haem onc 2 Flashcards
When is Prothrombin complex used?
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
what is cryoprecipitate?
ontains 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
when is cryoprecipitate used?
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 is FFP used?
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
what is Leukaemoid reaction?
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 of leukaemoid reaction?
severe infection
severe haemolysis
massive haemorrhage
metastatic cancer with bone marrow infiltration
how can you differentiate a leukaemoid reaction from chronic myeloid leukaemia
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
what should be given to prevent tumour lysis syndrome?
Rasburicase.
Rasburicase is a recombinant urate-oxidase enzyme that catalyses the oxidation of uric acid to allantoin, which is more soluble and easily excreted by the kidneys. It is given prior to chemotherapy in patients with a high risk of tumour lysis syndrome (TLS), such as those with Burkitt’s lymphoma
What is Burkett’s lymphoma?
Burkitt’s lymphoma is a 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
What is Burkett’s lymphoma associated with?
Burkitt’s lymphoma is associated with the 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.
Microscopy in burkitt’s lymphoma?
‘starry sky’ appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
complications of tumour lysis syndrome?
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
what’s transfusion associated graft versus host disease?
transfusion-associated graft versus host disease (TA-GvHD), which is a rare but lethal transfusion complication. The pathology of this condition is the failure of the recipient to eliminate donor-derived T-cells, which then recognize HLA class II in recipient and cause excessive release of cytokines.
It occurs 2-6 weeks after transfusion
What are the risk factors for transfusion associated graft vs host disease?
- volume and age of transfused blood
- Depressed immune function especially, that involving T-cells and cell-mediated immunity. Hodgkin’s disease is a risk factor which this patient has.
- Similar HLA haplotype sharing (reconvening blood from a relative increases the risk)
How does transfusion associated graft vs host disease present?
TA-GvHD is a delayed reaction that occurs 2-6 weeks after transfusion. The patient presents with diarrhoea, liver damage, and rash. Laboratory studies show pancytopenia. A biopsy of skin or bone marrow can be diagnostic. A biopsy specimen of the skin will show abundant necrotic keratinocytes. Bone marrow shows marked hypocellularity with macrophage infiltration.
what happens to haptoglobin levels in haemolysis?
decrease
The accelerated break down of red blood cells releases haemoglobin which haptoglobin binds to, therefore reducing the levels of haptoglobin in the blood.
What drugs can cause haemolysis in G6PD deficiency?
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
What is the pathophysiology of G6PD deficiency?
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 of G6PD deficiency?
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
What is Waldenstrom’s macroglobunlinaemia?
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
What are the features of waldenstrom’s macroglobulinaemia?
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
Investigations and management of Waldenstrom’s macroglobulinaemia?
Investigations
monoclonal IgM paraproteinaemia
bone marrow biopsy is diagnostic
infiltration of the bone marrow with lymphoplasmacytoid lymphoma cells
Management
typically rituximab-based combination chemotherapy
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.
how do you investigate 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
What are the symptoms of hereditary angioedema?
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
What is Burkitt’s Lymphoma?
high grade B cell neoplasm
What are the two forms of Burkitt’s lymphoma?
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
what gene translocation is asscoiated with Burkitt’s lymphoma?
Burkitt’s lymphoma is associated with the c-myc gene translocation, usually t(8:14).
What virus is associated with the forming of endemic (african form) of Burkitt’s lymphoma?
EBV
Microscopy findings in Burkitt’s lymphoma?
Starry sky appearance
what is given prior to treatment of Burkitt’s lypmhoma to prevent tumour lysis syndrome?
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 tumour lysis syndrome?
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
Differences between G6PD and Hereditary spherocytosis
causes of Vitamin B12 deficiency?
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)
Managament of Vb12 deficiency?
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
Should you treat b12 deficiency or folic acid deficiency first?
it is important to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord
Inherited causes of thrombophilia?
Gain of function polymorphisms
* factor V Leiden (activated protein C resistance): most common cause of thrombophilia
* prothrombin gene mutation: second most common cause
Deficiencies of naturally occurring anticoagulants
* antithrombin III deficiency
* protein C deficiency
* protein S deficiency
Prevalence and relative risk of VTE in inherited thrombophillia?
What are acquired causes of thrombophilia?
Antiphospholipid syndrome
Drugs
the combined oral contraceptive pill
What is chronic lymphocytic leukaemia (CLL)?
A monoclonal proliferation of well-differentiated lymphocytes, almost always B-cells (99%)
What is the most common form of leukaemia seen in adults?
Chronic lymphocytic leukaemia (CLL)
What are common symptoms of CLL?
- Often none
- Anorexia
- Weight loss
- Bleeding
- Infections
- Lymphadenopathy more marked than chronic myeloid leukaemia
What is the typical finding in a full blood count for CLL?
Lymphocytosis
anaemia: may occur either due to bone marrow replacement or autoimmune hemolytic anaemia (AIHA)
thrombocytopenia: may occur either due to bone marrow replacement or immune thrombocytopenia (ITP)
What is a characteristic feature seen in the blood film of CLL?
Smudge cells (smear cells)
What is the key investigation for diagnosing CLL?
Immunophenotyping
Which panel of antibodies is used to identify most cases of CLL?
- CD5
- CD19
- CD20
- CD23
Aeitology of CLL?
exact cause not known
genetics - most common genetic change is the deletion in chromosome 13, but other chromosomes such as 11 and 17 can also be affected.
Fam History - 6- to 9-fold increased risk for first degree relatives of CLL patients.
Imuunology. - People with low immunity due to HIV or AIDS are three times more likely than the general population to develop leukaemia.
Pathophysiology of CLL
Chronic lymphocytic leukaemia (CLL) is a neoplastic disorder characterised by the progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. The pathogenesis of CLL involves a stepwise progression that begins with the development of a monoclonal B-cell lymphocytosis, followed by clonal expansion and eventual evolution into clinically apparent disease.
The initial event in the pathogenesis of CLL is thought to be a genetic mutation in a single B-lymphocyte progenitor cell. This mutation confers a survival advantage on the cell, leading to the development of monoclonal B-cell lymphocytosis (MBL), a pre-leukaemic condition characterised by low levels of circulating monoclonal B cells. MBL can exist for many years without progressing to CLL.
what are the molecular events driving CLL progression?
- The most common genetic abnormalities associated with CLL include deletion 13q (del[13q]), trisomy 12, deletion 11q (del[11q]) and deletion 17p (del[17p]). These genetic changes are often detected at diagnosis and can provide prognostic information.
- Another key event in the pathogenesis of CLL is the dysregulation of apoptosis, or programmed cell death. In normal lymphocytes, apoptosis serves as a mechanism to remove aged or damaged cells. However, in CLL, apoptotic pathways are disrupted resulting in an overaccumulation of these abnormal cells.
- A further contributor to disease progression is microenvironment interaction. The tumour microenvironment plays an important role in promoting survival and proliferation of malignant B cells. Signals from stromal cells within lymphoid tissues can protect CLL cells from spontaneous and drug-induced apoptosis.
Do all patients with MBL progress to CLL?
It’s important to note that not all patients with MBL will progress to CLL, and the rate at which this occurs can vary widely. Some patients may remain in a stable MBL phase for many years, while others may rapidly progress to symptomatic disease. This variability is likely due to differences in underlying genetic abnormalities and microenvironment interactions.
Symptoms of CLL?
B Symptoms
Fatugue
Lymphadenopathy - painless, usually symmetrical
Hepatosplenomegaly
Bone marrow failure: As CLL progresses, bone marrow infiltration can lead to cytopenias including anaemia, thrombocytopenia and neutropenia resulting in fatigue, increased bleeding tendency and susceptibility to infections respectively.
What are the Autoimmune complications of CLL?
Autoimmune haemolytic anaemia (AIHA): This is characterised by destruction of red blood cells by autoantibodies. Patients may present with symptoms of anaemia such as fatigue, pallor and jaundice.
Immune thrombocytopenia (ITP): Here, autoantibodies destroy platelets leading to thrombocytopenia. This may result in easy bruising, petechiae or more serious bleeding complications.
Why do patients with CLL develop recurrent infections?
due to hypogammaglobulinaemia and neutropenia associated with CLL. Infections commonly involve the respiratory tract but can also include herpes zoster reactivation.
What is Richter’s transformation?
Richter’s transformation, although rare, is a serious complication where CLL transforms into an aggressive lymphoma. Patients may present with rapidly enlarging lymph nodes, splenomegaly and B symptoms.
Differentials for CLL?
- Mantle cell lymphoma
It is a type of non-Hodgkin’s lymphoma which is very similar to CLL, but more aggressive. Mantle cell lymphoma expresses CD5 but not CD23 antigen, which is expressed in CLL. - Marginal zone lymphoma
It has a similar presentation and immunophenotype as CLL, but typically has a bright surface immunoglobulin and CD20, and bone marrow examination often reveals lymphocytes with notched nuclei. - B-cell pro-lymphocytic leukemia
It is a very rare and typically aggressive malignancy and has similar clinical features as CLL. Circulating cells are greater than 55% pro-lymphocytes that are often CD5 negative. - Lymphoplasmacytic lymphoma
CLL and lymphoplasmacytic lymphoma are lymphoproliferative disorders with similar presentation. However, the later can also manifest as hyperviscosity syndrome associated with macroglobulinemia, where the clinical picture varies.
*
what staging is used for CLL?
The Binet staging system is commonly used in the UK for CLL staging and it has 3 stages.
Stage A: Hb at least 10 g/dL, platelets at least 100 x 109/L, and fewer than three lymph node areas involved.
Stage B: Hb and platelet levels as in stage A and three or more lymph node areas involved.
Stage C: Hb <10 g/dL, platelets <100 x 109/L, or both.
How is CLL managed?
watch and wait in early disease with no symptoms
Chemotherapy should only be given to patients with active, symptomatic disease
Inidcations for Chemotherapy in CLL?
Evidence of progressive marrow failure
Massive or progressive or symptomatic splenomegaly
Massive or progressive or symptomatic lymphadenopathy
Progressive lymphocytosis with an increase of more than 50% over a 2-month period
Lymphocyte doubling time of less than 6 months
Autoimmune anaemia or thrombocytopenia not responding to prednisolone
One or more of the following CLL-related symptoms or signs such as
Night sweats
High fever
Extreme fatigue
Unintentional weight loss >10%
What Chemotherapy agent causes hypomagnaesaemia?
Cisplatin
What is the 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 of SERMs?
menstrual disturbance: vaginal bleeding, amenorrhoea
hot flushes - 3% of patients stop taking tamoxifen due to climacteric side-effects
venous thromboembolism
endometrial cancer
What is the mechanism of action of anastrozole?
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.
What are the adverse effects of aromatase inhibitors?
osteoporosis
NICE recommends a DEXA scan when initiating a patient on aromatase inhibitors for breast cancer
hot flushes
arthralgia, myalgia
insomnia
What mutation is associated with prostate cancer?
BRAC2
This mutation is more common in those with Ashkenazi Jewish heritage.
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
what chromosome is BRAC1 and BRCA 2 carried on?
Carried on chromosome 17 (BRCA 1) and Chromosome 13 (BRCA 2)
Which BRCA gene is more commonly associted with ovarian cancer?
Associated risk of developing ovarian cancer (55% with BRCA 1 and 25% with BRCA 2).
What is the inheritance of Lynch syndrome and what cancer is it associated with?
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
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
what subtypes of HPV are associated with cervical cancer?
Subtypes 16,18 & 33 are particularly carcinogenic.
which subtypes of HPV are assoicated with genital warts?
6 and 11
How does HPV lead to cervical cancer?
HPV viruses 16 and 18 produces oncoproteins which causes inhibition of tumour suppressor genes causes cervila carcinoma?
what are Koilocytes and what are the characteristics of Koilocytes?
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
Causes of DIC?
sepsis
trauma
obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)
malignancy
what is seen in the bloods in DIC?
A typical blood picture includes:
↓ platelets
↓ fibrinogen
↑ PT & APTT
↑ fibrinogen degradation products
schistocytes due to microangiopathic haemolytic anaemia
Differentiating between causes of derranged coagulation screen?
Wha is AML?
a malignant disease of the bone marrow that arises from myeloid cell lines
The immature cells, arrested in early stages of development, are released into the blood and impair normal haematopoiesis causing anaemia, bleeding, and infections.
what is the most common cause of acute leukaemia in adults?
AML
median age of onset in 65 years
Aeitology of AML?
- Genetic Factors:
Chromosomal abnormalities such as translocations (e.g., t(8;21), t(15;17), and t(9;11))
Gene mutations impacting cell proliferation and apoptosis, including FLT3, NPM1, and CEBPA - Environmental Exposures:
Previous chemotherapy or radiation therapy, termed therapy-related AML
Exposure to benzene and other petrochemicals
Radiation exposure, notably ionising radiation - Haematological Disorders:
Antecedent haematologic disorders like myelodysplastic syndromes and myeloproliferative neoplasms predisposing to secondary AML - Genetic Syndromes:
Conditions such as Down syndrome, Fanconi anaemia, and Li-Fraumeni syndrome associated with increased AML risk
Why does AML arise?
AML arises due to the acquisition of genetic mutations in haematopoietic progenitor cells that disrupt normal cell proliferation and differentiation. This disruption results in the accumulation of immature cells, known as blasts, in the bone marrow and peripheral blood, leading to bone marrow failure.
What is first hit and second hit mutations and blast accumulation in AML?
First hit: The pathogenesis of AML often begins with a ‘first hit’ mutation that confers a proliferative advantage to a haematopoietic stem cell. This leads to clonal expansion of this cell and its progeny. Common ‘first hit’ mutations occur in genes such as FLT3, NPM1, or DNMT3A.
Second hit: A ‘second hit’ mutation subsequently occurs in one of the clonally expanded cells, affecting a gene involved in haematopoietic differentiation, such as RUNX1 or CEBPA. This ‘second hit’ mutation further promotes proliferation and blocks differentiation, leading to the accumulation of immature blasts.
Blast accumulation: The accumulation of immature blasts in the bone marrow leads to bone marrow failure due to the suppression of normal haematopoiesis. This can present clinically as anaemia, thrombocytopenia, or neutropenia.
Invasion of other organs: As the disease progresses, the leukaemic blasts can invade other organs, such as the spleen, liver, and central nervous system, leading to organomegaly and other clinical manifestations.
What are the 6 groups of AML on WHO classification?
AML with recurrent genetic abnormalities
AML with myelodysplasia-related features
Therapy-related AML and MDS
AML, not otherwise specified
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
What are the 8 types of AML in the FAB classification system?
French-American-British (FAB)
M0: Acute myeloblastic leukaemia without maturation
M1: Acute myeloblastic leukaemia with minimal granulocyte maturation
M2: Acute myeloblastic leukaemia with granulocyte maturation
M3: Acute promyelocytic leukaemia (APL)
M4: Acute myelomonocytic leukaemia
M5: Acute monocytic leukaemia
M6: Acute erythroid leukaemia
M7: Acute megakaryoblastic leukaemia
Features of AML?
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
what predisposes to infection in AML?
mmature leucocytes predisposes to frequent infections.
What is seen on FBC in AML
Normocytic, normochromic anaemia
Thrombocytopenia
Leucocyte count: maybe low, normal, or raised.
What is seen on blood smear in AML?
Raised myeloblasts: myeloblasts are immature cells with large nuclei, usually with prominent nucleoli, and pale blue cytoplasm with Wright Giemsa stain.
Auer rods:
Pink/red, rod-shaped cytoplasmic granular inclusions.
Myeloperoxidase positive.
Pathognomonic of myeloblasts.
Mostly seen with acute promyelocytic leukaemia.
What confirms AML on bone marrow bisopsy?
≥ 20% myeloblasts in the bone marrow confirm the diagnosis
DDx for AML?
AML must be distinguished from other haematologic malignancies with shared clinical features.
Acute lymphocytic leukaemia:
Similarities: clinical features are mostly similar (fever, anaemia, thrombocytopenia, infections).
Differences: no Auer rods, lymphoblasts, myeloperoxidase negative, terminal deoxynucleotidyl transferase (TdT) positive.
Myelodysplastic syndrome
Similarities: anaemia, thrombocytopenia, infections
Differences: blasts (< 20%), pseudo-Pelger-Huet abnormality (neutrophils with bilobed nuclei)
Myeloproliferative neoplasms:
Similarities: infections, abnormalities in different cell lines
Differences: JAK2 mutation, thrombocytosis.
Chronic myeloid leukaemia in blast crisis
Similarities; anaemia, thrombocytopenia, infections
Differences: Philadelphia chromosome or t (9:22), raised matured cells (myelocytes)
What is acute promyelocytic leukaemia?
A distinct form of AML that represents a medical emergency
APML, the M3 subtype of AML
The importance of identifying APML lies in both the presentation (classically disseminated intravascular coagulation) and management.
What translocations is APML associated with?
APML is associated with the t(15;17) translocation which causes fusion of the PML and RAR-alpha genes.
what are the features of APML?
Features
presents younger than other types of AML (average = 25 years old)
DIC or thrombocytopenia often at presentation
good prognosis
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.
what is the ECOG score?
The ECOG score is a ‘performance status’ scale, or a score that measures the functional status a patient. It is used to decide if a patient is a good or poor candidate for future oncological therapies.
Those with a poor functional status is a poor candidate for further chemotherapy.
What are the different scores on the ECOG score
What is oral allergy syndrome?
an IgE-mediated hypersensitivity reaction to specific raw, plant-based foods including fruits, vegetables, nuts and certain spices.
This hypersensitivity reaction is initiated by cross-reaction with a non-food allergen, most commonly birch pollen whereby the protein in the food is similar but not identical in structure to the original allergen. This explains why OAS is strongly linked with pollen allergies and presents with seasonal variation. It also explains why cooking culprit food, and thereby denaturing the proteins, prevents symptoms occurring.
How does Oral allergy syndrome present?
It typically presents with mild tingling or pruritus of the lips, tongue and mouth
oral allergy syndrome vs food allergeis?
A food allergy is caused by direct sensitivity to a protein present in food. OAS is caused by cross-sensitisation to a structurally similar allergen present in pollen.
Non plant foods do not cause OAS because there are no cross reactive allergens in pollen which would be structually similar to meat.
Food allergies are more likely to cause systemic symptoms (vomiting and diarrhoea) and are more likely to lead to anaphylaxis because the allergens are not readily broken down. The symptoms of OAS are normally limited to the oropharynx because the proteins that cause the symptoms are denatured by stomach enzymes.
How does oral allergy syndrome present?
OAS should be suspected in patients with a history of seasonal allergy symptoms (rhinitis, conjunctivitis and asthma) who present with symptoms minutes after eating a specific raw food.
Itching and tingling of the lips, tongue and mouth are the most common symptoms
Mild swelling and redness of the lips, tongue and throat may occur.
In severe cases, patients develop nausea and vomiting.
Symptoms fully resolve within one hour of contact.
Anaphylaxis is a very rare complication.
Key features to suggest CLL and key investigation?
Markedly elevated white cell count with almost all being lymphocytes, which is more characteristic of CLL
Smudge cells seen on blood film
Invesitgaiton of Choice Immunophenotyping with flow cytometry
What is G6PD deficiency?
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect
What is the inheritance of G6PD deficiency?
x-linked recessive
Pathophysiology of G6PD deficiency?
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 of G6PD deficiency?
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
Diagnosis of G6PD deficiency?
Diagnosis is made by using a G6PD enzyme assay
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
what drugs may precipitae haemolysis in G6PD deficiency?
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
what are the crises recognised in sickle cell?
thrombotic, ‘vaso-occlusive’, ‘painful crises’
acute chest syndrome
anaemic
aplastic
sequestration
infection
what is a thrombotic crises in sickle cell?
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
what is acute chest syndrome in haemolysis?
vaso-occlusion within the pulmonary microvasculature → infarction in the lung parenchyma
dyspnoea, chest pain, pulmonary infiltrates on chest x-ray, low pO2
management
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
the most common cause of death after childhood
what is aplastic crises in sickle cell?
caused by infection with parvovirus
sudden fall in haemoglobin
bone marrow suppression causes a reduced reticulocyte count
what is sequestration crises in sickle cell?
sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
associated with an increased reticulocyte count
What is Sideroblastic anaemia?
Sideroblastic anaemia is a condition where 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.
whatare the congenital and acquired causes of sideroblastic anaemia?
Congenital cause: delta-aminolevulinate synthase-2 deficiency
Acquired causes
myelodysplasia
alcohol
lead
anti-TB medications
Managment of sideroblastic anaemia?
supportive
treat any underlying cause
pyridoxine may help
Investigations for Sideroblastic anaemia?
full blood count
hypochromic microcytic anaemia (more so in congenital)
iron studies
high ferritin
high iron
high transferrin saturation
blood film
basophilic stippling of red blood cells
bone marrow
Prussian blue staining will show ringed sideroblasts
Management of TTP?
Management
no antibiotics - may worsen outcome
plasma exchange is the treatment of choice
steroids, immunosuppressants
vincristine
What does lead poisoning result in?
Lead poisoning results in defective ferrochelatase and ALA dehydratase function.
What are the investigations for lead poisoning?
the blood lead level is usually used for diagnosis. Levels greater than 10 mcg/dl are considered significant
FBC - 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
What is seen on the bloods in common variable immunodeficiency?
Low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Recurrent chest infections. May also predispose to autoimmune disorders and lymphona
What is methaemoglobinaemia?
Methaemoglobinaemia describes haemoglobin which has been oxidised from Fe2+ to Fe3+.
This is normally regulated by NADH methaemoglobin reductase, which transfers electrons from NADH to methaemoglobin resulting in the reduction of methaemoglobin to haemoglobin. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left
What is the consequence of Fe3+ in methaemoglobinaemia?
Fe3+ cannot bind oxygen, leading to tissue hypoxia.
What happens to the oxidation dissociation curve in methaemoglobinaemia?
The oxidation dissociation curve is moved to the left.
What are congenital causes of methaemoglobinaemia?
- haemoglobin chain variants: HbM, HbH
- NADH methaemoglobin reductase deficiency.
What are acquired causes of methaemoglobinaemia?
- drugs: sulphonamides, nitrates (e.g. amyl nitrite), dapsone, sodium nitroprusside, primaquine
- chemicals: aniline dyes.
What are some features of methaemoglobinaemia?
- ‘chocolate’ cyanosis
- dyspnoea
- anxiety
- headache
- severe: acidosis, arrhythmias, seizures, coma
- normal pO2 but decreased oxygen saturation.
What is the management for NADH methaemoglobinaemia reductase deficiency?
Ascorbic acid.
What is the management for acquired methaemoglobinaemia?
IV methylthioninium chloride (methylene blue).
what is a thymoma?
Thymomas are the most common tumour of the anterior mediastinum and is usually detected between the sixth and seventh decades of life.
What is associated with thymoma?
myasthenia gravis (30-40% of patients with thymoma)
red cell aplasia
dermatomyositis
also : SLE, SIADH
what may lead to death in thymoma?
compression of airway
cardiac tamponade
What is Polycythaemia 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.
what mutation is present in Polycythaemia vera?
t has recently been established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera
Features of Polycythaemia vera?
pruritus, typically after a hot bath
splenomegaly
hypertension
hyperviscosity
arterial thrombosis
venous thrombosis
haemorrhage (secondary to abnormal platelet function)
low ESR
Investigations for Polycythaemia vera?
full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in half of patients)
JAK2 mutation
serum ferritin
renal and liver function tests
Diagnositc criteria for Polycythaemia vera?
Peak Incidence of polycythaemia vera?
It has a peak incidence in the sixth decade, with typical features including hyperviscosity, pruritus and splenomegaly.
Management of Polycythaemia vera?
aspirin
reduces the risk of thrombotic events
venesection
first-line treatment to keep the haemoglobin in the normal range
chemotherapy
hydroxyurea - slight increased risk of secondary leukaemia
phosphorus-32 therapy
Prognosis of Polycythaemia vera?
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)
what are types of combined B and T cell disorders?
Combined B- and T-cell disorders: SCID WAS ataxic (SCID, Wiskott-Aldrich syndrome, ataxic telangiectasia)
hat is the mechanism of action of DDAVP in von Willebrand’s disease?
Desmopressiin -raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
Drugs thought to be safe in G6PD deficiency?
penicillins
cephalosporins
macrolides
tetracyclines
trimethoprim
Why are platelets transfusions at higher risk of bacterial contamination?
Platelets are stored at room temperature, which increases the risk of bacterial proliferation. Common contaminants include Staphylococcus epidermidis and Bacillus cereus.
Clinical impact: Bacterial contamination of platelets is more likely to lead to rapid onset of sepsis and septic shock, given the optimal growth conditions during storage.
what is the most common inherited cause of thrombophillia?
Factor V Leiden is the commonest inherited thrombophilia
