9. Haematology I: Clinical Aspects Of Haematological Disorders Flashcards
LOs
what is haematopoiesis?
- the process through which all blood cells are derived
haematopoietic system composed of?
- bone marrow
- spleen
- liver
- lymph nodes
- thymus
where does haematopoiesis occur?
- It occurs in different sites depending on the individuals age:
~ Childhood = bone marrow of nearly all bones
~ Adults = axial skeleton and proximal parts of the long bones
what does haematopoiesis start with?
The process starts with a pluripotent stem cell, which is capable of both self-renewal and differentiation
Haematopoiesis progress (stem cells to mature cell lines)
Main Functions of Cell Lines:
- red blood cells
- neutrophils
- eosinophils
- basophils
- monocytes + macrophages
- platelets
- lymphocytes
red blood cells function
Transport O2 from lungs to tissues
neutrophils function
Chemotaxis, phagocytosis, killing of phagocytosed cells
eosinophils function
Neutrophil functions + antibody-dependent damage to parasites, immediate hypersensitivity
basophils function
Immediate hypersensitivity, modulate inflammatory response via proteases & heparin
monocytes + macrophages function
Chemotaxis, phagocytosis, killing of micro-organisms, antigen presentation and release of IL-1 & TNF
platelets function
Primary haemostasis (adhere to subendothelial connective tissue when exposed)
lymphocytes function
Immune response and haemopoietic growth factors
red blood cells indices
(normal haemoglobin values for diff ages)
- Children 6mths – 6yrs
- Children 6yrs – 14yrs
- Adult males
- Adult females
- Pregnant females
Children 6mths – 6yrs 110 – 145 g/L
Children 6yrs – 14yrs 120 – 155 g/L
Adult males 130 – 170 g/L
Adult females 120 – 155 g/L
Pregnant females 110 – 140 g/L
*NOTE change in Hb units from g/dL to g/L
may be diff in older textbooks
Mean cell volume (MCV)
80 – 95 fL
what is anaemia?
- Reduction in haemoglobin level below reference range for age and sex of individual
- Rate at which anaemia develops dictates symptoms and signs
symptoms of anaemia
- Symptoms:
~ Lassitude
~ Fatigue
~ Dyspnoea on exertion
~ Palpitations
~ Headache
~ Chest pain
signs of anaemia
- Signs:
~ Pallor
~ Tachycardia
~ Wide pulse pressures
~ Systolic flow murmurs
~ Congestive cardiac failure
what are the classifications of anaemia?
- mechanism of how it develops
- morphology of how it develops
Classification – mechanism
- Blood loss
- Decreased red cell lifespan (haemolytic)
~ Congenital (sickle cell anaemia)
~ Acquired (malaria, drugs) - Impairment of red cell formation
~ Insufficient erythropoiesis
~ Ineffective erythropoiesis - Pooling and destruction in spleen
- Increased plasma volume (pregnancy)
Classification – morphologies and common causes of these
- Microcytic (decrease in size)
~ Iron deficiency
~ Thalassaemias
Normocytic
~ Acute blood loss
~ Anaemia of chronic disease
~ Chronic renal failure
Macrocytic (increase in size)
~ Alcoholism
~ Folate deficiency
~ Vitamin B12 deficiency
~ Drugs
What is iron deficiency anaemia?
- Iron deficiency most common cause of anaemia worldwide
- Excess iron potentially toxic so body tightly controls absorption
How does iron deficiency anaemia develop?
- Develops via 3 mechanisms:
- Poor dietary intake (vegetarians and vegans)#
- Malabsorption (duodenum in Coeliac disease or jejenum in Crohn’s disease)
- Increased loss of iron through loss of red blood cells (commonly menorrhagia or gastrointestinal – peptic ulceration, inflammatory bowel disease, malignancy or hookworm infestation)
Manifestations of iron deficiency
clinical presentations
- Mild deficiency typically asymptomatic
- Classic presentation includes:
~ Koilonychia
~ Angular cheilitis
~ Atrophic glossitis
~ Recurrent oral ulceration
~ Burning mouth
~ Oesophageal web (Plummer-Vinson / Patterson-Brown Kelly Syndrome)
management of iron deficiency anaemia?
- Identify cause
- Red flags include men and post-menopausal women (may have unexplained blood loss which may be associated with a malignancy)
- Investigations:
~Blood film
~ Iron studies - Treatment:
~ Address underlying cause
~ Oral supplementation (ferrous sulphate 200mg
x3/day for 3 months)
~ Parenteral available (fever, arthropathy,
anaphylaxis)
~ Blood transfusion (only in severe compromise)
What is normocytic anaemia?
associated with?
- Anaemia’s of chronic disease
- Associated with:
~ Chronic inflammatory / connective tissue
conditions (rheumatoid arthritis)
~ Chronic infections (tuberculosis)
~ Chronic renal disease (due to reduction in
erythropoietin)
~ Malignancies (bone marrow infiltration)
what is Macrocytic anaemia divided into?
this is where you have the large RBCs
Divided into:
- Megaloblastic erythropoiesis - abnormal red cell development due to disordered DNA synthesis
- Normoblastic erythropoiesis – normal red cell maturation
What is megaloblastic anaemia - folate?
folate deficiency
what is folate used for?
derived from?
- Folate essential for DNA synthesis
- Derived from many food sources (especially green leafy vegetables)
causes of megaloblastic anaemia - folate deficiency?
- Causes of deficiency:
~ Inadequate intake (elderly, alcoholism)
~ Malabsorption (Coeliac disease, Crohn’s disease,
resection)
~ Increased requirement (pregnancy, haemolytic
anaemias, myelofibrosis)
~ Increased loss (dialysis, liver disease, congestive
heart failure)
~ Drugs (methotrexate, phenytoin, trimethoprim)
what is B12 used for?
derived from?
what does deficiency impact?
- Vitamin B12 required in number of enzymatic reactions
- Found only in foods of animal origin
- Deficiency impacts on DNA synthesis
causes of megaloblastic anaemia - vitamin B12 deficiency?
Causes of deficiency:
~ Inadequate intake
~ Inadequate secretion of intrinsic factor
(pernicious anaemia, gastrectomy)
~ Inadequate release from food (gastritis, PPI,
EtOH abuse)
~ Diversion of dietary B12 (bacterial overgrowth,
small intestinal strictures)
~ Malabsorption (Crohn’s disease, ileal resection)
Clinical features of folate and B12 deficiencies
FOLATE & VITAMIN B12
- Generic symptoms & signs of anaemia
- Occasionally mild jaundice
- Glossitis
- Oral ulceration
VITAMIN B12
- Peripheral neuropathy (loss of proprioception and vibration sense) (nerve related damage) (typically periphery = fingers + toes)
- Demyelination with subacute combined degeneration of spinal cord (serious complication)
- Dementia
management of megaloblastic anaemia?
- Identify cause
- Investigations
~ Blood film
~ Serum folate and B12 (*low B12 can lead to low
folate – always test together) - Treatment
~ Address underlying cause
~ Oral supplementation (never folate only if B12
level not known)
~ Parenteral vitamin B12 (IM) required in
pernicious anaemia
Normoblastic macrocytosis causes?
- Alcohol excess
- Liver dysfunction
- Hypothyroidism
- Drugs (methotrexate, azathioprine)
Haemolytic anaemias
- in which there is a disruption in RBCs (haemolysis) is divided into?
congenital haemolytic anaemias may be associated with?
- MEMBRANE DEFECTS
- ENZYME DEFECTS
- GLOBIN DEFECTS
EXTRA INFO
MEMBRANE DEFECTS
- Number of proteins essential to maintain cell membrane integrity
- Any mutation leads to increased fragility and haemolysis
- Hereditary spherocytosis most common congenital
ENZYME DEFECTS
- Glucose-6-phosphate dehydrogenase (G6DP) deficiency
- Involved in glucose metabolism
- Deficiency results in increased sensitivity to oxidative stress
acquired haemolytic anaemia are divided into?
- immune and non-immune causes
EXTRA INFO
IMMUNE
- occurs when IgG coated red cells interacting with marcophages resulting in phagocytosis
- Include autoimmune processes with antibodies against red cells (including idiopathic or secondary to infections, drugs, SLE, haematological malignancies)
- Alloimmune results from transfusion and production of antibodies to transfused red cell
NON-IMMUNE
- Include mechanical trauma (metallic valves), burns, infections (malaria) or drugs (dapsone)
Clinical features of haemolytic anaemia?
- Vary greatly depending on cause
- Common features include:
~ Pallor
~ Jaundice (due to elevated bilirubin)
~ Splenomegaly
~ Expansion of erythropoiesis leading to bone
deformities (frontal bossing) and pathological
fractures
Haemoglobin (Hb) normal structure?
- Normal Hb comprises of 2 alpha and 2 beta chains
- Each globin group is associated with a haem group (protoporphyrin ring and iron)
- Adult Hb composition
~ Hb A (α2β2) 97%
~ HbA2 (α2δ2) 1.8-3.6%
~ HbF (α2γ2) <1.5%
main function of Hb?
- Fundamental role of O2 transportation
- Hb undergoes conformational change between O2 bound and unbound states
- Altering affinity for O2 (loads O2 in high O2 tension environment and releases in low)
- what is thalassaemia?
- main groups?
- what does severity depend on
- what is used to diagnose thalassaemia
1
- Common genetic disorder with significant associated morbidity and mortality
- Excess chains precipitate in precursor red cells leading to premature death
- Precipitated chains also result in oxidative damage to the cell membrane leading to haemolysis
2
- 2 main groups depending on whether α or β chain defect
~ α-Thalassaemia
~ β-Thalassaemia
3
- Severity depends on degree of globin chain imbalance
4
- Diagnosis made on Hb electrophoresis (to identify various chains present in individual)
α-Thalassaemia
- where most common
- prevalence?
- structure/ cause?
- Most common SE Asia (Thailand, Indonesia) and W Africa
2.
Prevalence 20-30%
- 4 α-globlin genes on 2 chromosomes
- depending on number of genes affected, affects the severity?
a) α+-thalassaemia trait (deletion of 1 gene) – asymptomatic with normal Hb and reduced MCV
b) α0-thalassaemia trait (deletion of 2 genes on 1 chromosome) – slight reduction Hb and reduced MCV
c) Hb H disease (deletion of 3 genes) – chronic haemolytic anaemia however transfusion independent
d) Hb Bart’s hydrops fetalis syndrome (deletion of all 4 genes) – intrauterine or neonatal death
β-Thalassaemia
- carriers % in world pop?
- most common where + prevalence
- why does it occur?
1.
~1.5% world population are β-thalassaemia carriers
2.
Southern Europe 10-30% especially Greece
3.
- Usually due to mutation rather than deletion affecting β-gene
a) Heterozygous β-thalassaemia (trait) –
asymptomatic
b) Homozygous β-thalassaemia – moderate to
marked anaemia developing within 1st 2 years
(may be transfusion dependent)
- what do clinical classifications depend on?
- clinical classification of thalassaemia?
1.
- depends on the degree of anaemia seen
- based on minor or major presentation
2.
- Thalassaemia minima
~ Presence of mutation without clinical
consequence
- Thalassaemia minor
~ Microcytosis and hypochromic red cells - Thalassaemia intermedia
~ Microcytic hypochromic anaemia
~ Extramedullary haematopoiesis with
splenomegaly - Thalassaemia major
~ As above with severe anaemia and
transfusion dependent
- Clinical presentations of thalassaemia
- dental relevance?
1
- Typically those of anaemia unless severe
- If untreated leads to growth retardation, splenomegaly and bony deformities due to marrow expansion
2
ORAL
- Enlargement of maxilla (chipmunk facies)
- Migration and spacing of upper anterior teeth
- Main concern = iron overload due to transfusion leading to iron accumulation in myocardium (cardiac failure), liver (cirrhosis), pancreas (DM) and salivary glands
- what is HbS?
- what causes it?
- where is prevalence highest?
1
Most common structural variant of Hb is HbS
2
- Due to mutation in β-globin gene
- Interaction of sickle β-globin chains with normal α-globin chains = HbS
- Results in deformation of cell into sickle shape
3
- Prevalence greatest in tropical Africa, Middle East and southern India
- Areas in which falciparum malaria is endemic
sickle cell trait occurs in?
- Occurs in Heterozygotes (20-40% HbS & remaining HbA)
- Usually asymptomatic
- Rarely experience spontaneous haematuria
Sickle cell anaemia occurs in?
Clinical manifestations?
Sickling?
- Homozygotes (100% HbS)
- Clinical manifestations
~ Chronic haemolytic anaemia (60-90 g/L)
~ Hyposplenism (due to infarcts = increased risk
of infection)
~ Splenic sequestration
~ Acute chest syndrome
~ CVA / TIA
~ Bone infarction and subsequent infections
~ Chronic leg ulcers
~ Haematuria and chronic renal disease
Sickling
~ shortened erythrocyte survival
~ microcirculation obstruction
sickle cell anaemia management?
- Diagnosed with Hb electrophoresis
- Transfusion when necessary
- Pneumococcal, Hib (Haemophilus influenzae type b) and meningococcal vaccinations (increased susceptibility due to hyposplenism)
- Prophylactic penicillin
CRISES
- Acute vaso-occlusive painful episodes
- Precipitated by infection, dehydration, hypoxia
- Oral and IV fluids
- Analgesics (opiates)
Why do transfusion reactions occur?
BLOOD GROUP DIFFERENCES
- due to the Variation in surface constituents of red cells can lead to immunological reaction between donor and recipient
- 30 major blood group systems
- Most important ABO and Rh systems
- Compatibility or cross-matching essential
ABO
- H antigen is attached to cell membrane
- Presence of A or B allele lead to H antigen modification whereas O encodes for no modification
6 possible genotypes
~ AA
~ AB
~ AO
~ BB
~ BO
~ OO
4 phenotypes
~ A (can receive A or O)
~ AB (can receive A, B or O)
~ B (can receive B or O)
~ O (can only receive O)
Rh
- More complex than ABO
- Encoded by 2 genetic loci on one chromosome (RHD and RHCE)
- D antigen in most clinically relevant
- RhD-negative person at significant risk of developing anti-D antibodies after transfusion of RhD-positive blood
- Main relevance is to pregnant RhD-negative mothers
- Fetus may be RhD-postive and placental transfer may lead to an adverse reaction
- Pregnant women have Rh status tested and antenatal anti-D prophylaxis given if necessary
Transfusion reactions
- Immune-mediated transfusion reactions can be classified:
ACUTE REACTIONS
~occur within 24 hours of transfusion and include
acute haemolytic, febrile non-haemolytic,
allergic, and transfusion-related acute lung injury
DELAYED REACTIONS
~ occur days to weeks after the transfusion and
include delayed haemolytic transfusion
reactions, transfusion-associated graft-versus-
host disease and post-transfusion purpura
clinical features of transfusion reactions
10% mortality
- Fever
- Agitation / anxiety
- Rigor
- Rash
- Flushing and sweating
- Chest / abdominal pain
- Profound hypotension
- Bleeding
- Diarrhoea
Management of transfusion reactions
- Stop transfusion
- Check patient identity against donor blood product unit
- Replace giving set
- Paracetamol
- IV fluids
- If suspect anaphylaxis IM Adr
- Contact Haematology
dental relevance of anaemia
- May present with oral features suggestive of anaemia
- Alternatively anaemia may complicate treatment
- Without a clear explanation it may be sensible to delay treatment
oral features of Haematinic deficiencies (iron, vitamin B12 and folate)
- Angular cheilitis
- Glossitis
- Oral ulceration
- Peripheral neuropathies
oral features of Sickle cell
- Oral pain possibly due to infarction
- Osteomyelitis
- Trigeminal neuropathy (due to osteomyelitis)
- Hypomineralised dentition
oral features - radiographic features
- Dense lamina dura
- Hypercementosis
- Radio-opacities due to previous infarcts
Treatment issues
BLEEDING
- If bone marrow infiltration there may be failure of other cell lines including platelets with increased risk of bleeding
- Liver disease may result in anaemia as well increased risk of bleeding due to impact on clotting factors synthesis
ANAESTHESIA
- Avoid prilocaine (methaemoglobinaemia)
- Thalassaemia and sickle cell anaemia can complicate procedures performed under general anaesthesia
