HAEM Flashcards
Define Macrocytic Anaemia
Anaemia associated with a high MCV of erythrocytes (>100fl in adults)
Aetiology/ Risk Factors of macrocytic anaemia
• Megaloblastic - when the bone marrow produces unusually large, structurally
abnormal, immature red cells
o Caused by deficiency of B12 or folate required for the
conversion of deoxyuridate to thymidylate, DNA
synthesis and nuclear maturation
o Causes of Vitamin B12 Deficiency:
• Reduced absorption (e.g. post-gastrectomy, pernicious anaemia, terminal ileal resection or disease)
• Reduced intake (vegans)
• Abnormal metabolism (congenital transcobalamin II deficiency)
o Causes of Folate Deficiency:
• Reduced intake (alcoholics, elderly, anorexia)
• Increased demand (pregnancy, lactation, malignancy, chronic inflammation)
• Reduced absorption
• Jejunal disease (e.g. coeliac disease)
• Drugs (e.g. phenytoin)
o Drugs
• Methotrexate (dihydrofolate reductase inhibitor)
• Hydroxyurea
• Azathioprine
• Zidovudine
• Non-Megaloblastic
o Alcohol excess
o Liver disease
o Myelodysplasia
o Multiple myeloma
o Hypothyroidism
o Haemolysis (shift to immature red cell form - reticulocytosis)
o Drugs (e.g. tyrosine kinase inhibitor)
Epidemiology of macrocytic anaemia
- More common in ELDERLY FEMALES
* Pernicious anaemia is the MOST COMMON cause of B12 deficiency in the West
Presenting symptoms of macrocytic anaemia
• Non-specific symptoms of anaemia:
o Tiredness
o Lethargy o Dyspnoea
• Family history of autoimmune disease
• Previous GI surgery
• Symptoms of the CAUSE (e.g. weight loss, diarrhoea)
Signs of macrocytic anaemia on physical examination
• Signs of Anaemia o Pallor o Tachycardia o Breathlessness • Signs of Pernicious Anaemia o Mild jaundice o Glossitis o Angular stomatitis o Weight loss • Signs of B12 Deficiency o Peripheral neuropathy o Ataxia o Subacute combined degeneration of the spinal cord o Optic atrophy o Dementia
Investigations for macrocytic anaemia
• Bloods
o FBC
• High MCV
• Pancytopaenia in megaloblastic anaemia
• Different degrees of cytopaenia in myelodysplasia
• Exclude reticulocytosis
o LFT
• High bilirubin (due to ineffective erythropoiesis or haemolysis)
o ESR
o TFT
o Serum vitamin B12
o Red cell folate
o Anti-parietal cell and anti-intrinsic factor antibodies
o Serum protein electrophoresis - looking for a dense band in myeloma
• Blood Film
o Large erythrocytes
o In megaloblastic anaemia:
• Megaloblasts
• Hypersegmented neutrophil nuclei
• Schilling Test
o Method of testing for pernicious anaemia
o B12 will only be absorbed when given with intrinsic factor
• Bone Marrow Biopsy (rarely needed)
• Investigations for the cause
Management plan for macrocytic anaemia
• Pernicious Anaemia o IM hydroxycobalamin for life • Folate Deficiency o Oral folic acid o If B12 deficiency is present, it must be treated before the folic acid deficiency
Complications of macrocytic anaemia
- Pernicious anaemia –> increased risk of gastric cancer
* Pregnancy - folate deficiency increases the risk of neural tube defects
Prognosis for patients with macrocytic anaemia
• Majority are treatable if there are no complications
Define microcytic anaemia
Anaemia associated with a low MCV (<80 fl)
Aetiology/ Risk factors of microcytic anaemia
• Iron Deficiency - MOST COMMON
o Iron deficiency can be caused by:
• Blood loss (e.g. GI)
• Reduced absorption (e.g. small bowel disease)
• Increased demands (e.g. growth, pregnancy)
• Reduced intake (e.g. vegans)
• Anaemia of Chronic Disease
o Microcytic anaemia in a patient with chronic disease
• Thalassemia
• Sideroblastic Anaemia
o Abnormality of haem synthesis
o It can be inherited or it can be secondary (e.g. to alcohol, drugs)
Epidemiology of microcytic anaemia
• Iron deficiency anaemia is the MOST COMMON form of anaemia worldwide
Presenting symptoms of microcytic anaemia
• Non-Specific o Tiredness o Lethargy o Malaise o Dyspnoea o Pallor o Exacerbation of ischaemic conditions (e.g. angina, intermittent claudication) • Lead Poisoning - can cause microcytic anaemia Symptoms of lead poisoning o Anorexia o Nausea/Vomiting o Abdominal pain o Constipation o Peripheral nerve lesions
Signs of microcytic anaemia on physical examination
• Signs of anaemia o Pallor o Brittle nails and hair o Koilonychia (if severe) • Glossitis • Angular stomatitis • Signs of thalassemia • Lead poisoning signs: o Blue gumline o Peripheral nerve lesions (causing wrist or foot drop) o Encephalopathy o Convulsions o Reduced consciousness
Investigations for microcytic anaemia
• Bloods o FBC • Low Hb • Low MCV • Reticulocytes o Serum iron (low in iron deficiency) o Total iron binding capacity (high in iron deficiency) o Serum ferritin (low in iron deficiency) o Serum lead • Blood Film o Iron deficiency anaemia: • Microcytic • Hypochromic • Anisocytosis • Poikilocytosis o Sideroblastic anaemia: • Dimorphic blood film • Hypochromic microcytic cells o Lead poisoning: • Basophilic stippling • Hb Electrophoresis o Checking for haemoglobin variants and thalassemia • Sideroblastic Anaemia o Ring sideroblasts in the bone marrow • Special investigations for iron deficiency anaemia if > 40 yrs and post-menopausal women These are considered if no obvious cause of blood loss is identified o Upper GI endoscopy o Colonoscopy o Haematuria
Management plan for microcytic anaemia
• Iron Deficiency - oral iron supplements • Sideroblastic Anaemia o Treat the cause o Pyridoxine used in inherited forms o Blood transfusion and iron chelation can be considered if there is no response to other treatments • Lead Poisoning o Remove the source o Dimercaprol o D-penicillinamine
Complications of microcytic anaemia
- High-output cardiac failure
* Complications related to the CAUSE
Prognosis for patients with microcytic anaemia
• Depends on the CAUSE
Define Normocytic Anaemia
Anaemia with a normal MCV (80-100)
Aetiology/ Risk Factors of normocytic anaemia
• Causes:
o Decreased production of normal-sized blood cells (e.g. anaemic of chronic disease, aplastic anaemia)
o Increased production of HbS (sickle cell disease)
o Increased destruction of red blood cells (e.g. haemolysis, post-haemorrhagic anaemia)
o Uncompensated increase in plasma volume (e.g. pregnancy, fluid overload) o Vitamin B2 deficiency
o Vitamin B6 deficiency
Epidemiology of normocytic anaemia
Common
Presenting symptoms and signs of normocytic anaemia
• Typical symptoms and signs of anaemia (depends on severity)
o E.g. breathlessness, fatigue, conjunctival pallor
Investigations for normocytic anaemia
- FBC - check Hb and MCV
* Check history for haemorrhage
Define Aplastic Anaemia
Characterised by diminished haematopoietic precursors in the bone marrow and deficiency of all blood cell elements (pancytopenia)
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)
Epidemiology of aplastic anaemia
- Annual incidence: 2-4/1,000,000
* Slightly more common in males
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
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
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 Disseminated Intravascular Coagulation (DIC)
A disorder of the clotting cascade that can complicate a serious illness.
- 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
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 of DIC (acute and chronic)
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
Epidemiology of DIC
Seen in any severely ill patient
Presenting symptoms of DIC
- The patients will tend to be severely unwell with symptoms of the underlying disease
- Confusion
- Dyspnoea
- Evidence of bleeding
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
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 Haemochromatosis
An autosomal recessive disease in which increased intestinal absorption of iron causes accumulation of iron in tissues, which may lead to organ damage
Aetiology/ Risk Factors of haemochromatosis
- Autosomal recessive
- Caused be a defect in the HFE gene
- NOTE: the genetic penetrance of haemochromatosis is complex - not everyone who is homozygous will develop the clinical disease
Epidemiology of haemochromatosis
• RARE
Recognise the presenting symptoms and signs of haemochromatosis
• Often ASYMPTOMATIC until the late stages of the disease • Symptoms usually start between 40-60 yrs • EARLY symptoms are vague: o Fatigue o Weakness o Arthropathy o Erectile dysfunction o Heart problems • May be an incidental finding (e.g. LFTs, serum ferritin) • LATE symptoms: o Diabetes mellitus o Bronzed skin o Hepatomegaly o Impotence o Amenorrhoea o Hypogonadism o Cirrhosis o Cardiac - arrhythmias and cardiomyopathy o Neurological and psychiatric problems
Investigations for haemochromatosis
• Haematinics - serum ferritin (HIGH), transferrin (LOW), transferrin saturation (HIGH), TIBC (LOW)
o NOTE: serum ferritin is NOT very specific because it is an acute phase protein
o Serum iron concentration and transferrin saturation do NOT accurately reflect
total body iron stores
• Tests to exclude other causes of high ferritin:
o CRP - inflammation
o Chronic alcohol consumption
o ALT - liver necrosis
• LFTs
• Other investigations for abnormal liver function (e.g. hepatitis serology)
• Genetic testing
• Liver biopsy (rarely required)
Define haemolytic anaemia
Premature erythrocyte breakdown causing shortened erythrocyte life span (<120 days) with anaemia)
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
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
Presenting symptoms of haemolytic anaemia
- Jaundice
- Haematuria
- Anaemia
Signs of haemolytic anaemia on physical examination
- Pallor
- Jaundice
- Hepatosplenomegaly
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 Haemolytic Uraemic Syndrome and Thrombotic Thrombocystopaenic Purpura (HUS and TTP)
Definition: triad of :
- microangiopathic haemolytic anaemia (MAHA)
- acute renal failure
- thrombocytopenia
There are two forms of HUS:
- D+ = diarrhoea- associated form
- D- = no prodromal illness identified
HUS overlaps with TTP , which has additional features of
- fever
- fluctuating CNS signs
Aetiology/ Risk Factors for HUS and TTP (Haemolytic Uraemic Syndrome and Thrombotic Thrombocystopaenic Purpura)
- 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
Epidemiology of HUS and TTP (Haemolytic Uraemic Syndrome and Thrombotic Thrombocystopaenic Purpura)
- UNCOMMON
- D+ HUS often affects YOUNG CHILDREN
- It is the most common cause of acute renal failure in children
- TTP mainly affects ADULT FEMALES
Presenting symptoms of HUS and TTP (Haemolytic Uraemic Syndrome and Thrombotic Thrombocystopaenic Purpura)
• 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
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
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
• Haemophilia A: MOST COMMON - deficiency in factor 8
• Haemophilia B: deficiency in factor 9
• Haemophilia C: RARE - deficiency in factor 11
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
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
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 (right) • 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)
