Haematology COPY Flashcards
What is a myeloma?
A malignant proliferation of the Plasma cells (Type of B lymphocytes)
Define multiple myeloma (MM)?
Malignant proliferation of plasma cells (B lymphocytes) accumulating in the bone marrow that affects multiple areas of the body
What is the second most common haematological cancer?
Multiple Myeloma
What is the pathogenesis of Multiple Myeloma?
Malignant proliferation of plasma cells (B lymphocytes) accumulating in the bone marrow
This leads to overproduction of IgG/IgA or Ig fragment (monoclonal paraprotein) and underproduction of others
Causes dysfunction of many organs (especially the kidney), bone marrow failure, destructive bone disease and hypercalcaemia
Characterised by excess secretion of a monoclonal antibody
What is a paraprotein?
Paraprotein → abnormal immunoglobulins produced by monoclonal plasma cells
They can be intact immunoglobulins (usually IgG, IgA or IgM) or parts of immunoglobulins (usually light chains, very rarely heavy chains)
What are the main paraproteins produced in multiple myeloma?
Typically excess production of 1 specific type of Ig.
55% are IgG
20% are IgA.
What are the preceding steps before established multiple myeloma?
Development of Mammyloid gammopathy of undetermined significance (MGUS)
Smouldering myeloma
What is Mammyloid Gammopathy of Undetermined significance (MGUS)?
where there is an excess of a single type of antibody or antibody components without other features of myeloma or cancer.
This is often an incidental finding in an otherwise healthy person and as the name suggests the significance is unclear.
May progress to MM and patients are often routinely monitored.
What is Smouldering Myeloma?
where there is progression of MGUS with higher levels of antibodies or antibody components. It is premalignant and more likely to progress to myeloma than MGUS
What is Waldenstrom’s macroglobulinemia
Waldenstrom’s macroglobulinemia is a type of smouldering myeloma where there is excessive IgM specifically.
What is the rate of progression of MGUS to MM?
1% per year
What is the clinical presentation of multiple myeloma related to?
Infiltration of plasma cells
Secretion of monoclonal antibodies
What are the Risk Factors of Multiple Myeloma?
Older age
Male
Black African ethnicity
Family history
Obesity
Give some symptoms of Myeloma?
Tiredness
Bone/back pain
Infections
What are the signs and symptoms of multiple myeloma?
OLD CRAB:
Old - 70+
C - Hypercalcaemia (& associated symptoms)
R - Renal Failure (hypercalcaemia causes calcium oxalate renal stones and immunoglobulin light chain kappa deposition is nephrotoxic)
A - Anaemia (Bone Marrow Infiltration causing; Neutropenia (infections), Thrombocytopenia (bleeding)
B - Bone Lesions - increased osteoclastic activity - Pepperpot Skull
How does bone disease arise in multiple myeloma?
Proliferation in bone marrow
Lytic lesions
Fractures
How does impaired renal function arise in multiple myeloma?
Kappa Immunoglobulin light chains (Bence Jones Protein) are nephrotoxic.
& Hypercalcaemia
Why may Renal disease worsen the effects of Anaemia in MM?
Renal disease can lead to EPO deficiency contributing to the anaemia
How does hypercalcaemia arise in multiple myeolma?
Multiple myeloma-induced bone demineralisation and bone resorption
How does recurrent/persistent bacterial infection arise in multiple myeloma?
Immune dysfunction and hypogammaglobulinemia
Suppression of normal plasma cell function
Why does anaemia occur in multiple myeloma?
The cancerous plasma cells invade the bone marrow.
This is described as bone marrow infiltration.
This causes suppression of the development of other blood cell lines leading to:
Anaemia (low red cells),
Neutropenia (low neutrophils)
Thrombocytopenia (low platelets).
What initial diagnostic investigations are ordered in someone with suspected multiple myeloma?
Serum and urine electrophoresis – B2 microglobulin
Blood film – Rouleaux formation (aggregations of RBCs)
Bence Jones protein in urine
BM aspiration shows excess plasma cells
X-ray – shows pepperpot skull and lyses in long bones, pelvis and spine
What Investigations are needed to confirm a diagnosis of Multiple Myeloma?
Bone marrow biopsy is necessary to confirm the diagnosis of myeloma and get more information on the disease.
>10% plasma cells
Imaging is required to assess for bone lesions.
X-ray – shows pepperpot skull and lyses in long bones, pelvis and spine
What is indicative of MM on bone marrow biopsy?
> 10% plasma cells
What bloods results would be indicative of multiple myeloma?
FBC - marrow failure
ESR - raise
Blood film - Rouleaux formation (RBC Aggregations)
U&Es - raised urea and creatinine
Hypercalcaemia
What are some important differential diagnoses of Multiple Myeloma?
MGUS
What is the treatment for MGUS and asymptomatic myeloma?
Watch and wait.
What is the principle behind treatment of MM?
Multiple myeloma is an incurable condition → treatment aims to increase periods of disease remission
What is the first line treatment for multiple myeloma?
A combination of chemotherapy with:
Bortezomid - proteasome inhibitor
Thalidomide
Dexamethasone - steroid
What else may you consider to treat multiple myeloma?
Stem cell transplant
Bisphosphonates - bone protection
Name the 3 broad categories of red cell disorders.
- Haemoglobinopathies.
- Membranopathies.
- Enzymopathies.
What is a haemoglobinopathy?
Deficiency related to quality or quantity of haemoglobin production
What is a membranopathy?
Deficiency related to red blood cell membrane protein
What is an enzymopathy?
Deficiency related to RBC enzyme synthesis, leads to shortened lifespan due to oxidative stress
What is the normal range for haemoglobin?
120-180g/L
What is normal adult haemoglobin made of?
HbA1:
2 alpha and 2 beta chains.
What is foetal haemoglobin made of?
HbF:
2 alpha and 2 gamma chains.
What are the common Symptoms of Anaemia?
Fatigue
Lethargy
Dyspnoea – difficulty or laboured breathing
Palpitations
Headache
What are the common signs of anaemia?
Pale skin
Pale mucous membranes – nose and eyelids
Systolic flow murmur
Tachycardia (compensatory to meet demand)
What are the common consequences of anaemia?
Reduced O2 transport
Tissue hypoxia
Compensatory changes:
Increased tissue perfusion
Increased O2 transfer to tissues
Increased RBC production
What is haemoglobin S?
Haemoglobin S is a variant of Hb arising from a point mutation in the beta globin gene.
The mutation leads to a single amino acid change, valine -> glutamine.
What is sickle cell disease?
Auto recessive disorder
A Hb disorder of quality; polymerisation of HbS results in characteristic sickle shaped RBCs
What is the genetics of Sickle Cell disease and what ethnicity is at increased risk?
Afro-Caribbean
1 in 4 chance of disease,
50% chance of being a carrier
1 in 4 chance of being disease free
What are the types of Sickle Cell disease based on Inheritance?
- Sickle cell anaemia (HbSS) = inheritance of 2 abnormal sickle genes
- Sickle cell disease (HbSC) = Inheritance of one abnormal sickle gene and second haemoglobin variant of the beta chain that causes sickling. E.g. haemoglobin C
- Sickle cell trait (HbS) = Inheritance of one abnormal sickle gene. Sickle carrier.
- Sickle-thalassaemia (H
What is the lifespan of a Sickle Cell?
5-10 days - described as haemolytic
What is the Pathophysiology of Sickle Cell Anaemia?
- Point mutation of the B globin gene (glutamic acid to Valine) resulting in a HbS variant
- Under stress (cold/infection/dehydration/hypoxia/acidosis), the RBCs become deoxygenated and the HbS polymerises causing the cells to become rigid and sickle
- This leads to vaso-occlusion and significantly shortens the life span of an RBC to 10-20 days
- Causing chronic haemolysis and tissue infarction
What can precipitate sickling in Sickle Cell Anaemia?
Trauma
Cold
Stress
Exercise
infection
dehydration
hypoxia
acidosis
Why does Sickle Cell Anaemia not present until after 6 months of age?
HbF is not affected by sickle cell anaemia as it is made up of 2 alpha and 2 gamma chains.
Prior to 6 months of age the body still produces HbF
What are reticulocytes?
Immature RBCs that still have RNA material.
Their percentage increases in haemolytic anaemia
What effect does Sickle Cell Anaemia have on reticulocyte count?
Raised - 2-3% (normally 0.45-1.8%)
Why is reticulocyte count raised in Sickle Cell Anaemia?
Sickle cell disease is haemolytic - increased degradation of RBC’s
What is the pathogenesis of sickle cell disease?
Point mutation in the Beta globin gene (GAG to GTG) swapping valine for glutamic acid.
This causes irreversible RBC sickling which makes the RBC fragile.
A decreased surface area also means the RBCs are less efficient.
What are the symptoms of Sickle Cell disease?
Jaundice - haemolytic anaemia releasing bilirubin
Acute pain in hands and feet (vaso-occlusion)
+ complications of anaemia
Give 4 acute complications of sickle cell disease.
- Vaso-occlusive painful Crisis
- Mesenteric Ischaemia
- Splenic Sequestration crisis - blocked blood flow to spleen
- Infections - due to hyposlenysm
Give 3 chronic complications of sickle cell disease.
- Renal impairment.
- Pulmonary hypertension.
- Joint damage.
What are some complications of Sickle cell disease?
Anaemia
Increased risk of infection
Stroke
Avascular necrosis in large joints such as the hip
Pulmonary hypertension
Painful and persistent penile erection (priapism)
Chronic kidney disease
Sickle cell crises
Acute chest syndrome
What is Vaso-occlusive Crisis (AKA painful crisis) in sickle cell disease?
Sickle shaped blood cells clogging capillaries causing distal ischaemia.
It is associated with dehydration and raised haematocrit.
Symptoms are typically pain, fever and those of the triggering infection.
What is Splenic Sequestration Crisis?
Sickled Red blood cells blocking blood flow within the spleen.
This causes an acutely enlarged and painful spleen.
The pooling of blood in the spleen can lead to a severe anaemia and circulatory collapse (hypovolaemic shock).
What is the significance of parvovirus for someone with sickle cell disease?
Common infection in children (URTI), leading to decreased RBC production
What are the diagnostic tests for Sickle cell disease?
Screen neonates – blood/heel prick test
FBC:
Low Hb
High reticulocyte count
Blood film – sickled erythrocytes, Howell Jolly bodies
Hb electrophoresis for differential diagnosis – Hb SS present and absent Hb A confirms diagnosis of sickle cell disease
What is the management of Sickle Cell Disesae?
Supportive:
Folic acid
Aggressive analgesia i.e. opiates
Treat underlying cause e.g. antibiotics
Fluids
Disease modifying:
Hydroxycarbamide – increases HbF concentrations
Transfusion
Stem cell transplant
If hyposplenic:
Prophylactic antibiotics
Pneumococcal and meningococcal vaccination
What are the treatments of acute complicated attacks in sickle cell disease?
IV fluids
Analgesia (NSAIDs)
O2
What are the long term treatments for sickle cell disease?
Avoid Dehydration
Hydroxycarbamide - stimulates HbF production
Blood transfusion
Bone marrow transplant
What is the relationship between Sickle cell disease and Malaria?
Having one copy of the sickle cell gene reduces the severity of malaria and is protective.
There is a high proportion of the population in Africa & other malaria associated areas with at least one sickle cell gene.
What is the most common cause of death in adults with Sickle Cell Disease?
Pulmonary HTN and chronic lung disease most common cause of death in adults with SCD
What is thalassaemia?
An autosomal recessive disorder of haemoglobin quantity.
There is reduced synthesis of one or more globin chains leading to a reduction in Hb -> anaemia.
Degree of anaemia depends on the type of mutation
Px with defects in Alpha chain synthesis have alpha Thalassaemia
Px with defects in Beta chain synthesis have beta Thalassaemia
If someone has beta thalassaemia do they have more alpha or beta globin chains?
They have very few beta chains, alpha chains are in excess.
Which is more common, alpha or beta thalassaemia?
Beta thalassaemia is more common
What are some potential signs and symptoms of Thalassaemia?
Microcytic anaemia (low mean corpuscular volume)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly
Poor growth and development
Pronounced forehead and malar eminences
Why do you get splenomegaly in thalassaemia?
RBCs in thalassaemia are more fragile and break down easily.
In thalassaemia the spleen collects all the destroyed red blood cells and swells, resulting in splenomegaly.
What are mutations that result in alpha Thalassaemia?
4 genes on chromosome 16
Deletion mutations
What is produced in alpha thalassaemia as a result of the decreased alpha chains?
Excess beta chains form an unstable beta tetramer (HbH)
This is a poor carrier of O2
Where is alpha thalassaemia most prevalent?
- Sub-Saharan Africa
- Middle East
- Mediterranian
- Areas of Asia
What mutations cause Alpha Thalassaemia?
4 genes control production of alpha globin chains. α thalassaemia is caused by gene deletions (unlike B which is due to gene defects)
1 deletion: blood picture normal.
2 deletions: Asymptomatic with possible mild microcytic anaemia.
3 deletions: Common in parts of Asia. Patients have low levels of HbA and Hb Barts. Severe haemolytic anaemia, and splenomegaly. Sometimes transfusion dependent.
4 deletions = no a-chain synthesis, only Hb Barts present. Hb Barts CANNOT CARRY OXYGEN and is incompatible with life. (Infants stillborn; they are pale, oedematous with huge livers and spleens.
What is the Pathogenesis of Beta Thalassaemia?
In homozygous ß-thalassemia 🡪 little/no normal ß chain production 🡪 therefore, EXCESS α chain production 🡪 α chains combining with whatever ß, 𝛿 or γ chains available 🡪 increased production of HbA2 and HbF 🡪 resulting in ineffective erythropoiesis and haemolysis
What are mutations that result in Beta Thalassaemia?
2 genes on chromosome 11
Can have abnormal functional genes or deletion genes that are non functional resulting in different types of Beta Thalassaemia
What are the 3 clinical syndromes of Beta Thalassaemia?
Thalassaemia Minor
Thalassaemia Intermedia
Thalassaemia Major
What is Thalassaemia Minor?
One abnormal and One functional beta globin gene
Asymptomatic heterozygous carrier state
Mild/absent anaemia – low MCV and hypochromic
Iron stores and ferritin normal
What is Thalassaemia Intermedia?
Either:
2 defective beta globin genes - retain some function
OR
1 defective and 1 deletion gene
Moderate anaemia – patients don’t require transfusions
Splenomegaly, bone abnormalities, recurrent leg ulcers and gallstones
What is Thalassaemia Major?
Px with Homozygous Beta globin deletion genes.
No functioning beta globin genes
Presents in 1st year of life with severe anaemia (Cooley’s anaemia) – failure to thrive and recurrent infections
Bony abnormalities due to hypertrophy of ineffective BM e.g. skull bossing, thalassaemic faces with an enlarged maxilla and prominent frontal and parietal bones (hair on end sign on skull XR)
Hepatosplenomegaly – due to haemolysis
What are the diagnostic investigations for Thalassaemia?
FBC and blood film – hypochromic and microcytic anaemia, target cells visible on film
Irregular and pale RBCs
Increased reticulocytes and nucleated RBCs in peripheral circulation
Diagnosis by Hb electrophoresis – shows increased HbF and absent/low HbA
Skull XR – hair on end sign, enlarged maxilla
Why is Iron overload an issue in Thalassaemia?
Iron overload occurs in thalassaemia as a result of faulty creation of red blood cells, recurrent transfusions and increased absorption of iron in response to the anaemia.
How is Iron overload in Thalassaemia managed?
Monitored Serum Ferritin levels
Limiting transfusions
Iron Chelation - SC desderrioxamine
What is the key clinical symptom of Beta Thalassaemia?
Chipmunk Face - due to enlarged forehead and cheekbones due to decreased RBCs and extramedullary haematopoiesis
What is the treatment for Thalassaemia?
Regular Blood transfusions
Iron Chelation - prevent Iron overload (as thats a risk of recurrent transfusions)
Splenectomy
Folate supplements
Bone marrow stem cell transplant
What is a potential Curative option for thalassaemia?
Bone marrow stem cell transplant
Describe the inheritance pattern for Membranopathies
Autosomal dominant
Name two most common Membranopathies
Spherocytosis (horizontal deformity) - more severe, present neonatal jaundice and haemolysis
Elliptocytosis (vertical deformity)
Describe the pathophysiology of Membranopathies
Deficiency of red cell membrane proteins caused by genetic lesions leading to haemolytic anaemia.
What are the common clinical features of Membranopathies?
Jaundice
Anaemia
Splenomegaly
What is Hereditary Spherocytosis?
Deficiency in structural membrane protein Spectrin
Makes RBCs more spherical and rigid
Mistaken to be damaged and therefore prematurely destroyed by the spleen
Causes Splenomegaly
What are the symptoms of Hereditary Spherocytosis?
General Anaemia
Neonatal Jaundice
Splenomegaly
50% have Gallstones
What is the investigations of Hereditary Spherocytosis and Elliptocytosis?
Direct Coombs Negative (positive = Autoimmune Haemolytic Anaemia)
FBC and blood film:
Normocytic Normochromic
Increased Reticulocytes + Spherocytes
What is the treatment for Hereditary Spherocytosis?
Splenectomy
Folic Acid
Neonatal Jaundice - Phototheraphy
Name a common Enzymopathy.
Glucose-6-Phosphate Dehydrogenase deficiency
What is G6PD Deficiency?
X linked recessive enzymopathy causing 1/2 RBC lifespan and RBC degradation
What is the pathology of G6PD Deficiency?
G6PD vital in hexose monophosphate shunt which maintains glutathione in reduce state. Glutathione protects the RBC from oxidative crisis
Why does a deficiency in glucose-6-phosphate dehydrogenase lead to shortened red cell lifespan?
G6PD is required for glutathione synthesis
Glutathione protects Red blood cells against oxidative damage
How does G6PD deficiency present?
Mostly asymptomatic unless precipitated by oxidative stressor causing an attack:
Back pain
Chronic haemolytic anaemia
Acute haemolysis
Rapid anaemia
Jaundice + Dark urine
Caused by
Ingestion of fava beans
Common drugs – quinine, sulphonamides, quinolones and nitrofurantoin
What is the diagnostic investigations for G6PD Deficiency?
Reduced G6PD levels
FBC - anaemia and raised reticulocytes
Blood film:
Normal in between attacks
Attack - increased reticulocytes and HEINZ bodies and BITE cells
What is the treatment for GP6D Deficiency?
Avoid Precipitants - Oxidative drugs
Blood transfusions when attacks come on.
What precipitants can lead to attacks of GP6D Deficiency?
Naphthalene
Anti-malarials
Aspirin
FAVA beans
Nitrofurantoin
What are lymphomas?
Malignant proliferation of lymphocytes which accumulate in lymph nodes 🡪 lymphadenopathy
What are the two main categories of lymphoma?
Hodgkin’s Lymphoma - a specific disease
Non-Hodgkin’s Lymphoma - encompasses all other lymphomas
What are the main Lymph node sites?
Cervical Lymph Nodes
Axillary Lymph Nodes
Inguinal Lymph Nodes
What are some Potential causes of Lymphoma?
Primary Immunodeficiency - Ataxia Telangiectasia
Secondary Immunodeficiency - HIV, Transplant recipients
Infection - EBV, HIV, HTL virus, H-pylori
Autoimmune disorders - SLE
What is the pathophysiology of Lymphoma?
Not well understood
Thought to be multifactorial - Genetic factors + Environment
Impaired Immunosurveillance
Infected B cells escape regulation and proliferate
What are the general symptoms of Lymphoma?
Lymphadenopathy
SVC obstruction
B symptoms
Weight loss
Appetite loss
Night sweats
Fever
What is Hodgkin’s Lymphoma?
Cancerous Proliferation of Lymphocytes
Bimodal age distribution - affects teens (13-19) and elderly (75+)
Associated with EBV infection
What are the 2 types of Hodgkin’s Lymphoma?
Classical - Reed Sternberg cells with mirror-Image nuclei
Nodular Lymphocyte Predominates Hodgkin’s Lymphoma (NLPL) - Reed Sternberg cell variant - Popcorn cell
What are the risk factors for Hodgkin’s Lymphoma?
HIV
Epstein-Barr Virus
Autoimmune conditions such as rheumatoid arthritis and sarcoidosis
Family history - affected sibling
How does Hodgkin’s Lymphoma normally Present?
Lymphadenopathy - non-tender, feel rubbery
Pain in lymph nodes when drinking alcohol.
B symptoms - Fever, Weight loss, Night sweats
What are the B Symptoms associated with Lymphoma/other haematological disorders?
Fever
Weight Loss >10% in 6 months
Night Sweats
What other symptoms may be associated with Hodgkin’s Lymphoma?
Fatigue
Pruritus’ (itching)
cough
SOB
Abdominal Pain
Recurrent infections
What are the diagnostic investigations for Hodgkin’s Lymphoma?
Lymph Node Biopsy - Reed Sternberg cell positive with mirror image nuclei
Lactate Dehydrogenase - Often raised by not specific to Hodgkin’s
Decreased Hb (normo-chromatic, Normocytic anaemia), Increased ESR - indicates worse prognosis
CT/MRI - Fir staging and diagnostics
What type of Biopsy is done to Diagnose Lymphoma?
Core Needle Biopsy
Lymph Node Excision
What are Reed Sternberg cells?
Abnormally large B cells with multiple nuclei that are the key finding on lymph node biopsy in Hodgkin’s Lymphoma.
What is the Ann Arbor Staging system?
Used for Staging Hodgkin’s and Non-Hodgkin’s Lymphoma
Stage 1 - Single Lymph node region
Stage 2 - In more than 1 lymph node region but same side of the diaphragm
Stage 3 - Lymph nodes both above and below Diaphragm affected
Stage 4 - Widespread involvement including other non-lymphatic organs (lungs/liver)
A = NO B symptoms
B = HAS B symptoms
What other organs may be affected in Stage 4 Hodgkin’s Lymphoma?
Blood
Bone Marrow
Liver
Spleen
What is used to stage lymphomas using the Ann Arbor staging system?
CT/MRI/PET scans
What is the Treatment for Hodgkin’s Lymphoma?
ABVD Chemotherapy:
Adriamycin
Bleomycin
Vinblastine
Dacarbazine
(Potentially Radiotherapy)
What are the different courses of treatment for Hodgkin’s Lymphoma?
Stage IA - IIA (< 3 areas involved):
Short course ABVD
Stage IIA - IVB (> 3 areas involved):
Longer courses of ABVD
What is the Aim of Treatment for Hodgkin’s Lymphoma?
To cure the condition
Usually successful however there is a risk of relapse and SE of treatment.
What are the side effects of Chemotherapy?
Infertility
Nausea
Alopecia
Vomiting
Constipation/diarrhoea
Rash
What are the Side effects of Radiotherapy?
IHD
Second malignancies
Hypothyroidism
What are the side effects of:
Anthracyclines
Bleomycin
Vinka alkaloids
Anthracyclines – cardiomyopathy
Bleomycin – lung damage
Vinka alkaloids – peripheral neuropathy
What are some side effects of Hodgkin’s Lymphoma Treatment?
Chemotherapy:
Alopecia
N+V
Myelosuppression & BM failure = Infection
Radiotherapy - Increased risk of second malignancies
What is Febrile Neutropenia?
A condition marked by Fever and very low neutrophil numbers in the blood.
Massive risk in Px who have had recent/High dose Chemo (or on Carbimazole)
What is the treatment for Febrile Neutropenia?
Immediate Broad Spec Antibiotics
(Amoxicillin + Fluoroquinolone)
What is Non-Hodgkin’s Lymphoma?
malignant clonal expansion of lymphocytes which occurs at different stages of lymphocyte development.
All lymphomas without Reed Sternberg cells.
80% are B cell origin and 20% T cell origin.
Give some Key Non-Hodgkin’s Lymphomas
Low Grade - Follicular
High Grade - Diffuse Large B cell Lymphoma
Very high Grade - Burkitt Lymphoma
What are the risk factors of Non-Hodgkin’s Lymphoma?
HIV
Epstein-Barr Virus
H. pylori (MALT lymphoma)
Hepatitis B or C infection
Exposure to pesticides and a specific chemical called trichloroethylene used in several industrial processes
Family history
What are some Specific Symptoms of Burkitt Lymphoma?
Linked to EBV infection.
Causes Massive Jaw Lymphadenopathy in children
What are the symptoms of Non-Hodgkin’s Lymphoma?
Variable symptoms due to the range of subtypes however Px generally present in a similar way to Hodgkin’s Lymphoma:
Painless Rubbery Lymphadenopathy
B Symptoms
Lymph nodes NOT Painful with Alcohol.
What are the Diagnostic tests for Non-Hodgkins Lymphoma?
Lymph Node Biopsy - No RS/Popcorn Cells confirms NHL lymphoma
CT/MRI for Ann Arbor Staging
What is the Treatment for Non-Hodgkin’s Lymphoma?
R-CHOP:
Rituximab - Targets CD20 on B cells
Cyclophosphamide
Hydroxy-Daunorubicin
Vincristine (Oricovin)
Prednisolone
+ radiotherapy
Describe the prognosis of low-grade Non-Hodgkin’s Lymphoma
Slow growing, advanced at presentation, incurable
Median survival; 10 years
Describe the prognosis of high-grade Non-Hodgkins Lymphoma
Nodal presentation; presents early than low grade, therefore often curable
Aggressive - can make patient very unwell.
How does the treatment for low and high-grade Non-Hodgkins Lymphoma, differ?
In general, if the patient is symptomless - watch and wait.
Low grade; no chemotherapy may be required - radiotherapy may be curative in localised disease.
If symptomatic, Chemotherapy radiotherapy, combination chemotherapy and mAb
High Grade:
Early - Short course R-CHOP
Advanced - Combination R-CHOP + Rituximab
How does the treatment differ between High grade Non-Hodgkin’s lymphoma that is detected early and late?
Early - 3 months of RCHOP with radiotherapy
Late - 6 months of RCHOP with Radiotherapy
What is Myelodysplastic Syndrome?
Myelodysplastic syndrome is caused by the myeloid bone marrow cells not maturing properly and therefore not producing healthy blood cells.
There are a number of specific types of myelodysplastic syndrome.
What happens to the blood cell maturation in Myelodysplastic Syndrome?
Causes low levels of blood components that originate from the myeloid cell line:
Anaemia - Low RBC
Neutropenia - Low neutrophils
Thrombocytopenia - Low platelets
What do patients have an increased risk of developing if they have Myelodysplastic Syndrome?
Acute Myeloid Leukaemia (AML)
How does Myelodysplastic Syndrome Present?
May be Asymptomatic and the diagnosis is made incidentally
May present with symptoms of:
Anaemia - fatigue, pallor, SOB
Neutropenia - Recurrent/severe infections
Thrombocytopenia - Bleeding/bruising
What are the diagnostic investigations for Myelodysplastic syndrome?
FBC - Low RBC, Neutrophils, Platelets
Blood Film - Blasts present (immature myeloid derived progenitors)
Bone marrow aspiration biopsy
What is the management of Myelodysplastic Syndrome?
Watchful Waiting
Supportive Treatment with blood transfusions if severely anaemic
Chemotherapy
Stem Cell Transplant
Define Leukaemia?
The malignant Proliferation (Cancer) of a particular line of haematopoietic stem cells (blast cells) in the bone marrow. This causes unregulated production of certain types of blood cells.
What is the pathophysiology of Leukaemia?
A genetic mutation in one of the precursor cells (myeloblast or lymphoblast) in the bone marrow leads to excessive production of a single type of abnormal white blood cell.
This can lead to suppression of other cell lines causing underproduction of those types.
This causes Pancytopenia - Combination of anaemia, leukopenia and thrombocytopenia
Why is there suppression of other cell lines in leukaemia?
Rapid proliferation of one leukocyte takes up lots of space in the bone marrow.
This leaves less space for functioning cells to be produced.
What are the 4 main types of leukaemia?
Acute Myeloid Leukaemia (AML)
Acute Lymphoblastic Leukaemia (ALL)
Chronic Myeloid Leukaemia (CML)
Chronic Lymphoblastic Leukaemia (CLL)
What age ranges are at increased risk of the different types of leukaemia?
Mnemonic: ALL CeLL mates have CoMmon AMbitions
under 5 and over 45 - ALL
Over 55 - CLL
Over 65 - CML
Over 75 - AML
What age group does ALL commonly affect?
children under 5
What clinical symptoms are associated with Leukaemia?
Fatigue - anaemia
Fever + infections
Failure to thrive (children)
Pallor due to anaemia
Petechiae and abnormal bruising due to thrombocytopenia
Abnormal bleeding - thrombocytopenia
Lymphadenopathy
Hepatosplenomegaly
What is the presentation of leukaemia?
Quite non specific.
Symptoms are associated with affects of pancyotpenia
AML arises from abnormalities in which type of cell?
Common myeloid progenitor cells → abnormal myeloblasts
No differentiation
ALL arises from abnormalities in which type of cell?
Common lymphoid progenitor cells → abnormal lymphoblasts
No differentiation
CLL arises from abnormalities in which type of cell?
Mature B-lymphocyte
Partial differentiation
CML arises from abnormalities in which type of cell?
Basophils, neutrophils and eosinophils
Partial differentiation
CMML arises from abnormalities in which type of cell?
Chronic Myelomonocytic Leukaemia
Mature monocytes
What may be the white cell counts for some of the different types of leukaemia?
Symptomatically high WCC
- > 100x10^9/L for AML
- > 200x10^9/L for ALL
- > 400x10^9/L for CML
What diagnostic investigations are used in leukaemia?
FBC - Pancytopenia
Blood film - abnormal cells/inclusions
Lactate Dehydrogenase - often raised by non-specific
Bone Marrow Biopsy - Diagnostic
CXR - lymphadenopathy
CT/MRI for staging of lymphomas/other tumours
What are the different types of Bone marrow biopsy that may be used to diagnose leukaemias?
Bone Marrow Aspiration - liquid sample of cells
Bone Marrow Trephine - solid core of bone marrow
Bone marrow Biopsy - uses a specialist needle
What is Acute Myeloid Leukaemia (AML)?
Neoplastic common myeloid progenitor/ myeloblast proliferation
Most common acute leukaemia in adults and most commonly affects over 75 yrs.
What are the genetics of AML?
t(15:17)
Association with Downs and Radiation
What is the progression of AML like?
Rapid progression
If not Tx ASAP then 3 year survival =20%
What are the symptoms of AML?
Sx of Leukaemia
B symptoms
Gum infiltration
What are the investigations of AML?
FBC - Pancytopenia
Blood Film - High proportion of blast cells, Myeloperoxidase
AUER RODS (myeloperoxidase cytoplasmic aggregates in neutrophils)
BM Biopsy - > 20% myeloid Blast cells
What are Auer Rods?
Associated with AML
myeloperoxidase cytoplasmic aggregates in neutrophils
What is the treatment of AML?
Supportive treatment: (blood/platelets/fluids/antibiotics)
Correction of anaemia, thrombocytopenia and coagulation abnormalities
Treatment of infection with IV antibiotics
Allopurinol - prevention of acute tumour lysis syndrome
Chemo needed to induce remission
BM transplant and steroids to maintain
What is Tumour Lysis Syndrome?
Caused by the release of Uric Acid from cells that are destroyed by chemotherapy.
Uric acid can form crystals in interstitial tissue and the kidneys causing AKI.
Tx with Allopurinol
What is Chronic Myeloid Leukaemia?
Neoplastic Myelocyte proliferation (precursor for eosinophils, basophils, Neutrophils)
Associated with exposure to ionising radiation
What are the Genetics of CML?
Philadelphia chromosome (chromosome 9)
Cytogenetic translocation t(9:22)
What is the Pathogenesis of CML?
Philadelphia chromosome translocation
BCR ABL gene fusion causing Tyrosine Kinase irreversibly switched on.
Tyrosine kinase increases cell proliferation
What are the symptoms of CML?
General Sx of Leukaemia
B Symptoms
MASSIVE Hepatosplenomegaly
What are the investigations of CML?
FBC - anaemia (but leuko/granulocytosis)
BM biopsy - increased granulocytes
Philadelphia chromosome genetic test using FISH - look for BCR-ABLE
What is the treatment for CML?
Chemotherapy
Imatinib - T.K inhibitor
BM/stem cell Transplant
What is the risk of CML?
Risk of progression to AML
What is Acute Lymphoblastic Leukaemia (ALL)?
Neoplastic Lymphoblast proliferation
Most common Childhood malignancy - 75% of cases < 6 yrs
What are the genetics of ALL?
Mostly B cell lineage (not T cell)
t(12:22) w/ good prognosis
Associated with DOWNs (30x increased risk)
What are the symptoms of ALL?
General Sx of Leukaemia
B symptoms
except 6yr olds with DOWNs
hepatosplenomegaly and lymphadenopathy
What are the investigations of ALL?
FBC - Pancytopenia
Blood film - increased lymphoblast cells
BM Biopsy - >20% Lymphoblasts (diagnostic)
Immunofluorescence - TdT +tve lymphoblasts
What is the treatment for ALL?
Chemotherapy
Correct Pancytopenia
Consider ALLOPURINOL and Prophylactic Abx
Generally good prognosis
What is the treatment of Acute Promyelocytic Leukaemia?
All-Trans-Retinoic Acid (ATRA)
What is Chronic Lymphocytic Leukaemia (CLL)?
Neoplastic proliferation of Lymphocytes (most B cells)
Most common leukaemia overall often affecting adults >55yrs
multifactorial
What are the symptoms of CLL?
Often Asymptomatic
If Sx:
General Sx of Leukaemia
Lymphadenopathy (non tender)
Hepatosplenomegaly
What are the investigations for CLL?
FBC - Pancytopenia (except has lymphocytosis)
Blood Film - SMUDGE CELLS
Immunoglobulins - Hypogammaglobulinaemia
Why is there Hypogammaglobulinaemia in CLL?
B cells proliferate but do not differentiate into plasma cells and therefore few Igs are produced.
What is the Treatment of CLL?
Varies depending on stage
Early - watchful waiting
Advanced - Chemo
Radiotherapy to shrink lymphadenopathy
Splenectomy
BM transplant
Stem cell transplant
What is a complication of CLL?
Richter Transformation:
B cells massively accumulate in Lymph nodes causing massive lymphadenopathy.
CLL transforms to aggressive lymphoma
What are some complications of Chemotherapy used to treat leukaemia?
Failure
Stunted growth/development in children
Infections - immunodeficiency
Neurotoxicity
Infertility
Tumour Lysis Syndrome
What is a normal haematocrit?
45%
What is haematopoiesis?
Synthesis of blood cells
Where does haematopoiesis happen?
Bone marrow
How is haematopoiesis regulated?
Through the action of cytokines
What is Extramedullary Haemopoiesis?
Formation and activation of blood cells outside the bone marrow (BM), as a response to hematopoietic stress caused by microbial infections and certain diseases, such as myeloproliferative neoplasms (MPN), lymphomas, and leukemias
Define myeloproliferative neoplasms
Haematological malignancies
Chronic conditions - present and evolve over many years
How do myeloproliferative neoplasms manifest?
Accumulation of mature blood cells in circulation
Where do myeloproliferative neoplasms arise from?
Haematopoietic stem cells
What causes myeloproliferative neoplasms?
Genetic mutations in haematopoietic stem cells
Cells inappropriately and permanently switched on by signalling cytokines that control haematopoiesis
What genes are associated with Myeloproliferative diseases?
Mutations in:
JAK2
MPL
CALR
What are the 3 main myeloproliferative disorders?
Primary Myelofibrosis
Polycythaemia Vera
Essential Thrombocytopenia
What condition do myeloproliferative disorders have the risk of progressing to?
Acute Myeloid Leukaemia (AML)
What Proliferating cell line causes:
Primary Myelofibrosis
Polycythaemia Vera
Essential Thrombocytosis
Primary Myelofibrosis - Haematopoietic Stem Cell
Polycythaemia Vera - Erythroid Cells
Essential Thrombocytosis - Megakaryocyte
What is polycythaemia?
Erythrocytosis (increased Hb, Packed cell volume and RBCs) of any cause
(opposite to anaemia)
How common is polycythaemia vera?
Rare
2 cases/100,000 per year
What is the prognosis of polycythaemia vera?
13 years
What are some causes of Polycythaemia?
Primary - Polycythaemia Vera, Primary familial/Congenital Polycythaemia
Secondary - Hypoxia, increased EPO (secreting tumours), Dehydration, Alcohol
What is the pathology of Primary Polycythaemia?
Mutations in JAK2 or EPO
Increased sensitivity of BM cells to EPO
Increased RBC production
What is the Pathology of Secondary Polycythaemia?
Appropriate response:
Increased RBC production due to hypoxia, dehydration, alcohol, etc.
Inappropriate Response:
Increased EPO secretion from tumours
What causes Polycythaemia Vera?
JAK2 mutation V617 - EPO constantly switched on
Accounts for 95% of cases
What causes Primary familial and congenital polycythaemia?
Mutation in EPO receptor gene.
What are the symptoms of Polycythaemia Vera?
May be ASx
Easy bleeding/Bruising
Fatigue
Dizzinesss/Headaches.
Itchy after a bath
Burning in fingers and toes - Eryhtromyalgia
What are the signs of Primary Polycythaemia vera?
Plethoric complexion
Hepatosplenomegaly – result of extramedullary haemopoiesis
Hyperviscosity of blood - increased RBCs = increased haematocrit
What are the signs of Secondary Polycythaemia?
Plethoric complexion
Hyperviscosity of blood - increased RBCs = increased haematocrit
No splenomegaly
What are the diagnostic investigations of Polycythaemia Vera and Secondary Polycythaemia?
FBC:
P. Rubra Vera:
Raised WBC and platelets
Low serum EPO (negative feedback)
Secondary:
Normal WBC and platelets
Low serum EPO (negative feedback)
BM biopsy
Genetic testing for JAK2 gene
What is the treatment of Polycythaemia Vera?
Primary: Non curative
Venesection + Aspirin
Aim to maintain normal blood count and haematocrit (<45%):
Hydroxycarbamide - in high risk patients
Secondary Tx underlying cause.
What are some main complications of Polycythaemia Vera?
Arterial Thrombosis - Stroke/MI
Venous Thrombosis - DVT, Splanchnic vein thrombosis, Portal vein Thrombosis
What are the differential diagnosis for polycythaemia vera?
Eliminate secondary causes:
Lung disease
Alcohol
Apparent erythrocytosis
EPO (erythropoietin) secreting tumours
What is the prognosis of essential thrombocythaemia?
Life expectancy is normal
What is Essential Thrombocythaemia?
Elevated Platelet Count
What is the cause of Essential Thrombocytosis?
JAK mutation
TPO switched on
How is Thrombocytosis Diagnosed
FBC - increased platelets
Blood film - Platelet Islands/aggregations
Check For iron status
Increased ESR - signs of infection
Increased CRP - signs of infection
What is the management of Essential Thrombocythaemia?
Assess and manage CVD risk
<60yrs - Aspirin alone
> 60yrs or high risk - Aspirin + Hydroxycarbamide
What are the differential diagnosis of essential thrombocytosis?
Eliminate secondary causes:
Infection
Inflammation (including post-surgical)
Solid tumours
Steroids
Iron Deficiency
What are the complications of essential thrombocythaemia?
Arterial thrombosis
Venous thrombosis
What is the prognosis of myelofibrosis?
5 years
What is Myelofibrosis?
Proliferation of the cell lines in the bone marrow lead to fibrosis
What is the cause of myelofibrosis?
Predominantly JAK2 mutation
What are the symptoms of myelofibrosis?
Weight loss
Fatigue
Features of cytopenia
What is the management of myelofibrosis?
Supportive management:
Blood transfusions, EPO, treat infection
Hydroxycarbamide chemotherapy
Allogeneic stem cell transplant
Ruxolitinab (JAK1/2 inhibitor)
What are the stimulants of Erythropoiesis?
- Hypoxia
- EPO secreted by kidneys
- Thyroid hormone and testosterone can stimulate as well
What substances are required for healthy erythropoiesis?
- Iron - For haemoglobin formation
- Vitamin B12 and folic acid - Required for DNA maturation and condensation. Without it, you will have massive red blood cells
Discuss the process of erythropoiesis.
- Occurs in red bone marrow of the epiphyses of bone
- EPO will stimulate myeloid stem cell to commit to RBC lineage - proerythroblast
- Proerythroblast will become basophillic erythroblast due to increase in mRNA of haemoglobin products
- Nucleus condenses and organelles are ejected
What is the structure of haemoglobin?
- Haemoglobin has a quaternary structure
- 4 haem groups
- 4 four polypeptide chains (α1, α2, β1, and β2)
What is the signal for RBC breakdown?
Loss of RBC structure through breakdown of the cytoskeletal components spectrin and ankrin
What is the process of RBC breakdown?
- Macrophages or Kupffer cells in the spleen, liver or bone marrow phagocytose RBC
- Globin alpha and beta chains > recycled as AA
- Haem > iron and protoporphyrin
- Iron > ferritin > haemosiderin
- Protoporphyrin > Biliverdin > Bilirubin
Describe bilirubin metabolism.
- Haem > Biliverdin > Bilirubin
- Bilirubin binds with albumin = unconjugated bilirubin - travels to liver
- Unconjugated bilirubin combines with glucuronic acid (via UGT) = conjugated bilirubin
- Conjugated bilirubin forms bile, which gets pushed into the duodenum
- Bacteria in the gut breaks down conjugated bilirubin into urobilinogen (AKA faecal stercobilinogen)
- Urobilinogen can be reabsorbed and excreted via the urine as urobilin (makes urine yellow)
- Urobilinogen can become stercobilin and excreted in the faeces (makes poo brown)
What is anaemia?
- Low level of haemoglobin in the blood
- It is the result of an underlying disease, and not a disease itself
What are the normal haemoglobin and mean cell volume ranges for men and women?
Men:
Haemoglobin - 120-165 g/L
MCV - 80-100 femtolitres
Women;
Haemoglobin - 130-180 g/L
MCV - 80-100 Femtolitres
What is Mean Cell (corpuscular) Volume?
Size of the red blood cells
What level is considered anaemic in men and women?
- <135 g/L for men
- <115 g/L for women
What are the 3 main categories of anaemia?
- Microcytic anaemia (low MCV indicating small RBCs)
- Normocytic anaemia (Normal MCV indicating normal sized RBCs)
- Macrocytic anaemia (Large MCV indicating large RBCs)
What are the different Mean Corpuscular Volumes in the different types of anaemia?
Microcytic - CMV <80
Normocytic - CMV 80-95
Macrocytic - CMV >95
What can be reasons for Low blood count/anaemia?
Increased Loss:
BLEEDING
Haemolysis
Decreased Production:
Iron deficiency
B12 deficiency
Folate deficiency
BM failure
What are the main causes of microcytic anaemia?
TAILS:
- Thalassaemia
- Anaemia of chronic disease
- Iron deficiency anaemia
- Lead poisoning
- Sideroblastic anaemia
What are the main causes of normocytic anaemia?
AHAHA:
Acute blood loss
Haemolytic anaemia
Anaemia of chronic disease
Hypothyroidism + Renal disease
Aplastic anaemia
What are the main causes of Macrocytic Anaemia?
Megaloblastic:
B12 deficiency
Folate Deficiency
non-megaloblastic:
Alcohol Excess
What are the main causes of macrocytosis (large RBCs)?
Split into Megaloblastic and Normoblastic:
Megaloblastic:
- B12 Deficiency
- Folate Deficiency
Normoblastic:
- Alcohol
- Reticulocytosis
- Hypothyroidism
- Liver disease
- Drugs (Azathioprine)
What is a hypochromic cell?
Pale cells due to less haemoglobin
What is a Megaloblastic Anaemia?
An anaemia characterised by large (macrocytic) non-condensed chromatin due to impaired DNA synthesis.
B12 deficiency
Folate Deficiency
What are the general Symptoms of Anaemia?
Tiredness
Shortness of breath
Headaches
Dizziness
Palpitations
Worsening of other conditions such as angina, heart failure or peripheral vascular disease
What are the general signs of anaemia?
Pale skin
Conjunctival Pallor
Tachycardia
Raised Respiratory Rate
What are some symptoms specific to iron deficiency anaemia?
Pica - dietary cravings for abnormal things such as dirt
Hair loss - Can indicate Iron Deficiency Anaemia
What are some Signs of specific causes of Anaemia?
Iron Deficiency Anaemia:
Koilonychia - Spoon shaped nails
Angular Chelitis
Brittle hair and nails
Haemolytic Anaemia:
Jaundice
Thalassaemia:
Bone Deformities
What is Anaemia of Chronic Disease?
Secondary anaemia due to underlying pathology.
Commonest anaemia in hospitals
Occurs in patients with inflammatory disease
What are the causes of anaemia of chronic disease?
Crohn’s
RA
TB
SLE
Malignant disease
CKD
What is the pathology of anaemia of chronic disease?
These conditions can cause either a shortening of RBC life or reducing RBC production
Decreased release of iron from BM to developing erythroblasts
Less erythropoietin produced in response to the anaemia
High levels of hepcidin expression – inhibits duodenal iron absorption and macrophage release of iron
Decreased RBC survival
What are the investigations of anaemia of chronic disease?
FBC and blood film
Normocytic/microcytic and hypochromic (pale)
Low serum iron and low total iron-binding capacity (TIBC)
Increased or normal serum ferritin
What is the treatment for anaemia of chronic disease?
Treat underlying cause
Recombinant erythropoietin
What is Iron Deficiency Anaemia?
Iron is required for the synthesis of Haemoglobin.
Therefore in Iron deficiency there is impaired synthesis of haemoglobin leading to Microcytic anaemia.
What is the presentation of anaemia of chronic disease?
Anaemia symptoms and signs
What is the most common form of anaemia world wide?
Iron Deficiency anaemia
What are some reasons a person may become iron deficient/causes of iron deficiency anaemia?
Iron is being lost (BLEEDING)
Insufficient dietary iron
Iron requirements increase (for example in pregnancy)
Inadequate iron absorption
Where is Iron mainly absorbed?
Duodenum and Jejunum
How is Iron Transported and stored?
Transported - Transferrin
Stored - Ferritin and Haemosiderin
Why do medications that reduce stomach acid production lead to impaired absorption of iron?
Iron is kept in the soluble ferrous (Fe2+) form by the stomach acid.
When it enters the intestines and the acid drops, it changes to Insoluble ferric iron (Fe3+)
The ferric iron is required for absorption.
PPIs will increase insoluble ferric iron in the stomach that cannot be absorbed.
What conditions may reduce iron absorption?
GI tract Cancer
Oesophagitis and Gastritis - GI bleeding
IBD, Colitis and Coeliacs - Impaired absorption
What are the Signs and Symptoms of Iron deficiency anaemia?
General Anaemia Sx
Koilonychia
Angular Stomatitis, Cheilitis
Atrophic Glossitis
What are the diagnostic investigations for Iron Deficiency Anaemia?
FBC - MCV = Low (microcytic anaemia)
Blood Film - Hypochromic RBC, Target cells, Howell Jolly Bodies
Iron Studies - Low Ferritin (<15), Low transferrin Saturation (<15%), Increased Total Iron Binding Capacity (TIBC)
Endoscopy/Colonoscopy if >60 yrs to look for GI bleed
What are some differential Diagnoses for Iron deficiency anaemia?
Thalassaemia
Anaemia of chronic disease
What is the treatment of Iron Deficiency Anaemia?
Oral Fe - Ferrous Sulphate (Ferrous Gluconate if poorly tolerated)
Blood Transfusion
What are some Side effects of Treating Iron deficiency anaemia with Ferrous sulphate?
Cause GI Upset
Diarrhoea
Constipation
Black stools
What is Sideroblastic Anaemia?
A microcytic anaemia characterised by ineffective erythropoiesis due to having too much Iron
What is the Pathogenesis of Sideroblastic anaemia?
Defective Hb synthesis within Mitochondria
Often X linked inheritance
A Functional Iron deficiency where there is increased Fe but it is not used in Hb Synthesis
What are the investigations for Sideroblastic anaemia?
FBC - Microcytic
Blood film - Ringed Siderobasts
What is the Treatment for Sideroblastic Anaemia?
- Mainly supportive
- Iron chelation (Desferrioxamine)
- Consider B6 (Pyridoxine) if hereditary
What is Pernicious Anaemia?
- Autoimmune condition in which atrophic gastritis leads to a lack of intrinsic factor secretion from the parietal cells in the stomach
- Dietary B12 remains unbound and cannot be absorbed at the terminal ileum
- Therefore B12 deficiency leads to impaired maturation of RBCs and anaemia
What is vitamin B12 deficiency anaemia?
- Macrocytic anaemia with peripheral neuropathy and neuropsych complaints
- It is a megaloblastic anaemia, as well as folate deficiency anaemia
What are the causes of B12 deficiency?
Low dietary intake - vegans
Atrophic gastritis
Gastrectomy
Crohn’s disease
Coeliac disease = malabsorption
Drugs (Metformin, PPI, H2 antagonists)
What is the cause of pernicious anaemia?
Autoimmune atrophic gastritis
What is B12 used for and how is it absorbed?
- DNA synthesis cofactor and the production of red blood cells
- required for cell division - Without it, cells remain large (megaloblast)
- It is normally present in meat, fish and dairy, and it absorbed in the terminal ileum combined with intrinsic factor
What is the normal physiology of Vitamin B12 absorption
B12 typically binds to Transcobalamin in the saliva (provides protection against stomach acid)
Parietal cells release Intrinsic factor (IF)
IF forms complexes with Vit B12 which is then absorbed in the ileum
B12 is then used for RBC production
What is the Pathophysiology of B12 deficiency and Pernicious anaemia?
Autoimmune destruction of Parietal cells
Therefore reduced intrinsic factor produced
Therefore poor absorption of B12
B12 cannot be used to produced RBCs
Anaemia
What are the signs and symptoms of Pernicious anaemia?
General Anaemia Sx
Signs:
Lemon Yellow Skin
Angular Stomatitis and glossitis
Neurological SX - B12 def causes demyelination
What neurological symptoms may be seen in Pernicious anaemia?
Symmetrical paraesthesia
Muscle Weakness
What are the diagnostic investigations of B12 Deficiency and Pernicious Anaemia?
MCV Increased - macrocytic anaemia
Blood film - Megaloblasts + Oval Macrocytes
Low serum B12 levels
Anti-IF antibodies and Anti-parietal Abs
How long does B12 deficiency and pernicious anaemia take to develop?
Years
What is the treatment of Pernicious anaemia?
Dietary advice (Salmon and eggs)
B12 Supplements
PO Hydroxocobalamin
What would you not treat B12 deficiency anaemia with?
Folic acid supplements
Can cause fulminant neurological Deficits
What are some complications of Pernicious anaemia?
Heart failure
Angina
Neuropathy
What is Folate Deficiency Anaemia?
- A type of MACROcytic anaemia with absence of neurological signs
- Folate is required for cell division and DNA synthesis.
Without it maturing RBCs wont divide - Megalobastic
How long does Folate deficiency anaemia take to develop?
Months
What are the causes of folate deficiency anaemia?
- Poor diet (poverty, alcohol, elderly)
- Increased demand (Pregnancy, renal disease)
- Malabsorption (Coeliac)
- Drugs, alcohol and methotrexate
What is the hallmark symptom of megalobastic anaemia?
Headache
Loss of appetite and weight
What are the signs and symptoms of folate-deficiency anaemia?
General Anaemia Sx
Angular Stomatitis and Glossitis
No Neurological Sx - distinguish between B12 Def.
What is the diagnostic test for Folate deficiency Anaemia?
FBC and Blood film - Macrocytic and Megaloblasts
Decreased serum folate
What is the treatment for Folate deficiency anaemia?
Dietary advice - leafy greens and brown rice
Folate supplements
If pancytopenic then give packed RBC Transfusion
How can you tell the difference between B12 and folate deficiency anaemia?
Both macrocytic megaloblastic anaemias
B12 presents with anaemia Sx and Neurological deficits.
Folate has no neurological deficits.
What is Haemolytic Anaemia?
Anaemia caused by haemolysis - early breakdown of RBCs
Where does haemolysis occur?
Intravascular - within blood vessels
Extravascular - within reticuloendothelial system (most common)
By macrophages in spleen (mainly), liver and bone marrow
What are the hereditary causes of haemolytic anaemia?
- Enzyme defects (G6P dehydrogenase deficiency)
- Membrane defects (Spherocytosis, elliptocytosis)
- Haemoglobinopathies (Abnormal Hb production) (Sickle cell, thalassaemia)
What are the acquired causes of haemolytic anaemia
Autoimmune haemolytic anaemia
Infections - malaria
Secondary to systemic disease
What is Autoimmune Haemolytic Anaemia?
Autoimmune Abs against RBCs causing intra and extravascular haemolysis
What are the types of Autoimmune haemolytic anaemia?
- Divided into two subtypes depending on temperature:
- WARM type - IgG mediated - occurs at normal or warm temperatures (Idiopathic)
- COLD type - IgM mediated - also called cold agglutinin disease
What is the specific test to Diagnose Autoimmune Haemolytic Anaemia?
Direct Coombs Test - Agglutination of RBCs with Coombs reagent
What are the signs and symptoms of haemolytic Anaemia?
- Anaemia symptoms (Pallor, fatigue, dyspnoea)
- Jaundice (Increase in bilirubin)
- Splenomegaly (increased haemolysis)
- Dark urine (PNH)
What are the investigations for haemolytic anaemia?
Low Hb
FBC - Normocytic Anaemia
Blood film - Shistocytes, increased reticulocytes’
Jaundice features: Inc bilirubin, Inc urinary urobilin, High faecal stercobilin
Direct coombs Test - positive for autoimmune
What is the treatment of Coombs +ve haemolytic anaemia?
- Treat underlying condition
- RBC transfusion and folic acid
- Prednisolone
- Rituximab
- Splenectomy
What is the treatment of haemolytic anaemia?
Folate and iron supplementation
Immunosuppressives
Splenectomy
How does CKD cause anaemia?
Decreased EPO causes reduced erythropoiesis
Normocytic and Normochromic anaemia
What is Aplastic Anaemia?
A Pancytopenia where Bone Marrow fails and stops making haematopoietic stem cells from pluripotent cells..
What are the causes of aplastic anaemia?
Congenital
Acquired e.g. aplastic anaemia
Chemotherapeutic drugs
Infections – EBV, HIV, TB, Hepatitis
Pregnancy
What are the signs and symptoms of aplastic anaemia?
Anaemia
Increased susceptibility to infection
Increased bruising
Increased bleeding (especially from nose and gums)
What are the investigations for aplastic anaemia?
FBC – would show pancytopenia (low levels of all blood cells i.e. RBCs, WBCS etc.)
Reticulocyte count – low or absent
BM biopsy – hypocellular marrow with increased fat spaces
What is the treatment for aplastic anaemia?
Remove causative agent
Blood/platelet transfusion
BM transplant
Immunosuppressive therapy – anti-thymocyte globulin (ATG) and ciclosporin
What are the main causes of splenomegaly?
Infection
Liver disease
Autoimmune disease - SLE/RA
Cancers (often haematological)
What is Haemophilia A?
A bleeding disorder caused by a deficiency in Factor VIII
What is Haemophilia B?
A bleeding disorder caused by a deficiency in Factor IX
What are the genetics of Haemophilia?
These are X linked Recessive disorders and therefore will only tend to affect males.
What do the symptoms of haemophilia depend on?
Plasma levels of factor 8/9 (A/B)
<1 IU/dl = severe disease:
frequent spontaneous bleeding into muscles and joints that can lead to crippling arthropathy
1-5 IU/dl = moderate disease:
severe bleeding following injury and occasional apparently spontaneous episodes
> 5 IU/dl = mild disease:
bleeding only with trauma or surgery
What are signs and symptoms of Haemophilia?
Excessive Bleeding to minor trauma
Intra-cranial haemorrhage, haematomas, chord bleeding in neonates
Spontaneous bleeding into joints and muscles (haemoarthrosis)
GI bleeding
Haematuria
Haematomas (blood collections outside vessels)
What is Prothrombin Time (PTT) a measure of?
Extrinsic clotting pathway
What is the activated partial thromboplastin time (APTT) a measure of?
Intrinsic clotting pathway
What diagnostic investigations are used to diagnosed Haemophilia?
Bleeding scores
Coagulation factor assays:
Normal prothrombin time (PTT) and VWF – Factor 8/9 not in extrinsic pathway
Prolonged activated partial thromboplastin time (APTT) – Factor 8/9 are in intrinsic pathway
Reduced plasma factor 8/9
Genetic testing
What is the management of Haemophilia?
Affected clotting factors (VIII or IX) can be replaced by IV.
Desmopressin can stimulate the release of VwF and raise level of factor 8/9
Antifibrinolytics - Tranexamic Acid
What is the main complication of haemophilia and how is it treated?
Joint deformities and arthritis from recurrent bleeding into joints
Tx: Encouragement to join exercise regimes and avoid contact sport and aspirin
What is Von Willebrand Disease (VWD)?
An autosomal dominant condition where there is a deficiency, absence or malfunction of VWF leading to abnormal bleeding.
What is the most common inherited cause of abnormal bleeding?
Von Willebrand Disease
What is the presentation of VWD?
Hx of easy, prolonged or heavy bleeding:
Bleeding gums w/ bruising
Nose bleeds (Epistaxis)
Menorrhagia (heavy menstrual bleeding)
FHx of VWD.
What is the diagnosis of VWD?
Hx or FHx of abnormal bleeding
Bleeding assessment tools
What is the management of VWD?
Does not require day to day Tx
Tx is in response to major bleeding or trauma.
Tx:
Desmopressin can be used to stimulates the release of VWF
VWF can be infused
Factor VIII is often infused along with plasma-derived VWF
What can be given to Women with VWD that suffer from heavy periods?
Tranexamic acid
What is Rheumatic Fever?
Autoimmune disease that mostly occurs after a group A strep infection.
It causes joint pain and can affect other areas such as the heart (carditis) brain and skin.
How would a patient with Rheumatic fever present?
Fever
Joint pain
Recent infection (sore throat/scarlet fever)
Chest pain
SOB
What are some risk factors for rheumatic fever?
Infection
FHx of rheumatic fever
Overcrowded living.
What are the first line investigations to diagnose rheumatic fever?
Blood tests:
ESR/CRP
WCC
Blood cultures
ECG - Shows heart block
ECHO - if mitral regurgitation murmur
What is the Treatment for Rheumatic fever?
Benzylpenicillin
Diuretic +/- ACEi if heart failure present
What is infectious mononucleosis?
Glandular Fever caused by EBV infection.
What conditions are associated with EBV?
Burkitts Lymphoma
Hodgekin’s Lymphoma
nasopharyngeal carcinoma
Who is typically presenting with infectious mononucleosis?
How is infectious. mononucleosis spread?
15-24yr olds
EBV spread via saliva or body fluids
What is the Diagnostic investigations for glandular fever?
FBC
Blood film - Atypical Lymphocytes
EBV serology
EBV PCR
What is the management of glandular fever?
Generally self limiting
Supportive therapy
Good hydration and analgesics
What is Immune thrombocytopenic Purpura (ITP)?
Autoimmune destruction of platelets (IgG)
What is the pathophysiology of ITP?
Autoimmune destruction of platelets (IgG antibodies to platelets and megakaryocytes)
Often triggered by viral infection or malignancy
The IgG antibodies coat the platelets which are then removed by binding to Fc receptors on macrophages
What are the symptoms of ITP?
Purpuric rash - red spots on skin caused by bleeding underneath
easy bruising
Epistaxis - nosebleeds
menorrhagia
Gum bleeding
What are the investigations for ITP?
FBC
Thrombocytopenia – low levels of platelets
Increased megakaryocytes on BM examination
May have detection of platelet autoantibodies
What is the treatment of ITP?
1st Line:
Prednisolone + IV IgG
2nd Line:
Splenectomy
What is Thrombotic Thrombocytic purpura (TTP)?
Why does it occur?
Extensive microvascular clots form in small vessels in the body, resulting in a low platelet count (due to platelet consumption) and organ damage
Occurs due to deficiency of ADAMTS 13, a protease which is normally responsible for degradation of VWF
What are the symptoms of Thrombotic thrombocytic purpura?
Purpuric rash
AKI
Haemolytic anaemia
Easy bruising
Fever
Neurological Sx
What are the investigations for Thrombotic thrombocytic purpura?
Thrombocytopenia
Schistocytes
ADAMTS-13 deficiency
Coagulation screen - normal but lactate
dehydrogenase raised as a sign of haemolysis
How is Thrombotic thrombocytic purpura treated?
Plasmapharesis (plasma exchange to remove ADAMTS 13 Ab)
2nd line - IV methylprednisolone + Rituximab
What is Prothrombin time and INR?
What is the normal range?
PT - how long it takes for the blood to clot.
INR - international normalised ratio
PT range = 11-13.5 seconds
INR = 0.8-1.1
What is the aPTT test?
Partial thromboplastin time (activated Partial Thromboplastin Time)
Normal range is 21-35 seconds.
When higher than normal this suggests there may be bleeding or liver disease etc.
Explain the process of Heamostasis?
Prothrombin (II) 🡪 thrombin (IIa) – converted by factor Xa
Thrombin function:
Converts fibrinogen 🡪 fibrin
Activates XIII into XIIIa
Positive feedback effect on further thrombin production
Fibrin is an essential component of a blood clot
What is the Intrinsic, Extrinsic and Common clotting cascade?
Intrinsic:
Factor XII -> XIIa
Factor XI -> XIa
Factor IX -> IXa
Factor VIII -> VIIIa
Extrinsic:
Tissue factor (III) + VII –> VIIa
Common:
Factor X -> Xa
Factor V –> Va
Prothrombin to Thrombin
Fibrinogen to Fibrin
What factors does Warfarin inhibit?
10, 9, 7 ,2
What factors do Heparin/NOACs inhibit?
Xa
What is the Fibrinolytic System?
Plasminogen 🡪 Plasmin via TPA
Plasmin cuts fibrin into fragments
This prevents blood clots from growing and becoming problematic
What clotting factors is the liver responsible for and what vitamin is required for this?
10, 9, 7, 2
Vitamin K
What does a reticulocyte tell you?
Reticulocyte count – enables you to see how quickly the bone marrow is producing new RBCs. Reticulocytes are immature RBCs
Low reticulocyte count – indicative that something is preventing RBCs from being produced e.g. haematinic deficiency
High reticulocyte count – indicative that RBCs are being lost or destroyed (e.g. bleeding/haemolytic anaemia). New RBS production is increased to act asa compensatory mechanism
What are some differential Diagnoses for Iron deficiency anaemia?
Thalassaemia
Anaemia of chronic disease
What are some differential Diagnoses for Iron deficiency anaemia?
Thalassaemia
Anaemia of chronic disease
What is Disseminated Intravascular Coagulopathy (crisis) (DIC)?
Wide spread clotting and bleeding (as all platelets and CFs used for blood clots)
Haemostasis is out of control. get areas of lots of small clots which can lead to organ Ischaemia.
As lots of Platelets and Clotting Factors are used up, other areas can start to bleed and these do not clot.
I.e. there will be initial thrombosis followed by bleeding tendency
When does DIC occur?
Occurs when the balance between forming new clots and breaking down clots is tipped in favour of clots 🡪 widespread clotting (organ ischaemia) 🡪 depleted clotting factors 🡪 bleeding
What is the pathophysiology of DIC?
Wide spread clotting and bleeding (as all platelets and CFs used for blood clots)
Involves widespread generation of fibrin clots within the blood vessels caused by initiation of coagulation pathway due to tissue damage/ promotion of clotting.
There is also consumption of platelets/coagulation factors as well as secondary activation of fibrinolysis 🡪 production of Fibrin and Fibrinogen Degradation Products (FDPs) which contribute to bleeding by inhibiting fibrin polymerisation
I.e. there will be initial thrombosis followed by bleeding tendency
What are the causes of DIC?
Massive activation of clotting cascade
Malignancy – leukaemia t(15:17) translocation
Obstetrics causes – amniotic fluid embolism and abruptio placentae
Septicaemia
Trauma
Infections - meningitis
Haemolytic transfusion reactions
Liver disease
How does DIC present?
Varies from no bleeding at all to complete haemostatic failure
Bleeding typically occurs from venepuncture/IV sites and the nose and mouth
Bruising
SOB
Haemoptysis
How is DIC Diagnosed?
Diagnosis suggested by history (severe sepsis, trauma, malignancy), clinical presentation and presence of severe thrombocytopenia
Prolonged PTT, APTT and Thrombin Time (TT)
Decreased fibrinogen and increased FDPs
Blood film – shows fragmented red cells
What is the treatment for DIC?
Treat underlying cause – maintain blood volume and tissue perfusion
May need transfusions – platelets, RBCs and Fresh Frozen Plasma (FFP)
Activated C protein
