Haematology Flashcards
What is the definition an epidemiology of aplastic anaemia?
Aplastic anaemia is defined by pancytopenia (deficiency of all blood cell elements) with diminished haematopoietic precursors in the bone marrow. It is quite rare (2-4 in 1,000,000), can occur at any age and is slightly more common in males.
What is the aetiology of aplastic anaemia?
Aetiology:
• Idiopathic (>40%): May be due to the destruction or suppression of the stem cell by autoimmune mechanisms.
- Acquired: Drugs (chloramphenicol, gold, alkylating agents, antiepileptics, sulphonamides, methotrexate, nifedipine), chemicals (DDT [insecticide], benzene), radiation, viral infections (B19 parvovirus, HIV, EBV), paroxysmal nocturnal haemoglobinuria.
- Inherited: Fanconi’s anaemia, dyskeratosis congenita.
What are the clinical features of aplastic anaemia?
Slow (months), or rapid (days) onset. History and examination findings can be divided by causes due to anaemia, thrombocytopaenia and leukopaenia:
- Anaemia: Patient may complain of tiredness, lethargy and dyspnoea. On examination, may notice patient to be pale (pallor).
- Thrombocytopaenia: Patient may complain of easy bruising, bleeding gums and epistaxis (nose bleeds). On examination, may notice bruising and petechiae.
- Leukopaenia: Patient may present with multiple bacterial or fungal infections. No hepatomegaly, splenomegaly (as points to myeloproliferative disorders) nor lymphadenopathy. Frequency and severity of infections increased.
How can aplastic anaemia be investigated?
Bloods:
• ↓Hb, ↓Platelets, ↓WCC, normal MCV, low or absent reticulocytes. This is to establish pancytopenia.
• Blood film to exclude leukaemia (absence of abnormal circulating white blood cells)
A bone marrow biopsy to show a hypocellular marrow is the definitive test for AA. Moreover, there should be an absence of abnormal cells (exclude malignancy) and no fibrosis (exclude myelodisplastic syndromes), as pancytopenia is common, but AA is not.
Define the types of DIC
DIC is a disorder of the clotting cascade that can complicate a serious illness. DIC may occur in two forms.
1. Acute overt form where there is bleeding and depletion of the platelets and clotting factors.
- Chronic non-overt form where thromboembolism is accompanied by generalised activation of the coagulation system.
What is the aetiology of DIC?
Aetiology:
• Infection: Particularly gram-negative sepsis (due to endotoxin).
• Obstetric complications: Missed miscarriage, severe pre-eclampsia, placental abruption and amniotic emboli.
• Malignancy: Acute promyelocytic leukaemia (acute DIC); lung, breast, GI malignancy (chronic DIC).
• Severe trauma or surgery
• Others: Haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas.
What are the clinical features of DIC?
Patient already severely unwell with symptoms of underlying disease. Symptoms and signs associated with DIC include:
• Petechiae, purpura, epistaxis, ecchymoses, mucosal bleeding and overt haemorrhage. Generalised bleeding in at least 3 different locations is highly suggestive of DIC.
• Delirium, confusion or coma.
• Oliguria, hypotension, or tachycardia (circulatory collapse)
• Purpura fulminans, gangrene or acrocyanosis.
How can DIC be investigated?
Bloods: • FBC (↓platelets, ↓Hb) • Clotting (↑APTT/PT/TT) • ↓fibrinogen • ↑fibrin degredation products and d-dimers.
Blood film may show schistocytes (RBC fragments).
What is the definition and epidemiology of Haemochromatosis?
Haemochromatosis is a multisystem disorder resulting from excessive intestinal iron absorption which may lead to organ damage (particularly liver, joints, pancreas, pituitary and heart).
The most common form occurs mainly in people of northern European descent. Carrier frequency is ~1 in 10, but not all express disease. Prevalence of those affected 1 in 400. Typical age of presentation is 40-60 years. Females have a later onset and a less severe presentation as a result of iron loss through menstruation.
What is the aetiology of Haemochromatosis?
Primary haemochromatosis is caused by a mutation in HFE gene, decreased levels of hepcidin, and thus increased duodenal iron absorption. Secondary haemochromatosis is a result from blood transfusions, as after the erythrocytes are broken down, the iron is recycled.
How can Haemochromatosis be investigated?
- ↑Iron, ↓TIBC (Total Iron Binding Capacity measures ferritin), ↑ferritin and transferrin saturation.
- HFE mutation analysis
- Test various organs for complications e.g. liver biopsy, LFTs, fasting blood sugar, echocardiogram, ECG, testosterone, FSH and LH assays.
What is the definition and epidemiology of haemolytic anaemia?
Haemolytic anaemia encompasses a number of conditions that result in premature erythrocyte breakdown. Relatively common haematological disease.
What are the risk factors for haemolytic anaemia?
Strong risk factors include:
• Hx of autoimmune disorders
• Lymphoproliferative disorders (particularly those with CLL and NHL)
• Prosthetic heart valve
• Family origin in Mediterranean, Middle East, Sub-Saharan Africa, or Southeast Asia (haemoglobinopathies more common)
• Family history of haemoglobinopathy or RBC membrane defects
• Recent exposure to cephalosporins, penicillins, quinine derivatives, or NSAID
What is the aetiology of haemolytic anaemia?
Hereditary causes include:
• Membrane defects: hereditary spherocytosis, eliptocytosis
• Metabolic defects: Glucose-6 Phosphate Dehydrogenase deficiency.
• Abnormal haemoglobin production: Sickle-cell disease, thalassaemias.
Acquired causes include:
• Autoimmune: Warm or cold antibodies attach to erythrocyte causing intravascular haemolysis and extravascular haemolysis.
• Isoimmune: transfusion reaction, haemolytic disease of the newborn.
• Drugs: Penicillin, quinine (through formation of drug-antibody-erythrocyte complex)
• Trauma: Microangiopathic haemolytic anaemia caused by red cell fragmentation in abnormal circulation (e.g. haemolytic uraemic syndrome, DIC, malignant hypertension, pre-eclampsia) and artificial heart valves.
• Infection: malaria and sepsis.
• Paroxysmal nocturnal haemoglobinuria.
What are the clinical features of haemolytic anaemia?
Commonly presents with jaundice (due to increased bilirubin in blood), haematuria, and symptoms of anaemia (fatigue, dyspnoea, dizziness).
On examination, many patients have pallor (due to anaemia), are jaundiced and have hepatosplenomegaly.
How can haemolytic anaemia be investigated?
Bloods:
• FBC: ↓Hb, ↑reticulocytes, ↑MCV, also ↑unconjugated bilirubin, ↓haptoglobin
Blood film:
Leucoerythroblastic picture, macrocytosis, nucleated erythrocytes or reticulocytes, polychromasia. Identifies specific abnormal cells, such as spherocytes, elliptocytes, sickle cells, fragmented erythrocytes, malarial parasites, erythrocyte Heinz bodies (denatured Hb, stained with methyl violet seen in G6PD deficiency).
Urine: ↑urobilinogen. If haemolysis is intravascular (extravascular is where macrophages in spleen an liver break down RBCs), there is haemoglobinuria and haemosiderinuria.
Direct Coomb’s test can identify erythrocytes coated with antibodies (agglutinins) using antihuman globulin. Warm agglutinins and cold agglutinins.
Ham’s test for paroxysmal nocturnal haemoglobunuria; Hb electrophoresis or enzyme assay for sickle-cell or thalassemia.
What is the definition and epidemiology of haemolytic uraemic syndrome and TTP?
Haemolytic Uraemic Syndrome (HUS) is characterised by a triad of haemolytic anaemia, thrombocytopenia and acute renal failure. 90% of cases occur in the paediatric population, related to outbreaks of gastroenteritis caused by verotoxin-producing E.Coli.
In adults, a sporadic form is seen, which is often impossible to distinguish from thrombotic thrombocytopenic purpura (TTP). TTP has additional features of fever and fluctuating CNS signs.
What is the [pathophysiology] and aetiology of haemolytic uraemic syndrome and TTP?
[ Factors that cause endothelial injury particularly in renal glomerulus. This results in exposure of basement membrane with resultant microvascular thrombosis, fragmentation of erythrocytes, and destruction of platelets, and ultimately causing renal insufficiency. ]
Causes include:
• Infectious causes: Verotoxin producing E. Coli, Shigella, neuraminidase-producing infections, HIV.
• Drugs: Oral contraceptive pill, cyclosporine, mitomycin, 5-fluorouracil.
• Others: Malignant hypertension, malignancy, pregnancy, SLE, scleroderma.
What are the clinical features of haemolytic uraemic syndrome and TTP?
GI symptoms: Severe abdominal pain, nausea and vomiting. Diarrhoea, especially bloody diarrhoea. On examination, patients show abdominal tenderness.
General: Malaise, fatigue, nausea, fever <38. On examination, pallor, slight jaundice, bruising (severe thrombocytopenia), generalised oedema, hypertension and retinopathy.
Renal: Oliguria or anuria, haematuria.
In TTP, note CNS signs, which may be weakness, problems in vision, fits, and decreased consciousness.
How can haemolytic uraemic syndrome and TTP be investigated?
Blood:
• FBC: normocytic anaemia, ↑neutrophils, ↓↓platelets
• U&Es: ↑Urea, createnine, urate, K+ and ↓Na+
• Clotting (Normal PT, APTT) to exclude other causes of thrombocytopenia.
• LFTs: ↑unconjugated bilirubin, ↑LDH (from haemoloysis)
• Blood cultures, ABG, Blood film (shows schistocytes)
Urine: >1g protein/24h, haematuria, fractional excretion Na+ >1%.
Stool sample: stool culture to detect E. Coli O157:H7
What are the types of haemophilia?
Haemophilia results from the inherited deficiency of clotting products. There are three subtypes:
- Haemophilia A: (most common) caused by deficiency in factor VIII.
- Haemophilia B: Caused by deficiency in factor IX (Christmas disease).
- Haemophilia C: (rare) caused by deficiency in factor XI.
What is the aetiology and epidemiology of haemophilia?
Haemophilia A and B exhibit X-linked recessive inheritance. A variety of genetic mutations in the factor VIII and XI genes have been described. 30% of cases are new mutations. X-linked pattern means it affects males (1-5/10,000 for Haemophilia A and 1/30,000 for Haemophilia B).
[Rare cases of women
with severe haemophilia are described because of extreme lyonization, homozygosity, mosaicism, or Turner syndrome.]
What are the symptoms of haemophilia?
Symptoms usually begin in early childhood (sometimes noticed after prolonged bleeding after heel-prick or circumcision) .
• History of recurrent or severe bleeding. Spontaneous or trauma-induced (onset may be delayed after several days after bleeding - as primary haemostasis [platelet plug formation] still works).
• Painful bleeding into muscles is a hallmark of haemophilia. Patients will complain of pain and swelling in the area, decreased motility, erythema and increased local warmth.
• Haemarthrosis is another hallmark of haemophilia. Painful bleeding into joints, causing swelling.
• Mucocutaneous bleeding after dental work, and easy bruising is common.
Female carriers are often asymptomatic, but may have low enough levels to cause excess bleeding after trauma.
What are the examination features of haemophilia?
On Examination: Patients usually have multiple bruises, muscle haematomas, haemarthroses, and joint deformities. May also have signs of iron-deficiency anaemia.
How is haemophilia investigated?
Clotting screen: ↑APTT (reflects the activity of the intrinsic and common pathway), coagulation factor assay shows ↓Factor VIII or IX or XI (depending on type of haemophilia).
Other investigations according to complications e.g. arthroscopy, head/neck CT/MRI, pelvic US.
What is the definition, epidemiology and aetiology of ITP?
ITP is a syndrome characterised by immune destruction of platelets resulting in bruising or bleeding tendency. Presents in children between 2-7 years. Chronic ITP is seen in adults and is four times more common in women.
It is often idiopathic. Acute ITP is usually seen after a viral infection in children, while the chronic form is more common in adults. The aetiology responsible for breaking tolerance and for initiating autoimmune attack is unknown.
What are the clinical features of ITP?
Patients present with easy bruising, mucosal bleeding, menorrhagia and epistaxis.
On examination, find visible petechiae, bruises (purpura or eccymyoses).
Typically, signs of other illness (e.g. infections, wasting, splenomegaly) would suggest other causes.
How is ITP investigated?
ITP is diagnosed by exclusion. Exclude myelodysplasia, acute leukaemia, marrow infiltration.
Blood:
• FBC (decreased platelets, normal clotting screen)
• May detect autoantibodies
Blood film used to diagnose psuedothrombocytopaenia where platelet clumping gives falsely low platelet counts.
Bone marrow biopsy to exclude other pathology. May notice an increase in megakaryocytes.
What is the definition and epidemiology of ALL?
ALL is a malignancy of the bone marrow and blood characterised by the proliferation of lymphoblasts (primitive lymphoid cells). It is the most common malignancy of childhood, with peak incidence occurring between 2 and 5 years of age. The second peak is in the elderly.
What is the pathophysiology of ALL?
In ALL, the lymphoblast is arrested in development due to cytogenetic abnormalities, gene mutations and chromosomal translocations. They also undergo malignant transformation and proliferation, with subsequent replacement of normal marrow elements. This leads to bone marrow failure and infiltration into tissues.
What are risk factors for ALL?
Risk Factors include:
• Environmental - irradiation and viruses
• Genetic - down’s syndrome, neurofibromitosis type 1, Fanconi’s anaemia, achrondraplasia, ataxia telangiectasia, xeroderma pigmentosum, and X-linked agammaglobuminaemia.
What are the clinical features of ALL?
These arise due to bone marrow failure, and tissue infiltration.
Bone Marrow Failure:
• Symptoms include: anaemia (fatigue, dyspnoea), bleeding (spontaneous bruising, bleeding gums, menorrhoagia), and opportunistic infections (bacterial, viral, protozoal). Anaemia and thrombocytopaenia occur due to bone marrow replacement.
• On examination, can cause pallor, bruising, bleeding, and infection.
Organ Infiltration:
• Symptoms of tender bones/bone pain, lymph node enlargement, mediastinal compression (in T-cell ALL as thymic involvement). Symptoms of meningeal involvement such as headache, visual disturbances and nausea.
• On examination, lymphadenopathy, hepatosplenomegaly, cranial nerve palsies, retinal haemorrhage, or papilloedema on fundoscopy, leukaemic infiltration of the anterior chamber of the eye, testicular swelling.
How is ALL investigated?
Bloods:
• FBC: normocytic normochromic anaemia with low reticulocyte count is present in 80% of patients. Thrombocytopaenia is present in 75% of patients, while leukocytosis is present in only 50% patients (and presence has poor prognosis).
• Serum electrolytes increased such as calcium and uric acid.
• ↑LDH (many cancers increase LDH as it is important when switching to anaerobic respiration).
Peripheral blood smear shows leukaemic lymphoblasts. However, this is not sufficient for the diagnosis of ALL, and thus a bone marrow biopsy/aspiration is needed. From this, many studies can be performed including:
• Immunophenotyping using cell-surface antigens e.g. CD20.
• Cytogenetics karyotyping chromosomal abnormalities.
• FISH (Flourescent In-Situ Hybridisation)
• PCR
CXR may show mediastinal involvement, thymic enlargement, lytic bone lesions.
What is the definition and epidemiology of AML?
AML is a malignancy of primitive myeloid lineage white blood cells with proliferation in the bone marrow and blood. It is the most common acute leukaemia in adults, with incidence increasing with age.
What are the clinical features of AML?
Like other acute leukaemias, symptoms are due to bone marrow failure and tissue infiltration.
Bone marrow failure:
• Patients present with anaemia (lethargy, dyspnoea), bleeding (thrombocytopaenia or DIC), and opportunistic/recurrent infections.
• Signs include pallor, cardiac flow murmur, ecchymosis, bleeding and signs of infection.
Tissue infiltration:
• Patients present with gum swelling or bleeding, CNS involvement (headaches, nausea, diplopia) especially with M4 and M5 variants.
• Signs include skin rashes, gum hypertrophy, deposit of leukaemic blasts may rarely be seen in the eye, tongue and bone (and cause fractures).
How can AML be investigated?
Blood:
• FBC (↓Hb, ↓platelets, ↓variable WCC)
• ↑Uric acid, ↑LDH, ↑Clotting studies, fibrinogen, and D-dimers
Blood film shows blast cells with cytoplasmic granules or Auer rods.
Bone marrow aspirate or biopsy shows hypercellular marrow with >30% blast cells.
Immunophenotyping used to classify the lineage of abnormal cells, for categorisation.
Cytogenetics for diagnostic and prognostic information.
Immunocytochemistry: Myeloblast granules are positive for Sudan black, chloroacetate esterase and myeloperoxidase, monoblasts are positive for non-specific and butyrate esterase.
Define CLL
CLL is characterised by the progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. There is an overlap between CLL and non-Hodgkin’s lymphoma. It is also called B-CLL, because it is a malignant disease of B-cells.
What is the epidemiology of CLL?
CLL commonly affects the elderly (90% >50), and males more than females. CLL is rare in Asians.
