Haematology I: Clinical Aspects of Haematological Disorders Flashcards
What is haematopoiesis and what does the process start with?
The process through which all blood cells are derived
The process starts with a pluripotent stem cell, which is capable of both self-renewal & differentiation
What is the haematopoietic system composed of?
The bone marrow, spleen, liver, lymph nodes & thymus.
Where does haematopoiesis occur?
Depends on the individual’s age:
Childhood= bone marrow of nearly all bones
Adults= axial skeleton & proximal parts of the long bones
What are the main functions of the mature cell lines?
Red blood cells - Transport O2 from lungs to tissues
Neutrophils - Chemotaxis, phagocytosis, killing of phagocytosed cells
Eosinophils - Neutrophil functions + antibody-dependent damage to parasites, immediate hypersensitivity
Basophils - Immediate hypersensitivity, modulate inflammatory response via proteases & heparin
Monocytes and macrophages - Chemotaxis, phagocytosis, killing of micro-organisms, antigen presentation and release of IL-1 & TNF
Platelets - Primary haemostasis (adhere to subendothelial connective tissue
Lymphocytes -Immune response and haemopoietic growth factors
What are the normal red blood cell indices?
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
Mean cell volume (MCV): 80-95 fL
What is anaemia?
Reduction in haemoglobin level below reference range for age and sex of individual
What are some of the symptoms and signs of anaemia?
Symptoms:
Lassitude - a condition of weariness or debility
Fatigue
Dyspnoea on exertion - he sensation of running out of the air and of not being able to breathe fast or deeply enough during physical activity.
Palpitations -
Headache
Chest pain
Signs:
Pallor
Tachycardia
Wide pulse pressures
Systolic flow murmurs
Congestive cardiac failure
By what mechanisms can anaemia develop?
-Blood loss
-Decreased red cell lifespan (haemolytic)
-Congenital (sickle cell anaemia)
-Acquired (malaria, drugs)
-Impairment of red cell formation
I-nsufficient erythropoiesis
-Ineffective erythropoiesis
-Pooling and destruction in spleen
-Increased plasma volume (pregnancy)
How can the morphology of red blood cells be described?
Microcytic - commonly seen in Iron deficiency and Thalassaemias
Normocytic - commonly seen in Acute blood loss, Anaemia of chronic disease, Chronic renal failure
Macrocytic - commonly seen in Alcoholism, Folate deficiency, Vitamin B12 deficiency or
Drugs
What are the 3 main mechanisms by which iron deficiency can develop?
Poor dietary intake (vegetarians and vegans)
Malabsorption (duodenum in coeliac disease or jejunum in Crohn’s disease)
Increased loss (commonly menorrhagia or gastrointestinal- peptic ulceration, inflammatory bowel disease, malignancy or hookworm infestation)
What is the most common cause of anaemia worldwide?
Iron deficiency
(Excess iron is potentially toxic so the body tightly controls its absorption)
How does iron deficiency typically manifest?
Koilonychia - a deformity of the nails where the central portion of the nail is depressed and the lateral aspects of the nail are elevated.
Angular cheilitis - an inflammatory skin process of variable etiology occurring at the labial commissure, the angle of the mouth
Atrophic glossitis - characterized by the partial or complete absence of filiform papillae on the dorsal surface of the tongue.
Recurrent oral ulceration
Burning mouth
Oesophageal web (Plummer-Vinson/Patterson-Brown Kelly Syndrome
How do you manage iron deficiency in a patient?
Identify the cause and investigate by doing blood films & 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 are normocytic anaemias?
-The anaemias of chronic disease
-These can be 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 can macrocytic anaemia be divided into?
Megaloblastic erythropoiesis- abnormal red cell development due to disordered DNA synthesis
Normoblastic erythropoiesis- normal red cell maturation
What are megaloblastic anaemias associated with?
Folate deficiency
folate is essential for DNA synthesis & is derived from many food sources
What are the possible causes of folate 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 (DMARDs), phenytoin (medicine used to treat epilepsy), trimethopriman (antibiotic))
What is vitamin B12 required for and where is it found?
It’s required in a number of enzymatic reactions & its deficiency impacts on DNA synthesis
It’s found only in foods of animal origin
What are the possible causes of vitamin B12 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)
What are the clinical features of folate & vitamin B12 deficiency?
Folate & Vitamin B12:
-Generic symptoms & signs of anaemia
-Occasionally mild jaundice
-Glossitis
-Oral ulceration
Vitamin B12 :
-Peripheral neuropathy (loss of proprioception and vibration sense)
-Demyelination with subacute combined degeneration of spinal cord
-Dementia
How do you treat folate & B12 deficiency?
Identify cause, and investigate by doing blood films & checking serum folate & B12 (low B12 can lead to low folate- always check together)
Treat by addressing underlying cause, give oral supplementation (never folate only if B12 level not known); parenteral vitamin B12 (IM) required in pernicious anaemia
What are some of the causes of normoblastic macrocytosis?
Alcohol excess
Liver dysfunction
Hypothyroidism
Drugs (methotrexate, azathioprine both are DMARDs)
How are haemolytic anaemias classified?
Congenital
1. 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
1. Immune:
-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 - leprosy, skin disorders)
What are the clinical features of haemolytic anaemias?
They vary greatly depending on cause but generally include:
-Pallor
-Jaundice (due to elevated bilirubin)
-Splenomegaly
-Expansion of erythropoiesis leading to bone deformities (frontal bossing) and pathological fractures
What does adult Hb comprise?
Hb A (97%)
HbA2 (1.8-3.6%)
HbF (<1.5%)
What is thalassaemia?
Common genetic disorder with significant associated morbidity and mortality
There are 2 main groups depending on whether it’s an alpha or beta chain defect
What are the potential implications of thalassaemia and how is thalassaemia diagnosed?
-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
-Severity depends on degree of globin chain imbalance
-Diagnosis made on Hb electrophoresis
What are the different forms of alpha-thalassaemia?
4 α-globlin genes on 2 chromosomes
- α+-thalassaemia trait (deletion of 1 gene) – asymptomatic with normal Hb and reduced MCV
- α0-thalassaemia trait (deletion of 2 genes on 1 chromosome) – slight reduction Hb and reduced MCV
- Hb H disease (deletion of 3 genes) – chronic haemolytic anaemia however transfusion independent
- Hb Bart’s hydrops fetalis syndrome (deletion of all 4 genes) – intrauterine or neonatal death
Where is alpha-thalassaemia most common?
SE Asia (Thailand, Indonesia) & W Africa
Prevalence is 20-30%
What are the forms of beta-thalassaemia?
Usually due to mutation rather than deletion affecting β-gene
- Heterozygous β-thalassaemia (trait) – asymptomatic
- Homozygous β-thalassaemia – moderate to marked anaemia developing within 1st 2 years (may be transfusion dependent)
How many people are affected by beta-thalassaemia and where is it most common?
~1.5% of the world population are beta-thalassaemia carriers
Prevalent in Southern Europe (10-30%), especially Greece
What are the clinical classifications of the different thalassaemias?
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
What is the clinical presentation of someone with thalassaemia?
Typically similar to those of anaemia unless it’s severe
If untreated, it can lead to growth retardation, splenomegaly & bony deformities due to marrow expansion
Oral manifestations:
Enlargement of maxilla (chipmunk facies)
Migration and spacing of upper anterior teeth
What is the main concern with a thalassaemia patient requiring transfusions?
Iron overload- the repeated tranfusions can lead to iron accumulation in myocardium (cardiac failure), liver (cirrhosis), pancreas (DM) & salivary glands
What is the most common structural variant of Hb and how does it arise?
HbS
Due to mutation in beta-globin gene which then leads to an interaction of the sickle beta-globin chains with normal alpha-globin chains= HbS
This results in the deformation of cell into sickle shape
Where is the prevalence of HbS greatest?
Prevalence greatest in tropical Africa, Middle East & southern India and areas where falciparum malaria is endemic
In what kind of individuals does sickle cell trait occur?
Heterozygous individuals (20-40% HbS & remaining HbA)
Do people with sickle cell trait have any symptoms?
They’re usually asymptomatic but can rarely experience spontaneous haematuria (presence of blood in urine)
In what kind of individuals does sickle cell anaemia occur?
Homozygous individuals (100% HbS)
What are the clinical manifestations of sickle cell anaemia?
-Chronic haemolytic anaemia (60-90 g/L)
-Hyposplenism (due to infarcts = increased risk of infection)
-Splenic sequestration
-Acute chest syndrome
-CVA / TIA
-Bone infarction & subsequent infections
-Chronic leg ulcers
-Haematuria & chronic renal disease
What can sickling result in?
Shortened erythrocyte survival and microcirculation obstruction
How do you manage sickle cell anaemia?
Diagnosed with Hb electrophoresis
Transfusion when necessary
Pneumococcal, Hib (Haemophilus influenzae type b) and meningococcal vaccinations (increased susceptibility due to hyposplenism)
Prophylactic penicillin
How do you manage sickle cell anaemia crises, in which you have acute vaso-occlusive painful episodes?
It’s precipitated by infection, dehydration, hypoxia so:
Oral and IV fluids
Analgesics (opiates)
How does a transfusion reaction come about?
Variation in surface constituents of RBCs can lead to immunological reactions between donor and recipient
Compatibility/cross-matching is essential for the transfusion to take place successfully otherwise you get reactions
How does the ABO system work?
It relates to the H antigen attached to the cell membrane
The presence of either the A or B allele leads to H antigen modification whereas O encodes for no modification
How many blood group systems are there and which ones are most important?
30 major blood group systems
The most important ones are the ABO and Rh systems
What are the possible genotypes and phenotypes in the ABO system?
6 possible genotypes: AA, AB, AO, BB, BO, OO
4 possible 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)
Describe the Rh system.
It’s more complex than ABO
It’s encoded by 2 genetic loci on 1 chromosome (RHD & RHCE)
The D antigen is the most clinically relevant, especially in pregnant women
Why are immune-mediated transfusion reactions important to manage promptly?
Because they are associated with a 10% mortality rate
Why is the D antigen most clinically relevant?
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
How can immune-mediated transfusion reactions 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
How do you manage the 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
What is the dental relevance of all of these disorders?
They may present with oral features suggestive of anaemia
Alternatively, anaemia may complicate treatment
Without a clear explanation, it may be sensible to delay treatment
What are some oral manifestations of haematinic deficiencies (iron, vitamin B12, folate) and sickle cell anaemia?
Haematinic deficiencies:
-Angular cheilitis
-Glossitis
-Oral ulceration
-Peripheral neuropathies
Sickle cell anaemia:
-Oral pain possibly due to infarction
-Osteomyelitis
-Trigeminal neuropathy (due to osteomyelitis)
-Hypomineralised dentition
(Radiographic features may also include dense lamina dura, hypercementosis, & radio-opacities due to previous infarcts)
What are some other important treatment issues to consider as a dentist?
- Bleeding:
-If there is a 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
