Haematology Flashcards
Acute myeloid leukaemia
-Is this found in adults or children?
-How does this occur
Acute myeloid leukaemia is the more common form of acute leukaemia in adults. It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder.
Give 5 features of AML>=
Features are largely related to bone marrow failure:
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
Acute promyelocytic leukaemia M3
-What is this assoc with?
-What gene fusion is this assoc with?
-When does this present?
-What is seen on myeloperoxidase stain?
-What is the prognosis?
Acute promyelocytic leukaemia M3
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
What is the classification of acute myeloid leukaemia?
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
what is ALL?
-Who does this affect?
-when is the peak incidence?
Acute lymphoblastic leukaemia (ALL) is the most common malignancy affecting children and accounts for 80% of childhood leukaemias. The peak incidence is at around 2-5 years of age and boys are affected slightly more commonly than girls
what are three features of ALL predictable by bone marrow failure?? And features that are not predictable by bone marrow failure
Features may be divided into those predictable by bone marrow failure:
anaemia: lethargy and pallor neutropaenia: frequent or severe infections thrombocytopenia: easy bruising, petechiae
And other features
bone pain (secondary to bone marrow infiltration) splenomegaly hepatomegaly fever is present in up to 50% of new cases (representing infection or constitutional symptom) testicular swelling
What are three types of ALL?
Types
common ALL (75%), CD10 present, pre-B phenotype T-cell ALL (20%) B-cell ALL (5%)
What are poor prognostic factors for ALL?
Poor prognostic factors
age < 2 years or > 10 years WBC > 20 * 109/l at diagnosis T or B cell surface markers non-Caucasian male sex
What is CLL? who is this seen in?
Chronic lymphocytic leukaemia (CLL) is caused by 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.
What are the features of CLL (4)
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
What are the investigations of CLL? 3
Investigations
full blood count:
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)
blood film: smudge cells (also known as smear cells)
immunophenotyping is the key investigation
most cases can be identified using a panel of antibodies specific for CD5, CD19, CD20 and CD23
What are the complications of CLL? 4
Complications
anaemia hypogammaglobulinaemia leading to recurrent infections warm autoimmune haemolytic anaemia in 10-15% of patients transformation to high-grade lymphoma (Richter's transformation)
What is richters transformation?
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma. Patients often become unwell very suddenly.
Ritcher’s transformation is indicated by one of the following symptoms:
lymph node swelling fever without infection weight loss night sweats nausea abdominal pain
What warrants a very urgent FBC to investigate leukaemia in aged 0-24?
Any of the following features in a person aged 0-24 years should prompt a very urgent full blood count (within 48 hours) to investigate for leukaemia:
Pallor Persistent fatigue Unexplained fever Unexplained persistent infections Generalised lymphadenopathy Persistent or unexplained bone pain Unexplained bruising Unexplained bleeding
What is hodgkins lymphoma?
Hodgkin’s lymphoma (HL) is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades
What are 2 risk factors for hodgkins lymphoma?
Risk factors
HIV Epstein-Barr virus
Describe the lymphadenopathy found in hodgkins lymphoma?
Features
lymphadenopathy (75%)
most commonly in the neck (cervical/supraclavicular) > axillary > inguinal
usually painless, non-tender, asymmetrical
alcohol-induced lymph node pain is characteristic of Hodgkin's lymphoma but is seen in less than 10% of patients
What are B symptoms in lymphoma?
systemic - ‘B symptoms’ (25%)
weight loss
pruritus
night sweats
fever (Pel-Ebstein)
In hodgkins lymphoma what may be seen on CXR?
other possible presentations include a mediastinal mass
may be symptomatic (e.g. cough) or found incidentally on a chest x-ray
What four investigations are indicated in hodgkins lymphoma?
Investigations
-normocytic anaemia
may be multifactorial e.g. hypersplenism, bone marrow replacement by HL, Coombs-positive haemolytic anaemia etc
-eosinophilia
caused by the production of cytokines e.g. IL-5
-LDH raised
-lymph node biopsy
Reed-Sternberg cells are diagnostic: these are large cells that are either multinucleated or have a bilobed nucleus with prominent eosinophilic inclusion-like nucleoli (thus giving an ‘owl’s eye’ appearance)
What is burkitts 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 gene translocation is assoc. with burkitt’s lymphoma?
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.
What gene translocation is assoc. with burketts lymphoma
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.
Burketts lymphoma
-what is seen on miscroscopy?
Microscopy findings
'starry sky' appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
What is the management of of burkitt’s lymphoma
-what is given before chemo in burkitts
-
Management is with chemotherapy. This tends to produce a rapid response which may cause ‘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.
What are 5 compliactions of tumour lysis syndrome?
Complications of tumour lysis syndrome include:
hyperkalaemia hyperphosphataemia hypocalcaemia hyperuricaemia acute renal failure
What is myeloma?
Multiple myeloma (MM) is a haematological malignancy characterised by plasma cell proliferation. It arises due to genetic mutations which occur as B-lymphocytes differentiate into mature plasma cells.
Features of myeloma
-What is the age at presentation?
-CRABBI pneumonic
-What are other features?
The median age at presentation is 70 years old.
Use the mnemonic CRABBI:
Calcium
hypercalcaemia
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
this leads to constipation, nausea, anorexia and confusion
Renal
monoclonal production of immunoglobulins results in light chain deposition within the renal tubules
this causes renal damage which presents as dehydration and increasing thirst
other causes of renal impairment in myeloma include amyloidosis, nephrocalcinosis, nephrolithiasis
Anaemia
bone marrow crowding suppresses erythropoiesis leading to anaemia
this causes fatigue and pallor
Bleeding
bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
Bones
bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity creates lytic bone lesions
this may present as pain (especially in the back) and increases the risk of pathological fractures
Infection
a reduction in the production of normal immunoglobulins results in increased susceptibility to infection
Other features include
amyloidosis e.g. macroglossia carpal tunnel syndrome neuropathy hyperviscosity
What is including in investigations for myeloma
Bloods
Protein electrophoresis
Bone marrow biopsy/aspiration
Imaging
What is seen on bloods in myeloma?
-FBC
-Blood film
-U+Es
-Bone profile
Bloods
full blood count: anaemia peripheral blood film: rouleaux formation urea and electrolytes: renal failure bone profile: hypercalcaemia
What is seen on bone marrow aspiration in myeloma?
Bone marrow aspiration
confirms the diagnosis if the number of plasma cells is significantly raised
Describe the imaging in myeloma
maging
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'
What is the diagnostic criteria in myeloma?
The diagnostic criteria for multiple myeloma requires one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of multiple myeloma.
What are the major criteria in myeloma?
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
What is MGUS and does this lead to myeloma?
Monoclonal gammopathy of undetermined significance (MGUS, also known as benign paraproteinaemia and monoclonal gammopathy) is a common condition that causes a paraproteinaemia and is often mistaken for myeloma. Differentiating features are listed below. Around 10% of patients eventually develop myeloma at 10 years, with 50% at 15 years
Is MGUS symptomatic? IS there bone pain? is there a risk of infection? what can this cause in some patients?
Features
usually asymptomatic no bone pain or increased risk of infections around 10-30% of patients have a demyelinating neuropathy
Differentiating features MGUS from myeloma
-immune function
-beta 2 microglobulin levels
-paraproteinaemia levels
-clinical features
Differentiating features from 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 waldenstom’s macrogloulinaemia?
-who is this seen in?
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 5 clinical features of macroglobulinaemia?
Features
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 are the investigations for macroglobulinaemia?
Investigations
monoclonal IgM paraproteinaemia
bone marrow biopsy is diagnostic
infiltration of the bone marrow with lymphoplasmacytoid lymphoma cells
What is the management of macroglobulinaemia?
Management
typically rituximab-based combination chemotherapy
What is seen on:
-FBC
-Ferritin
-TIBC
-Transferrin
In iron deficiency anaemia
Full blood count (FBC) demonstrates hypochromic microcytic anaemia
Serum ferritin this will likely be low, as serum ferritin correlates with iron stores. However, it is important to recognise that ferritin can be raised during states of inflammation; so a raised ferritin does not necessarily rule out iron deficiency anaemia if the is co-occurring inflammation. For patients with co-occurring inflammatory disease, other iron studies can be performed.
Total iron-binding capacity (TIBC)/transferrin this will be high. A high TIBC reflects low iron stores. . Note that the transferrin saturation will however be low
What is seen on blood film in iron deficiency anaemi?
Blood film anisopoikilocytosis (red blood cells of different sizes and shapes) , target cells, ‘pencil’ poikilocytes
Who warrants endoscopy for iron deficiency anaemia
Endoscopy to rule out malignancy, males and post-menopausal females who present with unexplained iron-deficiency anaemia should be considered for further gastrointestinal investigations. Post-menopausal women with a haemoglobin level ≤10 and men with a haemoglobin level ≤11 should be referred to a gastroenterologist within 2 weeks.
How can you divide up macrocytic anaemia?
Macrocytic anaemia can be divided into causes associated with a megaloblastic bone marrow and those with a normoblastic bone marrow
What are megaloblastic causes of macrocytic anaemia? 2
Megaloblastic causes of macrocytic anaemia
vitamin B12 deficiency folate deficiency e.g. secondary to methotrexate
What are normoblastic causes of macrocytic anaemia? 7
Normoblastic causes of macrocytic anaemia
alcohol liver disease hypothyroidism pregnancy reticulocytosis myelodysplasia drugs: cytotoxics
What are 5 causes of vit b12 deficiency?
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)
What are four features of B12 deficiency?
Features of vitamin B12 deficiency
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
What is the management of B12 deficiency?
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 the long term management of sickle cell anaemia? do they receive vaccines?
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
What are the 4 types of sickle cell crisis?
A number of types of crises are recognised:
thrombotic, ‘vaso-occlusive’, ‘painful crises’
acute chest syndrome
anaemic
aplastic
sequestration
infection
What is sickle cell thrombotic crisis? what are they precipitated by? how is this diagnosed?
Thrombotic crises
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 sickle cell acute chest syndrome?
-what is this cause by?
-What clinical features exist?
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
What is the management of sickle cell crisis acute chest syndrome? is this common?
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 sickle cell aplastic crisis caused by? what is seen on blood tests?
Aplastic crises
caused by infection with parvovirus sudden fall in haemoglobin bone marrow suppression causes a reduced reticulocyte count
What is sickle cell sequestration crisis? what is seen on blood film?
Sequestration crises
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 the indications for blood transfusion in sickle cell crisis?
blood transfusion
indications include: severe or symptomatic anaemia, pregnancy, pre-operative do not rapidly reduce the percentage of Hb S containing cells
What is the indications for exchange transfusion in sickle cell crisis?
exchange transfusion
indications include: acute vaso-occlusive crisis (stroke, acute chest syndrome, multiorgan failure, splenic sequestration crisis rapidly reduce the percentage of Hb S containing cells
What is aplastic anaemia characterised by? when is the peak incidence?
Characterised by pancytopenia and a hypoplastic bone marrow
Peak incidence of acquired = 30 years old
What are the 5 features of aplastic anaemia?
Features
normochromic, normocytic anaemia
leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature of acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
What are 5 causes of aplastic anaemia?
Causes
idiopathic congenital: Fanconi anaemia, dyskeratosis congenita drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold toxins: benzene infections: parvovirus, hepatitis radiation
What is autoimmune haemolytic anaemia subdivided into? What can this be caused by?
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.
What is found on investigations in haemolytic anaemia?
-general features of haemolytic anaemia (5)
-Specific features of autoimmune haemolytic anaemia
Investigations
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).
What is the most common type of AIHA? what does this cause? what antibody is seen?
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.
What are 5 causes of warm haemolytic anaemia
Causes of warm AIHA
idiopathic
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia
lymphoma
chronic lymphocytic leukaemia
drugs: e.g. methyldopa
What is the management of warm AIHA?
Management
treatment of any underlying disorder steroids (+/- rituximab) are generally used first-line
What is the antibody found in cold AIHA? what are features of this?
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
What are 2 causes of cold AIHA?
Causes of cold AIHA
neoplasia: e.g. lymphoma infections: e.g. mycoplasma, EBV
How is fanconi anaemia inherited?
Autosomal recessive.
What are 4 features of fanconi anaemia?
Features
haematological:
aplastic anaemia
increased risk of acute myeloid l
eukaemia
neurological
skeletal abnormalities:
short stature
thumb/radius abnormalities
cafe au lait spots
Hereditary spherocytosis
-Is this
Basics
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
What is PNH?
-what is this caused by?
-What does this increase the risk of?
Paroxysmal nocturnal haemoglobinuria (PNH) is 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
what is the pathophysiology of PNH?
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
What are 5 features of paroxysmal nocturnal haematuria?
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
What is the gold standard test in PNH?
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)
what are 4 management options for PNH?
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
What is beta thalassaemia trait? how is this inherited? what is seen on FBC?
The thalassaemias are a group of genetic disorders characterised by a reduced production rate of either alpha or beta chains. Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic
What are 2 features of beta thalassaemia trait?
Features
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia HbA2 raised (> 3.5%)
What is haemophillia? how is this inherited? which factors are deficient in either one?
Haemophilia is an 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
what are 3 features of haemophillia?
Features
haemoarthroses haematomas prolonged bleeding after surgery or trauma
What bloods tests are seen in haemophillia?
Blood tests
prolonged APTT bleeding time, thrombin time, prothrombin time normal
What can happen during treatment of haemophilia A?
Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment.
What is von-willebrands disease? how is this inherited?
Von Willebrand’s disease is the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
What is the role of von willebrand factor?
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
What are the three types of von willebrand disease?
Types
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
What are 4 investigations for von-willebrand disease?
Investigation
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
What is the management of von willbrand disease?
Management
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
What is the most common cause of inherited thrombophilia? what is the second most common cause? what are three other causes?
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
What are 2 acquired causes of thrombophilia?
Antiphospholipid syndrome
Drugs
the combined oral contraceptive pill
What is antiphospholipid syndrome? what can this occur due to?
Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)
What 6 compliations can occur in pregnancy of antiphospholipid syndrome?
In pregnancy the following complications may occur:
recurrent miscarriage IUGR pre-eclampsia placental abruption pre-term delivery venous thromboembolism
What is the management of antiphospholipid syndrome in pregnancy?
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
What is cryoglobulinaemia?
Immunoglobulins which undergo reversible precipitation at 4 deg C, dissolve when warmed to 37 deg C. One-third of cases are idiopathic
Type 1 cryoglobulinaemia:
-How common is this?
-What abs are involved?
-What are 2 associations?
type I (25%):
monoclonal - IgG or IgM associations: multiple myeloma, Waldenstrom macroglobulinaemia
Type 2 cryoglobulinaemia:
-How common is this?
-What abs are involved?
-What are 2 associations?
type II (25%)
mixed monoclonal and polyclonal: usually with rheumatoid factor associations: hepatitis C, rheumatoid arthritis, Sjogren's, lymphoma
Type 3 cryoglobulinaemia:
-How common is this?
-What abs are involved?
-What are 2 associations?
type III (50%)
polyclonal: usually with rheumatoid factor associations: rheumatoid arthritis, Sjogren's
What are 4 possible features of cryoglobulinaemia?
Possible features
Raynaud's only seen in type I
cutaneous
vascular purpura
distal ulceration
ulceration
arthralgia
renal involvement
diffuse glomerulonephritis
What are 2 investigations for cryoglobulinaemia
Investigations
low complement (esp. C4) high ESR
What is the management of cryoglobulinaemia?
Management
treatment of underlying condition e.g. hepatitis C immunosuppression plasmapheresis
What is the management of DVT first line vs pregnancy? Is
NICE updated their guidelines on the investigation and management of venous thromboembolism (VTE) in 2020. Some of the key changes include recommending the following:
the use of direct oral anticoagulants (DOACs) as first-line treatment for most people with VTE, including as interim anticoagulants before a definite diagnosis is made the use of DOACs in patients with active cancer, as opposed to low-molecular weight heparin as was the previous recommendation routine cancer screening is no longer recommended following a VTE diagnosis
What clinical features are involved in a well’s score?
Clinical feature Points
Active cancer (treatment ongoing, within 6 months, or palliative) 1
Paralysis, paresis or recent plaster immobilisation of the lower extremities 1
Recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or regional anaesthesia 1
Localised tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling at least 3 cm larger than asymptomatic side 1
Pitting oedema confined to the symptomatic leg 1
Collateral superficial veins (non-varicose) 1
Previously documented DVT 1
An alternative diagnosis is at least as likely as DVT -2
What well’s score makes a DVT likely vs unlikely?
Clinical probability simplified score
DVT likely: 2 points or more DVT unlikely: 1 point or less
What is the protocol if the score shows a DVT is ‘likely’?
If a DVT is ‘likely’ (2 points or more)
a proximal leg vein ultrasound scan should be carried out within 4 hours
-if the result is positive then a diagnosis of DVT is made and anticoagulant treatment should start
-if the result is negative a D-dimer test should be arranged. A negative scan and negative D-dimer makes the diagnosis unlikely and alternative diagnoses should be considered
-if a proximal leg vein ultrasound scan cannot be carried out within 4 hours a D-dimer test should be performed and interim therapeutic anticoagulation (DOAC) administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours)
if the scan is negative but the D-dimer is positive: stop interim therapeutic anticoagulation and offer a repeat proximal leg vein ultrasound scan 6 to 8 days later
What is the protocol if a DVT is ‘unlikely’ using the wells scoring system?
If a DVT is ‘unlikely’ (1 point or less)
perform a D-dimer test
this should be done within 4 hours. If not, interim therapeutic anticoagulation should be given until the result is available
if the result is negative then DVT is unlikely and alternative diagnoses should be considered
if the result is positive then a proximal leg vein ultrasound scan should be carried out within 4 hours
-if a proximal leg vein ultrasound scan cannot be carried out within 4 hours interim therapeutic anticoagulation should be administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours)
What is the treatment for DVT?
apixaban or rivaroxaban (both DOACs) should be offered first-line following the diagnosis of a DVT
if the patient has active cancer
previously LMWH was recommended
the new guidelines now recommend using a DOAC, unless this is contraindicated
if renal impairment is severe (e.g. < 15/min) then LMWH, unfractionated heparin or LMWH followed by a VKA
if the patient has antiphospholipid syndrome (specifically ‘triple positive’ in the guidance) then LMWH followed by a VKA should be used
(VKA - warfarin)
What are the indications for DOAC?
Direct oral anticoagulants (DOACs) are currently used for the following indications:
prevention of stroke in non-valvular AF. NICE stipulate that certain other risk factors should be present. These are complicated and differ between the DOACs but generally require one of the following to be present:
prior stroke or transient ischaemic attack
age 75 years or older
hypertension
diabetes mellitus
heart failure
prevention of VTE following hip/knee surgery
treatment of DVT and PE
Give the
Mechanism of action
Excretion
Reversal
of dabigatran
M - direct thrombin inhibitor
E - Majority renal
R - Idarucizumab
Give the
Mechanism of action
Excretion
Reversal
of Rivaroxaban
M - Direct factor Xa inhibitor
E - Majority liver
R - Andexanet alfa*
*Andexanet alfa is a recombinant form of human factor Xa protein
Give the
Mechanism of action
Excretion
Reversal
of Edoxaban
M - Direct factor Xa inhibitor
E - Majority faecal
R - nil available
Give the
Mechanism of action
Excretion
Reversal
of Apixaban
M - Direct factor Xa inhibitor
E - Majority faecal
R - Andexanet alfa*
*Andexanet alfa is a recombinant form of human factor Xa protein
What is post-thrombotic syndrome?
-what are the clinical features
It is increasingly recognised that patients may develop complications following a DVT. Venous outflow obstruction and venous insufficiency result in chronic venous hypertension. The resulting clinical syndrome is known as post-thrombotic syndrome.
The following features maybe seen:
painful, heavy calves
pruritus
swelling
varicose veins
venous ulceration
what is the management of post-thrombotic syndrome?
However, once post-thrombotic syndrome has developed compression stockings are a recommended treatment. Other recommendations including keeping the leg elevated.
What is hereditary spherocytosis?
-is this common?
-how is this inherited?
-what happens to the blood cell in shape and survival?
Basics
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
What are 6 features of presentation of hereditary spherocytosis?
Presentation
failure to thrive jaundice, gallstones splenomegaly aplastic crisis precipitated by parvovirus infection degree of haemolysis variable MCHC elevated
How is hereditary spherocytosis diagnosed?
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 EMA binding test and the cryohaemolysis test for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
What is the management of hereditary spherocytosis?
Management
acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
What is G6PD?
-is it common?
-how is it inherited?
-what can precipitate a crisis?
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans
What is the pathophysiology of G6PD?
Pathophysiology
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
What are 5 features of G6PD?
Features
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
How is the diagnosis of G6PD made?
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 can causes haemolysis in G6PD? 3 types
Some drugs causing haemolysis
anti-malarials: primaquine ciprofloxacin sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
What 5 drugs are thought to be safe in G6PD?
Some drugs thought to be safe
penicillins cephalosporins macrolides tetracyclines trimethoprim
What is seen on blood film of spherocytosis vs G6PD?
Spherocytosis - spherocytes
G6PD - heinz bodies
What should be considered in questions giving a combo abdominal pain and neuro signs?
Along with acute intermittent porphyria, lead poisoning should be considered in questions giving a combination of abdominal pain and neurological signs. Lead poisoning results in defective ferrochelatase and ALA dehydratase function.
What are 6 features of lead poisoning?
Features
abdominal pain peripheral neuropathy (mainly motor) neuropsychiatric features fatigue constipation blue lines on gum margin (only 20% of adult patients, very rare in children)
What is used for diagnosis of lead poisoning?
-What is seen on FBC, blood film?
-What is raised in serum and urine?
-what can happen to bones?
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
What are 4 management options of lead poisoning?
Management - various chelating agents are currently used:
dimercaptosuccinic acid (DMSA) D-penicillamine EDTA dimercaprol
What are 6 causes of drug induced pancytopenia?
Drug causes of pancytopaenia
cytotoxics antibiotics: trimethoprim, chloramphenicol anti-rheumatoid: gold, penicillamine carbimazole* anti-epileptics: carbamazepine sulphonylureas: tolbutamide
What is ITP?
-what is seen in children vs adults?
Immune (or idiopathic) thrombocytopenic purpura (ITP) is an immune-mediated reduction in the platelet count. 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 contrast, adults tend to have a more chronic condition
ITP in adults - who is this most common in?
Epidemiology
more common in older females
What is seen at presentation of ITP in adults??
Presentation
may be detected incidentally following routine bloods
symptomatic patients may present with
petechiae, purpura
bleeding (e.g. epistaxis)
catastrophic bleeding (e.g. intracranial) is not a common presentation
What investigations are used in ITP in adults?
Investigations
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
What is the management of ITP
Management
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
What is evans syndrome?
Evan’s syndrome
ITP in association with autoimmune haemolytic anaemia (AIHA)
What is wiskott-aldrich syndrome?
Wiskott-Aldrich syndrome causes primary immunodeficiency due to a combined B- and T-cell dysfunction. It is inherited in a X-linked recessive fashion and is thought to be caused by mutation in the WASP gene
What are 4 features of wiskott aldrich syndrome?
Features
recurrent bacterial infections (e.g. Chest) eczema thrombocytopaenia low IgM levels
What is neutropenic sepsis?
Neutropenic sepsis is a relatively common complication of cancer therapy, usually as a consequence of chemotherapy. It most commonly occurs 7-14 days after chemotherapy. It may be defined as a neutrophil count of < 0.5 * 109 in a patient who is having anticancer treatment and has one of the following:
a temperature higher than 38ºC or other signs or symptoms consistent with clinically significant sepsis
What is the most common causative organism in neutropenic sepsis?
Aetiology
coagulase-negative, Gram-positive bacteria are the most common cause, particularly Staphylococcus epidermidis
this is probably due to the use of indwelling lines in patients with cancer
Is prophylaxis used to prevent neutropenic sepsis?
Prophylaxis
if it is anticipated that patients are likely to have a neutrophil count of < 0.5 * 109 as a consequence of their treatment they should be offered a fluoroquinolone
Describe the management of neutropenic sepsis?
-what abx are used?
-what happens if patients are still febrile after 48hrs?
-what happens if patients are not responding after 4-6 days?
Management
antibiotics must be started immediately, do not wait for the WBC NICE recommends starting empirical antibiotic therapy with piperacillin with tazobactam (Tazocin) immediately many units add vancomycin if the patient has central venous access but NICE do not support this approach following this initial treatment patients are usually assessed by a specialist and risk-stratified to see if they may be able to have outpatient treatment if patients are still febrile and unwell after 48 hours an alternative antibiotic such as meropenem is often prescribed +/- vancomycin if patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections (e.g. HRCT), rather than just starting therapy antifungal therapy blindly there may be a role for G-CSF in selected patients
