Haematology Flashcards
Learning objectives
Answer
Define anti-phospholipid syndrome
• Characterised by the presence of antiphospholipid antibodies (APL) in the plasma, venous and arterial thrombosis, recurrent foetal loss and thrombocytopaenia
Explain the aetiology/risk factors of anti-phospholipid syndrome
- Antiphospholipid antibodies (APL) are directed against plasma proteins bound to phospholipids
- APL may develop in susceptible individuals following exposure to infectious agents
- Once APL are present, a second event is needed for the syndrome to develop
- APL has effects on a number of coagulation factors (e.g. protein C, annexin V, platelets, fibrinolysis)
- Complement activation by APL is critical for the complications
Summarise the epidemiology of anti-phospholipid syndrome
- More common in YOUNG WOMEN
- Accounts for 20% of strokes in < 45 yrs
- Accounts for 27% of women with > 2 miscarriages
Recognise the presenting symptoms of anti-phospholipid syndrome
• RECURRENT MISCARRIAGES • History of: o Arterial thromboses (stroke) o Venous thromboses (DVT, PE) • Headaches (migraine) • Chorea • Epilepsy
Recognise the signs of anti-phospholipid syndrome on physical examination
• Livedo reticularis
o A skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discolouration of the skin
• Signs of SLE (e.g. malar rash, discoid lesions)
• Signs of valvular heart disease
Identify appropriate investigations for anti-phospholipid syndrome
• FBC - low platelets
• ESR - usually normal
• U&Es - can get APL nephropathy
• Clotting screen - high APTT
• Presence of antiphospholipid antibodies may be demonstrated by:
o ELISA testing for anticardiolipin antibodies
o Lupus anticoagulant assays
Define aplastic anaemia
• Characterised by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopaenia)
Explain the aetiology/risk factors of aplastic anaemia
• Idiopathic (> 40%)
o May be due to destruction or suppression of stem cells via autoimmune mechanisms
• Acquired
o Drugs (e.g. chloramphenicol, sulphonamides, methotrexate)
o Chemicals (e.g. benzene, DDT)
o Radiation
o Viral infection (e.g. parvovirus B19)
o Paroxysmal nocturnal haemoglobinuria
• Inherited
o Fanconi’s anaemia
o Dyskeratosis congenita (a rare, progressive bone marrow failure syndrome)
Summarise the epidemiology of aplastic anaemia
- Annual incidence: 2-4/1,000,000
* Slightly more common in males
Recognise the presenting symptoms of aplastic anaemia
• Can be both slow-onset (months) or rapid-onset (days) • Anaemia Symptoms: o Tiredness o Lethargy o Dyspnoea • Thrombocytopaenia Symptoms: o Easy bruising o Bleeding gums o Epistaxis • Leukopaenia Symptoms: o Increased frequency and severity of infections
Recognise the signs of aplastic anaemia on physical examination
• Anaemia Signs: o Pallor • Thrombocytopaenia Signs: o Petechiae o Bruises • Leukopaenia Signs: o Multiple bacterial and fungal infections o No hepatomegaly, splenomegaly or lymphadenopathy
Identify appropriate investigations for aplastic anaemia
• Bloods o FBC • Low Hb • Low platelets • Low WCC • Normal MCV • Low or absent reticulocytes • Blood Film o Exclude leukaemia (check for abnormal circulating white blood cells) • Bone Marrow Trephine Biopsy • Fanconi's Anaemia o Check for presence of increased chromosomal breakage in lymphocytes cultures in the presence of DNA cross-linking agents
Define DIC
• A disorder of the clotting cascade that can complicate a serious illness.
o DIC can occur in TWO forms:
• Acute overt form where there is bleeding and depletion of platelets and clotting factors
• Chronic non-overt form where thromboembolism is accompanied by generalised activation of the coagulation system
Explain the aetiology/risk factors for DIC
• Infection - particularly GRAM-NEGATIVE sepsis
• Obstetric Complications
o Missed miscarriage (when the foetus dies but the body doesn’t realise it and the placenta continues to release hormones)
o Severe pre-eclampsia
o Placental abruption (separation of the placenta from the wall of the uterus during pregnancy)
o Amniotic emboli
• Malignancy
o Acute promyelocytic leukaemia - ACUTE DIC
o Lung, breast and GI malignancy - CHRONIC DIC
• Severe trauma or surgery
• Others: haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas
• Pathophysiology
o Acute DIC
• Endothelial damage and the release of granulocyte/macrophage procoagulant substances (e.g. tissue factor) lead to activation of coagulation
• This leads to explosive thrombin generation, which depletes clotting factors and platelets, whilst also activating the fibrinolytic system
• This leads to bleeding in the subcutaneous tissues, skin and mucous membranes
• Occlusion of blood vessels by fibrin in the microcirculation leads to microangiopathic haemolytic anaemia and ischaemic organ damage
o Chronic DIC
• IDENTICAL process to acute DI
• Happens at a slower rate with time for compensatory responses
• The compensatory responses diminish the likelihood of bleeding but give rise to hypercoagulable states and thrombosis can occur
Summarise the epidemiology of DIC
• Seen in any severely ill patient
Recognise the presenting symptoms of DIC
- The patients will tend to be severely unwell with symptoms of the underlying disease
- Confusion
- Dyspnoea
- Evidence of bleeding
Recognise the signs of DIC on physical examination
• Signs of underlying disease • Fever • Evidence of shock (hypotension, tachycardia) • Acute DIC o Petechiae, purpura, ecchymoses o Epistaxis o Mucosal bleeding o Overt haemorrhage o Signs of end organ damage o Respiratory distress o Oliguria due to renal failure • Chronic DIC o Signs of deep vein and arterial thrombosis or embolism o Superficial venous thrombosis
Identify appropriate investigations for DIC
• Bloods o FBC • Low platelets • Low Hb • High APTT/PT • Low fibrinogen • High fibrin degradation products • High D-dimers • Peripheral Blood Film o Schistocytes
Define haemolytic anaemia
• Premature erythrocyte breakdown causing shortened erythrocyte life span (< 120 days) with anaemia
Explain the aetiology/risk factors of haemolytic anaemia
• Hereditary o Membrane Defects • Hereditary spherocytosis • Elliptocytosis o Metabolic Defects • G6PD deficiency • Pyruvate kinase deficiency o Haemoglobinopathies • Sickle cell disease • Thalassemia • Acquired o Autoimmune • Antibodies attach to erythrocytes causing intravascular and extravascular haemolysis o Isoimmune • Transfusion reaction • Haemolytic disease of the newborn o Drugs • Penicillin • Quinine • NOTE: this is caused by the formation of a drug-antibody-erythrocyte complex o Trauma • Microangiopathic haemolytic anaemia (caused by RBC fragmentation in abnormal microcirculation) E.g. haemolytic uraemic syndrome, DIC, malignant hypertension o Infection • Malaria • Sepsis o Paroxysmal nocturnal haemoglobinuria
Summarise the epidemiology of haemolytic anaemia
- COMMON
- Genetic causes are prevalent if African, Mediterranean and Middle Eastern populations
- Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europe
Recognise the presenting symptoms of haemolytic anaemia
- Jaundice
- Haematuria
- Anaemia
Recognise the signs of haemolytic anaemia on physical examination
- Pallor
- Jaundice
- Hepatosplenomegaly
Identify appropriate investigations for haemolytic anaemia
• Bloods o FBC: • Low Hb • High reticulocytes • High MCV • High unconjugated bilirubin • Low haptoglobin (a protein that binds to free Hb released by red blood cells) o U&Es o Folate • Blood Film o Leucoerythroblastic picture o Macrocytosis o Nucleated erythrocytes or reticulocytes o Polychromasia o May identify specific abnormal cells such as: • Spherocytes • Elliptocytes • Sickle cells • Schistocytes • Malarial parasites • Urine o High urobilinogen o Haemoglobinuria o Haemosiderinuria • Direct Coombs' Test o Tests for autoimmune haemolytic anaemia o Identifies erythrocytes coated with antibodies • Osmotic fragility test or Spectrin mutation analysis o Identifies membrane abnormalities • Ham's Test o Lysis of erythrocytes in acidified serum in paroxysmal nocturnal haemoglobinuria • Hb Electrophoresis or Enzyme Assays o To exclude other causes • Bone Marrow Biopsy (rarely performed)
Define HUS and TTP
• DEFINITION: triad of: o Microangiopathic haemolytic anaemia (MAHA) o Acute renal failure o Thrombocytopaenia • There are TWO forms of HUS: o D+ = diarrhoea-associated form o D- = no prodromal illness identified • HUS overlaps with TTP, which has additional features of: o Fever o Fluctuating CNS signs
Explain the aetiology/risk factors for HUS and TTP
• Endothelial injury results in platelet aggregation and the release of unusually large vWF multimers and activation of platelets and the clotting cascade • This leads to small vessel thrombosis • The glomerular-afferent arteriole and capillaries are particularly vulnerable - they undergo fibrinoid necrosis • This leads to renal ischaemia and acute renal failure • The thrombi also promote intravascular haemolysis • CAUSES: o Infection • Escherichia coli O157 • Shigella • Neuraminidase-producing infections • HIV o Drugs • COCP • Ciclosporin • Mitomicin • 5-fluorouracil o Others: • Malignant hypertension • Malignancy • Pregnancy • SLE • Scleroderma
Summarise the epidemiology of HUS and TTP
- UNCOMMON
- D+ HUS often affects YOUNG CHILDREN
- It is the most common cause of acute renal failure in children
- TTP mainly affects ADULT FEMALES
Recognise the presenting symptoms of HUS and TTP
• GI o Severe abdominal colic o Watery diarrhoea that becomes bloodstained • General o Malaise o Fatigue o Nausea o Fever < 38 degrees (D+) • Renal o Oliguria or anuria o Haematuria
Recognise the signs of HUS and TTP on physical examination
• General o Pallor o Slight jaundice (due to haemolysis) o Bruising o Generalise oedema o Hypertension o Retinopathy • GI o Abdominal tenderness • CNS Signs o Occurs in TTP o Weakness o Reduced vision o Fits o Reduced consciousness
Identify appropriate investigations for HUS and TTP
• FBC o Normocytic anaemia o High neutrophils o Very low platelets • U&Es o High urea o High creatinine o High K+ o Low Na+ • Clotting o Normal APTT and fibrinogen levels (abnormality may indicate DIC) • LFTs o High unconjugated bilirubin o High LDH from haemolysis • Blood cultures • ABG o Low pH o Low bicarbonate o Low PaCO2 o Normal anion gap • Blood Film o Schistocytes o High reticulocytes and spherocytes • Urine o 1+ g protein/24 hrs o Haematuria • Stool Samples o MC&S • Renal Biopsy o Can distinguish between D+ and D- HUS
Define haemophilia
• Bleeding diatheses resulting from an inherited deficiency of a clotting factor
o THREE subtypes:
• Haemophilia A: MOST COMMON - deficiency in factor 8
• Haemophilia B: deficiency in factor 9
• Haemophilia C: RARE - deficiency in factor 11
Explain the aetiology/risk factors of haemophilia
- Haemophilia A and B have X-linked recessive inheritance
- 30% of cases are new mutations
- Due to its inheritance pattern, Haemophilia is mainly seen in MALES
Summarise the epidemiology of haemophilia
- Haemophilia A incidence: 1/10,000 males
- Haemophilia B incidence: 1/25,000 males
- Haemophilia C is more common in Ashkenazi Jews
Recognise the presenting symptoms of haemophilia
- Symptoms usually begin in early childhood
- Swollen painful joints occurring spontaneously or with minimal trauma (haemarthroses)
- Painful bleeding into muscles
- Haematuria
- Excessive bruising or bleeding after surgery or trauma
- FEMALE carriers are usually asymptomatic, but may experience excessive bleeding after trauma
- Generally speaking, bleeding in haemophilia is DEEP (into muscles and joints)
Recognise the signs of haemophilia on physical examination
- Multiple bruises
- Muscle haematomas
- Haemarthroses
- Joint deformity
- Nerve palsies (due to nerve compression by haematomas)
- Signs of iron deficiency anaemia
Identify appropriate investigations for haemophilia
- Clotting screen (high APTT)
- Coagulation factor assays (low factor 8, 9 or 11 (depending on type of haemophilia))
- Other investigations may be performed if there are complications (e.g. arthroscopy)
Define ITP
• Syndrome characterised by immune destruction of platelets resulting in bruising or a bleeding tendency
Explain the aetiology/risk factors of ITP
• Often IDIOPATHIC
• Acute ITP is often seen after viral infection in children
• Chronic ITP is more common in adults
• ITP may be associated with:
o Infections (e.g. malaria, EBV, HIV)
o Autoimmune diseases (e.g. SLE, thyroid disease)
o Malignancies
o Drugs (e.g. quinine)
• Autoantibodies are generated, which bind to platelet membrane proteins (e.g. GlpIIb/IIIa) resulting in thrombocytopaenia
Summarise the epidemiology of ITP
• Acute ITP presenting CHILDREN aged 2-7 yrs
• Chronic ITP is seen in ADULTS
o 4 x more common in WOMEN
Recognise the presenting symptoms of ITP
- Easy bruising
- Mucosal bleeding
- Menorrhagia
- Epistaxis
Recognise the signs of ITP on physical examination
- Visible petechiae and bruises
* Signs of other illness (e.g. infections, wasting, splenomegaly) would suggest that other causes
Identify appropriate investigations for ITP
• Diagnosis of exclusion - exclude: o Myelodysplasia o Acute leukaemia o Marrow infiltration • Bloods o FBC - low platelets o Clotting screen - normal PT, APTT and fibrinogen o Autoantibodies (e.g. antiplatelet antibody) • Blood Film o To rule out pseudothrombocytopaenia (which is caused by platelets clumping together and giving falsely low counts) • Bone Marrow o To exclude other pathology
Define ALL
• Malignancy of the bone marrow and blood characterised by the proliferation of lymphoblasts (primitive lymphoid cells)
Explain the aetiology / risk factors of ALL
- Lymphoblasts undergo malignancy transformation and proliferation
- This leads to the replacement of normal marrow elements, leading to bone marrow failure and infiltration into other tissues
Risk Factors: o Environmental (radiation, viruses) o Genetic (Down's syndrome, Neurofibromatosis type 1, Fanconi's anaemia, xeroderma pigmentosum)
Summarise the epidemiology of ALL
- MOST COMMON malignancy of CHILDHOOD
- Peak incidence: 2-5 yrs old
- There is a second peak in incidence in the elderly
- Annual UK incidence: 1/70,000
Recognise the presenting symptoms of ALL
Symptoms of Bone Marrow Failure:
o Anaemia (fatigue, dyspnoea)
o Bleeding (spontaneous bruising, bleeding gums, menorrhagia)
o Opportunistic infections
Symptoms of Organ Infiltration: o Tender bones o Enlarged lymph nodes o Mediastinal compression o Meningeal involvement (headache, visual disturbances, nausea)
Recognise the signs of ALL on physical examination
Signs of Bone Marrow Failure: o Pallor o Bruising o Bleeding o Infection
Signs of Organ Infiltration: o Lymphadenopathy o Hepatosplenomegaly o Cranial nerve palsies o Retinal haemorrhage o Papilloedema on fundoscopy o Leukaemic infiltration of the anterior chamber of the eye o Testicular swelling
Identify appropriate investigations for ALL and interpret the results
Bloods o FBC - normochromic normocytic anaemia, low platelets, variable WCC o High uric acid o High LDH o Clotting screen
Blood Film
o Abundant lymphoblasts
Bone Marrow Aspirate or Trephine Biopsy
o Hypercellular with > 20% lymphoblasts
Immunophenotyping - using antibodies to recognise cell surface antigens
Cytogenetic - karyotyping to look for chromosomal abnormalities or translocations
Cytochemistry
Lumbar Puncture - check for CNS involvement
CXR - may show mediastinal lymphadenopathy, lytic bone lesions
Bone Radiographs - mottled appearance with punched out lesions due to leukaemic infiltration
Define AML
• Malignancy of primitive myeloid lineage white blood cells (myeloblasts) with proliferation in the bone marrow and blood
o Classified using the FAB (French-American-British) System into EIGHT morphological variants
Explain the aetiology / risk factors of AML
- Myeloblasts undergo malignant transformation and proliferation
- This leads to replacement of normal marrow and bone marrow failure
Summarise the epidemiology of AML
- MOST COMMON acute leukaemia in ADULTS
* Incidence INCREASES with age
Recognise the presenting symptoms of AML
Symptoms of Bone Marrow Failure:
o Anaemia (lethargy, dyspnoea)
o Bleeding (due to thrombocytopaenia or DIC)
o Opportunistic or recurrent infections
Symptoms of Tissue Infiltration:
o Gum swelling or bleeding
o CNS involvement (headaches, nausea, diplopia)
Recognise the signs of AML on physical examination
Signs of Bone Marrow Failure: o Pallor o Cardiac flow murmur o Ecchymosis o Bleeding o Opportunistic or recurrent infections (e.g. fever, mouth ulcers, skin infections)
Signs of Tissue Infiltration:
o Skin rashes
o Gum hypertrophy
o Deposit of leukaemic blasts in the eye, tongue and bone (RARE)
Identify appropriate investigations for AML and interpret the results
Bloods
o FBC - low Hb, low platelets, variable WCC
o High uric acid
o High LDH
o Clotting studies, fibrinogen and D-dimers (to check for DIC)
Blood Film
o Myeloblasts
Bone Marrow Aspirate or Biopsy
o Hypercellular with > 20% blasts
Immunophenotyping
o Antibodies against surface antigens used to classify the lineage of the abnormal clones
Cytogenetics
Immunocytochemistry
Define CLL
• Characterised by progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. There is an overlap between CLL and non-Hodgkin’s lymphoma
Explain the aetiology / risk factors of CLL
• Malignant cells may accumulate as a result of their inability to undergo apoptosis
The most common chromosomal changes include:
o Trisomy 12
o 11q and 13q deletions
Summarise the epidemiology of CLL
- 90% are > 50 yrs
- More common in MALES
- Rare in Asians
Recognise the presenting symptoms of CLL
Asymptomatic - 40-50% of cases are diagnosed following routine blood tests
Systemic Symptoms:
o Lethargy
o Malaise
o Night sweats
Symptoms of Bone Marrow Failure:
o Recurrent infections
o Herpes zoster infection
o Easy bruising or bleeding
Recognise the signs of CLL on physical examination
- Non-tender lymphadenopathy
- Hepatomegaly
- Splenomegaly
LATE STAGE signs of bone marrow failure:
o Pallor
o Cardiac flow murmur
o Purpura/ecchymosis