ham-onc Flashcards
1
Q
what is hereditary spherocytosis
A
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
2
Q
How does Hereditary Spherocytosis present?
A
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
MCHC elevated
3
Q
How is hereditary spherocytosis diagnosed
A
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 EMA binding test and the cryohaemolysis test
for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
4
Q
How is Hereditary Sperocytosis managed?
A
Acute haemolytic crisis:
- treatment is generally supportive
- transfusion if necessary
longer term treatment:
- folate replacement
- splenectomy
5
Q
What is present in hereditary spherocytosis post splenectomy
A
Howell-Jolly bodies
Howell-Jolly bodies are remnants of the red blood cell (RBC) nucleus which are normally removed by the spleen. Post-splenectomy these Howell-Jolly bodies persist and can be observed on histology.
6
Q
What type of RBCs are seen in microangiopthic haemolytic aneamia
A
Schistocytes are sheared RBCs seen in microangiopathic haemolytic anaemia
7
Q
when are heinze bodies seen ?
A
Heinz bodies and bite cells are characteristic of glucose-6-phosphate dehydrogenase (G6PD) deficiency
8
Q
what are Howell-Joly bodies
A
Howell-Jolly bodies are seen in hyposplenism
9
Q
what are pencil cells
A
pencil cells are a feature of iron deficiency anaemia
10
Q
when are target cells seen
A
Sickle-cell/thalassaemia
Iron-deficiency anaemia
Hyposplenism
Liver disease
11
Q
when are ‘tear drop’ poikiolcytes seen?
A
myelofibrosis
12
Q
when are spherocytes seen?
A
Hereditary spherocytosis
Autoimmune hemolytic anaemia
13
Q
When do you see Basophilic stippling
A
Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia
14
Q
when do you see Schistocytes (‘helmet cells’)
A
Intravascular haemolysis
Mechanical heart valve
Disseminated intravascular coagulation
15
Q
When do you see Burr cells
A
Uraemia
Pyruvate kinase deficiency
16
Q
when do you see Acanthocytes
A
Abetalipoproteinemia
17
Q
what is hereditary angioedema?
A
AD condition associated with low plasma levels of C1 inhibitor
18
Q
what investigations would be done for hereditary angioedema?
A
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
19
Q
what are the symptoms of hereditary angioedema?
A
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
20
Q
how do you manage hereditary angioedema?
A
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
21
Q
what is ITP
A
Immune (or idiopathic) thrombocytopenic purpura (ITP) -
an immune mediated reduction in the platelet count
Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex.
22
Q
when does ITP occur in children
A
usually following infection or vaccination
23
Q
what are the symptoms of ITP
A
isolated thrombocytopenia in a well adult - often not symptomatic
symptomatic patients may present with:
petechiae, purpura
bleeding (e.g. epistaxis)
catastrophic bleeding (e.g. intracranial) is not a common presentation
24
Q
what investigations for ITP
A
full blood count: isolated thrombocytopenia
blood film
a bone marrow examination is no longer used routinely
antiplatelet antibody testing has poor sensitivity and doesn’t affect clinical management so is not commonly done
25
what is the management of ITP
first-line treatment for ITP is oral prednisolone
pooled normal human immunoglobulin (IVIG) may also be used
- it raises the platelet count quicker than steroids, therefore may be used if active bleeding or an urgent invasive procedure is required
splenectomy is now less commonly used
26
What is Evan's syndrome
ITP in association with autoimmune haemolytic anaemia (AIHA)
27
what is tumour lysis syndrome
Tumour lysis syndrome (TLS) is a potentially deadly condition related to the treatment of high-grade lymphomas and leukaemias. It can occur in the absence of chemotherapy but is usually triggered by the introduction of combination chemotherapy. On occasion, it can occur with steroid treatment alone.
28
when does tumour lysis syndrome occur?
TLS occurs from the breakdown of the tumour cells and the subsequent release of chemicals from the cell.
29
what would bloods show in tumour lysis syndrome?
It leads to a high potassium and high phosphate level in the presence of a low calcium. It should be suspected in any patient presenting with an acute kidney injury in the presence of a high phosphate and high uric acid level.
30
how do you prevent tumour lysis syndrome?
IV fluids
patients are higher risk should receive either allopurinol or rasburicase
rasburicase - a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Allantoin is much more water-soluble than uric acid and is, therefore, more easily excreted by the kidneys
generally preferred now for patients at a higher risk of developing TLS
allopurinol - generally used for patients in lower-risk groups
rasburicase and allopurinol should not be given together in the management of tumour lysis syndrome as this reduces the effect of rasburicase
31
what grading system is used for tumour lysis syndrome?
Cairo-Bishop system
Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring within three days before or seven days after chemotherapy.
uric acid > 475umol/l or 25% increase
potassium > 6 mmol/l or 25% increase
phosphate > 1.125mmol/l or 25% increase
calcium < 1.75mmol/l or 25% decrease
Clinical tumor lysis syndrome: laboratory tumour lysis syndrome plus one or more of the following:
increased serum creatinine (1.5 times upper limit of normal)
cardiac arrhythmia or sudden death
seizure
32
what is used for the management of vWD
desmopressin
33
how is VWD inherited?
AD
34
what is the role of von willer brand 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
35
what are the types of vWD
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
36
what is the investigations for vWD
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
37
how is vWD managed?
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
38
what are the symptoms of lead poisoning
Basophillic stippling on blood film
abdo pain
constiation
peripheral neuropathy
associated microcytic anaemia
fatigue
39
how is lead poisoning managed?
Management - various chelating agents are currently used:
dimercaptosuccinic acid (DMSA)
D-penicillamine
EDTA
dimercaprol
40
what chromosome is found in CML
t(9;22) - Philadelphia chromosome
present in > 95% of patients with CML
this results in part of the Abelson proto-oncogene being moved to the BCR gene on chromosome 22
the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
poor prognostic indicator in ALL
41
what chromosome is seen in acute promyelocytic leukaemia?
t(15;17)
42
what chromosome is seen in burkitt's symphoma
t(8;14)
MYC oncogene is translocated to an immunoglobulin gene
43
what chromosome is seen in mantle cell lymphoma
t(11;14)
deregulation of the cyclin D1 (BCL-1) gene
44
what chromosome is seen in follicular lymphoma?
t(14;18)
increased BCL-2 transcription
45
what gene is associated with prostate cancer ?
BRCA 2
46
what gene is associated with familial adenomatous polyposis?
APC
47
what is Li-Fraumeni syndrome?
Autosomal dominant
Consists of germline mutations to p53 tumour suppressor gene
High incidence of malignancies particularly sarcomas and leukaemias
Diagnosed when:
*Individual develops sarcoma under 45 years
*First degree relative diagnosed with any cancer below age 45 years and another family member develops malignancy under 45 years or sarcoma at any age
47
what is lynch syndrome
Autosomal dominant
Develop colonic cancer and endometrial cancer at young age
80% of affected individuals will get colonic and/ or endometrial cancer
High risk individuals may be identified using the Amsterdam criteria
Amsterdam criteria
Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two.
Two successive affected generations.
One or more colon cancers diagnosed under age 50 years.
Familial adenomatous polyposis (FAP) has been exclude
48
what is Gardners syndrome
Autosomal dominant familial colorectal polyposis
Multiple colonic polyps
Extra colonic diseases include: skull osteoma, thyroid cancer and epidermoid cysts
Desmoid tumours are seen in 15%
Mutation of APC gene located on chromosome 5
Due to colonic polyps most patients will undergo colectomy to reduce risk of colorectal cancer
Now considered a variant of familial adenomatous polyposis coli
49
what is oral allergy syndrome
Oral allergy syndrome, also known as pollen-food allergy, is an IgE-mediated hypersensitivity reaction to specific raw, plant-based foods including fruits, vegetables, nuts and certain spices. It typically presents with mild tingling or pruritus of the lips, tongue and mouth.
50
what is used to avoid transfusion-associated graft versus host disease?
irradiated blood products
his is particularly important in immunocompromised patients, such as those with lymphoma who have undergone chemotherapy.
51
what is beta-thalassemia trait?
Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic
52
what are the features of beta thalassaemia trait
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
HbA2 raised (> 3.5%)
53
what are the common tumours that cause bone mets?
prostate
breast
lung
54
what kind of infection is most likely to occur following platelet transfusion?
Platelet transfusions are at particular risk of bacterial contamination as they are stored at room temperature
55
what will be on the blood tests in microangiopathic haemolytic anaemia?
anaemia, low haptoglobin and schistocytes
56
what it TTP?
Pathogenesis of thrombotic thrombocytopenic purpura (TTP)
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
57
what are the features of TTP
Features
rare, typically adult females
fever
fluctuating neuro signs (microemboli)
microangiopathic haemolytic anaemia
thrombocytopenia
renal failure
58
what are the causes of TTP
Causes
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
59
what leads to TTP in pregnancy?
Pregnancy is a secondary cause of this condition, which is caused by acquired inhibition of ADAMTS13. This is a metalloproteinase responsible for breaking large multimers von Willebrand factor (vWF) into smaller sub-units. The increased amount of circulating vWF results in platelet adhesion and thrombosis. Platelets are used up in creating thrombi and paradoxically, the overall amount of circulating platelets is subsequently reduced, resulting in a tendency to bleed.
60
how does anastrozole and letrozole work?
they are aromatase inhibitors that reduce peripheral oestrogen synthesis
61
what symptoms do you get in neoplastic spina cord compression?
back pain - may be worse on lying down/coughing
lower limb weakness
sensory changes: sensory loss and numbness
neurological signs depend on the level of the lesion. Lesions above L1 usually result in upper motor neuron signs in the legs and a sensory level. Lesions below L1 usually cause lower motor neuron signs in the legs and perianal numbness. Tendon reflexes tend to be increased below the level of the lesion and absent at the level of the lesion
62
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
63
features of myelofibrosis?
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
64
what are the lab findings in myelofibrosis ?
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)
65
what is autoimmune haemolytic anaemia?
Autoimmune haemolytic anaemia (AIHA) may be divided in to 'warm' and 'cold' types, according to at what temperature the antibodies best cause haemolysis. It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infection or drugs.
Warm is the most common type of AIHA. 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
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
66
what are the investigations for autoimmune haemolytic anaemia?
general features of haemolytic anaemia
anaemia
reticulocytosis
low haptoglobin
raised lactate dehydrogenase (LDH) and indirect bilirubin
blood film: spherocytes and reticulocytes
specific features of autoimmune haemolytic anaemia
positive direct antiglobulin test (Coombs' test).
67
what are the causes and management of warm autoimmune haemolytic anaemia?
Causes
idiopathic
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia
lymphoma
chronic lymphocytic leukaemia
drugs: e.g. methyldopa
Management
treat underlying disorders
steroid (+/- rituximab)
## Footnote
Warm is the most common type of AIHA. 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.
68
what are the causes of cold autoimmune haemolytic anaemia?
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
## Footnote
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
69
what cytotoxic agent is most commonly associated with ototoxicity?
Cisplatin
70
what cn H.pylori infection lead to?
Helicobacter pylori infection can lead to gastric lymphoma (MALT). These are typically arise in the antrum of the stomach and can present with systemic features such as fevers and night sweats.
71
what malignancy can EBV lead to
Hodgkin's and Burkitt's lymphoma, nasopharyngeal carcinoma
72
what can HTLV-1 lead to
Adult T-cell leukaemia/lymphoma
73
what can HIV-1 lead to
high grade B Cell lymphoma
74
what malignancy can malaria lead to
Burkitts lymphoma
75
what are patients with polycythaemia vera at risk of developing?
myelopfibrosis - approx 6-10% of patients develop it
76
what cancer is CA 15-3 a marker for?
breast cancer
77
what is acute promyelocytic leukaemia?
type of AML - M3 subtype
associated with the t(15;17) translocation which causes fusion of the PML and RAR-alpha genes
78
what are the features of APML?
presents younger than other types of AML (average = 25 years old)
DIC or thrombocytopenia often at presentation
good prognosis
79
how is APML treated?
APML is treated with all-trans retinoic acid (ATRA) to force immature granulocytes into maturation to resolve a blast crisis prior to more definitive chemotherapy.
80
what are the side effects of cisplatin?
peripheral neuropathy, ototoxicity and hypomagnesaemia, as seen here
81
what is a comm complication of cyclophosphamide treatment? and how is this complication prevented?
haemorrhagic cystitis, which is a known complication of this treatment. Mesna detoxifies acrolein, a urotoxic metabolite of cyclophosphamide that accumulates in the bladder. It is typically co-administered with cyclophosphamide to prevent this complication.
82
what are aromatase inhibitors and what are the adverse effects?
Anastrozole and letrozole are aromatase inhibitors that reduces peripheral oestrogen synthesis. This is important as aromatisation accounts for the majority of oestrogen production in postmenopausal women and therefore anastrozole is used for ER +ve breast cancer in this group.
Adverse effects
osteoporosis- NICE recommends a DEXA scan when initiating a patient on aromatase inhibitors for breast cancer
hot flushes
arthralgia, myalgia
insomnia
83
what are the clinical signs of TTP
Classically characterised as a pentad of: thrombocytopenia, microvascular haemolysis, fluctuating neurological signs, renal impairment and fever.
84
what is the management of TTP?
rapid plasma exchange and the IV methylpred
platelet tansfusion only indicated if there is an ongoing life threatening bleed
85
what is Wiskott-Aldrich syndrome?
This condition is an X-linked recessive disorder characterized by the triad of eczema, recurrent infections, and thrombocytopenia.
86
what is ataxic telangiectasia ?
autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immune deficiency, and increased risk for malignancies
87
what is Chediak-Higashi syndrome?
an autosomal recessive disorder characterized by partial albinism, peripheral neuropathy, and neutropenia.
88
what is the defect found in acute intermittent porphyria?
defect in porphobilinogen deaminase
89
what is DiGeorge syndrome
a genetic disorder caused by a deletion in chromosome 22q11.2, leading to thymic hypoplasia or aplasia and resulting in T-cell deficiency.
90
what is the defect found in porphyria cutanea tarda?
defect in uroporphyrinogen decarboxylase
91
what is haemophilia?
Haemophilia A is due to reduced synthesis of Factor VIII
Haemophilia B (Christmas disease) is due to a deficiency is factor IX
they are inherited as X-genetic recessive disorders - generally affects male boys born to mother carriers
some woman who carry haemophilia gene may have prolongation of APTT
All types of haemophilia effect the intrinsic pathway
92
what are inactive clotting factors called?
zymogens
93
what are the three pathways in the clotting cascade?
The extrinsic and intrinsic coagulation pathways both lead into the final common pathway by independently activating factor X.
94
Which factors are used in the extrinsic pathway?
The extrinsic pathway involves initiation by factor III (i.e., tissue factor) and its interaction with factor VII.
95
Which clotting factors are utilised in the intrinsic pathway?
factors XII, XI, IX, and VIII are utilized in the intrinsic pathway
96
Which factors are used in the common pathway?
The common pathway uses factors X, V, II, I, and XIII.
97
What causes the extrinsic pathway to begin?
It begins when the is injury to the endothelial tissue exposing tissue factor (factor III) to the blood. Tissue factor then become bound with calcium and factor VIIa to activate factor X. Factor VII is present in the blood and requires vitamin K to be activated.
98
When does in the intrinsic pathway begin?
The intrinsic pathway begins when factor XII or the Hageman factor is exposed to collagen kallikrein, and high molecular weight kininogen (HMWK) and is subsequently activated.
Factor XIIa activates factor XI into XIa. With a calcium ion, factor XIa activates factor IX. Then, factor IXa, factor VIIIa, and calcium form a complex to activate factor X. Factor VIII is found in the blood and is often activated by thrombin (factor IIa).
99
When does the common pathway begin?
The common pathway may result after the activation of factor X at the end of either pathway. The common pathway begins when factor Xa, Va, and calcium bind together, forming a prothrombinase complex. The prothrombinase complex then activates prothrombin (factor II) into thrombin (factor IIa). Next, thrombin cleaves fibrinogen (factor I) into fibrin (factor Ia). Afterwards, thrombin cleaves the stabilizing factor (factor XIII) into XIIIa. Factor XIIIa binds with calcium to then create fibrin crosslinks to stabilize the clot. Thrombin has several functions, including activating platelets (cell fragments involved in clot formation) and activating factors V, VIII, and IX.
100
How is Haemophilia classified and how does it present?
Severe Haemophilia (
101
How is haemophilia diagnosed?
plasma factor VIII and IX assay
FBC and LFTs
coagulation profile - APTT will be prolonged, PT and VWF normal
102
How is Haemophilia managed?
Factor VII/IX concentrate IV infusion
Acquired factor VII deficiency can be treated in mild cases with desmopressin or factor VIII but in severe bleeding an agent that bypasses factor VIII either an activated prothrombin complex concentrate or recombinant factor VIIa is required
Tranexamic acid usually effective for mild haemophilia - however it should be avoided in haemarthorsis or deep muscular haematomas
They require vaccination against Hep B
103
what are the features of transfusion associated graft vs host disease?
fever, rash, diarrhoea, abdominal pain, pancytopenia and abnormal liver function tests. TA-GVHD can occur when a patient receives non-irradiated blood products, which may lead to the engraftment of viable donor T-cells.
104
Why are irradiated blood products used?
Irradiated blood products are used to avoid transfusion-associated graft versus host disease
The purpose of irradiating blood products is to damage the DNA within donor T-cells to prevent them from mounting an immune response following transfusion.
105
what does it mean to irradiate blood products?
to deplete blood products of T-lymphocytes
106
When should irradiated blood products be used?
granulocyte transfusions
Intra-uterine transfusions
Neonates
Pregnancy (elective transfusions)
bone barrow/stem cell transplants
immunocompromised
patients with lymphoma
107
How is aplastic anaemia managed?
Supportive management - 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%
108
what is aplastic anaemia?
a rare, potentially life-threatening haematological condition characterised by pancytopenia and hypocellular bone marrow. It results in insufficiency of all three blood cell lines: erythrocytes, leukocytes, and thrombocytes. The pathophysiology typically involves damage to the pluripotent stem cells leading to bone marrow failure.
109
What are the causes of aplastic anaemia?
- Idiopathic
Congenital: Fanconi anaemia, dyskeratosis congenita
Drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
Toxins: benzene
Infections: parvovirus, hepatitis
Radiation
110
what is the pathophysiology of aplastic anaemia?
The initial insult often involves damage to HSCs or their microenvironment.
The damaged HSCs undergo apoptosis or become senescent, reducing the pool of progenitor cells available for haematopoiesis --> there is inadequate replenishment of erythrocytes, leukocytes, and thrombocytes. The resultant erythropoiesis insufficiency leads to anaemia, manifesting as fatigue, pallor, and dyspnoea due to reduced oxygen-carrying capacity.
111
what would a bone marrow biopsy show in aplastic anaemia?
a hypocellular marrow with fatty infiltration and residual islands of haematopoietic tissue. This histopathological finding confirms the diagnosis when correlated with peripheral blood pancytopenia.
112
What are inherited causes of aplastic anaemia?
Fanconi anaemia: Autosomal recessive disorder characterised by congenital abnormalities, progressive pancytopenia, and increased cancer risk. Diagnosed via chromosomal breakage tests.
Dyskeratosis congenita: X-linked recessive or autosomal dominant disorder involving mutations in telomerase complex genes. Presents with mucocutaneous abnormalities and bone marrow failure.
Shwachman-Diamond syndrome: Autosomal recessive disorder featuring exocrine pancreatic insufficiency, skeletal abnormalities, and bone marrow dysfunction. Associated with SBDS gene mutations.
Diamond-Blackfan anaemia: Congenital pure red cell aplasia presenting in infancy or early childhood. Involves mutations in ribosomal protein genes.
113
what are acquired causes of aplastic anaemia?
Idiopathic: No identifiable cause, accounts for the majority of cases.
Drug-induced: Commonly associated with medications such as chloramphenicol, non-steroidal anti-inflammatory drugs (NSAIDs), and chemotherapeutic agents.
Chemical exposure: Including benzene and other organic solvents.
Infectious causes: Viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis viruses, and HIV.
Radiation-induced: Resulting from ionising radiation exposure.
114
what are the clinical features of aplastic anaemia?
Normochromic, normocytic anaemia
Leukopenia, with lymphocytes relatively spared
Thrombocytopenia
May be the presenting feature acute lymphoblastic or myeloid leukaemia
A minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
115
what are differentials for aplastic anaemia?
Myelodyplastic syndrome (clonal bone marrow disorders characterised by ineffective haematopoiesis, leading to blood cytopenias. Unlike aplastic anaemia, which typically presents with pancytopenia in the peripheral blood and a hypocellular bone marrow on biopsy, MDS often presents with macrocytic anaemia and may show hypercellular or normocellular marrow with dysplasia in one or more cell lines.)
Paroxysmal natural haemoglobinuria - an acquired stem cell disorder that leads to the production of defective red blood cells susceptible to complement-mediated lysis. It can mimic aplastic anaemia due to similar presentations of pancytopenia and marrow failure. However, it has unique features including episodic haemolysis often associated with dark urine in the morning.
Hypoplastic myelodysplastic syndrome - This is a subtype of MDS where the bone marrow is hypocellular, similar to aplastic anaemia. However, unlike aplastic anaemia, dysplasia in one or more cell lines is present.
115
How can you distinguish between aplastic anaemia and myeoldysplastic anaemia, paroxysmal nocturnal haemoglobinuria and hypo plastic myelodysplastic syndrome?
MDS - they can have isolated cytopenias or bicytopenia rather than pancytopenia.
PNH - The Ham test or sugar water test are diagnostic for PNH but not for aplastic anaemia. Additionally, flow cytometry showing CD55/CD59 deficient red cells supports the diagnosis of PNH.
Hypoplastic myerlodysplastic syndrome - unlike aplastic anaemia, dysplasia in one or more cell lines is present. Cytogenetic analysis showing abnormalities can help differentiate this from aplastic anaemia.
116
What is acute intermittent porphyria?
a rare AD condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem
117
How does acute intermittent porphyria usually present?
characteristically presents with abdominal pain and neuropsychiatric symptoms
20-40 year olds
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
118
How is acute intermitted porphyria diagnosed?
classically urine turns deep red on standing
raised urinary porphobilinogen (elevated between attacks and to a greater extent during acute attacks)
assay of red cells for porphobilinogen deaminase
raised serum levels of delta aminolaevulinic acid and porphobilinogen
119
How is acute intermittent porphyria managed?
avoiding triggers
acute attacks
IV haematin/haem arginate
IV glucose should be used if haematin/haem arginate is not immediately available
120
what is there an accumulation of in acute intermitted porphyria?
toxic accumulation of delta aminolaevulinic acid and porphobilinogen
121
what is anti phospholipid syndrome?
an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia.
122
what condition is anti-phospholipid syndrome linked to?
SLE
123
what are the complications in pregnancy with anti-phospholipid syndrome?
recurrent miscarriage
IUGR
pre-eclampsia
placental abruption
pre-term delivery
venous thromboembolism
124
how do you manage antiphosopholipid syndrome?
low dose aspirin
LMWH once feral heart is seen on USS - this should be stopped at around 34 weeks
125
what are causes of thrombocytosis?
Reactive (plts are an acute phase reactant)
malignancy
essential thrombocytosis
hyposplenism
126
What is essential thrombocytosis?
one of the myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis. Megakaryocyte proliferation results in an overproduction of platelets.
127
what are the features of essential thrombocytosis?
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
128
How do you manage thrombocytosis?
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
129
what antigen is foundd in heparin induced thrombocytopenia?
Platelet factor 4 (PF4 complex) i
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What genes are associated with essential thrombocytosis ?
JAK-2 (50% of patients)
CALR (calreticulin) seen in 20% of JAK -ve patients
MPL - less common - seen in 10% of patients
131
What is the benefit of using capecitabine over fluoracil in metastatic colorectal cancer?
oral administration
Capecitabine is an orally administered prodrug which is enzymatically converted to 5-fluorouracil in the tumour.
132
what are the different forms of cytotoxic agents?
Alkylating agents - cyclophosphamide
Cytotoxic abx - bleomycin, anthracyclines (e.g. doxorubicin)
Antimetabolites.- methotrexate, Fluorouracil (5-FU), 6-mercaptopurine, cytarabine
Acts on microtubules - vincristine, vinblastine, docetaxel
Topoisomerase inhibitors - Irinotecan
others
Cisplatin - causes cross likening in DNA
Hydroxycarbamide - inhibid ribonucleotine reductase, decreasing DNA synthesisi
133
what are the adverse effects of Cyclophosphamide?
Haemorrhagic cystitis, myelosuppression, transitional cell carcinoma
134
What are the adverse effects of Bleomycin?
lung fibrosis
135
what are the adverse effects of doxorubicin?
cardiomyopathy
136
what are the adverse effects of methotrexate ?
Myelosuppression, mucositis, liver fibrosis, lung fibrosis
137
what are the adverse effects of 5-FU ?
Myelosuppression, mucositis, dermatitis
138
what are the effects of 6-mercaptopurine ?
Myelosuppression
139
what are the adverse effects of cytarabine
Myelosuppression, ataxia
140
what are the adverse effects of vincristine and vinblastine?
Vincristine: Peripheral neuropathy (reversible) , paralytic ileus
Vinblastine: myelosuppression
141
What are the adverse effects of Docetaxel ?
Neutropaenia
142
What are the adverse effects of Irinotecan ?
myelosupression
143
what are the adverse effects of cisplatin?
Ototoxicity, peripheral neuropathy, hypomagnesaemia
144
what is hereditary angioedema?
Autosomal dominant
associated with low plasma levels of the C1 inhibitor protein. (C1-INH, C1 esterase inhibitor)
C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
145
what are the adverse effects of hydroxycarbamide?
Myelosuppression
146
What investigations would you do for hereditary angioedema?
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
The most commonly used test is C4
C1 esterase inhibitor is the most specific test but it is expensive and not widely available
147
what are the symptoms of hereditary angiooedema ?
painful macular rash
painless, no pruritic swelling of the 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
148
how do you managed hereditary angioedema?
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
149
what are the causes of intravascular haemolytsis
mismatched blood transfusion
G6PD deficiency*
red cell fragmentation: heart valves, TTP, DIC, HUS
paroxysmal nocturnal haemoglobinuria
cold autoimmune haemolytic anaemia
150
what are the causes of extravascular haemolysis?
haemoglobinopathies: sickle cell, thalassaemia
hereditary spherocytosis
haemolytic disease of newborn
warm autoimmune haemolytic anaemia
151
What happens to the haemoglobin in intravascular haemolysis?
In intravascular haemolysis, free haemoglobin is released which then binds to haptoglobin. As haptoglobin becomes saturated haemoglobin binds to albumin forming methaemalbumin (detected by Schumm's test). Free haemoglobin is excreted in the urine as haemoglobinuria, haemosiderinuria
152
what will cause a sudden fall in Hb, small rise in reticulocytes, parvovirus +ve in sickle cell?
The sudden fall in haemoglobin without an appropriate reticulocytosis (3% is just above the normal range) is typical of an aplastic crisis, usually secondary to parvovirus infection
153
what are the types of crisis that occur In sickle-cell disease?
thrombotic, 'vaso-occlusive', 'painful crises'
acute chest syndrome
anaemic
aplastic
sequestration
infection
154
what precipitates a thrombotic crisis in sickle cell disease and what are the symptoms?
also known as painful crises or vaso-occlusive crises
precipitated by infection, dehydration, deoxygenation (e.g. high altitude)
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
155
what is acute chest syndrome?
vaso-occlusion within the pulmonary microvasculature → infarction in the lung parenchyma
dyspnoea, chest pain, pulmonary infiltrates on chest x-ray, low pO2
156
How do you manage acute chest syndrome?
pain relief
respiratory support e.g. oxygen therapy
antibiotics: infection may precipitate acute chest syndrome and the clinical findings (respiratory symptoms with pulmonary infiltrates) can be difficult to distinguish from pneumonia
transfusion: improves oxygenation
157
what causes aplastic crisis and what are the features?
caused by infection with parvovirus
sudden fall in haemoglobin
bone marrow suppression causes a reduced reticulocyte count
158
what is a sequestration crisis?
sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
associated with an increased reticulocyte count
159
what staging system is used for Hodgkins lymphoma?
Ann-Arbor
Luango classification is also used
160
what are the stages of Ann-Arbor staging?
Stage
I: single lymph node
II: 2 or more lymph nodes/regions on the same side of the diaphragm
III: nodes on both sides of the diaphragm
IV: spread beyond lymph nodes
Each stage may be subdivided into A or B
A = no systemic symptoms other than pruritus
B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)
161
what are lymphocytes characterised by in Hodgkins lymphoma?
lymphocytes characterised by the presence of the Reed-Sternberg cell
162
What are the stages used in Lugano classification ?
Stage I: Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE).
Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE).
Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIE+S).
Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
In addition to these stages, the classification includes the following:
A/B Symptom Designation: The absence of significant symptoms is designated as 'A', while the presence of fever, night sweats, or weight loss is designated as 'B'.
E: The presence of extranodal disease is denoted by the letter 'E'.
S: Involvement of the spleen is denoted by the letter 'S'.
X: Bulky disease (large tumor mass) is denoted by the letter 'X'.
163
How is Hodkins lymphoma managed?
Chemotherapy
ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - considered standard regimen
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone): alternative regime with better remission rates but higher toxicity
Radiotherapy
Combines chemo followed by radio
hamatopietic cell transplantation
164
what is Hodgkins lymphoma?
uncontrolled proliferation of B-lymphocytes
164
what is the peak incidence of Hopkins lymphoma
20 -30 years
165
causes of Hodgkins lymphoma
though to be multifactorial
EBV infection in 40%
Immunosupression
autoimmune conditions
Familial
166
what are the 4 classifications of Hodkins lymphoma?
Nodular sclerosino (70% of cases, good prognosis)
Mixed cellularity (20-25% of cases, worse prognosis, 75% of cases associated with EBV)
Lymphocyte rich - 5% - has the best prognosis, affects older age groups
Lymphocyte deplete <1%, worst prognosis - more common with HIV patients
167
clinical features of Hodkin's ?
lymphadenopathy - painless
asymmetrical - cervical or mediastinal involvement in 60% of cases
If mediastinal lymph nodes are involved, this can compress the airway and lead to dyspnoea, chest pain, and dry cough. It may also cause superior vena cava obstruction.
Can also occur in the spleen (27%), and the axillary (14%), abdominal (11-14%), hilar (12%) or inguinal-femoral (1-3%) lymph nodes
Alcohol-induced pain at lymph node regions is a non-specific symptom as it can also occur in patients with alcohol intolerance and carcinoid syndrome. There's a lack of research regarding alcohol-induced pain in Hodgkin's lymphoma, but a paper published in 1983 estimated the incidence to be 1.5-5%.
B symptoms - fevers, night sweats weight loss
168
Ix for Hodgkins lymphoma?
FBC - may be anaemic, lymphopenic, and thrombocytopenic which can be associated with bone marrow involvement
Baseline U&E and LFTs
ESR tends to be elevated
LDH correlates with disease activity
Viral screen
Lymph note excision biopsy
PET scans
contrast CR
Bone marrow biopsy
169
what in an FBC is a poor indicator for Hodgkins lymphoma?
neutrophilia and anaemia indicate a poorer prognosis
170
What is Non-Hodgkins lymphoma?
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of cancers occurring from the malignant proliferation of lymphocytes. The majority of these are derived from B cells (85-90%), with the remainder occurring from T cells or natural killer cells. Together, these comprise the sixth most common cancer in the UK.
NHL is 5 times as common as Hodgkin's lymphoma (HL). Differences between these two diseases are listed below:
171
what leads to an increase in risk of non-hodkins lymphoma?
Immunosuppression
Infections -
HIV relays a 60-100 fold increased risk for NHL - usually a diffuse large B cell lymphoma or Burkitt lymphoma
HTLV-I causes adult T cell leukaemia/lymphoma
EBV causes Burkitt lymphoma
H.pylori - mucosa-associated lymphoid tissue (MALT) lymphoma
Auto immune disease carry higher risk for NHL
172
what genetic abnormality is seen in follicular lymphoma?
Translocation of the BCL2 oncogene i
173
What genetic abnormality is seen in Burkitt lymphoma?
Translocation of the MYC oncogene
174
How is Non-Hodkin's lymphoma managed?
Options for indolent NHL:
Local radiotherapy is the first-line treatment to people with localised stage IIA follicular lymphoma
Watchful waiting for asymptomatic patients
Rituximab with/without chemotherapy
Combination chemotherapy
Palliative radiation therapy
Options for aggressive NHL:
R-CHOP = Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone
Radiation therapy
Bone marrow or stem cell transplantation
175
how may primary immunodeficiency disorders be classified?
according to the component of the immune system they affect
Neutrophil disorders
B- cell disorders
T cell disorders
Combined B and T cell disorders
176
what are neutrophil disorders?
Chronic granulomatous
Chediak-Higashi syndrome
Leukocyte adhesion deficiency
177
What are B-cell disorders?
common variable immunodeficiency
Burton's (X-linked) congenital agammaglobulinaemia
selective immunoglobulin A deficiency
178
what are examples of T-cell disorders ?
DiGeorge syndrome
179
What are examples of combined B- and T-cell disorders?
severe combined immunodeficiency
Ataxic telangiectasia
Wiskott-Aldrich syndrome
Hyper IgM syndromes
180
Steroid would cause a rise in what type of WCC?
Steroids tend to cause a neutrophilia.
