome
- leukocyte adhesion deficiency
what is chronic granulomatous disease?
Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species
Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus)
Negative nitroblue-tetrazolium test
Abnormal dihydrorhodamine flow cytometry test
What is Chediak-higashi syndrome?
Microtubule polymerization defect which leads to a decrease in phagocytosis Affected children have ‘partial albinism’ and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
what is leukocyte adhesion deficiency?
Defect of LFA-1 integrin (CD18) protein on neutrophils Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
what are the common B-cell disorders?
- Common variable immunodeficiency
- Bruxton’s congenital agammaglobulinaemia
- selective IgA deficiency
what is the common T-cell disorder?
DiGeorge syndrome 22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
what is common variable immunodeficiency?
Many varying causes Hypogammaglobulinemia is seen. May predispose to autoimmune disorders and lymphona
what is Bruton’s congenital agammaglobulinaemia?
Defect in Bruton’s tyrosine kinase (BTK) gene that leads to a severe block in B cell development X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes
what is selective IgA deficiency?
Maturation defect in B cells Most common primary antibody deficiency. Recurrent sinus and respiratory infections
Associated with coeliac disease and may cause false negative coeliac antibody screen
Severe reactions to blood transfusions may occur (anti-IgA antibodies → analphylaxis)
combine B and T cell disorders
- Severe combined immunodeficiency
- Ataxic telangiectasia
- Wiskott-Aldrich syndrome
- Hyper IgM Syndromes
what is Severe combined immunodeficiency?
Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency Recurrent infections due to viruses, bacteria and fungi.
Reduced T-cell receptor excision circles
Stem cell transplantation may be successful
what is ataxic telangiectasia?
Defect in DNA repair enzymes Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
what is Wiskott-Aldrich syndrome?
Defect in WASP gene X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia.
Low IgM levels
Increased risk of autoimmune disorders and malignancy
what is hyper IgM ?
Mutations in the CD40 gene Infection/Pneumocystis pneumonia, hepatitis, diarrhoea
what is Waldenstom’s macroglobulinaemia?
Waldenstrom’s macroglobulinaemia is an uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein
Features monoclonal IgM paraproteinaemia systemic upset: weight loss, lethargy hyperviscosity syndrome e.g. visual disturbance the pentameric configuration of IgM increases serum viscosity hepatosplenomegaly lymphadenopathy cryoglobulinaemia e.g. Raynaud's
What is the most common inherited bleeding disorder?
Von Willebrand’s disease
Autosomal dominant
types of von willebrand disease
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
role of von willebrand factor
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
promotes platelet adhesion to damaged endothelium
carrier molecule for factor VIII
investigations von willebrand disease
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
Mx of VWD
tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
factor VIII concentrate
follicular lymphoma translocation
t(14;18)
CML translocation
t(9;22)
Burkitt lymphoma translocation
t(8;14)
mantle cell lymphoma translocation
t(11;14)
acute promyelocytic leukaemia translocation
t(15;17)
which is more common, hodgkin’s or non-hodgkins?
non-hodgkin’s
non hodgkin’s lymphoma risk factors
Elderly
Caucasians
History of viral infection (specifically Epstein-Barr virus)
Family history
Certain chemical agents (pesticides, solvents)
History of chemotherapy or radiotherapy
Immunodeficiency (transplant, HIV, diabetes mellitus)
Autoimmune disease (SLE, Sjogren’s, coeliac disease)
non hodgkin’s lymphoma symptoms
Painless lymphadenopathy (non-tender, rubbery, asymmetrical) Constitutional/B symptoms (fever, weight loss, night sweats, lethargy) Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
differentiate non-hodkins from hodgkins lymphoma
Lymphadenopathy in Hodgkin’s lymphoma can experience alcohol-induced pain in the node
‘B’ symptoms typically occur earlier in Hodgkin’s lymphoma and later in non-Hodgkin’s lymphoma
Extra-nodal disease is much more common in non-Hodgkin’s lymphoma than in Hodgkin’s lymphoma
non-hodgkins lymphoma investigations
Excisional node biopsy is the diagnostic investigation of choice (certain subtypes will have a classical appearance on biopsy such as Burkitt’s lymphoma having a ‘starry sky’ appearance)
CT chest, abdomen and pelvis (to assess staging)
HIV test (often performed as this is a risk factor for non-Hodgkin’s lymphoma)
FBC and blood film (patient may have a normocytic anaemia and can help rule out other haematological malignancy such as leukaemia)
ESR (useful as a prognostic indicator)
LDH (a marker of cell turnover, useful as a prognostic indicator)
Other investigations can be ordered as the clinical picture indicates (LFT’s if liver metastasis suspected, PET CT or bone marrow biopsy to look for bone involvement, LP if neurological symptoms)
non-hodgkins lymphoma stageing
The most common staging system used for non-Hodgkin’s lymphoma is the Ann Arbor system.
Stage 1 - One node affected
Stage 2 - More than one node affected on the same side of the diaphragm
Stage 3 - Nodes affected on both sides of the diaphragm
Stage 4 - Extra-nodal involvement e.g. Spleen, bone marrow or CNS
The stage is combined with the letter A or B to indicate the presence of ‘B’ symptoms. With the letter A indicating no B symptoms present and B indicating any of the beta symptoms present. For example, a patient with a single node affected and no ‘B’ symptoms would be stage 1A.
non-hodgkins lymphoma management
Management is dependent on the specific sub-type of non-Hodgkin’s lymphoma and will typically take the form of watchful waiting, chemotherapy or radiotherapy.
All patients will receive flu/pneumococcal vaccines
Patients with neutropenia may require antibiotic prophylaxis
non-hodgkins lymphoma complications
Bone marrow infiltration causing anaemia, neutropenia or thrombocytopenia
Superior vena cava obstruction
Metastasis
Spinal cord compression
Complications related to treatment e.g. Side effects of chemotherapy
malignancy associated with EBV
Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
malignancy associated with HTLV-1
adult T-cell leukaemia/lymphoma
malignancy associated with HIV-1
High-grade B-cell lymphoma
malignancy associated with H.pylori
gastric lymphoma (MALT)
malignancy associated with protozoa
malaria- Burkitt’s lymphoma
multiple myeloma features
C - hypercalcaemia
R - renal insufficiency (suggested by the U&Es and complicated by the recurrent UTIs - patients are susceptible to infections as the production of antibodies by normal plasma cells is impaired)
A - this patient is short of breath due to her anaemia (and the FBC shows evidence of pancytopenia - typically due to plasma cells infiltrating the bone marrow)
B - bone pain (albeit subtle in the form of a vague history of lower back pain)
myeloma investigations
monoclonal proteins (usually IgG or IgA) in the serum and urine (Bence Jones proteins) increased plasma cells in the bone marrow historically a skeletal survey has been done to look for bone lesions. However, whole-body MRI is increasingly used and is now recommended in the 2016 NICE guidelines X-rays: 'rain-drop skull' (likened to the pattern rain forms after hitting a surface and splashing, where it leaves a random pattern of dark spots). Note that a very similar, but subtly different finding is found in primary hyperparathyroidism - 'pepperpot skull'
myeloma criteria
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 causes hypercalcaemia in myeloma?
primary factor: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells
much less common contributing factors: impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels
causes of thrombocytosis
reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis
malignancy
essential thrombocytosis (see below), or as part of another myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia rubra vera
hyposplenism
what is essential thrombocytosis?
Essential thrombocytosis is one of the myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis. Megakaryocyte proliferation results in an overproduction of platelets.
Features
platelet count > 600 * 109/l
both thrombosis (venous or arterial) and haemorrhage can be seen
a characteristic symptom is a burning sensation in the hands
a JAK2 mutation is found in around 50% of patients
essential thrombocytosis management
hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
interferon-α is also used in younger patients
low-dose aspirin may be used to reduce the thrombotic risk
what is a RAST test?
Determines the amount of IgE that reacts specifically with suspected or known allergens, for example IgE to egg protein. Results are given in grades from 0 (negative) to 6 (strongly positive)
Useful for food allergies, inhaled allergens (e.g. Pollen) and wasp/bee venom
Blood tests may be used when skin prick tests are not suitable, for example if there is extensive eczema or if the patient is taking antihistamines
causes of B12 def
pernicious anaemia: most common cause
post gastrectomy
vegan diet or a poor diet
disorders/surgery of terminal ileum (site of absorption)
Crohn’s: either diease activity or following ileocaecal resection
metformin (rare)
B12 def features
macrocytic anaemia
sore tongue and mouth
neurological symptoms
the dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesia
neuropsychiatric symptoms: e.g. mood disturbances
B12 def management
if no neurological involvement 1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 months
if a patient is also deficient in folic acid then it is important to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord
what is hereditary spherocytosis
most common hereditary haemolytic anaemia in people of northern European descent
autosomal dominant defect of red blood cell cytoskeleton
the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
red blood cell survival reduced as destroyed by the spleen
hereditary spherocytosis diagnosis
the osmotic fragility test was previously the recommend investigation of choice. However, it is now deemed unreliable and is no longer recommended
the British Journal of Haematology (BJH) guidelines state that ‘patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration[MCHC], increase in reticulocytes) do not require any additional tests
if the diagnosis is equivocal the BJH recommend the cryohaemolysis test and EMA binding
for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
what is hereditary angioedema?
Hereditary angioedema (HAE) is an autosomal dominant condition associated with low plasma levels of the C1 inhibitor (C1-INH, C1 esterase inhibitor) protein. C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
hereditary angioedema investigations
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
hereditary angioedema symptoms
attacks may be proceeded by painful macular rash
painless, non-pruritic swelling of subcutaneous/submucosal tissues
may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
urticaria is not usually a feature
hereditary angioedema management
acute
HAE does not respond to adrenaline, antihistamines, or glucocorticoids
IV C1-inhibitor concentrate, fresh frozen plasma (FFP) if this is not available
prophylaxis: anabolic steroid Danazol may help
mechanism of action of letrozole
Letrozole and anastrozole are aromatase inhibitors which are used as a treatment in post-menopausal women with hormone-dependent breast cancer. They work by reducing peripheral oestrogen synthesis from body fat and muscles. Common side effects include osteoporosis, hot flushes and vaginal bleeding.
mechanism of action of tamoxifen
Tamoxifen is a SERM which acts as an oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor-positive breast cancer.
Adverse effects
menstrual disturbance: vaginal bleeding, amenorrhoea
hot flushes - 3% of patients stop taking tamoxifen due to climacteric side-effects
venous thromboembolism
endometrial cancer
cyclophosphamide mechanism
Alkylating agent - causes cross-linking in DNA Haemorrhagic cystitis, myelosuppression, transitional cell carcinoma
Bleomycin mechanism
Degrades preformed DNA Lung fibrosis
Anthracyclines e.g. Doxorubicin mechanism
Stabilizes DNA-topoisomerase II complex inhibits DNA & RNA synthesis Cardiomyopathy
Methotrexate mechanism
Inhibits dihydrofolate reductase and thymidylate synthesis Myelosuppression, mucositis, liver fibrosis, lung fibrosis
5-FU mechanism
Pyrimidine analogue inducing cell cycle arrest and apoptosis by blocking thymidylate synthase (works during S phase) Myelosuppression, mucositis, dermatitis
6 mercaptopurine mechanism
Purine analogue that is activated by HGPRTase, decreasing purine synthesis Myelosuppression
cytarabine mechanism
Pyrimidine antagonist. Interferes with DNA synthesis specifically at the S-phase of the cell cycle and inhibits DNA polymerase Myelosuppression, ataxia
Vincristine mechanism
Inhibits formation of microtubules Vincristine: Peripheral neuropathy (reversible) , paralytic ileus
Vinblastine: myelosuppression
Docetaxel emchanism
Prevents microtubule depolymerisation & disassembly, decreasing free tubulin Neutropaenia
Irinotecan mechanism
Inhibits topoisomerase I which prevents relaxation of supercoiled DNA Myelosuppression
cisplatin mechanism
Causes cross-linking in DNA Ototoxicity, peripheral neuropathy, hypomagnesaemia
hydroxyurea mechanism
Inhibits ribonucleotide reductase, decreasing DNA synthesis Myelosuppression
what is polycythemia vera
Polycythaemia vera (previously called polycythaemia rubra vera) is a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera and this has resulted in significant changes to the diagnostic criteria. The incidence of polycythaemia vera peaks in the sixth decade.
polycythemia vera features
hyperviscosity pruritus, typically after a hot bath splenomegaly haemorrhage (secondary to abnormal platelet function) plethoric appearance hypertension in a third of patients low ESR
polycythemia vera investigations
full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in half of patients)
JAK2 mutation
serum ferritin
renal and liver function tests
If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests: red cell mass arterial oxygen saturation abdominal ultrasound serum erythropoietin level bone marrow aspirate and trephine cytogenetic analysis erythroid burst-forming unit (BFU-E) culture
polycythemia vera diagnostic criteria
JAK2-positive polycythaemia vera - diagnosis requires both criteria to be present
Criteria Notes
A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2
JAK2-negative PRV - diagnosis requires A1 + A2 + A3 + either another A or two B criteria
Criteria Notes
A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells
B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin
what is warm autoimmune haemolytic anaemia
In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen. Management options include steroids, immunosuppression and splenectomy
causes of warm haemolytic anaemia
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia: e.g. lymphoma, CLL
drugs: e.g. methyldopa
what is cold autoimmune haemolytic anaemia
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud’s and acrocynaosis. Patients respond less well to steroids
causes of cold haemolytic anaemia
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
types of hodgkins lymphoma
Nodular sclerosing Most common (around 70%) Good prognosis More common in women. Associated with lacunar cells
Mixed cellularity Around 20% Good prognosis Associated with a large number of Reed-Sternberg cells
Lymphocyte predominant A*round 5% Best prognosis
Lymphocyte depleted Rare Worst prognosis
hodgkins lymphoma B symptoms
weight loss > 10% in last 6 months
fever > 38ºC
night sweats
poor prognostic factors hodgkins lymphoma
age > 45 years stage IV disease haemoglobin < 10.5 g/dl lymphocyte count < 600/µl or < 8% male albumin < 40 g/l white blood count > 15,000/µl
AML features
anaemia: pallor, lethargy, weakness
neutropenia: whilst white cell counts may be very high, functioning neutrophil levels may be low leading to frequent infections etc
thrombocytopenia: bleeding
splenomegaly
bone pain
poor prognostic features AML
> 60 years
20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
what is acute promyelocytic leukaemia
associated with t(15;17)
fusion of PML and RAR-alpha genes
presents younger than other types of AML (average = 25 years old)
Auer rods (seen with myeloperoxidase stain)
DIC or thrombocytopenia often at presentation
good prognosis
AML classification
French-American-British (FAB) MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
haemophillia blood tests
prolonged APTT
bleeding time, thrombin time, prothrombin time normal
Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment.
what is haemophillia?
Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christmas disease) there is a lack of factor IX
MGUS criteria
(1) A monoclonal paraprotein band less than 30 g/l (< 3g/dl);
(2) Plasma cells less than 10% on bone marrow examination;
(3) No evidence of bone lesions, anemia, hypercalcemia, or
chronic kidney disease related to the paraprotein, and
(4) No evidence of another B-cell proliferative disorder.
what does lead poisoning do?
defective ferrochelatase and ALA dehydratase function.
lead poisoning features
abdominal pain peripheral neuropathy (mainly motor) fatigue constipation blue lines on gum margin (only 20% of adult patients, very rare in children)
lead poisoning investigations
the blood lead level is usually used for diagnosis. Levels greater than 10 mcg/dl are considered significant
full blood count: microcytic anaemia. Blood film shows red cell abnormalities including basophilic stippling and clover-leaf morphology
raised serum and urine levels of delta aminolaevulinic acid may be seen making it sometimes difficult to differentiate from acute intermittent porphyria
urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased)
in children, lead can accumulate in the metaphysis of the bones although x-rays are not part of the standard work-up
lead poisoning management
various chelating agents are currently used: dimercaptosuccinic acid (DMSA) D-penicillamine EDTA dimercaprol
Burkitt’s lymphoma is what?
high-grade B-cell neoplasm. There are two major forms:
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
burkitt’s lymphoma translocation
c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form.
how to reduce the chance of tumorlysis syndrome in burkitts lymphoma
Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring.
complications of tumor lysis
hyperkalaemia hyperphosphataemia hypocalcaemia hyperuricaemia acute renal failure
pathophysiology G6PD
G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone
this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH
NADPH is important for converting oxidizied glutathine back to it’s reduced form
reduced glutathine protects red blood cells from oxidative damage by oxidants such as superoxide anion (O2-) and hydrogen peroxide
↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress
features G6PD
neonatal jaundice is often seen intravascular haemolysis gallstones are common splenomegaly may be present Heinz bodies on blood films. Bite and blister cells may also be seen
G6PD diagnosis
levels should be checked around 3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results
drugs causing haemolysis in G6PD
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
prognostic marker myeloma
B2-microglobulin is a useful marker of prognosis - raised levels imply poor prognosis. Low levels of albumin are also associated with a poor prognosis
prognostic index myeloma
I B2 microglobulin < 3.5 mg/l
Albumin > 35 g/l 62
II Not I or III 45
III B2 microglobulin > 5.5 mg/l 29
thymoma associations
myasthenia gravis (30-40% of patients with thymoma)
red cell aplasia
dermatomyositis
also : SLE, SIADH
examples of IgG4 disease
Riedel’s Thyroiditis
Autoimmune pancreatitis
Mediastinal and Retroperitoneal Fibrosis
Periaortitis/periarteritis/Inflammatory aortic aneurysm
Kuttner’s Tumour (submandibular glands) & Mikulicz Syndrome (salivary and lacrimal glands)
Possibly sjogren’s and primary biliary cirrhosis
types of cryoglobulinaemia
type I (25%): monoclonal type II (25%): mixed monoclonal and polyclonal: usually with rheumatoid factor type III (50%): polyclonal: usually with rheumatoid factor
type 1 cryoglobulinaemia
monoclonal - IgG or IgM
associations: multiple myeloma, Waldenstrom macroglobulinaemia
type 2 cryoglobulinaemia
mixed monoclonal and polyclonal: usually with rheumatoid factor
associations: hepatitis C, rheumatoid arthritis, Sjogren’s, lymphoma
type 3 cryoglobulinaemia
polyclonal: usually with rheumatoid factor
associations: rheumatoid arthritis, Sjogren’s
causes of alpha -thalassaemia
chromosome 16
Clinical severity depends on the number of alpha globulin alleles affected:
If 1 or 2 alpha globulin alleles are affected then the blood picture would be hypochromic and microcytic, but the Hb level would be typically normal
If are 3 alpha globulin alleles are affected results in a hypochromic microcytic anaemia with splenomegaly. This is known as Hb H disease
If all 4 alpha globulin alleles are affected (i.e. homozygote) then death in utero (hydrops fetalis, Bart’s hydrops)
hairy cell leukaemia features
pancytopenia
splenomegaly
skin vasculitis in 1/3 patients
‘dry tap’ despite bone marrow hypercellularity
tartrate resistant acid phosphotase (TRAP) stain positive
hairy cell leukaemia management
chemotherapy is first-line: cladribine, pentostatin
immunotherapy is second-line: rituximab, interferon-alpha
drugs causing pancytopenia
cytotoxics antibiotics: trimethoprim, chloramphenicol anti-rheumatoid: gold, penicillamine carbimazole* anti-epileptics: carbamazepine sulphonylureas: tolbutamide
CLL indications for treatment
progressive marrow failure: the development or worsening of anaemia and/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
autoimmune cytopaenias e.g. ITP
CLL management
patients who have no indications for treatment are monitored with regular blood counts
fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial treatment of choice for the majority of patients
ibrutinib may be used in patients who have failed a previous therapy
haptoglobin is decreased in what?
intravascular haemolysis
when is MCHC increased?
hereditary spherocytosis
autoimmune haemolytic anemia
when is MCHC decreased?
microcytic anaemia (e.g. iron deficiency)
contraindication to platelet transfusion
Chronic bone marrow failure
Autoimmune thrombocytopenia
Heparin-induced thrombocytopenia, or
Thrombotic thrombocytopenic purpura.
what is the benefit of irradiated blood products?
depleted of T-lymphocytes and used to avoid transfusion-associated graft versus host disease (TA-GVHD) caused by engraftment of viable donor T lymphocytes.
aplastic anaemia management
Supportive
blood products
prevention and treatment of infection
Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG)
prepared in animals (e.g. rabbits or horses) by injecting human lymphocytes
is highly allergenic and may cause serum sickness (fever, rash, arthralgia), therefore steroid cover usually given
immunosuppression using agents such as ciclosporin may also be given
Stem cell transplantation
allogeneic transplants have a success rate of up to 80%
when to use FFp
most suited for ‘clinically significant’ but without ‘major haemorrhage’ in patients with a prothrombin time (PT) ratio or activated partial thromboplastin time (APTT) ratio > 1.5
typically 150-220 mL
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding
In contrast to red cells, the universal donor of FFP is AB blood because it lacks any anti-A or anti-B antibodies
when to use cryoprecipitate?
contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin, produced by further processing of Fresh Frozen Plasma (FFP). Clinically it is most commonly used to replace fibrinogen
much smaller volume than FFP, typically 15-20mL
most suited for patients for ‘clinically significant’ but without ‘major haemorrhage’ who have a fibrinogen concentration < 1.5 g/L
example use cases include disseminated intravascular coagulation, liver failure and hypofibrinogenaemia secondary to massive transfusion. It may also be used in an emergency situation for haemophiliacs (when specific factors not available) and in von Willebrand disease
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding where the fibrinogen concentration < 1.0 g/L
when to use prothrombin concentrate
used for the emergency reversal of anticoagulation in patients with either severe bleeding or a head injury with suspected intracerebral haemorrhage
can be used prophylactically in patients undergoing emergency surgery depending on the particular circumstance
CML presentation
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
an increase in granulocytes at different stages of maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
CML management
imatinib is now considered first-line treatment
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
Imatinib
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
very high response rate in chronic phase CML
leucocyte alkaline phosphate raised in
myelofibrosis leukaemoid reactions polycythaemia rubra vera infections steroids, Cushing's syndrome pregnancy, oral contraceptive pill
leucocyte alkaline phosphate low in
chronic myeloid leukaemia
pernicious anaemia
paroxysmal nocturnal haemoglobinuria
infectious mononucleosis
what is sideroblastic anaemia
red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired
causes of sideroblastic anaemia
Congenital cause: delta-aminolevulinate synthase-2 deficiency
Acquired causes myelodysplasia alcohol lead anti-TB medications
sideroblastic anaemia investigations
hypochromic microcytic anaemia (more so in congenital)
bone marrow: sideroblasts and increased iron stores
sideoblasstic anaemia management
supportive
treat any underlying cause
pyridoxine may help
beta thalassaemia features
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia HbA2 raised (> 3.5%)
sickle-cell crisis management acute
analgesia e.g. opiates
rehydrate
oxygen
consider antibiotics if evidence of infection
blood transfusion
exchange transfusion: e.g. if neurological complications
long-term sickle cell management
hydroxyurea
increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
NICE CKS suggest that sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years
anti emetic that acts on NK1
Aprepitant
polycythemia vera management
aspirin
venesection - first line treatment
hydroxyurea -slight increased risk of secondary leukaemia
phosphorus-32 therapy
polycythemia vera prognosis
thrombotic events are a significant cause of morbidity and mortality
5-15% of patients progress to myelofibrosis
5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment)
intravascular haemolysis casues
mismatched blood transfusion G6PD deficiency* red cell fragmentation: heart valves, TTP, DIC, HUS paroxysmal nocturnal haemoglobinuria cold autoimmune haemolytic anaemia
extravascular haemolysis causes
haemoglobinopathies: sickle cell, thalassaemia
hereditary spherocytosis
haemolytic disease of newborn
warm autoimmune haemolytic anaemia
atiphospholipid syndrome in pregancy management
low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing
low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation
these interventions increase the live birth rate seven-fold
cervical cancer and HPV
Human papilloma virus (HPV) infection is the most important risk factor for developing cervical cancer. Subtypes 16,18 & 33 are particularly carcinogenic. The other most common subtypes (6 & 11) are non-carcinogenic and associated with genital warts.
Infected endocervical cells may undergo changes resulting in the development of koilocytes. These have the following characteristics:
enlarged nucleus
irregular nuclear membrane contour
the nucleus stains darker than normal (hyperchromasia)
a perinuclear halo may be seen
CLL poor prognostic factors
male sex age > 70 years lymphocyte count > 50 prolymphocytes comprising more than 10% of blood lymphocytes lymphocyte doubling time < 12 months raised LDH CD38 expression positive TP53 mutation
CLL chromosomal changes
deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality, being seen in around 50% of patients. It is associated with a good prognosis
deletions of part of the short arm of chromosome 17 (del 17p) are seen in around 5-10% of patients and are associated with a poor prognosis
SVC obstruction features
dyspnoea is the most common symptom swelling of the face, neck and arms - conjunctival and periorbital oedema may be seen headache: often worse in the mornings visual disturbance pulseless jugular venous distension
SVC obstruction management
general: dexamethasone, balloon venoplasty, stenting
small cell: chemotherapy + radiotherapy
non-small cell: radiotherapy
leukaemoid raction causes
The leukaemoid reaction describes the presence of immature cells such as myeloblasts, promyelocytes and nucleated red cells in the peripheral blood. This may be due to infiltration of the bone marrow causing the immature cells to be ‘pushed out’ or sudden demand for new cells
Causes severe infection severe haemolysis massive haemorrhage metastatic cancer with bone marrow infiltration
leukaemoid reaction v CML
Leukaemoid reaction
high leucocyte alkaline phosphatase score
toxic granulation (Dohle bodies) in the white cells
‘left shift’ of neutrophils i.e. three or fewer segments of the nucleus
Chronic myeloid leukaemia
low leucocyte alkaline phosphatase score
TTP pathogenesis
abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels
in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns (‘cleaves’) large multimers of von Willebrand’s factor
overlaps with haemolytic uraemic syndrome (HUS)
TTP features
rare, typically adult females fever fluctuating neuro signs (microemboli) microangiopathic haemolytic anaemia thrombocytopenia renal failure
TTP causes
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
3 types of non-small cell cancer
squamous
adeno
large cell
squamous cell lung cancer
typically central
associated with parathyroid hormone-related protein (PTHrP) secretion → hypercalcaemia
strongly associated with finger clubbing
hypertrophic pulmonary osteoarthropathy (HPOA)
adenocarcinoma
typically peripheral
most common type of lung cancer in non-smokers, although the majority of patients who develop lung adenocarcinoma are smokers
large cell lung cancer
typically peripheral
anaplastic, poorly differentiated tumours with a poor prognosis
may secrete β-hCG
TTP management
no antibiotics - may worsen outcome
plasma exchange is the treatment of choice
steroids, immunosuppressants
vincristine
hereditary spherocytosis management
acute haemolytic crisis: treatment is generally supportive transfusion if necessary longer term treatment: folate replacement splenectomy
most common tumor causing bone metastasis
prostate
breast
lung
how to prevent haemorrhagic cystitis in cyclophosphamide treatment
Cyclophosphamide may be converted to urotoxic metabolites such as acrolein. Mesna binds to these metabolites through its sulfhydryl-moieties and reduces the incidence of haemorrhagic cystitis
MGUS V Myeloma
normal immune function
normal beta-2 microglobulin levels
lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
stable level of paraproteinaemia
no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease)
what is myelofibrosis?
a myeloproliferative disorder
thought to be caused by hyperplasia of abnormal megakaryocytes
the resultant release of platelet derived growth factor is thought to stimulate fibroblasts
haematopoiesis develops in the liver and spleen
myelofibrosis features
e.g. elderly person with symptoms of anaemia e.g. fatigue (the most common presenting symptom)
massive splenomegaly
hypermetabolic symptoms: weight loss, night sweats etc
melofibrosis investigations
anaemia
high WBC and platelet count early in the disease
‘tear-drop’ poikilocytes on blood film
unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
high urate and LDH (reflect increased cell turnover)
most common bacteria isolated in neutropenic sepsis
gram-positive cocci. Gram-negative bacilli used to be the most common pathogen isolated in neutropenic sepsis, but over time the most common pathogens are now gram-positive organisms. These accounts for a majority of the identified organisms, and are most commonly endogenous organisms. The most frequent cause is Staphylococcus epidermidis, and following this are other staphylococci and streptococci species.
acute chest syndrome management
Oxygen therapy to maintain saturations > 95%
Intravenous fluids to ensure euvolaemia
Adequate pain relief
Incentive spirometry in all patients presenting with rib or chest pain
Antibiotics with cover for atypical organisms
Early consultation with the critical care team and haematology
what is protein C deficiency?
Protein C deficiency is an autosomal codominant condition which causes an increased risk of thrombosis
Features
venous thromboembolism
skin necrosis following the commencement of warfarin: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis
genotypes sicklecell
HbAA Normal
HbAS sickle cell trait, usually asymptomatic
Hb SC/ Sβ+ moderate sickle cell disease (sickle cell beta + thalassemia indicates the blood has some normal haemoglobin)
Hb SS/ Sβ0 severe sickle cell disease/ Sickle cell beta 0 thalassemia (the zero indicates the blood has no normal haemoglobin)
antiphospholipid Mx in pregancy
low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing
low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation
these interventions increase the live birth rate seven-fold
