Haematology Flashcards
Multiple Myeloma
abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to secretion of Ig (paraprotein), causing the dysfunction of many organs (esp kidney).
Features of multiple myeloma
*Accumulation of malignant plasma cells in the bone marrow leading to progressive bone marrow failure (Anaemia, neutropenia or thrombocytopenia)
*Production of a characteristic paraprotein
*Kidney failure
*Destructive bone disease + hypercalcaemia
Multiple myeloma- Spikey Old CRAB
C- Ca level (high)
R- renal impairment
A- anaemia
B- B-lytic lesions
Myeloma- symptoms
Bone pain, recurrent infections, symptoms of anaemia/ renal failure /hypercalcemia
Myeloma- paraprotein
Mono clonal product of abnormal, proliferating plasma cells, mainly IgG (55%) or IgA (20%), rarely IgM or IgD
Myeloma- investigations
FBC (anaemic), Serum electrophoresis, tests for clinical presentations (serum Ca, U+E- renal impairment, skeletal survey- to find lytic lesions)
Serum electrophoresis (SEP)
Separation of proteins in blood by electrical charge, bands form with many identically charged molecules
Multiple myeloma- SEP investigation
presence of M spike (suggests paraproteins) can be a sign of a multiple myeloma
Monoclonal gammopathy of undetermined significance (MGUS)
non cancerous cause of paraprotein production, no ROTI (related organ or tissue impairment), no treatment
Smouldering vs Symptomatic myeloma
Smouldering- >diagnostic criteria for myeloma, but no ROTI
Symptomatic= >diagnostic criteria + ROTI/ amyloid
ONLY TREAT SYMPTOMATIC
Diagnostic criteria for myeloma
> 10% or more clonal plasma cells on bone marrow
30g/L of paraprotein
Myeloma- prognosis
With good supportive care and chemotherapy, median survival= 5 years, some surviving up to 10, young patients receiving more intensive treatment may live longer
AL (primary) amyloidosis
Proliferation of plasma cell clone. Production of abnormal forms of Ig called “light chains” and are deposited in various tissues, causing organ dysfunction and eventually death
AL amyloidosis vs multiple myeloma
Both disease in which identical clones of antibody-producing cells grow rapidly.
MM- growth of abnormal cells in the bone marrow
AL (primary) amyloidosis- build up of light chains produced by the abnormal cells
Myeloma Bone Disease (MBD)
> 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits
Multiple myeloma treatment- Bisphosphonates
inhibit osteoclast action, help ensure normokalaemia and can help reduce skeletal events in long term
Aims of myeloma treatment
Incurable
Reduce no myeloma cells
Reduce symptoms and complications
Improve quality and length of life
Haematopoietic Stem Cell Transplants (HSCT)
procedure where hematopoietic stem cells of any donor and any source are given to a recipient with intention of repopulating/ replacing the hematopoietic system
HSCT as treatment of blood cancers
Almost never first step, never offered instead of chemotherapy, control cancer 1st (using chemo/ targeted treatment), then perform HSCT
Stem cell transplant- Autologous
Obtained from the patient, frozen prior to chemo
no risk of rejection For Myeloma and Lymphoma
No Graft versus Malignancy Effect
HSCT- Graft versus Malignancy Effect
appears after HSCT. The graft contains donor T cells that can eliminate residual malignant cells
Stem cell transplant- Allogeneic
Stem cells from a suitable donor
Rejection/Graft vs Host Disease unique side effects
Takes longer for immune system to recover- infections common
Blood cancers like AML, ALL, MDS that cannot be cured by chemotherapy
Immunotherapy works against Cancer
Donors of stem cells
Related (siblings have 25% of being a match)
Unrelated (volunteer, cord blood)
Obtaining stem cells
Bone marrow- requires harvest in theatre
Peripheral blood- collected by leukapheresis after giving G-CSF to mobilise stem cells
Stem cell donation- match
Matching of genes at HLA locci,
all genes match= full match
most genes match = mismatch
half genes = half match (haplo)
Human Leukocyte Antigen (HLA)
present peptides to T cells, thus allowing elimination of foreign particles and recognition of self
HLA role in stem cell transplant
immune system is ‘trained’ to recognise self, based HLA molecules displayed on the cell surface. HLA typing- is critical for identifying suitable donor
Complications of HSCT
GvHD (Graft-versus-host disease)- alloimmune reaction of the donor cells against host cells- potentially fatal
Graft-versus-host disease (GvHD) prevention
Immunosuppression- from conditioning therapy (chemo typically) and immunosuppressive drugs, however risk of opportunistic infections and viral reactivation so prophylactics given
Importance of Psychosocial evaluation for pre stem cell transplant evaluation
Compliance and stable long-term caregiver support critical for success of allogeneic HSCT
Important to understand patient can be at higher risk of condtions further down the line
Conditioning chemotherapy
Combinations of chemotherapy, radiotherapy and/or immunotherapy, using different regimens
Lymphoproliferative disorders
Neoplastic, clonal proliferation of lymphoid cells
“A cancer of white blood cells”
Typically affects Lymph Nodes
Can be Extranodal – Bone Marrow / Liver / Spleen / Anywhere
Includes lymphomam, myeloma and leukaemia
Epidemiology of lymphoid malignancies
5th most common malignancy globally
Lymphoma
disorders caused by malignant proliferations of lymphocytes
The accumulate in the lymph nodes, peripheral blood and infiltrate organs
Classification of lymphoma
Lymphoma> Hodgkin’s lymphoma/ Non-Hodgkin’s lymphoma (NHL)
Hodgkin’s lymphoma vs Non-Hodgkin’s lymphoma
Hodgkin’s lymphoma- characteristic cells with mirror image nuclei are found, called Reed-Sternberg Cells
Classification of Non-Hodgkin’s lymphoma
NHL> aggressive/ indolent
Cells affected by NHL
B cell- 90%
T cell- 10%
NK cell< 1%
Why is B cell the most common cell affected by NHL
B cells go through 2 processes when maturing, somatic hypermutation and class switching
Somatic hypermutation is more likely to go wrong and produce a cancerous cell
Stages of NHL
Stage I- Lymphoma in one lymph node area or one group of lymph nodes
Stage II- Lymphoma in two or more lymph node areas, either above or below the diaphragm.
Stage III- Lymphoma found in the lymph nodes or the spleen above and below the diaphragm.
Stage IV- Lymphoma spread to the bone marrow, the bones, or to more than one organ
Indolent lymphoma (low grade)
Slow growing and advanced at presentation
Usually Incurable
Indolent
causing little or no pain
Richter transformation
CLL (type of indolent lymphoma) to more aggressive lymphoma
Indolent lymphoma- aetiology
Typically causes is unknown
RFs- Primary/secondary immunodeficiency, infection, autoimmune disorders
Indolent lymphoma- clinical signs
Majority present with painless lymphadenopathy
B symptoms- Fevers, Night Sweats and Weight Loss
Bone marrow involvement- leukemic component
Autoimmune Phenomena
Compression Syndromes
Indolent lymphoma- investigation
Lymph Node Biopsy – Core Needle Biopsy / Excision Node Biopsy
Can do bone marrow biopsy
Indolent lymphoma- staging
Lugano Staging Classification typical for most Indolent lymphomas
Requires Imaging – CT Neck/ Thorax/ Abdomen/ Pelvis or PET-CT
Bloods
Indolent lymphoma- treatment pathway
Watch and Wait / Active Surveillance- asymptomatic
Radiotherapy- local control
Chemoimmunotherapy +/- maintenance- depends on stage and type of lymphoma
Small molecules inhibitors / Novel therapies- more targeted
Immerging treatments for indolent lymphoma
Bi-Specific T-Cell engaging Antibodies
Chimeric Antigen Receptor T Cells
Bi-Specific T-Cell engaging Antibodies (BITE)
bispecific molecules are created by linking the targeting regions of two antibodies. T cell then destroyed cancerous cells
Chimeric Antigen Receptor T Cells (CAR-T/NK)
T cells are cells that are genetically engineered in the lab. They have a new receptor so they can bind to cancer cells and kill them
Treatment of lymphoid malignancies
Immunochemotherapy, radiotherapy, allograft, check point inhibitors, BITE, CAR-T/NK
Check point inhibitors
type of immunotherapy. They block proteins that stop the immune system from attacking the cancer cells
Myelodysplastic syndromes (MDS)
Group of acquired bone marrow disorders that are due to a defect in stem cells, manifest as marrow failure with risk of life threating infection/ bleeding
Myelodysplastic syndromes (MDS)- characteristics
Increasing bone marrow failure with quantitative and qualitative abnormalities in at least one of the 3 myeliod cell lines
3 myeloid cell lines
RBC, granulocytes/ monocytes, platelet
Medinan age of Myelodysplastic syndromes (MDS)
76 years old
Myelodysplastic syndromes (MDS)- clinical features
Low blood counts- RBC (fatigue, SOB, light-headedness), WBC (increased risk of severe +/ frequent infection), platelets (bleeding/ bruising)
Peripheral blood film demonstrates dysplastic features (e.g hypogranular neutrophils, platelet, blasts)
Acute myeloid leukaemia (AML)
Neoplastic proliferation of blast cells derived from marrow myeloid elements
Blast cells
immature cells known as precursor or stem cells
Acute myeloid leukaemia (AML)- incidence
Commonest acute leukaemia, risk incidence with age
Mean age of onset- 68 years old
Acute myeloid leukaemia (AML)- clinical features
Marrow failure- WBC- can be low, normal or high (WBC being abnormal causes symptoms)
-Low RBC (fatigue, SOB, light-headedness) and platelets (bruising/ bleeding)
Infiltration: Hepatomegaly, splenomegaly, gum hypertrophy, skin involvement.
Blast cells present on blood film
Myelodysplastic syndromes (MDS)/ Acute myeloid leukaemia (AML) differential diagnosis
B12/ folate or mix haematic deficiency, infection, medications, autoimmune, liver disease
Myelodysplastic syndromes (MDS)/ Acute myeloid leukaemia (AML) investigations
Review of previous blood test results
FBC (Low RBC/platelet, WBC can be high, normal or low)
Blood film- presence of blast cells
Bone marrow aspirate and trephine biopsy
Haematinic (B12, folate, ferritin)- for differential
What to do if there are blasts on peripheral blood?
Refer to haematologist
What to do if patient has low thresholds after FBC
Repeat FBC in 1-2 weeks, tell to ring if they notice any new symptoms (symptomatic anaemia, infection, bleeding/ bruising)
Morphology
appearance of cells on slides
Myelodysplastic syndromes (MDS) morphology
Requirement of 10% dysplasia in any cell line
0< blast% <19
Acute myeloid leukaemia (AML) morphology
20%< blasts
Myelodysplastic syndromes (MDS) prognosis
Low risk- 5,5 years
High risk- 2.2 years
No MDS same as the next, disease behaviour and affects can change over time
Myelodysplastic syndromes (MDS) treatment goals
Prolong survival, maintain good QoL (improve symptoms of low BC, delay/ supress progression to AML), minimise toxicity if treatment
Myelodysplastic syndromes (MDS) treatment
Depends on the individual, supportive treatments for low BC, immunosuppressive agents, allogenic MSCT
Myelodysplastic syndromes (MDS)- Supportive treatments to improve symptoms of low blood count
Anaemia- RBC transfusions, reduce/ treat associated bleeding, erythropoietin
Neutropenia- antibiotics, G-CSF injections (granulocyte-colony stimulating factor- increases WBC production)
Thrombocytopenia- platelet transfusions, tranexamic acid
Treatment of Acute myeloid leukaemia (AML)- intensive
Chemotherapy + supportive measures- fertility cryopreservation transfusion of RBC, platelets, treatment for infection
Allogeneic bone marrow transplants to repopulate marow
Treatment of AML- less intensive
Non curative- for older/ less fit patients
Aim to improve bone marrow function and QoL
Azacytidine, low dose subcutaneous cytarabine, trail drugs + supportive measures- transfusion of RBC, platelets, treatment for infection
Anaemia
Decrease in haemoglobin in the blood below the reference level for age and sex
Anaemia symptoms
can be asymptomatic
Symptoms are non specific- breathlessness, fatigue, headaches, palpitations and faintness
Can exacerbate CV problems
Anaemia- clinical signs
Pallor, tachycardia, systolic flow murmur, cardiac failure
Specific for diff types of anaemia- koilonychia (iron deficiency), jaundice (haemolytic anaemia), bone deformities (thalassaemia major), leg ulcers (sickle cell disease)
Koilonychia
Spoon-shaped dented nails seen in longstanding iron deficiency anaemia
3 types of Anaemia
Low MCV- microcytic anaemia
Normal MCV- normocytic anaemia
High MCV- macrocytic anaemia
Is anaemia a final diagnosis?
No, a cause should always be sought
Anaemia- decreased RBCs production
Iron/ folate/ B12 deficiency
Bone marrow failure
Anaemia - increased loss of RBCs
Bleeding
Haemolysis
Anaemia- FBC
Relevant parameters: low haemoglobin (are WBC and platelet also low), MCV (mean cell (corpuscular) volume), MCH (mean cell haemoglobin)
Specific request- reticulocyte count- no young RBCs
Sex adjusted haemoglobin
Female normal= 110-147g/l
Male normal= 131-166g/l
MCV (mean cell (corpuscular) volume)
Cell size, normal range (normocytic)= 80-98 fl
Macrocytic- cell larger than normal > 98 fl
Microcytic- cell smaller than normal < 80 fl
MCH (mean cell haemoglobin)
Amount of haemoglobin, normal range (normochromic)= 27-33pg
Hypochromic- less haemoglobin than normal < 27pg
Hyperchromic- more haemoglobin than normal > 33pg
Would a haemoglobin level of 120 g/l be considered normal?
Yes for females, within normal range range of 110-147g/l
No for males, below normal range of 131-166g/l- anaemic
Classification of anaemia by cell size- microcytic
TAILS- Thalassaemia (genetic low Hb),
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic anaemia
Thalassaemia
suspect if the MCV is ‘too low’ for the Hb level and the red cell count is raised, though definitive diagnosis needs DNA analysis
Classification of anaemia by cell size- normocytic
High reticulocytes with increased unconj bili + reduced haptoglobin= haemolysis
High reticulocytes= blood loss
Low reticulocytes- CKD, haem malg, mixed pict, endocrine
Classification of anaemia by cell size- normocytic + High reticulocytes with increased unconj bili + reduced haptoglobin
haemolysis
Classification of anaemia by cell size- normocytic + High reticulocytes without increased unconj bili + reduced haptoglobin
Blood loss
Classification of anaemia by cell size- normocytic + low reticulocytes
CKD, haem malg, mixed pict, endocrine
Classification of anaemia by cell size- macrocytic
Megaloblasts present- Folate/ B12 deficiency
No megaloblasts- liver disease, alcohol, hypothyroidism, myelodysplasia
Other- Reticulocytotisis, cytotoxics, antifolate drugs, marrow infiltration
Classification of anaemia by cell size- macrocytic with megaloblast present
b12/ folate deficiency
Classification of anaemia by cell size- macrocytic without megaloblast present
liver disease, alcohol, hypothyroidism, myelodysplasia
Normal iron metabolism
Normal diet- 15mg/day (~1mg absorbed/day)
Needed haemoglobin metabolism
Absorbed in duodenum/ upper jejunum
Iron deficiency anaemia- causes
Assume blood loss- (gastrointestinal, menstrual)
Pregnancy (500- 1000mg transferred daily, body stores 4g)
Impaired absorption- coeliac, gastrectomy
Dietary deficiency abnormal- risk in vegans, elderly
Iron deficiency anaemia- investigations
FBC- microcytic, hypochromic RBC
Fe studies:
Serum ferritin- Low ferritin diagnostic, normal/high ferritin difficult to interpret as acute phase protein
Low transferrin saturation, high total iron binding capacity
Iron deficiency anaemia- management
Investigate/ treat source of blood loss (treat cause)
Replace iron; oral iron preferred (e.g. ferrous sulphate)- IV no faster than oral
Hb should rise ~2g every 3-4 weeks. .
When Hb + MCV are normal- continue supplementation for a further 3 months to replenish stores.
Fe studies
Ferritin, serum iron, Transferrin, Transferrin saturation, TIBC (total iron binding capacity)
Fe studies- ferritin
Measure of iron stores. Male 30-400ug/L. Female age >60 30-400ug/L. Female age 17-60 15 – 150ug/L
Causes of increased ferritin
Inflammation, tissue destruction, liver disease, malignancy, iron replacement
Fe studies- Serum Iron
Female- 6.6 – 26 umole/l
Male 11 – 28 umole/litre
Variation day to day and circadian
Not helpful for clinical iron status
Fe studies- Transferrin saturation
Normal levels - 15-50%
Transferrin synthesis is increased in iron deficiency so as a proportion less of it is occupied by iron
Laboratory parameters in iron metabolism- TIBC
Total iron binding capacity- proteins in the serum that bind iron; transferrin is principle amongst these.
Plummer-Vinson syndrome
consists of a triad of dysphagia, iron deficiency anaemia, and oesophageal webs
Symptoms usually resolve by correction of anaemia
Anaemia of chronic disease
Commonest anaemia in hospital patients
Many causes ie chronic infection, vasculitis, rheumatoid, malignancy, renal failure
Anaemia of chronic disease- Fe studies
Ferritin- normal/ raised
Serum Fe- low
Transferrin- low
Transferrin sat- normal/ low
TIBC- Low
Thalassaemia- Fe studies
Ferritin- normal/ raised
Serum Fe- normal/ raised
Transferrin- normal/ low
Transferrin sat- normal/ raised
TIBC- normal/ Low
Thalassaemia
=lack of haemoglobin production
Inherited, caused mutations in alpha/ beat units, causes microcytosis, can lead to organ failure
Transfusion-Dependent β Thalassaemia
Transplant only curative option
Regular blood transfusions for survival
Iron overload – heart, liver and endocrine organs
Iron chelation
Deaths due to sepsis or cardiac iron overload
Thalassaemia- management and treatment
Hb electrophoresis- Hb A2, Hb H
Blood film
Treat with blood transfusions, venesection (procedure to reduce no RBS), splenectomy
Folate- normal metabolism
0.1-0.2mg/day required
NOTE minimal body stores; last 3-4 months
Needed for DNA replication
Absorbed in proximal jejunum
Normal levels > 3.9ug/L
Causes of folate deficiency (< 3.9 ug/L)
Poor nutrition- found in green vegetables, nuts, yeast; destroyed by cooking
malabsorption- coeliac, crohns, pregnancy, haemolysis.
Treatment of folate deficiency
Replace orally
Do not replace folate without checking B12
Why check and replace B12 before replacing folate?
folic acid treatment can sometimes improve your symptoms so much that it masks an underlying vitamin B12 deficiency
Untreated B12 deficiency can cause irreversible neurological damage
B12 normal metabolism
Normal levels 197- 771 ng/L
Exclusively found in animal-derived products; meat, fish, eggs, dairy.
Body stores last 3 years.
Absorbed in terminal ileum; requires intrinsic factor produced by gastric parietal
Required for DNA synthesis + fatty acid synthesis
B12 deficiency causes
Pernicious anaemia (autoimmune gastric atrophy; loss of intrinsic factor production)
Gastrectomy/ ileal resection
Vegan diet
bacterial overgrowth
oral contraceptives
nitric oxide- inactivates B12
Pernicious anaemia
Lack of intrinsic factor production due to autoimmune gastric atrophy, leads dietary B12 remain unbound and cannot be absorbed in to the terminal ileum
Lack of vitamin B12 or folate causes the body to produce abnormally large red blood cells that cannot function properly> anaemia
B12 deficiency clinical signs
Symptoms of anaemia, pallor and mild jaundice, red sore tongue and angular stomatitis
Neurological signs- Paraesthesia in extremities, early loss of vibrations sense + proprioception, progressive weakness and ataxia
B12 deficiency- management and investigation
Test for intrinsic factor antibodies.
IM replacement (initially frequent, then maintenance. Consider oral replacement if strongly suspect dietary deficiency).
In combined B12 and folate deficiency ensure B12 started before folate.
Important complication of untreated B12 deficiency
Can cause irreversible neurological changes
Classical neurological feature- Polyneuropathy progressively involving the peripheral nerves, posterior and then lateral columns of the spinal cord
Haemolysis
Premature breakdown of RBC before their normal lifespan of 120 days
Compensated vs decompensated haemolysis
Compensated haemolysis – increased destruction matched by increased synthesis
Decompensated haemolysis – rate of destruction exceeds rate of synthesis, causing anaemia
Haemolysis investigation
blood film (?spherocytes- abnormal, spherical RBC, polychromasia- high no immature RBC in blood, red cell fragments?)
reticulocyte count
bilirubin, including unconjugated bilirubin,
lactate dehydrogenase
haptoglobin
direct Coombs (antiglobulin) test
Haemolysis- causes
red cell membrane disorders (hereditary spherocytosis), abnormal haemoglobins (sickle cell), microangiopathic haemolytic anaemias, prosthetic heart valves, autoimmune haemolytic anaemias
Direct Coombs test
Identifies RBC coated with antibody or complement, the presence of which indicates an immune cause of anaemia
Indirect Coombs test
Used for prenatal testing and before blood transfusions
It detects antibodies against RBCs that are free in serum
Serum is incubated with RBCs of known antigenicity, if agglutination occurs, the test is positive
Indirect Coombs test- positive
suggests Erythroblastosis fetalis (blood types of a mother and baby are incompatible), Incompatible blood match (when used for blood transfusion)
Sickle cell disease
Abnormal Hb, caused by single point mutation in the beta globin gene causing HbS
Autosomal recessive
Shape change to sickle appearance when deoxygenated, initially reversible but after repeated sickling becomes irreversible
Sickle cell disease- causes of complications
Blocks blood vessels – ischaemia, sequestration
Chronic haemolysis – low baseline Hb
Sickle cell disease- complications
Vaso-occlusive crises, acute chest syndrome, pulmonary hypertension, anaemia, sequestration blood pools in liver and spleen, cardiac/ renal/ liver failure + many long term problems (ie growth and development, bones, infections ect)
Sickle cell disease- diagnosis
Sickle solubility test
Hb electrophoresis
Antenatal: molecular genetics
Sickle cell disease- prognosis
Life Expectancy: Good Care Goes a Long Way, but Early Mortality Still Persists
Sickle cell syndrome- Acute chest syndrome
Lung damage, hypoxia, HbS polymerisation, reduced BF, lung damages
Exchange blood transfusion
Preventing Sickle Cell Disease Complications
Supportive- warm, hydrated, vaccinations, antibiotics + monitoring
Regular blood transfusion – exchange / top up
Hydroxycarbamide - ↑ HbF (foetal Hb)
Transplant only curative therapy- genetic therapies trials currently ongoing
Myeloproliferative neoplasms
Clonal stem cells disorders characterized by uncontrolled proliferation of 1 or more cell line in the bone marrow. Usually erythroid, myeloid +/ megakaryocyte lines
Myeloproliferative neoplasms- line affected
Usually erythroid, myeloid +/ megakaryocyte lines
Myeloproliferative disorders
Polycythaemia Vera (PV)
Essential thrombocythemia (ET)
Myelofibrosis- all 3 have JAK-2 molecular lesion
Chronic myeloid leukaemia- genetic BCR-ABL lesion
Polycythaemia
increase in haemoglobin, PVC + RBC count
Polycythaemia- primary vs secondary
primary – abnormality of the cells in the bone marrow that form red blood cells commonest type- polycythaemia vera
secondary – disorder originating outside of the bone marrow that causes overstimulation of the normal bone marrow, leading to an overproduction of red blood cells, ie high altitude, chronic lung disease, heavy smoking
Polycythaemia vera (PV)
Malignant proliferation of a clone derived from on pluripotent stem cell. Most commonly due to mutation on the JAK2 gene
JAK2
transduces signals triggered by haemopoietic growth factors
Polycythaemia vera (PV) clinical features
Onset is insidious
Typically 60+, presents with tiredness, itching (after hot bath or when patient warm), vertigo, headache and visual disturbances.
May present with complications as result of thrombosis or haemorrhage
Polycythaemia vera (PV)- diagnostic criteria
Major- Haemoglobin high +/ increased RBC mass +/ increased number of RBC (haematocrit >49% in men, >48% in women)
-Bone marrow tri-linage proliferation with megakaryocytes
-presence of JAK2 mutation
Polycythaemia vera (PV)- main complications
Thrombosis and haemorrhage
Polycythaemia vera (PV)- treatment
Aimed to maintain normal blood count and reduce risk of complications
Daily low dose aspirin
Venesection
Hydroxycarbamide
Chemo- for high risk patient with venesection not working
Essential thrombocythemia (ET)
Clonal proliferation of megakaryocytes that leads to an increase in number of circulating platelets with abnormal function
Essential thrombocythemia (ET) symptoms
Bleeding or arterial + venous thrombosis
Microvascular thrombosis- headache, atypical chest pain, light-headedness,
Erythromelalgia
rare clinical syndrome characterized by a triad of redness, warmth, and burning pain, most notably affecting the extremities
Essential thrombocythemia (ET) treatment
Daily low dose aspirin
Hydroxycarbamide in high risk paitents
Myelofibrosis
Hyperplasia of megakaryocytes with produce platelet-derived growth factor, leads to intensive marrow fibrosis and haematopoiesis in liver and spleen (massive hepatosplenomegaly)
Myelofibrosis presentation
Hypermetabolic symptoms- night sweats, fever, weight loss
Abdominal discomfort due to hepatosplenomegaly
Bone marrow failure- low Hb, infections, bleeding
Myelofibrosis investigation and treatment
Film- Nucleated RBC, characteristic tear drop RBC
Bone marrow biopsy is diagnosis
Marrow supportive treatment
Allogeneic stem cell transplant may be curative in young people- high risk
Chronic myeloid leukaemia (CML)
Uncontrolled proliferation of myeloid cells,
15% of leukaemias- occurs most often between 40-60, male predominance, rare in childhood
Philadelphia chromosome
Present in >80% of CML, hybrid chromosomes when long arms 9 and 22 break off and trade places
Prognosis better when patient has CML with Philadelphia chromosome
Chronic myeloid leukaemia (CML)- signs and symptoms
Weight loss, tiredness, fever, sweats, may be asymptomatic
May be features of gout (purine breakdown), bleeding (platelet dysfunction) and abdominal discomfort (splenomegaly, >75%)
Other signs- Hepatomegaly, anaemia, bruising
Chronic myeloid leukaemia (CML)- investigation
Very high WBC
Low/normal Hb, platelets variable, High urate, B12
Cytogenetic analysis of bone marrow for Philadelphia chromosome
Chronic myeloid leukaemia (CML)- treatment
Imatinib- CML 1st cancer when knowledge of genotype has lead to a specifically targeted drugs
Allogeneic stem cell transplant may be curative- high risk
Classification of myeloproliferative disorders by proliferating cell type- RBC
Polycythaemia vera (PV)
Classification of myeloproliferative disorders by proliferating cell type- WBC
Chronic myeloid leukaemia (CML)
Classification of myeloproliferative disorders by proliferating cell type- Platelet
Essential thrombocythemia (ET)
Classification of myeloproliferative disorders by proliferating cell type- Fibroblasts
Myelofibrosis
Acute lymphoid leukaemia (ALL)
Malignancy of lymphoid cells, affecting B-/T-lymphocyte cell lineages, arresting maturation and promoting uncontrolled proliferation of immature blast cells with bone marrow failure and tissue infiltration
Acute lymphoid leukaemia (ALL) epidemiology
Associated with ionising radiation during pregnancy and down’s syndrome
Commonest cancer of childhood, rare in adults
Acute lymphoid leukaemia (ALL) classification
Morphological- divided in to 3 types by microscopic appearance (L1, L2, L3)
Immunological- Surface marker used to classify ALL into: Pre-cursor B-cell ALL, T-Cell ALL + B-cell ALL
Cytogenetic- chromosomal abnormalities, useful for predicting prognosis
Acute lymphoid leukaemia (ALL) signs and symptoms
Due to: Bone marrow failure- anaemia (low Hb), infection (low WBC) + Bleeding (low platelet)
Infiltration- Hepato/splenomegaly, lymphadenopathy (swelling of lymph nodes), orchidomegaly (testicle enlargement)
CNS involvement- CN palsies, meningism (neck stiffness, headaches without meninge inflammation)
Acute lymphoid leukaemia (ALL)- common infections
Chest, mouth, skin, perianal
Bacterial septicaemia, zoster, CMV, measles, candidiasis, Pneumocystis pneumonia
Acute lymphoid leukaemia (ALL)- investigations
Characteristic blast cells on blood film and bone marrow, high WBC
CXR/CT scan for mediastinal + abdominal lymphadenopathy
Lumbar puncture- look for CNS involvement
Acute lymphoid leukaemia (ALL)- treatment
Supportive- Blood/platelet infusions, IV fluids, infection management (dangerous due to neutropenia)
Chemotherapy- complex, multi-drug/phase, may take years
Allogeneic marrow transplant- best option for young adults in 1st remission
Acute lymphoid leukaemia (ALL)- prognosis
Children- 70-90% curative
Adults- 40% curative
Poorer prognosis if adult, Philadelphia chromosome present, CNS signs or B-cell ALL
Chronic lymphoid leukaemia (CLL)
Commonest leukaemia, more common males
Hallmark- progressive accumulation of of a malignant clone of functionally incompetent B cell
Chronic lymphoid leukaemia (CLL) staging + median survival- Rai stage 0
Lymphocytosis (increase number of lymphocytes)
>13 years
Chronic lymphoid leukaemia (CLL) staging + median survival- Rai stage 1
Lymphocytosis (increase number of lymphocytes) + lymphadenopathy
8 years
Chronic lymphoid leukaemia (CLL) staging + median survival- Rai stage 2
Lymphocytosis (increase number of lymphocytes) + spleno- or hepatomegaly
5 years
Chronic lymphoid leukaemia (CLL) staging + median survival- Rai stage 3
Lymphocytosis (increase number of lymphocytes) + anaemia
2 years
Chronic lymphoid leukaemia (CLL) staging + median survival- Rai stage 4
Lymphocytosis (increase number of lymphocytes) + low platelet count
1 year
Chronic lymphoid leukaemia (CLL) signs and symptoms
Often asymptomatic- present as surprise finding on RBC
May be anaemic or infection prone, or have weight loss, sweats, anorexia if severe
Enlarged, rubbery, non-tender nodes, spleno/hepatomegaly
Chronic lymphoid leukaemia (CLL) investigations
FBC- Increased lymphocytes
Later- autoimmune haemolysis, marrow infiltration (low Hb/neutrophils, platelets)
Chronic lymphoid leukaemia (CLL) complications
Autoimmune haemolysis
Infection due to reduced IgG, bacterial, viral (especially zoster)
Marrow failure
Chronic lymphoid leukaemia (CLL) treatment
Treat if symptomatic
Chemo and monoclonal antibody therapy
Steroids for autoimmune haemolysis
Radiotherapy helps lymphadenopathy and splenomegaly
Stem cell transplantation- for some patients
Supportive care- transfusion, IV human Ig if recurrent infection
Chronic lymphoid leukaemia (CLL) natural history
1/3 never progress
1/3 progress slowly
1/3 progress actively
Death often due to infection or transformation to aggressive lymphoma (Richter’s syndrome)
Leukaemia vs Lymphoma
Both originate in lymphocytes
Leukaemia typically originates in bone marrow and spreads through the bloodstream
Lymphoma usually originates in lymph nodes or the spleen and spreads through the lymphatic system
Hodgkin lymphoma
Malignant proliferations of lymphocytes that accumulate in the lymph nodes causing lymphadenopathy, but may also be found in peripheral blood or infiltrate organs
Characteristic cells with mirror-image nuclei known as Reed-Sternberg cells
Hodgkin lymphoma incidence
2 peaks- young adults (commonest malignancy in 15-24), elderly
Affects women more commonly than men
RFs- affected sibling, EBV (Epstein-Barr virus), Systemic lupus erythematosus (SLE), post-transplant
Hodgkin lymphoma symptoms
Enlarged, rubbery, non-tender nodes (60-70% cervical, can be axillary or inguinal)
Node size may fluctuate, may become matted, may be alcohol induced node pain
25% have constitutional upset- weight loss, fever, night sweats, pruritis + lethargy
Mediastinal lymph node involvement may cause local issues (SVC/bronchial obstruction, pleural effusions)
Hodgkin lymphoma signs
Lymphadenopathy
Also anaemia, spleno/hepatomegaly, cachexia (weakness/ wasting due to chronic disease)
Hodgkin lymphoma investigations + treatment
Tissue biopsy- Lymph node excision biopsy ideally
Bloods- increased ESR (erythrocyte sedimentation rate) / low Hb= poorer prognosis
Imaging- CXR, CT/PET scan of thorax, abdo + pelvis useful for staging
Hodgkin lymphoma Ann Arbor staging- stage 1
Confined to single lymph node region
Hodgkin lymphoma Ann Arbor staging- stage 2
Involvement of 2 or more lymph node region on the same side of diaphragm
Hodgkin lymphoma Ann Arbor staging- stage 3
Involvement of nodes on the both sides of diaphragm
Hodgkin lymphoma Ann Arbor staging- stage 4
Spread beyond lymphatic system into organs (ie liver or bone marrow)
Hodgkin lymphoma treatment
Chemoradiotherapy- length of chemo depends on stage (longer course for worse spread of disease)
Relapse- high dose chemo + allogenic stem cell transplant
Aplastic anaemia
Rare stem cell disorder in which bone marrow stops making cells leading to pancytopenia (deficiency of all 3 blood components; RBC, WBC, platelet)
Aplastic anaemia presentation
features of anaemia (low Hb), infection (low WBC), bleeding (low platelet)
Aplastic anaemia presentation
Mostly autoimmune, triggered by drugs, viruses (ie parvovirus, hepatitis), or irradiation
May be inherited
Aplastic anaemia investigations and treatment
Bone marrow biopsy is diagnostic
Supportive in asymptomatic patients- blood transfusion and neutropenic regimen
Young people with severe disease- Allogeneic blood transfusion can be curative
Immunosuppression may be effective but not curative
Glucose-6-phosphate deficiency
Main RBC enzyme defect
Affects 100 million (mainly women) people in the Mediterranean, Africa, Middle/far east
Avoid henna use in G6PD
Glucose-6-phosphate deficiency symptoms
Most are asymptomatic
May get oxidative crises due to decreased glutathione production, precipitated by drugs (eg primaquine, sulphonamides, aspirin), exposure to Vicia faba (broad beans/favism) or illness
Glucose-6-phosphate deficiency- oxidative crisis management
In attack, there is rapid jaundice + anaemia
Film- bite- + blister-cells
Test- enzyme array (>8 weeks after crisis, young RBC might have enough enzyme)
Haemolytic anaemia- Malaria
RBC lysis and blackwater fever (haemoglobinuria- HB is found in abnormally high conc in urine) can cause anaemia
Haemolytic anaemia- Alpha thalassemia
Genetic condition affecting alpha peptide chains of Hb- controlled 4 genes
Can cause death in utero (if all 4 genes are delete), moderate anaemia + features of haemolysis (if 3/4 genes are deleted) + asymptomatic carrier state with reduced MCV (if 2/4 are deleted)
Haemolytic anaemia- Membranopathy- spherocytosis
Autosomal dominant- membrane defect
Less deformable (more rigid) spherical RBCs, so trapped in spleen> extravascular haemolysis
Splenomegaly, jaundice
Haemolytic anaemia- Membranopathy- elliptocytosis
Autosomal dominant- membrane defect
Mostly asymptomatic- may protect from Malaria
10% present severe phenotype (can lead to death in utero)
Immune Thrombocytopenia (ITP)
Caused by antiplatelet antibodies
Acute- usually in children, 2 weeks after infection with life threating purpura
Chronic- usually in women, runs a fluctuating course of bleeding, purpura, epistaxis (bleeding from the nose) and menorrhagia (heavy menstrual bleeding)
Purpura
occurs when small blood vessels leak blood under the skin
Immune Thrombocytopenia (ITP) management
Test- Increased megakaryocytes, antiplatelet often present
No treatment if mild
If symptomatic or very low platelet count- Prednisolone to induce and maintain remission
Platelet transfusion ineffective (except in surgery or life threating bleed) as antibodies destroy them too quickly
Thrombotic Thrombocytopenia Purpura (TTP)
causes extensive clots (microscopic thromboses) to form in small blood vessels throughout the body (thrombotic microangiopathy).
Characterised by the presence in the plasma of large von Willebrand Factor (VWF) strings
Thrombotic Thrombocytopenia Purpura (TTP)- incidence
Very rare
Characterised into acquired (idiopathic) and congenital (familial) and affects 4-6 people per million, affecting women more than men with a peak incidence in your forties
Thrombotic Thrombocytopenia Purpura (TTP)- treatment
Acute- 1st line Plasma exchange + corticosteroid
Consider caplacizumab, aspirin, folic acid +/ transfusion
2nd line immunosuppression, 3rd line splenectomy
Long term- low dose aspirin
Thrombotic Thrombocytopenia Purpura (TTP)- presentation
non-specific prodrome
severe neurological symptoms (coma, focal abnormalities, seizures)
mild neurological symptoms (headache, confusion)
fever
Thrombotic Thrombocytopenia Purpura (TTP)- investigation
Degree of thrombocytopenia varies, but decreased platelets are required for the diagnosis of TTP
ADAMTS-13 (von Willebrand factor cleaving enzyme) activity levels of <5% to 10% are diagnostic.
