Haematology Flashcards
What is multiple myeloma?
Malignancy of plasma cells leading to progressive bone marrow failure. It is associated with production of characteristic paraprotein, bone disease and renal failure.
In order to make a diagnosis of myeloma, there must be evidence of mono-clonality. What is mono-clonality?
Abnormal proliferation of a single clone of plasma cell leading to immunoglobulin secretion and causing organ dysfunction especially to the kidney.
What disease often precedes multiple myeloma?
Monoclonal gammopathy of undetermined significance (MGUS).
What is MGUS?
A common disease with paraprotein present in the serum but no myeloma. Often asymptomatic. <10% plasma cells in the bone marrow.
Name 4 sub-types of leukaemia.
- AML - acute myeloid leukaemia.
- CML - chronic myeloid leukaemia.
- ALL - acute lymphoblastic leukaemia.
- CLL - chronic lymphoblastic leukaemia.
In approximately 2/3 of people with myeloma, what might their urine contain?
Immunoglobulin light chains with kappa or lamda lineage.
Give 3 symptoms of myeloma.
- Tiredness.
- Bone/back pain.
- Infections.
What are 5 key features to remember for multiple myeloma?
OLD → Over 75
C → Elevated Calcium → increased osteoclast activity
R → Renal impaired → due to calcium oxalate stones and bence jones is nephrotoxic
A → Anaemia → BM failure
B → Bone lesions / pain → BM failure is painful
Why is calcium elevated in myeloma?
There is increased bone resorption and decreased formation meaning there is more calcium in the blood.
Why might someone with myeloma have anaemia?
The bone marrow is infiltrated with plasma cells. Consequences of this are anaemia, infections and bleeding.
Why might someone with myeloma have renal failure?
Due to light chain deposition.
How to we test for multiple myeloma (initial + confirmatory)?
Blood film.
Bone marrow aspirate and trephine biopsy.
Electrophoresis.
X-ray.
CT scan.
MRI scan.
Chromosomal abnormalities.
What would you expect to see on the blood film taken from someone with myeloma?
Rouleaux formation (aggregations of RBC’s).
What are you looking for on a bone marrow biopsy taken from someone with myeloma?
Increased plasma cells.
What are you looking for on electrophoresis in a patient with myeloma?
Ig paraprotein ‘M spike’
hypergammaglobulinemia for that specific Ig
What are you looking for on an X-ray taken from someone with myeloma?
Bone lesions.
What is the treatment for MGUS and asymptomatic myeloma?
Watch and wait.
Describe the treatment for symptomatic myeloma.
- Bisphosphonate to protect bones
- Blood transfusions/EPO injections
- Antibiotics as needed
- Pain-killers as required
- Radiotherapy
- Kyphoplasty occasionally indicated
- Psychological support
A complication of myeloma is myeloma bone disease. What can MBD lead to?
Skeletal complications, including skeletal-related events, bone pain, and hypercalcemia
Aims of treatment for multiple myeloma
- Reduce number of myeloma cells
- Reduce symptoms and complications ie protect body organs and tissues
- Improve quality and length of life
Definition of Haematopoietic Stem Cell Transplants (HSCT)
Any procedure where hematopoietic stem cells of any donor and any source are given to a recipient with intention of repopulating/replacing the hematopoietic system in total or in part
Where does HSCT fit in the treatment of blood cancers?
Almost never done as a first step
Is not offered instead of chemotherapy
First, control the cancer with chemotherapy/targeted treatments
Then, perform HSCT
What are the two type of stem cell transplants?
Autologous and allogenic
Autologous stem cell transplant features
- Obtained from the patient
- No rejection
- For myeloma and lymphoma
- No Graft vs Malignancy effect
- Reliance on sheer chemotherapy action against cancer
Allogenic stem cell transplant features
- Stem cells from a suitable donor
- Rejection/Graft vs Host Disease unique side effects
- Takes longer for immune system to recover, opportunistic infections common
- Blood cancers like AML, ALL, MDS that cannot be cured by chemotherapy
Proof of principle: Immunotherapy works against Cancer
Who should be a donor for allogenic stem cell transplant? What is the source of the stem cells?
Donor:
Related
Unrelated (volunteer, cord blood)
Source:
Bone marrow (requires harvest in theatre)
Peripheral blood (collected by leukapheresis after giving G-CSF to mobilise stem cells)
What does it mean when saying that a donor is a ‘match’ ?
Match means at HLA loci
6 main HLA loci –A, B, C, DP, DQ, DR on each set of chromosome –total 12
10/10 = full match 8 or 9/10 = mismatch 5/10 = half match (haplo)
What is HLA? What is it for?
Human Leukocyte Antigen
Function: to present peptides to T cells, thus allowing elimination of foreign particles and recognition of self (so in transplants this has to be modulated)
Pre transplant: what should be evaluated? (List 3)
Past medical history, frailty factors
Cardiac assessment
Pulmonary assessment (PFTs)
Renal and liver function, cardiovascular markers, DM screening, Virology testing
Infectious disease markers –rarely a contraindication to transplant. Active infections should be treated and resolved
Psychosocial evaluation –Compliance and stable long-term caregiver support critical for success of allogeneic HSCT
Disease status assessment i.e bone marrow biopsy, PET-CT etc
Fertility counselling and preservation if relevant
What is given to the patient right before the stem cell infusion?
Conditioning chemotherapy
1. to suppress host immune system
2. exert anti-leukemic action
What are the 4 stages of transplant. What could go wrong?
- Engraftment - graft failure
- Immune reconstitution - infection
- Immune tolerance - GVHD
- GvT (Tumour free survival) - relapse
What is Graft-versus-Host Disease? (GvHD)
Immunocompetent donor lymphocytes recognize normal recipient tissues as foreign and react against them
Severity can be mild to life-threatening
What is the first line treatment for GvHD?
Corticosteroids
What is lymphoma?
A malignant growth of WBC’s predominantly in the lymph nodes.
What are the two sub-types of lymphoma?
- Hodgkins lymphoma.
- Non-hodgkins lymphoma. Two types:
Aggressive - quick onset but can be treated
- Indolent - worse prognosis
Low grade vs high grade vs very high grade non Hodgkin’s lymphoma
- Low grade - Follicular
- High grade - Diffuse large B cells
- Very high grade - Burkitt’s
Although predominantly in the lymph nodes, lymphoma is systemic. What other organs might it effect?
- Blood.
- Liver.
- Spleen.
- Bone marrow.
Give 4 risk factors for lymphoma.
- Primary immunodeficiency.
- Secondary immunodeficiency e.g. HIV.
- Infection e.g. EBV, HTLV-1.
- Autoimmune disorders e.g. RA.
Cells affected in Non-Hodgkin lymphoma
- B cells (90%)
- T cells (10%)
- NK cells (<1%)
Features of Indolent lymphoma
- Slow growing and advanced on presentation
- “Incurable”
- Many different sub types
- High on Ann Arbour scale
- Median survival 9-12 years variable across and within subtypes
Give 4 symptoms of lymphoma.
Enlarged lymph nodes in arm/neck.
Symptoms of compression syndromes.
General systemic ‘B’ symptoms e.g. weight loss, night sweats, malaise.
Liver and spleen enlargement.
Aetiology of indolent lymphoma
- Primary and secondary immunodeficiency
- Infection
- Autoimmune disease
What investigations might you do to diagnose someone with lymphoma?
Lymph node biopsy
- PET-CT/MRI chest/abdo/pelvis for staging
- Performance status score to establish treatment
How to distinguish between Hodgkin and non-Hodgkin lymphoma?
Lymph node biopsy (core needle/excision needle)
- Hodgkin’s shows Reed-Sternberg cells🦉
- Abnormally large B cells with multiple nuclei and nucleoli
- These aren’t present in Non-Hodgkin lymphoma, but you can still use the biopsy to determine NHL subtype, eg: Burkitt’s shows starry sky🌌
What are the symptoms of Hodgkins lymphoma?
- Painless lymphadenopathy.
- Presence of ‘B’ symptoms e.g. night sweats, weight loss.
Treatment for advanced stage, asymptomatic lymphoma?
Watch and Wait / Active Surveillance
- Asymptomatic, advanced stage patients
- Follow up regularly
- No compromise in overall survival
Describe the Ann Arbor staging of Hodgkins lymphoma.
Stage 1: confined to a single lymph node region.
Stage 2: Involvement of two or more nodal areas on the same side of the diaphragm.
Stage 3: involvement of nodes on both sides of the diaphragm.
Stage 4: Spread beyond the lymph nodes e.g. liver.
Each stage is either ‘A’ - absence of ‘B’ symptoms or ‘B’ - presence of ‘B’ symptoms.
Management of hodgkins lymphoma (first line + others)
- Chemotherapy ABVD
- Adriamycin
- Bleomycin
- Vincristine
- Dacarbazine
- +/- radiotherapy
- marrow transplant
What are myelodysplastic syndromes (MDS)
Bone marrow cells fail to make adequate numbers of healthy blood cells - both quantity and function of cell are affected
*Risk of progression to acute myeloid leukemia
What is acute myeloid leukaemia?
Acute myeloid leukaemia is a heterogenous clonal malignancy characterised by immature myeloid cell proliferation and bone marrow failure where abnormal cells crowd out remaining normal cells
Laboratory features of myelodysplastic syndrome - FBC
Low blood counts
red cells (symptoms include fatigue, shortness of breath, lightheadedness)
white cells (symptoms include increased risk of frequent and/or severe infections)
platelets (bleeding/ bruising)
Peripheral blood film demonstrates dysplastic features (e.g. hypogranular neutrophils, platelet anisopoikilocytosis, blasts)
Laboratory features of Acute myeloid leukaemia - FBC
White cell counts can be
Low
Normal
High
symptoms include increased risk of frequent and/or severe infections (because a large proportion of the white cells are abnormal)
Other blood parameters are usually low
red cells (symptoms include fatigue, shortness of breath, lightheadedness)
platelets (symptoms of bleeding/ bruising)
There may or may not be a history of pre-existing malignancy
Myelodysplastic syndrome (MDS)
Myeloproliferative neoplasm (MPN) e.g. myelofibrosis, polycythaemia vera, essential thrombocytosis
So there may be overlapping features of their pre-existing diagnosis evident on the FBC/ blood film
Differential diagnoses of acute myeloid leukaemia
B12/ folate or mixed haematinic deficiency
Infection (e.g. retroviral disease, herpesvirus)
Medications
Autoimmune
Liver disease (e.g. cirrhosis)
Primary investigations for patients with suspected MDS/AML
A good history
Review of previous blood test results
Was the FBC previously normal?
Has the Hb/ WC/ neutrophils/ platelet counts been downward trending for some weeks/ months/ years?
FBC and blood film
Haematinics (B12, folate, ferritin)
What results would indicate the need to contact a haematologist? (in a patient who has carried out primary investigations and is suspected of having MDS/AML)
Speak to a haematologist soonest if
There are blasts on peripheral blood
The deterioration in FBC parameters is very rapid (days/ weeks)
Have a low threshold for all other patients to repeat FBC in 1-2 weeks and tell them to ring if they notice any new symptoms (i.e. symptomatic anaemia, infection, bleeding/ bruising)
Is AML/MDS ever hereditary?
There are very rare, known genetic syndromes that present early in life (childhood/ early adulthood) that can increase the risk of developing AML/MDS e.g. trisomy 21
However the majority of MDS/AML are not hereditary
How would you diagnose MDS and AML?
Blood tests (full blood count & blood film)
Bone marrow aspirate and trephine biopsy
Morphology of patients with myelodysplastic syndrome vs acute myeloid leukaemia
For myelodysplastic syndrome:
Requirement of 10% dysplasia in any cell line(s)
Blast % can be anywhere from 0 – 19%
For acute myeloid leukaemia:
Blast % can be as low as 10% with “defining” genetic abnormalities
Treatment of myelodysplastic syndrome
If high blast % - Chemotherapy
If low blast % - Stimulate bone marrow to increase blood cells production
Supportive treatments:
- Red cell transfusion
- Treat infections with antibiotics
- GCSF injections for neutropenia
- Platelet transfusion for thrombocytopenia
Other available:
- Allogenic stem cells
- Immunosuppressive agents
- Azacytidine
Prognosis in acute myeloid leukaemia (parameters that dictate survival)
- Age of patient at diagnosis
- Genetics at baseline
- Response to treatment
1. has patient achieved remission
2. How deep a remission
Treatment of acute myeloid leukaemia
Chemotherapy
* 6 weeks duration
* Usually administered IV: Anthracycline (Daunorubicin/Idarubicin)
Cytarabine
* Hickman/ PICC line/ portacath insertion
Supportive measures
- fertility cryopreservation
- transfusion
- antibiotics
Clinical trial availability
Bystander damage to other organs can occur
When would you use less intensive (non curative) treatment options in managing acute myeloid leukaemia? What do these include
Usually reserved for older/ less fit individuals
Treatments include
* Azacytidine
* Low dose subcutaneous cytarabine
* Trial drugs e.g. targeted therapy FLT3i, IDH2i
Supportive measures (red cell transfusion, platelet transfusion, antibiotics for infection, contact numbers for haematology department if unwell)
What leads to decreased production of red blood cells?
- Iron deficiency
- Folate deficiency
- B12 deficiency
- Bone marrow failure
What leads to increased loss of red blood cells?
- Bleeding
- Haemolysis
What is the sex adjusted normal haemoglobin levels?
Female normal: 110 - 147 g/l
Male normal: 131 - 166 g/l
When someone has anaemia what investigations should you do?
- Take bleeding history
- Find out MCV (mean cell volume)
MCV for different types of anaemia. What conditions are they associated to?
<80 = microcytic
* iron deficiency
* Thalassaemia
80-95 = normocytic
* Chronic disease
* Renal disease
* Acute bleeding
* Mixed picture
> 95 = macrocytic
* Folate deficiency
* B12 deficiency
- Haemolysis
- Bone marrow disorders
- Reticulocytosis
- Raised Igs
- Hypothyroidism
- Alcohol
Normal B12 levels
197 - 771 ng/l
Normal folate levels
> 3.9 ug/l
What are oval macrocytes indicative of?
B12 or folate deficiency
How much iron intake does a normal person have? How much is absorbed?
15 mg/day in normal diet. Approx 1 mg/day absorbed
Where is iron absorbed?
Absorbed in duodenum and upper jejunum
Causes of iron deficiency?
Assume blood loss until proved otherwise
(?gastrointestinal, menstrual)
Pregnancy (500mg-1000mg transferred to foetus, body stores 4g)
impaired absorption, coeliac, gastrectomy. Dietary deficiency very unusual in adults, common in children
Treatment of iron deficiency anemia?
Ferrous sulphate 200 mg one to three times daily
Hb should rise approx 20 g every 3-4 weeks.
After Hb and MCV return to normal, continue supplementation for a further 3 months to replenish stores
Laboratory parameters in iron metabolism
- Ferritin – measure of iron stores.
* Male 30-400ug/L.
* Female age >60 30-400ug/L.
* Female age 17-60 15 – 150ug/L. (also increased in inflammation, tissue destruction, liver disease, malignancy, iron replacement). - Serum Iron
* Female 6.6 – 26 umole/l
* Male 11 – 28 umole/litre. (notable day to day and circadian variation) - Transferrin saturation
* Female 15 – 45%,
* Male 15 – 50%. (TIBC = total iron binding capacity, measures all of the proteins in the serum that bind iron; transferrin is principle amongst these.)
Transferrin synthesis is increased in iron deficiency,so as a proportion less of it is occupied by iron).
How much folate intake is required each day?
0.1 - 0.2 mg/day required
NOTE minimal body stores; last 3-4 months
Where is folate absorbed in the body?
Proximal jejunum
Causes of folate deficiency
Poor nutrition: found in green vegetables, nuts, yeast; destroyed by cooking
Malabsorption including coeliac, Crohns, pregnancy, haemolysis
Where is B12 found? (Diet)
Exclusively found in animal-derived products; meat, fish, dairy, eggs
How long can B12 be stored in their body?
Body stores last 3 years
Where is B12 absorbed in the body?
Absorbed in the terminal ileum; must bind to intrinsic factor, produced by gastric parietal cells
What is B12 needed for?
DNA synthesis and fatty acid synthesis; rapid sphingolipid turnover in myelin sheath means deficiency can cause neurological symptoms (paraesthesia, ataxia from subacute combined degeneration of the cord)
Causes for B12 deficiency?
Pernicious anaemia (autoimmune gastric atrophy; loss of intrinsic factor production), gastrectomy/ ileal resection, vegan diet, bacterial overgrowth, oral contraceptives, hypochloridia, nitric oxide
If someone has folate deficiency, what is important to consider before starting them on folate supplements?
Check their B12 first, if B12 deficient ensure B12 started before folate.
What is haemolysis
Reduction in red cell lifespan due to increased red blood cell destruction.
What investigations should you do to check for haemolysis
- blood film (spherocytes, polychromasia, red cell fragments?)
- reticulocyte count
- bilirubin, including unconjugated bilirubin
- lactate dehydrogenase
haptoglobin - direct antiglobulin test.
List 3 causes of haemolysis
- red cell membrane disorders (hereditary spherocytosis)
- abnormal haemoglobins (sickle cell)
- microangiopathic haemolytic anaemias
- prosthetic heart valves
- autoimmune haemolytic anaemias
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.
Disease Pathology of sickle cell anaemia?
An autosomal recessive disorder causing production of abnormal β globin chains
This results in production of HbS instead of HbA
HbS polymerizes when deoxygenated, causing RBCs to sickle
This is initially reversible, but with repeated sickling, the cells lose all flexibility and become irreversibly sickled
Tests for sickle cell anaemia
Sickle solubility test
Hb separation:
HPLC
Capillary electrophoresis
Gel electrophoresis
Isoelectric focusing
Antenatal: molecular genetics
Types of sickle cell crises
- Vaso-occlusive (aka painful crisis)
- Splenic sequestration
- Acute chest syndrome
- Aplastic crisis (from parvovirus)
- Osteomyelitis
What is the advantage of being a carrier of sickle cell disease?
Carriage offers protection against falciparum malaria.
Describe the inheritance pattern of sickle cell disease.
Autosomal recessive. Sickle cell disease is homozygous SS.
What is acute chest syndrome (sickle cell crisis)
- Caused by pulmonary vessel vaso-occlusion
- Fever or resp symptoms with new infiltrates seen on Xr
- Can be due to infection or non-infective causes
- Medical emergency with high mortality
Treatment for acute chest syndrome
Exchange blood transfusion - sickle cell blood replaced w healthy blood
How to prevent sickle cell disease complications
- Supportive
- stay warm and hydrated
- vaccinations and antibiotics
- monitoring including transcranial dopplers - Regular blood transfusion – exchange / top up
- Hydroxycarbamide - ↑ HbF
- New drugs: crizanlizumab, voxelotor
- Transplant only curative therapy currently available
- Genetic therapies – in clinical trials
What is thalassaemia?
- Autosomal recessive haemoglobinopathy
- A type of haemolytic anaemia
- Defective alpha-globin chain = alpha thalassaemia
- Defective beta-globin chain = beta thalassaemia
Pathophysiology of thalassaemia
- RBCs are more fragile and break down more easily
- Spleen collect all the destroyed RBCs, resulting in splenomegaly
- Bone marrow expands to produce extra RBCs -> susceptibility to fractures, pronounced forehead and molar eminence
Where is thalassaemia prevalent?
Where malaria is as it is protective from it (like sickle cell)
Alpha thalassaemia
- Less common
- 4 gene deletions on chromosome 16
- Associated with HbH
- Can cause death in utero if severe
Beta thalassaemia
- More common
- 2 gene mutations in chromosome 2
- Normal Hb isoforms, just depletion of beta chains
What is the clinical classification of beta thalassaemia?
- Thalassaemia major.
- Thalassaemia intermedia.
- Thalassaemia carrier/heterozygote.
Which clinical classification of thalassaemia relies on regular transfusions?
Thalassaemia major.
Which clinical classification of thalassaemia is often asymptomatic?
Thalassaemia carrier/heterozygote.
When do people with beta thalassaemia major usually present and why?
These patients usually present very young due to having severe anaemia and so a failure to feed/thrive.
Why is it important to monitor iron levels in someone with beta thalassaemia major?
There is a risk of iron overload from the regular transfusions. Excess iron will be deposited in various organs e.g. the liver and spleen and cause fibrosis.
Disease Pathology of Polycythaemia
Polycythaemia is defined as an increase in Hb or packed cell volume (PCV) / haematocrit. This is the percentage of red cells in blood
- Primary polycythaemia = increase in red cells
- Secondary polycythaemia = PCV normal, but plasma volume low due to hypertension, obesity or smoking
Due to JAK2V617 Mutation. Primary polycythaemia (rubra) is due to a malignant proliferation of a cloned pluripotent marrow stem cell → RBC grow uncontrollably.
Management of polycythaemia
Aim to keep Haematocrit down (<0.45) to reduce risk of thrombosis
*Aspirin 75 mg daily
* Venesection on 2 occasions
* Hydroxycarbamide 500 mg daily
*Annual cardiovascular risk assessment *
Investigations of Polycythaemia
FBC – Increased WCC, Platelets and RBCs
Increased Hb
Genetic test for JAK2V617 Mutation
Differentiate primary from secondary polycythaemia
Splenomegaly distinguishes polycythaemia vera from secondary polycythaemia
Diagnostic pathway for thrombocytosis
- Check for abnormal platelet count
- If high - review blood film, acute phase reactants and iron status
Acute phase response = reactive thrombocytosis
Iron deficiency = treat and repeat blood count
- If normal, repeat blood count. Persistent unexplained thrombocytosis = further investigations (molecular genetics, bone marrow examination, cytogenetics)
- Further diagnoses
Diagnosis of thrombocytosis
- Ferritin 221, Serum iron 15, % iron saturation 23%
- Blood film: Platelet anisocytosis (Platelets with size variation)
- BCR::ABL1 no rearrangement on FISH
- JAK2V617F mutated
Treatment of thrombocythemia
Aspirin 75mg daily
Hydroxycarbamide 500mg daily
Aim to keep platelet 150-400
Treat cardiovascular risk factors
What is myelofibrosis?
Rare blood cancer that causes scarring of the tissue in the bone marrow
Criteria for primary myelofibrosis
Diagnosis requires all three major criteria and one minor criterion:
- Typical megakaryocyte changes accompanied by reticulin/collagen fibrosis
- Presence of JAK2, CALR, or MPL mutations
- Not meeting WHO criteria for other myeloid neoplasms
Minor Criteria:
- unexplained anaemia
- Leukocytosis
- Palpable splenomegaly
- Increased serum lactate dehydrogenase
Treatment of myelofibrosis
Ruxolitinib (JAK2 inhibitor)
Erythropoietin injections
Analgesia for splenic discomfort
Blood transfusion support if require
