Haematology Flashcards
Define anaemia (and its initial subtypes)
Anaemia is defined as a low level of haemoglobin in the blood
Anaemia is initially subdivided into three main categories based on the size of the red blood cell (the MCV). These have different underlying causes:
- Microcytic anaemia(low MCV indicating small RBCs)
- Normocytic anaemia(normal MCV indicating normal sized RBCs)
- Macrocytic anaemia(large MCV indicating large RBCs)
Normochromia and hypochromia refers to the colour (MHCH: mean corpuscular haemoglobin concentration)
Parameters for Anaemia
Anaemia is defined by measurable variables such as:
- Red blood cell (RBC) count
- Haemoglobin (Hb) concentration
- Haematocrit - proportion of RBC
- MCV (mean cell volume - a measurement of the size of RBCs)
Normal ranges for Haemoglobin and MCV for men and women
Women:
Haem: 120-165 grams/litre
MCV: 80-100 femtolitres
Men:
Haem: 130-180 grams/litre
MCV: 80-100 femtolitres
General causes of Microcytic anaemia and types of microcytic anaemia
Caused by problems in producing RBCs or Hb
Causes: (mnemonic TAILS)
- T–Thalassaemia
- A–Anaemia of chronic disease
- I–Iron deficiency anaemia
- L–Lead poisoning
- S–Sideroblastic anaemia
Brief overview of Iron deficiency anaemia
- Generally occurs in people with chronic slow bleeding - where the iron in the red blood cells is lost with the blood e.g. women with frequent or heavy menstruation or patients with colon cancer.
- Pregnancy: due to increased iron requirements for fetal development.
- Lack of iron in the diet.
- Can be due to refractory iron deficiency due to H.pylori infection: the bacteria can sequester iron and it can cause gastric bleeding, or inflammatory bowel disease or coeliac disease, both of which can cause malabsorption.
Treatment:
- Treat the cause
- Oral iron supplements
- If oral iron isn’t effective, or the side effects can’t be tolerated, IV iron can be used instead.
Brief overview of Anaemia of chronic disease
- Characterised by inflammation. During inflammation the body likes to store away iron.
- Often develops in people with chronic inflammatory diseases, like infections, autoimmune disorders, and various cancers, and typically resolves once that underlying condition resolves.
Brief overview of Thalassaemia
- Issue with the production of globin chains in Hb
- Alpha thalassaemia: issue with the alpha chain
- Beta thalassaemia: issue with the beta chain
- Can cause disease of varying severity depending on number of mutations
Treatment:
- Mild thalassaemia’s don’t require treatment
- Severe thalassaemia’s require blood transfusions + iron chelating agents to prevent iron overload
Brief overview of Sideroblastic anaemia
- Characterised by sideroblasts: immature red blood cells found in the bone marrow.
- These erythrocytes cannot utilise iron for the synthesis of heme, so iron accumulates inside the mitochondria.
- Causes of sideroblastic anaemia
- Congenital e.g. genetic mutations
- Acquired e.g. myelodysplastic syndrome, excessive alcohol use, copper or vitamin B6 deficiency, or intake of certain antimicrobial drugs.
Treatment:
- Treatment depends on the cause e.g.
- Stopping the use of alcohol or medication
- Some congenital cases respond to vitamin and mineral supplements
- Myelodysplastic syndrome requires a bone marrow transplant.
What are the main causes of Normocytic anaemia?
Generally caused by the destruction of RBCs. Sometimes replacement of RBC is not possible, due to bone marrow suppression or chronic kidney disease
Causes: 3 A’s and 2 H’s
A - Acute blood loss
A - Anaemia of chronic disease
A - Aplastic anaemia
H - Haemolytic anaemia
H - Hypothyroidism
What is aplastic anaemia
bone marrow suppression or chronic kidney disease (lack of EPO)
What are the four types of inherited Haemolytic anaemia
Hereditary spherocytosis, G6PD deficiency, Sickle cell, Thalassaemia
Brief overview of Hereditary spherocytosis
- A genetic disorder caused by defects in the structural proteins ankyrin, spectrin, or band 3
- Without these proteins, the red blood cells can’t keep their shape and become spherical
- The misshapen cells are less flexible than normal red blood cells and get stuck in the spleen, where they are destroyed by macrophages
Treatment: Splenectomy
Brief overview of G6PD deficiency
- An X-linked recessive disorder that results in defects of the enzyme
- Normally, it protects the red blood cells from oxidative stress, so in affected individuals, there’s haemolysis when there is exposure to oxidative stressors
- When there’s oxidative stress, haemoglobin gets damaged and forms heinz bodies inside the red blood cell.
- Macrophages in the spleen detect the abnormal red blood cells and try to remove the heinz bodies by taking out a chunk of the cell.
- During a haemolytic attack, the deficient cells die
Treatment:
- Acute phase treatment: blood transfusions
- Prevention of haemolytic attack: avoid the triggers; splenectomy
Give a brief overview of Sickle Cell disease
- An autosomal recessive disorder
- Caused by a mutated haemoglobin gene that encodes for an abnormal adult hemoglobin called HbS
- When there’s acidosis, hypoxia, or dehydration, the red blood cells sickle, and that causes either haemolysis or capillary obstruction causing ischemia and pain.
- These episodes are known as sickle crises
Treatment:
- IV fluids, oxygen, and pain control are used to manage the symptoms
- Blood transfusion may be needed + iron chelating agents to prevent iron overload
- Hydroxycarbamide: increase level of HbF, as this is protective
Explain acquired haemolytic anaemia
- Autoimmune haemolytic anaemia: red blood cells are attacked by either IgM or IgG antibodiesIgM: cause cold agglutinin - haemolysis happens in the cool extremities, and it’s associated with infections like mycoplasma and mononucleosis.IgG: cause warm agglutinin - haemolysis happens when it’s warm, and it’s associated with lupus and drugs like penicillin and cephalosporin.
- Non-immune (e.g. mechanical trauma, hypersplenism, infections, drugs)
How can you subdivide Macrocytic anaemia causes
Megaloblastic or Non-megaloblastic
What are the two causes of Megaloblastic anaemia
B12 deficiency
Folate deficiency
What causes megaloblastic macrocytic anaemia
Imapaired DNA synthesis preventing the cell from dividing normally
Give an overview of B12 deficiency
- Found in animal protein so vegans who don’t take supplements may be deficient
- May also be an issue with malabsorption
- Normally, meat or dairy are broken down in the stomach and the B12 is released. Intrinsic factor, made by parietal cells binds to the B12. Then, the B12-intrinsic factor complex moves through the intestines to the terminal ileum, where the complex is absorbed
- In pernicious anaemia: IgA antibodies attack intrinsic factor or the parietal cells
- In Crohn’s disease: the terminal ileum is damaged which affects absorption
- In patient’s with a gastric bypass, food moves through too quickly for effective absorption of B12
- B12 is used throughout the body, so people with B12 deficiency develop a variety of neurologic symptoms.
Treatment:
- Oral B12 supplements
- If issues with malabsorption, extremely high doses or IV B12 could be given
Explain Folate deficiency anaemia
- We have up to six weeks supply of folate in the body, but this can get used up even quicker during pregnancy.
- Individuals on a restricted diet may also have folate deficiency
Treatment:
- Folate supplements
What are some non-megaloblastic causes of marcocytic anaemia
- Alcohol
- Reticulocytosis(usually from haemolytic anaemia or blood loss)
- Hypothyroidism
- Liver disease
- Drugs such asazathioprine
Generic signs of anaemia
Pale skin, Conjunctival pallor, Tachycardia, Bounding pulse, Raised Respiratory rate, Postural hypotension, Shock
Specific signs for Anaemia
- Koilonychia: spoon shaped nails and can indicate iron deficiency
- Angular chelitiscan indicate iron deficiency
- Atrophic glossitis: smooth tongue due to atrophy of the papillae and can indicate iron deficiency
- Brittle hair and nails: can indicate iron deficiency
- Jaundice:occurs inhaemolytic anaemia
- Bone deformities: occur inthalassaemia
- Oedema, hypertension and excoriations on the skin:can indicatechronic kidney disease
Symptoms of anaemia
Tired, Short of breath, Headaches, Dizziness, Palpitations, Confusion, Syncope, Worsening of other conditions such as angina, Pica (abnormal cravings) and hair loss
Primary investigations for anaemia
FBC - haem and MCV
Blood film
Reticulocyte count
Ferritin
B12 and folate
Bilirubin
Direct Coombs test
Haemoglobin electrophoresis
Further investigations for anaemia
- Oesophago-gastroduodenoscopy(OGD) andcolonoscopy:to investigate for a gastrointestinal cause of unexplainediron deficiency anaemia. This is done on an urgent cancer referral for suspected gastrointestinal cancer.
- Bone marrow biopsy:may be required if the cause is unclear
General management for anaemia
Management depends on establishing the underlying cause and directing treatment accordingly. Iron deficiency can be treated with iron supplementation. Severe anaemia may require blood transfusions.
Epidemiology of iron deficiency anaemia
Most common
RF for iron deficiency anaemia
Vegetarian, H.pylori infection, Pregnant, Young children and adolescents, IBD, Coeliac, Certain drugs (e.g. PPI’s)
Pathophysiology of iron deficiency anaemia
Bone marrowrequiresironto producehaemoglobin.
There are several scenarios whereiron storescan be used up and the patient becomesiron deficient:
- Dietary insufficiency
- Loss of iron e.g. inheavy menstruation, gastric ulcers, and colon cancer
- Inadequate iron absorption e.g. after gastric surgery resulting in less HCl production, Crohn’s disease, coeliac disease
- Increased requirements e.g. during pregnancy, growing children and adolescents
Other causes include H.pylori infection, which causes gastric ulcers and gastrointestinal bleeding. H.pylori also traps dietary iron for itself, preventing it from reaching the duodenum.
Iron is mainly absorbed in the duodenum and jejunum. It requires the acid from the stomach to keep the iron in the soluble ferrous (Fe2+) form. When there is less acid in the stomach, it changes to the insoluble ferric (Fe3+) form. Therefore, medications that reduce the stomach acid, such as proton pump inhibitors (lansoprazole and omeprazole) can interfere with iron absorption.
Regardless of the cause, iron deficiency leads to impaired haemoglobin production.
Since there’s not enough haemoglobin for a normal sized RBC, the bone marrow starts pumping out microcytic RBCs. These cells containing less haemoglobin are called hypochromic, since they appear pale.
These microcytic RBCs can’t carry enough oxygen to the tissues - hypoxia.
Hypoxia signals the bone marrow to increase RBC production.
The bone marrow goes into overdrive and pumps out incompletely formed RBCs.
In addition to anaemia, iron deficiency also results in defective production of mitochondrial enzymes that generate necessary ATP for growth and development and this affects fast growing tissues, like hair and nails the most.
Sometimes iron deficiency anaemia may occur in the context of Plummer-Vinson syndrome, resulting in features such as glossitis and oesophageal webs.
Signs of iron deficiency anaemia
Pallor, Conjunctival pallor, Glossitis, Koilonychia, Angular stomatits
Symptoms of iron deficiency anaemia
Fatigue, Dyspnoea, Dizziness, Headache, Nausea, Bowel disturbance, Hair loss, Pica, Exacerbation of other cardiac syndromes
Investigations for iron deficiency anaemia
- FBC: low Hb, low MCV, low MCHC
- Iron studies:
- Serum iron
- Serum ferritin: low in anaemia
- Total iron binding capacity: can be used as a marker for how much transferrin is in the blood. Increased in anaemia
- Transferrin saturation: gives a good indication of the total iron in the body. Decreased in anaemia
Normal ranges for Serum ferritin, Serum iron and Total iron binding capacity
Ferritin: 12 - 200 ug/l
Iron: 14 - 31 umol/l
Total iron binding capacity: 54 - 75 umol/l
Management for iron deficiency anaemia
Treat cause, oral iron (ferrous sulphate or ferrous fumarate), Iron infusion (cosmofer), Blood transfusion if severe
Side effects of Iron Supplements
Constipation, black coloured stools, diarrhoea, nausea and dyspepsia/epigastric discomfort
Define Anaemia of chronic disease
Anaemia of chronic disease (ACD) is a complex and multi-factorial condition due to a chronic inflammatory process from underlying infection, malignancy or systemic disease.
ACD is classically described as a normocytic, normochromic anaemia, but can also be microcytic anaemia.
Epidemiology of ACD
ACD is the second most common cause of anaemia worldwide, and commonly seen among hospitalised patients.
Pathophysiology of ACD
- ACD may be associated with many chronic disease states like infections, malignancy, diabetes, or autoimmune disorders.
- The continuous inflammation generated by chronic disease impairs iron metabolism and, in turn, RBC production.
- In general, the disease mechanism is a two fold process; decreased RBC lifespan and decreased RBC production.
- Shortened RBC lifespan is a result of direct cellular destruction via toxins from cancer cells, viruses, or bacterial infections.
- Decreased RBC production involves several mechanisms:
- In chronic disease states, cytokines mediate this pathologic process in the kidney, immune system, and the GI tract. Two cytokines called TNF-a and IFN-y inhibit the production of erythropoietin in the kidney, which subsequently prevents RBC production in the bone marrow.
Additionally,
- TNF-a promotes RBC degradation in macrophages via phagocytosis
- IF-Y increases the expression of a protein channel called divalent metal transporter one on the surface of macrophages. This channel serves as a pathway for iron to enter the macrophage at increased rates, so less iron is available for the production of haemoglobin.
- IL-10 mediates the expression of increased ferritin receptors on the surface of macrophages, which then sequesters even more iron.
- IL-6 also works in the liver by increasing production of a molecule called hepcidin, which blocks further uptake of iron from the small intestine.
Clinical manifestations of ACD
Fatigue, Pallor, Shortness of breath, Headache, Dizziness, may worsen palpitations, angina and intermittent claudication
Investigations
- FBC: normocytic normochromic anaemia (approx. 75%) OR microcytic anaemia
- CRP
- Blood film
- Haematinics: check for iron, B12 and folate deficiencies
- Iron studies:
- Serum ferritin: normal or raised
- Serum iron: tends to be low
- Total iron binding capacity: tends to be low
Management for ACD
- Treatment of underlying cause e.g.
- Antibiotics for infection
- Surgical resection of tumour
- Treatment of diabetes
- EPO injections
- Parenteral iron
- Transfusions
Hereditary Spherocytosis
Hereditary spherocytosis (HS) is an inherited haemolytic anaemia and is autosomal dominant in the majority of cases (75%), but can also be autosomal recessive.
Epidemiology of Hereditary Spherocytosis
- HS is the most common genetic haemolytic disease.
- It is more common in Northern Europe and North America but can affect people of any race.
- It is diagnosed in 1 in 2000 people, whilst a large proportion of these individuals are asymptomatic
Risk factors for Hereditary spherocytosis
Family history, Northern European descent
Pathophysiology of Hereditary Spherocytosis
- HS occurs due to a defect in red cell membrane proteins, such as ankyrin and spectrin.
- This causes red blood cells (RBCs) to lose their biconcave shape and appear spherical.
- Subsequently, there is accelerated degradation of RBCs in the spleen (extravascular haemolysis), resulting in a normocytic anaemia.
- Splenomegaly occurs because the spleen has to work harder (hypersplenism) to clear out the abnormal RBCs and their products.
- As haemolysis occurs, haemoglobin is broken down to bilirubin by macrophages, which increases the risk of gallstones and cholecystitis.
- Patients can have episodes of haemolytic crisis, often triggered by infections, where the haemolysis, anaemia and jaundice is more significant.
- Patients with hereditary spherocytosis can develop aplastic crisis. During aplastic crisis there is increased anaemia, haemolysis and jaundice, without the normal response from the bone marrow of creating new red blood cells. This is often triggered by infection with parvovirus.
Signs of HS
Splenomegaly, Pallor, Jaundice, Tachycardia, Flow murmur
Symptoms of HS
Fatigue, Dizziness, Palpitations, RUQ pain, Neonatal jaundice, Failure to thrive
Diagnostic criteria for HS
No further tests are needed for diagnosis, if:
- Family history of HSand
- Typical clinical featuresand
- Positive laboratory investigations (spherocytes, raised MCHC, increase in reticulocytes)
Other investigations for HS
- FBC:normocytic anaemia with an increased reticulocyte count and raised MCHC
- MCHC is increased as spherical RBCs lead to water diffusing out of the cell
- Blood film:spherocytosis
- LFTs:increased (unconjugated) bilirubin due to haemolysis
- Coombs test:negativein hereditary spherocytosis. This is an important test to perform as spherocytes are also seen in autoimmune hemolytic anaemia (Coombs positive) and will, therefore, allow for differentiation between the two conditions
Management of HS
- Phototherapy or exchange transfusion:conducted in neonatal jaundice to reduce bilirubin levels
- Blood transfusion:patients should be managed with transfusions for symptomatic anaemia until splenectomy is possible or deemed appropriate
- Folic acid: all patients require daily folic acid supplementation until splenectomy
- Splenectomy:removing the spleen reduces haemolysis
- Splenectomy is delayed until patients are> 6 years oldto reduce the risk of post-splenectomy sepsis
- Patients must bevaccinatedagainst encapsulated bacteria and be prescribed lifelongphenoxymethylpenicillin
Complications of HS
- Gallstones: the high level of bilirubin due to haemolysis increases the risk of gallstones
- Aplastic crisis: parvovirus B12 infection attacks erythroid precursors in the marrow, resulting in anaemia with reduced reticulocyte count. Any patient with a haemolytic condition is at risk due to reduced RBC life span
- Bone marrow expansion:in conditions where there is a chronic, increased need for RBC production, such as haemolytic anaemias, bone marrow can expand. This particularly affects the face and skull
- Post-splenectomy sepsis:prevented by lifelong penicillin and vaccination againstS. pneumoniae*,H. influenzae, influenza, and meningitis A&C. Vaccination is offered two weeks prior to the procedure
Prognosis of HS
Most patients with HS are asymptomatic with a near-normal Hb post-splenectomy, as this increases RBC lifespan
Define G6PD deficiency
G6PD deficiency is a condition where there is a defect in the G6PD enzyme normally found in all cells in the body.
Epidemiology of G6PD deficiency
- It is inherited in an X linked recessive pattern, meaning it usually affects males.
- It is more common in Mediterranean, Middle Eastern and African patients.
- 6DPD deficiency can be protective against malaria
RF for G6PD deficiency
- Fava beans
- Soy products
- Red wine
- Infections (viral hepatitis or pneumonia)
- Metabolic acidosis
- Medications:
- Primaquine (an antimalarial)
- Ciprofloxacin
- Nitrofurantoin
- Trimethoprim
- Sulfonylureas (e.g gliclazide)
- Sulfasalazine and other sulphonamide drugs
Pathophysiology of G6PD deficiency
G6PD deficiency is caused by mutations on the G6PD gene which is found on the X chromosome and thus it’s an X-linked recessive genetic condition and it almost exclusively manifests as a disease in men.
The G6PD mutations cause defective G6PD enzymes to be produced that have a shorter half-life. There are two common types of G6PD deficiency: a Mediterranean and an African variant.
Low levels of G6PD causes low levels of NADPH, leading to low levels of reduced glutathione.
G6PD is the only way for red blood cells to get NADPH so they are especially susceptible to damage caused by free radicals.
When these build up, it causes the cell membrane to become unstable, causing haemolysis.
Free radicals can also directly damage haemoglobin molecules which are the oxygen carrying protein in red blood cells. These damaged proteins precipitates inside the cells and are called Heinz bodies.
The spleen macrophages notice these Heinz bodies and try to remove them by taking a chunk out of the cells, leaving these red blood cells partially devoured. These are known as bite cells.
When haemolysis occurs, this leads to conversion to bilirubin, which can result in jaundice and further complications e.g. gallstones. Some of the bilirubin is converted to urobilin, which builds up to give the urine a dark tea-like colour. This could cause damage to the kidneys.
Triggers:
Periods of increased stress, with a higher production of ROS, can lead to acute haemolytic anaemia.
e.g. infections (viral hepatitis or pneumonia), metabolic acidosis, fava beans, soy products, red wine, certain medications
Signs of G6PD deficiency
Jaundice, pallor, Splenomegaly, Dark tea-like coloured urine
Symptoms of G6PD deficiency
Shortness of breath, Fatigue, Dizziness, Headaches, Palpitations
Investigations for G6PD Deficiency
FBC, Blood film, LDH, Bilirubin, Haptoglobin, Coomb’s test, G6PD enzyme assay
Management of G6PD deficiency
- Avoid trigger of haemolysis e.g. fava beans and certain medications
- In certain cases, transfusions may be needed
Complications of G6PD deficiency
Gallstones, Kidney damage
Define Aplastic anaemia
Aplastic anaemia is a stem cell disorder characterised by pancytopenia.
This means there is anaemia, leukopenia, and thrombocytopenia.
It is usually an acquired condition but may be inherited
Aetiology of Aplastic anaemia
- Idiopathic (most common)
- Radiation and toxins
- Drugs e.g. certain chemotherapeutic agents, anti-seizure medication, anti-inflammatory medications, anti-thyroid medications and certain antibiotics
- Infections e.g. HIV, EBV
- Clonal or genetic disorders e.g. Fanconi’s anaemia
Pathophysiology of Aplastic anaemia
- The most common cause of aplastic anaemia is autoimmune destruction of haematopoietic stem cells.
- Research shows that there are alterations in the immunologic appearance of haematopoietic stem cells because of genetic disorders, or after exposure to environmental agents, like radiation or toxins.
- This means that the hematopoietic stem cells start expressing non-self antigens and the immune system subsequently targets them for destruction.
Signs of Aplastic anaemia
Pallor
Symptoms of Aplastic anaemia
Fatigue, Palpitations, dizziness, Headaches, Chest pain and SOB, Increased bleeding, recurrent infections
Investigations of aplastic anaemia
FBC, Erthyropoetin, Bleeding time, Bone marrow biopsy
Management for aplastic anaemia
Removal/treatment of cause, Tranfusions, Stem cell transplant, Immunosuppressive treatments
Define sickle cell anaemia
Sickle cell anaemia is an autosomal recessive mutation in the beta chain of haemoglobin, resulting in sickling of red blood cells (RBCs) and haemolysis.
Epidemiology of sickle cell
The prevalence of sickle cell trait in sub-Saharan Africa is the highest in the world. This may be because it is protective against malaria.
RF for sickle cell
- African: 8% of black people carry the sickle cell gene
- Family history: autosomal recessive pattern
- Triggers of sickling: dehydration, acidosis, infection, and hypoxia
Pathophysiology of sickle cell
- Sickle cell is a genetic disease where red blood cells can take the shape of a crescent, or sickle, and that change allows them to more easily be destroyed.
- Sickle cell disease is caused by defective haemoglobin. Specifically, the β-globin chains end up misshapen. This is because of a mutation in the beta globin gene, or HBB gene.A point mutation results in a hydrophilic glutamic acid being substituted for a hydrophobic valine, changing the structure of the beta chain.
- If only one gene is mutated, this is called sickle cell trait. If both are mutated, this is known as sickle cell disease.
- Due to the abnormal beta chain, patients with the sickletraithave reduced levels of HbA, whilst those with sickle celldiseasehave absent HbA. Instead, sickle patients have theabnormal HbSisoform consisting of 2 alpha chains and 2 abnormal beta chains. HbS is prone tosicklingand haemolysis.
- HbS carries oxygen perfectly well, but when deoxygenated, HbS changes its shape, which allows it to aggregate with other HbS proteins and form long polymers that distort the red blood cell into a crescent shape, a process called sickling.Sickling is triggered by dehydration, acidosis, infection, and hypoxia. HbAS(trait) patients sickle at PaO22.5 - 4 kPa, whilstHbSS(disease) patients at PaO25 - 6 kPa.
- Repeated sickling of red blood cells damages their cell membranes and promotes premature destruction - haemolysisThis destruction of red blood cells leads to anaemia as well as increased free haemoglobin.Free haemoglobin in the plasma is bound by haptoglobin and gets recycled; which is why a low haptoglobin level is a sign of intravascular haemolysis.Recycling of that heme group yields unconjugated bilirubin, which at high concentration can cause scleral icterus, jaundice, and gallstones.
- To counteract the anaemia of sickle cell disease, the bone marrow makes increased numbers of reticulocytes. This can cause the bones to enlarge.Extramedullary hematopoiesis can also happen - leading to splenomegaly.
- In sickled form, red blood cells tend to get stuck in capillaries, called vaso-occlusion. This can lead to vaso-occlusive crisis causing symptoms e.g. dactylitis, priapism, acute chest syndrome, stroke, depending on where the occlusion is.
- Neonates with sickle cell disease are often asymptomatic for the first 4-6 months of life due to high levels of HbF (foetal haemoglobin), which is protective against sickling due to its high oxygen affinity. Over time, as HbF falls and HbS predominates, patients eventually become symptomatic.
Chronic symptoms of sickle cell
- Pain
- Related to anaemia: fatigue, dizziness, palpitations
- Related to haemolysis: jaundice, and gallstones
4 types of sickle crisis
Sequestrian, Aplastic, Haemolytic and Vaso-occlusive
Symptoms of sickle sequestrian crisis
- RBCs sickle in the spleen, causing pooling of blood and a rapid drop in Hb and platelets
- Abdominal painsecondary to massive splenomegaly, possibly with hypovolaemic shock
- Autosplenectomy: repeated episodes lead to splenic infarction, fibrosis, and atrophy.
Symptoms of sickle aplastic crisis
- Infection withparvovirus B19causes bone marrow suppression
- Sudden onsetpallor, fatigue, and anaemia
- Differentiated from sequestration as it usually causes anaemia withreducedreticulocyte count andno splenomegaly
Symptoms of haemolytic crisis
Increased rate of intravascular and extravascular haemolysis; rare
Vaso-occlusive sick cell crisis symptoms in bone, lungs, spleen, cns, kidney and genitalia
Bone:
- Dactylitis: inflammation of digits
- Avascular necrosis: death of bone tissue due to a lack of blood supply
- Osteomyelitis: most commonly due to salmonella
Lungs:
- Acute chest syndrome:severe and potentially life-threatening
- Dyspnoea
- Chest pain
- Hypoxia
- Pulmonary infiltrates on chest X-ray
Spleen:
- Autosplenectomy
- Patients are at risk of infection from encapsulated bacteria
CNS:
- Stroke
Kidney:
- Renal papillary necrosis
Genitalia:
- Priapism
Primary investigations for sickle cell
- Newborn screening with Guthrie heel prick:sickle cell anaemia is one of a number of conditions screened for in all neonates in the UK at 5 days of age
- FBC:normocytic anaemia with reticulocytosis
- Blood film:sickled RBCs, target cells, Howell-Jolly bodies (RBC nuclear remnants seen later in the disease due to hyposplenism)
- Hb electrophoresis and solubility: diagnosticinvestigation, demonstrating increased HbS (2 alpha chains and 2 abnormal beta chains) and reduced/absent HbA (α2β2)
Investigations for sickle cell in an acute crisis
- Bedside
- Urinary Legionella/Pneumococcal antigen:in chest crisis
- Sputum culture and sputum/nasopharyngeal aspirate: in chest crisis
- Bloods
- ABG: if SpO2 < 94%
- FBC: normocytic anaemia, generally reticulocytosis; aplastic crisis causes reduced reticulocytes
- U&Es and LFTs
- G&S and crossmatch: in case of transfusion
- Blood cultures: in all febrile patients with chest crisis
- Serology(atypical respiratory organisms): in chest crisis
- Imaging
- CXRpulmonary infiltrates in chest crisis
- Bone X-ray:if suspecting osteomyelitis or dactylitis
Acute Management of sickle cell
Acute management depends on which type of complication has occurred.
- Analgesia:patients often require opiates or patient-controlled analgesia
- Hydration:dehydration precipitates sickling so it is important that patients are well hydrated
- Oxygen:used if hypoxic or there is evidence of chest crisis
- Antibiotics:used in chest crisis or if evidence of infection, e.g. osteomyelitis
- Blood transfusion:in a severe crisis, a blood transfusion reduces the proportion of HbS and is often required in a chest crisis
- Exchange transfusion: involves removal of HbS in exchange for normal Hb in a life-threatening crisis, for example, a severe chest crisis or stroke
- Penile aspiration: in priapism
Long term management of sickle cell
Chronic management is largely supportive and aimed at preventing infections and sickle crises, as well as managing anaemia.
- Pain management:regularly prescribed medications to manage chronic pain
- Hydroxycarbamide: increases the level of HbF, which is protective against sickling and reduces the frequency of crises and blood transfusions
- Lifelong phenoxymethylpenicillin: patients are at risk of infection from encapsulated bacteria due to hyposplenism from autosplenectomy. Lifelong penicillin V prophylaxis for patients with sickle cell disease, starting from 3 months old, is required
- Regular vaccinations: pneumococcal polysaccharide vaccine every 5 years and yearly influenza
- Blood transfusion
- Iron chelation: to prevent iron overload from blood transfusions
- Folic acid supplementation: offered to all patients as it raises haemoglobin levels
- Bone marrow transplant: could be curative
Complications of sickle cell
Sickle cell crises, Anaemia, Increased risk of infection
Prognosis for sickle cell
Prognosis is variable. The median age at death is 40-50 for patients with sickle cell disease, with a third of patients dying during an acute crisis
Define B12 deficiency anaemia
Anaemia (low levels of Hb in the blood) caused by B12 deficiency.
This is a macrocytic megaloblastic anaemia.
Epidemiology of B12 deficiency anaemia
- Vitamin B12 is predominantly found in meat and dairy products (due to bacterial synthesis) and is not present in plants. Thus, dietary deficiency is uncommon and typically seen in strict vegans.
- Vitamin B12 deficiency increases with age.
- Unlike folate, vitamin B12 stores last for years before deficiency develops.
- B12 deficiency most commonly due to pernicious anaemia
- Pernicious anaemia: relatively common amongst Northern Europeans, with a high prevalence in those aged 60-70 years old
- F>M
Pathophysiology of B12 anaemia deficiency
- Vitamin B12 (cobalamin) is found in meats and diary products. It is an essential vitamin for DNA synthesis in cells undergoing rapid proliferation.
- Deficiency of Vitamin B12 affects rapidly dividing cells, such as those in the bone marrow. This can lead to pancytopenia. As compensation for anaemia, the bone marrow produces abnormal precursors of RBCs - macrocytic, megaloblastic RBCs
- Other cells that are affected include rapidly dividing mucosal epithelium cells of the tongue, causing glossitis.
- Vitamin B12 also plays a role in keeping levels of methylmalonic acid low. This is a harmful substance that can cause neurological damage.
- Neurological features:
- Peripheral neuropathy
- Subacute degeneration of the cord
- Focal demyelination
- Neurological features:
- Causes of vitamin B12deficiency include:
- Inadequate intake(e.g. strict vegetarians, vegans)
- Inadequate secretion of intrinsic factor(e.g. pernicious anaemia, gastrectomy)
- Malabsorption(e.g. Crohn’s, tropical sprue, patients who have had gastric bypass)
- Inadequate release of B12from food(e.g. gastritis, alcohol abuse)
Signs of B12 deficiency anaemia
pallor, Signs of neurological deficit e.g. confusion, ataxia etc
Symptoms of B12 Deficiency
SOB, Fatigue, Palpitations, Headaches, Glossitis, Personality change, Depression, Memory loss, Visual disturbances, Numbness, Weakness, paraesthesia, Ataxia, Loss of vibration sense or proprioception, Autonomic dysfucntion
Investigations of B12 deficiency anaemia
1st line:
FBC, Blood film, Haematinics, Lactate dehydrogenase (may be elevated), LFT
Other:
Bone marrow aspirate, Schillings test, serological assessment, gastroscopy
Management of B12 deficiency anaemias
- Treatment of the underlying cause
- B12 supplementation e.g. oral cyanocobalamin; intramuscular hydroxocobalamin
Define folate deficiency anaemia
Anaemia (low levels of Hb in the blood) caused by folate (vitamin B9) deficiency. This is a type of macrocytic megaloblastic anaemia.
Epidemiology of folate deficiency anaemia
- In general, megaloblastic anaemia and folate deficiency are seen most commonly in countries where malnutrition is problematic.
- High-risk patient groups include: children, pregnant women and the elderly.
RF for folate deficiency anaemia
Elderly, Poverty, Alcoholic, Pregnant, Crohns or coeliac
Pathophysiology of folate deficiency anaemia
- Folate (vitamin B9) is another important molecule which acts as a cofactor in amino acid metabolism and DNA/RNA synthesis.
- This DNA impairment will affect all cells, but bone marrow is most affected since its the most active in terms of cell division. This means that folate deficiency can eventually lead to pancytopenia. In response to the anaemia, the bone marrow compensates by releasing megaloblasts into the blood - and the final result is macrocytic, megaloblastic anaemia.
- Other rapidly dividing cells, include mucosal epithelial cells of the tongue. These are affected, preventing healing. This leads to glossitis.
- Folate is also essential for foetal development - deficiency can result in neural tube defects e.g. spina bifida. So supplementation is essential during pregnancy!
- Folate is commonly found in a variety of food sources.
- Absorption of folate occurs within the proximal part of the small intestines (e.g. duodenum & jejunum).
- There are plenty of hepatic stores of folate (approx. 8-20 mg), but this reserve is lost rapidly from cellular metabolism and the shedding of epithelial cells. There is an estimated loss of 1-2% of stores per day. Therefore, folate deficiency can develop after months, compared to vitamin B12 deficiency, which tends to develop over years.
- Causes of folate deficiency:
- Inadequate intake
- Malabsorption(e.g. coeliac disease, resection)
- Increased requirements(e.g. pregnancy, malignancy disease)
- Increased loss(e.g. Chronic liver disease)
- Other(e.g. anti-convulsants, alcohol abuse)
Signs of folate deficiency anaemia
Pallor
Symptoms of folate deficiency anaemia
Fatigue, Dyspnoea, Palpitations, Headache, Glossitis, Feature of pancytopenia, Symptoms of underlying cause
Investigations for folate deficiency anaemia
- FBC: high MCV
- Blood film: macrocytic, megaloblastic RBC
- Haematinics: search for iron, B12 and folate deficiencies
- Serum and red cell folate: low
- GI investigations
Management of folate deficiency anaemia
- Treat underlying cause e.g. stopping drugs or alcohol consumption
- Folic acid supplements: always give alongside B12, because replacement of folic acid in the presence of vitamin B12 deficiency may cause significant neurological disease.
Define DVT
A deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the leg or pelvis (as opposed to the superficial veins).
Epidemiology of DVT
- DVT is a very common medical condition, with the incidence increasing with age.
- 65% of below-knee DVTs are asymptomatic and these rarely embolise to the lung
RF/Aetiology for DVT
Age, Smoking, Drugs (the pill, hormone replacement therapy), Immobility, Pregnancy, Trauma, Malignancy, Polycythaemia, SLE, Thrombophilia, Virchow’s triad (hypercoagulability, Venous stasis and endothelial damage)
Signs and symptoms of DVT
Unilateral swelling, Oedema, tender and erthymatous, Distension of superficial veins, Phlegmasia cerulea dolens, Unilateral calf pain, Redness and swelling
What is the well score?
The Wells score calculates the risk of DVT and determines how the patient is investigated and managed. Those with a score ≥ 2 are deemed high risk.
+1 point: Active cancer, bedridden or recent surgery, Calf swelling, superficial veins, entire leg swollen, tenderness along veins, Pitting oedema, immobility of affected leg e.g. plaster, previous dvt, Alternative diagnosis likely
Investigations of DVT
Examination and Wells score, investigate for cancer and thrombophilia
Management for DVT
-
No renal impairment
- Offer apixaban or rivaroxaban
- If neither suitable, offerone of:
- LMWH for at least 5 days followed by dabigatranoredoxaban
- LMWH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone
-
Renal impairment (estimated creatinine clearance <15 ml/min)
- Offerone of:
- LMWH
- Unfractionated heparin (UFH)
- LMWHorUFH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone
- Offerone of:
- Consider a DOAC (e.g. rivaroxaban)
- Offer anticoagulation for 3 to 6 months, taking into account tumour site, drugs and bleeding risk
- If a DOAC is not suitable, considerone of:
- LMWH
- LMWH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone
- Inferior vena cava filters: devices inserted into the inferior vena cava designed to filter the blood and catch any blood clots traveling from the venous system towards the heart and lungs.
Prevention of DVT
- Compression stockings
- Frequent calf exercises during long periods of immobilisation
- Prophylactic anticoagulation with LMWH e.g. in patients who have had surgery and will be immobilised for a long period of time
Complications of DVT
- Pulmonary embolism:increased pressure in the vein can cause a part of the main clot to break free. Therefore, there is a risk of an embolism to the lungs. Pulmonary embolism can be diagnosed with a CT pulmonary angiogram or ventilation–perfusion (VQ) scan.
- Embolic stroke: in patients with an atrial septal defect, the clot may travel to the left atria and then the left ventricle. The clot can then embolise to any part of the body, including the brain causing an embolic stroke
- Post-thrombotic syndrome:this is a long term complication caused by chronic obstruction of venous blood, leading to venous hypertension, with pain, swelling, and ulceration
- Increased risk of bleeding:patients on anticoagulation are at risk of bleeding
- Phlegmasia cerulea dolens: occurs in a massive DVT, resulting in obstruction of venousandarterial outflow (rare). This leads toperipheral limb ischaemiaand a blue and painful leg
Prognosis for DVT
Patients are at an increased risk of future venous thromboemboli, with a 30% risk of recurrence in the subsequent 5 years.
Fatality in these patients is usually either related to a subsequent pulmonary embolism or major haemorrhage as a result of anticoagulation.
DOAC’s vs traditional anticoagulants
Traditional anticoagulants: warfarin, coumarin and heparin
Newer anticoagulants, novel oral anticoagulants (NOACs) aka directly acting oral anticoagulants (DOACs): direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban and apixaban)
Define Acute myeloid leukemia (AML)
Acute myeloid leukaemia (AML) involves the proliferation of myeloblasts (partially developed white blood cells).
