Blood - Level 2 Flashcards
Definitions of anaemia? Men, children, women, pregnant women and postpartum?
o In children aged 12–14 years — Hb concentration less than 120 g/L.
o In men (aged over 15 years) — Hb concentration less than 130 g/L.
o In women (aged over 15 years) — Hb concentration less than 120 g/L.
o In women who are pregnant — Hb concentration less than 110 g/L.
An Hb level of 110 g/L or more appears adequate in the first trimester, a level of 105 g/L appears adequate in the second and third trimesters.
o Postpartum — Hb concentration less than 100 g/L.
Definition of macrocytosis?
- Macrocytosis (MCV >100)
o Usually occurs due to problems with synthesis of RBCs
Physiology, absorption of folate?
Deficiency due to?
o Found in green vegetables and offal
o Absorbed in SI and stores last 4 months
o Deficiency by Diet, malabsorption, Leukaemia, heart failure, hepatitis, dialysis, drugs (alcohol, anticonvulsants, methotrexate, sulfasalazine, trimethoprim)
Physiology, absorption of vitamin B12?
Deficiency of B12 due to?
o Animal products provide only dietary source
o B12 binds to intrinsic factor secreted by gastric parietal cells and absorbed in terminal ileum
o Transported as transcobalamin and stored in liver with around 2-5 years supply
o Deficiency due to pernicious anaemia, surgery (ileal resection, gastrectomy), HIV, vegans, metformin, PPI, H2RA
Definition of pernicious anaemia?
Epidemiology?
Associated with?
o Autoimmune atrophic gastritis leading to achlorhydria and lack of gastric IF
o Usually >40 and women
o Associated with – myxoedema, thyrotoxicosis, Hashimoto’s, Addison’s, vitiligo
o Risk of gastric cancer
Causes of megaloblastic macrocytosis?
B12 deficiency
Folate deficiency
Cytotoxic drugs
Causes of non-megaloblastic macrocytosis?
Alcohol Reticulocytosis Liver disease Hypothyroidism Pregnancy
Other causes of megaloblastic macrocytosis?
Myelodysplasia, myeloma, aplastic anaemia
Symptoms of anaemia?
o Asymptomatic
o Symptoms - SOBOE, fatigue, palpitations, exacerbation of angina, pale
o Signs – pallor, bounding pulse, systolic pulmonary flow murmur
Symptoms of vitamin B12 and folate deficiency?
o Cognitive changes o SOB o Headache o Anorexia o Palpitations o Tachypnoea o Visual disturbance o Weakness, lethargy
Signs of B12 and folate deficiency?
o Anorexia o Angina o Angular stomatitis o Glossitis o Liver enlargement o Mild jaundice o Tachycardia o Weight loss
Bloods done in macrocytic anaemia?
o FBC (Low Hb, high MCV (>100))
o Serum B12 (<200ng/L) - If cobalamin levels low – check serum anti-IF antibodies
o Serum Folate (<3mcg/L) - If folate levels low & malabsorption history – Check anti-endomysial & anti-transglutaminase antibodies
o Other investigations to identify cause:
LFTs, GGT, TFTs
Blood film findings in macrocytic anaemia?
B12 and folate deficiency
• Hypersegmented polymorphs (neutrophil)
o >5% of neutrophils with 5 or more lobes, or 1 or more neutrophils with 6 or more lobes
• Oval macrocytes
Target cells if liver disease
What tests to perform to find cause of macrocytic anaemia?
o If low folate – assess dietary folic acid and check antiendomysial or anti-TTG antibodies for coeliac
o If low cobalamin – anti-IF antibodies for pernicious anaemia
When to refer to haematologist in macrocytic anaemia?
o Urgent – neurological symptoms, pregnant, malignancy suspected
o Routine – cause of B12 or folate deficiency uncertain following investigations
When to refer to gastroenterologist in macrocytic anaemia?
o Suspected malabsorption, pernicious anaemia with GI symptoms, gastric cancer suspected, coeliac disease
Management of vitamin B12 deficiency?
Treat cause
Dietary Advice - Food rich in B12 – eggs, fortified food (breakfast cereals, breads), meat, milk, dairy, salmon, cod
Hydroxocobalamin (B12) 1mg IM 3x a week for 2 weeks (if neurological symptoms - alternate days until no improvement)
If not diet related – hydroxocobalamin 1mg IM every 3 months for life
If diet – either oral cyanocobalamin 50-150mcg daily between meals or twice-yearly IM 1mg injection
Management of folate deficiency?
Assess underlying cause – poor diet, malabsorption
Dietary Advice - Foods rich in folate – asparagus, broccoli, brown rice, brussel sprouts, chickpeas, peas
Folic acid 5mg/day PO for 4 months (never without B12 unless known normal – worsens SACDC)
In pregnancy
Prophylactic 400mcg/day given from conception until 12 weeks recommended to all
5g/day up to 12 weeks – previous/FHx NTD, anti-epileptic meds, DM, SCC, thalassaemia, BMI>30
• SCC, thalassaemia – take throughout pregnancy
Monitoring in macrocytic anaemia?
o Within 7-10 days commencing treatment – FBC, reticulocyte count
o 8 weeks – FBC, reticulocyte count, iron and folate levels
o Completion of folic acid treatment – FBC, reticulocyte count
o Cobalamin levels 1-2 months after treatment if no symptom response
Complications of vitamin B12 deficiency?
Paraesthesia, ataxia, progressive symmetrical neuropathy, numbness, memory lapses
Neural tube defects
Sterility
Subacute combined degeneration of the spinal cord
Insidious onset of peripheral neuropathy – symmetrical posterior dorsal column loss causing vibration and proprioception and LMN signs & symmetrical corticospinal tract loss causing motor and UMN signs
Triad – extensor plantars, absent knee jerk, absent ankle jerk
Complications of folate deficiency?
o Prematurity
o CVD and colorectal cancers
o Neural tube defects
o Sterility
Acquired causes of haemolytic anaemia?
Immune-mediated and Coomb’s test positive Drug-induced Autoimmune haemolytic anaemia Paroxysmal cold haemoglobinuria Acute transfusion reaction Haemolytic disease of newborn Coombs Negative Autoimmune haemolytic anaemia Microangiopathic haemolytic anaemia Infection Paroxysmal Nocturnal Haemoglobinuria
Hereditary causes of haemolytic anaemia?
o Glucose-6-phosphate dehydrogenase (G6PD) deficiency
o Pyruvate kinase deficiency
o Hereditary Spherocytosis
o Hereditary elliptocytosis, ovalocytosis – refer to haematology
o Sickle cell disease
o Thalassaemia
Definition of drug-induced haemolytic anaemia?
• Formation of RBC autoantibodies from binding to RBC membranes (penicillin) or production of immune complexes (quinine)
Description, classification and management of autoimmune haemolytic anaemia?
• Autoantibodies causing extravascular haemolysis and spherocytosis
• Classified:
• Warm – IgG-mediated, bind at body temperature, Rx = steroids/immunosuppressants
• Cold – IgM-mediated, bind at low temperature (<4o), often with Raynaud’s or acrocyanosis,
o Rx = keep warm
o May be caused by CLL, lymphoma, drugs, SLE, infection (EBV, mycoplasma)
Description of paroxysmal cold haemoglobulinuria?
- With viruses/syphilis, caused by Donath-Landsteiner antibodies sticking to RBCs in cold
- Self-limiting complement-mediated haemolysis on rewarming
Description of Rhesus haemolytic disorder?
o Usually identified antenatally when woman Rh negative and baby Rh positive
o Presents with anaemia, hydrops, hepatosplenomegaly with rapidly developing jaundice
o Usually anti-D blood group
Description of ABO incompatibility haemolytic disorder?
o Now more common than Rhesus incompatibility
o Most ABO antibodies are IgM and do not cross placenta, but some blood group O women have IgG anti-A-haemolysin which haemolyses red blood cells of a group A infant
o Occasionally group B infants affected by anti-B haemolysins
o Can cause jaundice – peaks 12-72 hours
o Anaemia is less severe and no hepatosplenomegaly
o Coombs test positive
Causes of Coombs negative autoimmune haemolytic anaemia?
Autoimmune hepatitis, hepatitis B&C, post vaccinations, drugs (piperacillin, rituximab)
Description of microangiopathic haemolytic anaemia?
Disruption in RBC circulation, causing intravascular haemolysis and schistocytes
Causes include HUS, TTP, DIC, pre-eclampsia, eclampsia
Treat underlying disease, transfusion or plasma exchange may be needed
Description of paroxysmal nocturnal haemoglobinuria?
Stem cell disorder with haemolysis (especially at night – haemoglobinuria), marrow failure + thrombophilia
Diagnosed – urinary haemosiderin, Harris test positive
Management – anticoagulation, eculizumab
Description, symptoms and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency?
From Mediterranean, Middle-East and Far East Males mostly, develop severe jaundice Symptoms • Most asymptomatic, but get oxidative crisis due to low glutathione production precipitated by drugs (primaquine, sulphonamides, aspirin) or broad beans • In crisis – rapid anaemia and jaundice Film – bite and blister cells Diagnosis – Enzyme assay Management – Avoid precipitants, transfuse if severe Drugs need to be avoided • Henna • Sulfonamides • Aspirin • Primaquine • Broad beans
Description of pyruvate kinase deficiency?
Autosomal recessive low ATP production causes lower RBC survival
Homozygotes – neonatal jaundice, haemolysis and splenomegaly
Diagnosis – enzyme assay
Management – Often none, splenectomy may help
Description of hereditary spherocytosis?
Autosomal dominant inheritance with FHx in 75%
Early, severe jaundice in newborn infants
May cause anaemia, jaundice, splenomegaly, aplastic crisis and gallstones
Diagnosed on blood film
Treatment with folic acid, splenectomy if symptomatic
Symptoms and signs of haemolytic anaemia?
Anaemia – if longstanding may be asymptomatic but acute crisis causes: o Pallor o Tachycardia o SOB o Dizziness o Angina o Weakness Jaundice Gallstones Dark urine (haemoglobinuria) Splenomegaly
Investigations to perform in haemolytic anaemia? What are the findings?
- Bloods - FBC (Low Hb, platelets normal usually), reticulocytes, LFTs (bilirubin), LDH, Haptoglobin
- Coombs Test - Detects immune-mediated haemolytic anaemia
- Urinary urobilinogen
- Thick and thin blood films
Hypochromic microcytic cells (thalassaemia)
Sickle cells (SCD)
Schistocytes (microangiopathic haemolytic anaemia)
Abnormal cells in blood cancers
Spherocytes (hereditary spherocytosis or autoimmune haemolytic anaemia)
Heinz bodies, bite cells (glucose-6-phosphate dehydrogenase deficiency)
Further tests to perform in haemolytic anaemia?
o Direct antiglobulin test (Coomb’s test) – identifies autoimmune cause as red cells coated with antibody or complement
o RBC lifespan – chromium labelling
o Hb electrophoresis
o Enzyme assays
How to approach haemolytic anaemia?
Increased red cell breakdown?: Anaemia with normal or high MCV High bilirubin (unconjugated from haem breakdown – pre-hepatic jaundice) High urinary urobilinogen High serum LDH (released from RBCs)
Increased red cell production?:
High reticulocytes causing high MCV (large immature RBCs)
Polychromasia
Extra or intra-vascular?
Extravascular – splenomegaly
Intravascular
• Raised free plasma haemoglobin
• Methaemalbuminaemia (haem combines with albumin)
• Low plasma haptoglobin
• Haemoglobinuria – red-brown urine with no RBCs
• Haemosiderinuria – free Hb filtered by glomeruli (sloughed tubular cells by Prussian staining)
What is the cause?
Management of haemolytic anaemias?
- General Measures
o Folic Acid – if folate deficiency
o Stop precipitating medications - Transfusion
o Only when necessary
o Use most compatible blood if transfusions - Iron
o For severe intravascular haemolysis and iron deficient - Splenectomy
o Recommended in hereditary spherocytosis and when other measures failed
Definition of lymphoma?
- Malignancy of lymphocytes which can be divided into Hodgkin and non-Hodgkin lymphoma
Definition of Non-Hodgkin’s lymphoma?
o Group of lymphoproliferative malignancies
o A much greater predilection to disseminate to extranodal sites than in Hodgkin’s lymphoma
Definition of Hodgkin’s lymphoma?
o Malignant tumour of the lymphatic system that is characterised histologically by the presence of multinucleated giant cells (Reed-Sternberg cells)
o Mirror image nuclei in Reed-Sternburg cells
Epidemiology of lymphoma?
NHL more common
HL - peak around adolescence
NHL - peak around 50-70
Aetiology and risk factors of Hodgkin’s Lymphoma?
o Aetiology
Classical HL (95%) – nodular sclerosis, mixed cellularity, lymphocyte rich/depleted
Nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL)
o Risk Factors
EBV, HIV, immunosuppression, cigarette smoking
Aetiology of Non-Hodgkin’s Lymphoma?
Mature (peripheral) B-cell neoplasms • Diffuse large B-cell lymphoma (30-60%) • Mediastinal large B cell • Burkitt’s lymphoma • Follicular lymphoma (20-25%) • MALT lymphoma
Precursor T-cell neoplasms
Mature (peripheral) T-cell neoplasms
• Enteropathy-type T-cell lymphoma
• Peripheral T-cell lymphoma
Risk factors of Non-Hodgkin’s Lymphoma?
Chromosomal translocations EBV, HepC, Kaposi’s sarcoma Pesticides, herbicides, hair dye, chemo Hashimoto’s thyroiditis H.pylori
Symptoms and signs of Hodgkin’s lymphoma?
o Painless, large, firm lymphadenopathy
o May cause airway obstruction, SVC obstruction
o Several months
o Systemic B-symptoms
Sweating, pruritus, night sweats, weight loss, fever
Symptoms and signs of Non-Hodgkin’s lymphoma?
o Lymphadenopathy
o Skin - Sezary syndrome
o Other sites
Gastric
Small Bowel – diarrhoea, vomiting, abdominal pain, weight loss
Bone
CNS
Lung
o Mediastinal mass with bone marrow infiltration
o Superior vena cava obstruction
o Systemic symptoms (less common than in Hodgkin’s lymphoma)
Sweating, pruritus, night sweats, weight loss, fever
o Pancytopenia
When to refer lymphoma in primary care?
- Hodgkin’s Lymphoma referral in primary care:
o 2-week cancer referral in adults with unexplained lymphadenopathy or splenomegaly - Non-Hodgkin’s Lymphoma referral from primary care:
o 2-week cancer referral in adults with unexplained lymphadenopathy or splenomegaly
o Specialist assessment within 48 hours for children if unexplained lymphadenopathy or splenomegaly
Testing in lymphoma?
o Bloods FBC, film, ESR, LFT, LDH, urate, Ca o Lymph node excision biopsy o FISH gene testing if histological high-grade lymphoma o CT scan, CXR o PET scan staging if: Stage 1 diffuse large B-cell lymphoma Stage 1/2 follicular lymphoma Stage 1/2 Burkitt lymphoma
Staging system in Hodgkin’s Lymphoma?
o Ann Arbor system Stage 1: single site Stage 2: >1 site and on 1 side Stage 3: on both sides of diaphragm Stage 4: disseminated disease Each stage either A (no systemic symptoms other than pruritus) or B (weight loss >10% in 6m, fever >38, night sweats)
Staging system in Non-Hodgkin’s Lymphoma?
o St. Jude System
Stage 1: single site or nodal area (not abdomen or mediastinum)
Stage 2: regional nodes, abdominal
Stage 3: disease on both sides of diaphragm
Stage 4: bone marrow or CNS disease
Management in Hodgkin’s Lymphoma?
o Chemotherapy (ABVD) with radiotherapy (if high risk)
Adriamycin, bleomycin, vinblastine, dacarbazine
o PET scans monitor disease progression
o Pnuemococcal and influenza vaccine
o MenC and Hib vaccine
o Relapsed disease – high-dose chemo and stem cell transplantation
Management in Non-Hodgkin’s Lymphoma?
o MDT management
o Low Grade
Follicular, marginal zone, lymphocytic
If symptomless – watch and wait
Radiotherapy in local disease
o High grade
Burkitt’s (characteristic jaw lymphadenopathy), lymphoblastic, diffuse large B-cell
Chemotherapy (R-CHOP regimen) with radiotherapy
Rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine (oncovin) and prednisolone
G-CSF helps neutropenia (filgrastim, lenograstim)
o Pnuemococcal and influenza vaccine
o MenC and Hib vaccine
Survival rate of lymphoma?
- 5-year survival rate >90% (NHL 70%)
Definitions of myeloma?
Progressive malignant disease of plasma cells that normally produce immunoglobulin
o Proliferation of abnormal monoclonal immunoglobulins (M proteins) in the blood, referred to as paraproteinaemia
Genetic changes in terminal differentiation of B lymphocytes into plasma cells (1/2 translocation of oncogene onto heavy chain of chromosome 14)
o Affects multiple organs and systems including bones, kidneys, blood and immune systems
What does myeloma evolve from? What is smouldering myeloma?
- Almost all patients evolve from asymptomatic pre-malignant stage called – monoclonal gammopathy of undetermined significance (MGUS)
- Smouldering myeloma – asymptomatic myeloma with no evidence of myeloma-related organ or tissue injury or event
Epidemiology of myeloma?
- Second most common haematological malignancy
- 2% of cancer related deaths
- Prevalence increasing
- Classified according to which immunoglobulin produced - Most commonly IgG (other IgA, IgD, IgM)
Risk factors of myeloma?
o Men
o Black people, Pacific islanders and Maori
o Increasing age
o FHx
Incidental findings seen in myeloma?
o Normochromic, normocytic anaemia
o Renal Impairment
o Hypercalcaemia
o Raised ESR, plasma viscosity, serum protein or globulin
Suspect multiple myeloma in adults>60 if symptoms?
o Unexplained bone pain (often lower back or thoracic)
Osteolytic bone lesions
o Fatigue
o Hypercalcaemia (bone pain, abdominal pain, depression, confusion, muscle weakness, thirst, polyuria)
o Weight loss
o Hyperviscosity symptoms (headache, visual disturbances, cognitive impairment)
o SCC
o Fever
o Recurrent infections
Signs of myeloma?
o Hepatomegaly
o Splenomegaly
o Lymphadenopathy
When to perform tests in primary care when suspecting myeloma?
> 60 with persistent bone pain (particularly back) or unexplained fracture:
FBC, Ca, ESR and plasma viscosity
If possible myeloma & >60 with hypercalcaemia or leukopenia/raised plasma viscosity and ESR
Very urgent protein electrophoresis and Bence-Jones protein urine test (within 48 hours)
Consider – peripheral blood film, U&E, X-rays of bone pain
If results of protein electrophoresis or urinary Bence Jones protein suggest myeloma - refer for 2 week appointment
- Blood film Appearance (plasma cells and rouleux formation seen)
Laboratory, diagnostic tests in secondary care of myeloma?
Serum protein electrophoresis and serum-free light-chain assay
If serum electrophoresis abnormal – use serum immunofixation
Bone marrow aspirate and trephine biopsy confirms diagnosis of myeloma
Morphology and flow cytometry determine plasma cell percentage and phenotype
Diagnosis of myeloma, smouldering myeloma and monoclonal gammopathy of undetermined significance (MGUS)?
Symptomatic myeloma
• Clonal plasma cells >10% on bone marrow biopsy, monoclonal protein in either serum or urine, end-organ damage (CRAB)
Asymptomatic myeloma (smouldering)
• Serum paraprotein >30g/L, +/- clonal plasma cells >10% on bone marrow biopsy, no organ damage
Monoclonal gammopathy of undetermined significance (MGUS)
• Serum paraprotein <30g/L, clonal plasma cell <10% on bone marrow biopsy and no organ damage
Prognostic testing in myeloma?
Same sample for diagnostic and prognostic tests on bone marrow
FISH on CD-138-selected bone marrow plasma cells
• Identify t(4:14), t(14:16), 1q gain, del(1p) and del (17p)(TP53 deletion) – adverse risk abnormalities
• Consider t(14:20) and t(11:14) and hyperdiploidy
Immunophenotyping & immunohistochemistry on trephine biopsy
• Plasma cell phenotype
Imaging tests in myeloma?
o Offer to all people with plasma cell disorder suspected of myeloma
o Whole-body MRI (whole-body CT is MRI unsuitable, skeletal survey third-line)
Multiple well-defined lytic lesions – raindrop appearance
General management of myeloma?
o Prompt psychological assessment and support when needed – Refer if needed
o Lifestyle measures to optimise bone and renal function
o How to identify MSCC
o Patient support groups
Management of transplant eligible patients in myeloma?
First line
• Induction – bortezomib +/- dexamethasone and thalidomide
• Stem Cell Transplant – First autologous SCT or Allogenic SCT (Letermovir if CMV positive)
Second Line
• Daratumumab + Bortezomib + Dexamethasone (used for treating relapsed patients after 1 previous treatment)
Subsequent Treatment (treating relapsed and refractory multiple myeloma)
• Daratumumab
• Ixazomib + lenalidomide + dexamethasone
• Pomalidomide + dexamethasone
• Lenalidomide + Dexamethasone
Relapse
• Medical 2nd line treatment OR 2nd autologous stem cell transplantation
Management of transplant ineligible patients in myeloma?
First Line
• Induction – bortezomib +/- dexamethasone and thalidomide (OR lenalidomide + dexamethasone)
Second Line (used for treating relapsed patients after 1 previous treatment)
• Lenalidomide + Dexamethasone
• Daratumumab + Bortezomib + Dexamethasone
• Carfilzomib + Dexamethasone
Subsequent Treatments (treating relapsed and refractory multiple myeloma)
• Daratumumab
• Ixazomib + lenalidomide + dexamethasone
• Pomalidomide + dexamethasone
• Panobinostat + Bortezomib + Dexamethasone
• Lenalidomide + Dexamethasone
Prevention of bone disease and infection in myeloma?
Bone Disease
Zoledronic Acid (OR Disodium pamidronate OR Sodium Clodronate)
Dental Assessment
Infection Seasonal Influenza Vaccine Consider: • Pneumococcal vaccine (<65) • IVIG if hypogammaglobulinemia and recurrent infections • Aciclovir • Screen for HepB, HepC, HIV
Monitoring in smouldering myeloma, treated myeloma and disease progression?
o Smouldering Myeloma – every 3 months for 1st 5 years then decide
o Treated myeloma – at least every 3 months
Includes: FBC, U&E, bone profile, serum Ig and protein electrophoresis, serum-free light chain assay
o Disease progression – Whole-body MRI (Spinal MRI)
Complications of myeloma?
o Pathological bone fractures (osteolysis from proliferation of abnormal plasma cells)
o Spinal Cord Compression
o Renal Damage (obstruction of renal tubules by excess light chains)
o Impaired resistance to infection (leukopenia and abnormal immunoglobulins)
o Anaemia
o Bleeding disorders
o Hyperviscosity of blood
Management of acute renal disease in myeloma?
Start borezomib + dexamethasone immediately
Management of fatigue in myeloma?
Erythropoietin analogues if anaemic
Management of non-spinal bone disease in myeloma?
Zoledronic Acid (OR Disodium pamidronate OR Sodium Clodronate)
Consider surgical stabilisation, radiotherapy
Management of peripheral neuropathy in myeloma?
If on bortezomib – switch to SC, reduce dose or move to weekly
Management of spinal bone disease in myeloma?
Zoledronic Acid (OR Disodium pamidronate OR Sodium Clodronate)
Adjuncts – interventional pain management, bracing. Surgery, radiotherapy
Prognosis of myeloma?
- Usually incurable disease
- Survival ranges from weeks to years
- Most people respond to initial treatment and enter period of stability however, relapse is inevitable and usually occurs after 2-5 years
