Haematology Flashcards
RFs for Hodgkins lymphoma
EBV, FH, young adults, 16-65, peak in 30s, M>F, HIV
What is Hodgkins lymphoma
B cell tumours, no apoptosis, divides uncontrollably, don’t produce Ig, usually surrounded by t cells
Contiguously spread rarely extranodal.
Classical
95%, Reed-Sternberg cells (2 cells fused, owl eyes). CD15/30
Nodular sclerosis: 70%, young adults, neoplastic inflam cells surrounded by collagen from fibroblasts, forming nodules, lacunar cells (RS cells with shrunken cytoplasm, nucleus appears as if in middle of lake).
Mixed: 20%, HIV, mixed inflam, background, eosinophils, neutrophils, plasma cells, histiocytes surrounding RS cells, good prognosis.
Lymphocyte rich: 5% RS cells surrounded by lymphocytes, best prognosis.
Lymphocyte poor: rarest, 30-37, no reactive lymphocytes, abundance of RS cells, HIV, worst prognosis.
Nodular lymphocyte predominant
M>F, 5%
CD20/45. No RS cells
Large groups of lymphocytes form nodules around lobulate-nucleated popcorn cells
Slow growing, highly curable.
Features of Hodgkins lymphoma
Painless cervical/ supraclavic/ mediastinal (cough, SVCS, abdo pain, dyspnoea) lymphadenopathy, rubbery, painful with alcohol.
Cytokine release: fever, drenching night sweats, weight loss. NS 50%, mixed cellularity/ lymphocyte depleted common
Pruritis
Hepatosplenomegaly
Tonsillar enlargement
Pel Ebstein fever: cyclical fever, periods of high + normal temp.
Complications of Hodgkins lymphoma
Nodular lymphocyte predominant: transformation to aggressive NHL.
Poor prognosis: >45, stage 4, Hb <10.5, lymphocyte coung <600/8%, male, albumin <40, WBC >150,000
Diagnosis of Hodgkins lymphoma
Ann Arbor 1 LN/group of adjacent LN >2 LN regions, both on same side of diaphragm LN on both sides of diaphragm Liver/ spleen/ lungs/ bone marrow. A: no Sx other than pruritis B: B Sx E: organs/ tissues beyond lymph system
CT/PET scan Gallium scan: involved sites appear bright LN biopsy ↑LDH Normocytic anaemia, eosinophilia FBC: ↓Hb, plts, WBC ↑↓ ESR: ↑ CXR: mediastinal mass, large mediastinal lymphadenopathy
Tx of Hodgkins lymphoma
Rituximab: NLP > binds CD20 induces apoptosis.
Classical: ABVD /BEACOPP + radio
NLP: early > radio, advanced, R-CHOP
R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, pred
BEACOPP: bleomycin etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, pred
ABVD: doxorubicin, bleomycin, vinblastine, radiotherapy.
RFs for NHL?
ataxia telangiectasia, >50, M>F. Wiskott-Aldrich, Chediak Higashi, Klinefelter, HTCL virus, H pylori, IS, HIV, AI disease, aromatic hydrocarbons eg benzene, radiation, pesticides,
What is Non-Hodgkins lymphoma?
80% B cell, 20% t cell
Usually LN can be extra-nodal
Small bowel lymphoma: small intestine, MALT, coeliac, intra epithelial T cell.
B cell
Most common, aggressive
CD20
Diffuse large B cell: most common. Aggressive. t(3,4) BCL6. Germinal/ activated b cell.
Follicular: slow growing, 2nd most common. Middle > later life, rare in childhood. T(14, 18) > BCL2 gene.
Burkitt: highly aggressive, commonest childhood malig, M>F. endemic (EBV, Africa, rapidly growing maxilla/ mandible tumour), sporadic (30% EBV, most marrow involvement, or abdo mass > ileo-ceacal), AIDs. T(8, 14) > MyC.
Mantle cell: aggressive, t(11, 14) > BCL1 > cyclin D1
Marginal zone: indolent, MALT (chronic inflam eg H pylori), LN/ spleen.
Lymphoplasmacytic: ↑age indolent, uncommon, bone marrow, LN spleen. Waldenstrom macroglobulinulinemia > neoplastic cells produce IgM, ↑blood viscoscity t(9,14)
Cutaneous: extranodal marginal/ follicle centre
Hairy cell leukaemia: BRAF mutations
T cell
Less freq
Angioimmunoblastic, extranodal natural killer/ T cell lymphoma nasal type enteropathy associated T cell lymphoma, anaplastic, periph T cell lymphoma.
Middle aged > elderly.
Adult t cell lymphoma: leukaemia, human t lymphotropic virus
Mycosis fungoides: t cell lymphoma of skin, resembles fungal infection, confined to skin. Long Hx, preceded by scaly pre-mycotic phase.
Features of NHL?
DLBC: intra-abdo disease, bowel Sx due to compression/ infiltration of GIT. 30% present at extranodal site as opposed to nodal disease with extranodal spread.
Burkitt: abdo mass, bone marrow involvement, CNS, kidney, testis.
Lymphoplasmacytic: anaemia Sx, hyper viscosity (headaches visual disturbances), Raynauds.
Cutaneous: single or clustered lesions
Angioblastic: fevers, rashes, electrolyte abnormalities
Mycosis fungoides: multiple erythematous lesions, plaques + tumours, when spreads to blood/ bone becomes Sezary syndrome.
Generalised erythroderma.
Painless lymphadenopathy, non-tender, rubbery, asymmetrical
B Sx: fever, drenching night sweats, weight loss, malaise
Waldeyer’s ring: oropharynx Dx, sore throat, obstructed breathing.
Splenomegaly: marginal zone
Hepatomegaly, jaundice
SOB: pleural involvement
Cough: mediastinal mass/ lymphadenopathy, pneumonia
Anaplastic: t(2,5)
MALT: T(11,18)
B Sx appear later in NHL than HL.
Testicular mass
Complications of NHL?
Bone marrow involvement: fatigue, weakness, anaemia, bleeding, infections.
Extra-nodal: bowel obstruction.
SCC, motor/sensory deficits.
Meningeal involvement: headache, mental status
Bone pain
Follicular, transform into more aggressive NHL.
Diagnosis of NHL?
Follicular: large plasmablasts/ immunoblasts. Diagnostic biopsy may not be represenetative esp if abdo mass but periph LN biopsied. Percut needle biopsy of abdo may reveal DLBCL transformation.
Burkitt: starry sky, stars (tangible bodies, macrophages with phagocytosed dead neoplastic cells), sky (dark neoplastic lymphocytes)
Mycosis fungoides: CD4 helper t cells, cerebriform nucleus (looks like brain).
CT/PET
LN biopsy, skin biopsy
Adverse prognostic factors: >60y/o, stage 3/ 4, ↑LDH, performance status, >1 extranodal site involved
FBC: thrombocytopenia, pancytopenia, lymphocytosis, pancytopenia
Blood smear: nucleated RBCs, left shift
Immunohistochemistry/ flow cytometry: determines tumour surface markers
Lymphoplasmacytic: large amounts of basophilic cytoplasm, nucleus contains spoke wheel like chromatin.
Mantle: cells have notched nuclei.
Hairy cell: dry tap on bone marrow aspiration due to fibrosis, CD11c marker, leucopenia.
Ann Arbor system
Management of NHL?
DLCB: Tx immediately, R-CHOP, radiotherapy
Follicular: R-CHOP
Burkitt: rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate.
Mantle: rituximab, R-CHOP
Marginal: H pylori eradication, prognosis good, 6 monthly endoscopy, if spread chemo.
Lymphoplasmacytic: in emergency lower paraprotein by plasmapheresis. Chemo + rituximab.
Cutaneous B cell: excision, radiation. Good prognosis. If multiple sites rituximab.
Angioblastic: responsive to CS or low dose alkylating agents.
Allopurinol for TLS.
T cell: CHOP > no rituximab as no CD20
High grade lymphoma has a worse prognosis but higher cure rate.
Summary of tumour lysis syndrome?
Rapid destruction of tumour cells, massive release of intracellular components, damage kidneys > renal failure
Features - V/N/D, Lethargy, Haematuria, Muscle cramps, Paraesthesia
Complications - Ca phosphate crystals obstruct renal tubules > AKI, urate nephropathy, Cardiac arrhythmias, Tetany
Diagnosis - ↑K, P, ↓Ca due to phosphate binding
Management - Prophylaxis: hydration, avoid NSAIDs, allopurinol.
Tx electrolyte abnormalities
Haemodialysis
Rasburicase
Fluids, ± loop diuretics to aid renal excretion of uric acid crystals.
What is acute lymphoblastic leukaemia?
Most common malignancy affecting children and accounts for 80% of childhood leukaemias.
Lymphoblasts accumulate in BM, suppression, prevent maturation.
peak incidence is at around 2-5 years of age
B>G
common ALL (75%), CD10 present, pre-B phenotype
T-cell ALL (20%)
B-cell ALL (5%)
RFS for ALL?
most common leukaemia in children. B > 3, T > 15-20. 2 peak incidences, 2-5 + >50. Down syndrome (>5), Klinefelter’s, radiation exposure, genetic, Hx of malig, Tx with chemo, smoking
Features of ALL?
Abrupt onset
Pleural effusion
Hyperuricaemia, TLS
anaemia: lethargy and pallor
neutropaenia: frequent or severe infections
thrombocytopenia: easy bruising, petechiae
bone pain (secondary to bone marrow infiltration)
splenomegaly
hepatomegaly
fever is present in up to 50% of new cases (representing infection or constitutional symptom)
testicular swelling
Thymus: palpable mass, airway compression
Lymphadenopathy
Orchidomegaly: unilat
Abdo pain: splenomegaly
Skin infiltration by blast cells
Renal enlargement: infiltration of renal cortex by blast cells
Poor prognostic factors for ALL?
age < 2 years or > 10 years WBC > 20 * 109/l at diagnosis T or B cell surface markers non-Caucasian male sex
Complications for ALL?
Meningeal infiltration: headache, vomiting, nerve palsies, nuchal rigidity, papilloedema
Bone pain, limp in young child
Focal neurological signs: CN 3/4/6/7 CNS leukaemia
DIC
Diagnosis of ALL?
Blood count: ↑lymphocytes, WBCs
BM smear: hypercellular bone marrow, lymphoblast domination >20%. T-ALL starry sky of phagocytosing macrophages.
Condensed chromatin, scant cytoplasm, small nucleoli
↓WCC until spill out causing ↑
↑LDH
CT: mediastinal mass, LN involvement/ CNS infiltration.
B-ALL: CD10/19/20
T-ALL: CD1/2/5/7/H
Terminal deoxynucleotidyl transferase: pos, distinguish from AML
Management of ALL?
Aggressive chemo: prophylactic injections into scrotum, CSF as chemo can’t cross BBB or testicular. Methotrexate
95% remission, 75% cute rate.
Tyrosine-kinase inhib: imatinib
Blood/plt transfusion
Poor prognostic factors: <2 or >10, WBC >20, T/B cell surface markers, non-Caucasian, M
Induction: pred/ dexamethasone + cyclophosphamide + vincristine + doxorubicin
Consolidation Tx
Rituximab if CD20
What is acute myeloid leukaemia?
Acute myeloid leukaemia is the more common form of acute leukaemia in adults. It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder.
Myeloblasts accumulate in BM, suppression > prevents maturation, normal haematopoiesis ↓
Acute promyelocytic: t(15,17) > disruption of retinoic acid receptor > promyelocytes accumulate (cells with heavy granulation in cytoplasm). Good prog Fusion of PML + RARα genes
T(8:21), (q22:q22), inv(16 (p12:q22), t(16, 16)(p13q22) t(15:17), (q22:q12).
RFs for AML?
adult (60), M>F, radiation, benzene, dark coloured hair dyes, smoking, alcohol, agricultural workers, pesticides, fertilisers, chemo (alkylating agents eg cyclophosphamide, melphalan, nitrogen mustard, latency 4-8yrs, topoisomerase inhibs (etoposide, teniposide) latency 1-3yrs), myeloprolif/ haematological disorders eg myelodysplastic synd, anaplastic anaemia, paroxysmal nocturnal haemoglobinuria, polycythaemia vera, essential thrombocytopenia, downs, Klinefelter’s, Patau’s. p53.
Features of AML?
Abrupt onset
Bone marrow failure = Anaemia, thrombocytopenia, neutropenia, splenomegaly, bone pain
Skin or testicular mass
Abdo pain
Sx less common in AML than ALL: bone pain, thymus mass/ airway compression, hepatosplenomegaly, lymphadenopathy, meningeal infiltration.
Sx more common in AML than ALL: skin (leukaemia cutis, nodular skin lesion, purple or gravy-blue colour), Sweet’s syndrome (fever, leukocytosis, tender erythematous well demarcated papules + plaques which show dense neutrophilic infiltrates), pyoderma gangrenosum. Gum swelling, granulocytic sarcomas.
Poor prognostic features of AML?
> 60 years
> 20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
Complications of AML?
DIC Death in 2 mnth if untreated High relapse rate Mediastinal or thymic infiltration: SVCS, airway compromise Febrile neutropenia Leukostasis: ↑blood viscosity
Diagnosis of AML?
Blood smear: granulated + Auer rod content of blasts
Bone marrow smear: ↑myeloblasts >20%, auer rods. Large nucleus, prominent nucleoli, more cytoplasm visible than in ALL. Bone marrow hypercellularity.
↑WCC
Acute promyelocytic: abnormal WBCC, bi lobed nuclei, hyper granulated blasts, bundles of auer rods. DIC + thrombocytopenia at presentation.
FBC: anaemia, macrocytosis, leukocytosis, neutropenia, thrombocytopenia, ↓reticulocytes.
Classification - French-American-British (FAB) MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
Management of AML?
Cytarabine, daunorubicin, idarubicin
Stem cell transplant
APML: tretinoin, arsenic > causes blasts to differentiate,
What is chronic lymphocytic leukaemia?
Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%).
It is the most common form of leukaemia seen in adults.
Mature, functionally abnormal B lymphocytes in BM/ blood. Escape PCD + undergone cell cycle arrest in GO/G1. Suppression.
99% B cells, full maturation + apoptosis prevented, defective, non functional lymphocytes.
Premalig: monoclonal B cell lymphocytosis, where less than requires no of B cells for CLL diagnosis.
CD19/20 + CD5 B cells
Features of CLL?
late onset
B Sx - fever, chills, night sweats, fatigue, WL, anorexia
anaemia, thrombocytopenia, neutropenia
bone pain, hepatosplenomegaly, lymphadenopathy
meningeal infiltration
thymus mass - airway compression
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
Diagnosis of CLL?
full blood count:
lymphocytosis
anaemia
blood film: smudge cells (also known as smear cells)
immunophenotyping is the key investigation
LN biopsy - prolif centres, lymphocyte infiltration
Coombs test - positive if haemolytic present
Rai and Binet staging system
RFs for CLL?
most common leukaemia in adults, M>F, >60, white, FH, agent orange exposure
Complications of CLL?
Abnormal Ig secretion: hypogamma globulinemia, AI haemolytic anaemia
Richter syndrome: progresses to aggressive lymphoma eg DLBC, LN swelling, fever w/o infection, WL, night sweats, nausea, abdo pain
Management of CLL?
Median survival 10 yrs
Chemo
Immunotherapy
Radiation
Bone marrow transplant
Tx if: symptomatic, immunoglobulin genes unmutated, 17p deletion, marrow failure, recurrent infection, splenomeg/ lymphadenopathy, progressive Dx (doubling of lymphocyte count in 6mnths), systemic Sx, haemolysis or AI cytopenias.
What is chronic myeloid leukaemia?
Prolif of mature granulocytes/ precursors, accumulate in BM
Philadelphia Chr: t(9:22) BCR-ABL1 fusion. Strong tyrosine kinase activity
RFs for CML?
adult, >40, M, radiation, benzene
Features of CML?
60-70 years
Gout, purine breakdown, TLS
anaemia, WL, sweating, splenomegaly
Chronic phase: 85% at time of diagnosis. Leucocytosis (pred neutrophils), fatigue, WL, loss of energy, fever, sweats, pallor, abdo discomfort, malaise, headache, priapism.
Blast count <10%
Accelerated: >20% basophils in blood/BM, 10-19% myeloblasts in blood/BM, anaemia, SOB, bleeding, petechiae, ecchymosis, retinal haem, epistaxis, hepatosplenomeg, lymphadenopathy, arthralgia, sternal tenderness (BM expansion of sternum).
Blast crisis: terminal phase, rapid progression, >20% myeloblast in blood/BM. Sig splenomegaly. ↑anaemia, thrombocytopenia, basophilia.
Bone pain, fever.
Complications of CML?
may undergo blast transformation (AML in 80%, ALL in 20%)
Diagnosis of CML?
↑granulocytes > basophils, eosinophils, neurophils, WBCC WBCs bigger, more mature + blast like. ↑urate, B12, K, LDH ↓Plt Normochromic normocytic anaemia BM biopsy: hypercellularity, granulocytic hyperplasia Karyotypic analysis: BCR-ABL1, t(9,22). Pseudo Gaucher cells in marrow ↓leukocyte alkaline phosphatase
Management of CML?
Tyrosine kinase inhib: imatinib Hydroxycarbamide Hydroxyurea IFNα Bone marrow transplant
Summary of hairy cell leukaemia?
a chronic and rare form of adult leukemia
Prolif of abnormal B or very rarely T cells which accumulate in BM + spleen
Features - gradual onset, Anaemia Fever Weight loss, weakness Splenomegaly, lymphadenopathy neutropenia, thrombocytopenia, low monocyte counts
Diagnosis - Blood/BM film: irregular outline due to presence of filament like cytoplasmic projections (hairy rim), immunophenotyping, bone marrow biopsy
Management - Purine analogues 2 chloradenosine acetate Pentostatin Cladribine Rituximab IFN alpha
What is multiple myeloma?
a haematological malignancy characterised by plasma cell proliferation
It arises due to genetic mutations which occur as B-lymphocytes differentiate into mature plasma cells.
MM is the second most common haematological malignancy
Presentation of MM?
median age of onset - 70 yrs
CRABBI
Calcium
- Hypercalcaemia occurs as a result of increased osteoclast activity within the bones
This leads to constipation, nausea, anorexia and confusion
Renal
- Monoclonal production of immunoglobulins results in light chain deposition within the renal tubules
- This causes renal damage which presents as dehydration and increasing thirst
- Other causes of renal impairment in myeloma include amyloidosis, nephrocalcinosis, nephrolithiasis
Anaemia
- Bone marrow crowding suppresses erythropoiesis leading to anaemia
- This causes fatigue and pallor
Bleeding
- bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
Bones
- Bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity creates lytic bone lesions
- This may present as pain (especially in the back) and increases the risk of fragility fractures
- SCC pain
Infection
- a reduction in the production of normal immunoglobulins results in increased susceptibility to infection
Investigations for MM?
Bloods - anaemia, thrombocytopenia, raised urea and creatinine, raised calcium
peripheral blood film - rouleaux formation
serum or urine protein electrophoresis - raised concentrations of monoclonal IgA/IgG proteins will be present in the serum. In urine known as Bence Jones proteins
bone marrow aspiration and trephine biopsy - confirms diagnosis if number of plasma cells is significantly raised
whole-body MRI - surgery skeleton for bone lesions
Xray - rain drop skull - due to bone lysis
Symptomatic multiple myeloma is defined at diagnosis by the presence of the following three factors:
- Monoclonal plasma cells in the bone marrow >10%
- Monoclonal protein within the serum or the urine (as determined by electrophoresis)
- Evidence of end-organ damage e.g. hypercalcaemia, elevated creatinine, anaemia or lytic bone lesions/fractures
Management of MM?
It is important to accurately diagnose multiple myeloma, as unlike its pre-malignant counterparts (Monoclonal gammopathy of undetermined significance and Smoldering myeloma), treatment must begin immediately due to the risk of complications occurring as a result on end-organ damage.
Myeloma is a chronic relapsing and remitting malignancy which is currently deemed incurable. Management aims to control symptoms, reduce complications and prolong survival.
treatment begins with induction therapy:
For patients who are suitable for autologous stem cell transplantation* induction therapy consists of Bortezomib + Dexamethasone
For patients who are unsuitable for autologous stem cell transplantation*, induction therapy consists of Thalidomide + an Alkylating agent + Dexamethasone
After completion of treatment, patients are monitored every 3 months with blood tests and electrophoresis.
Many patients do relapse after initial therapy. If this occurs the 1st line recommended treatment is Bortezomib monotherapy
Autologous transplant: remove own SC prior to chemo + replaced after chemo
Complications of MM?
Pain: treat with analgesia (using the WHO analgesic ladder)
Pathological fracture: Zoledronic acid is given to prevent and manage osteoporosis and fragility fractures as these are a large cause of morbidity and mortality, particularly in the elderly.
Infection: patients receive annual influenza vaccinations. They may also receive Immunoglobulin replacement therapy.
VTE prophylaxis
Fatigue: treat all possible underlying causes. If symptoms persist consider an erythropoietin analogue.
RFs for MM?
alcohol consumption, obesity, radiation exposure, petroleum exposure, FHx, monoclonal gammopathy can progress to MM (initial conc of serum monoclonal protein sig predictor of progression, other prognostic factors< IgA or IgM monoclonal protein, BM plasmacytosis, bence jones proteinuria, ↓in polyclonal serum immunoglobulin, ↑ESR.
Causes of microcytic anaemia?
Find those small cells last: Fe def Thalassaemia minor Sideroblastic Chronic disease Lead poisoning
What is iron deficiency anaemia?
Microcytic, hypochromic
↓Fe for Hb synthesis, impaired erythropoiesis
Most absorption in proximal SI, duodenum + jejunum.
Causes of iron deficiency anaemia?
Low intake: EDs (e.g. pica, anorexia, bulimia), diet restrictions (e.g. vegan), food insecurity
Low absorption: celiac, surgical resection of GIT, bariatric surgery, XS dietary Ca, tannates, oxalates, gastrectomy/ achlorhydria, H pylori
↑need: pregnancy, lactation
↑growth: infants, children, adolescents
Overt loss: haematemesis, trauma, heavy menses, haematuria, multiple blood donations, haemodialysis
Occult: GI bleed (e.g. peptic ulcer, tumour), vascular lesions (e.g. haemorrhoids), hookworm/other helminthic infections
Features of iron deficiency anaemia?
Pallor
Fatigue, activity intolerance, exertional dyspnoea, angina
Palpitations, ↑HR, ↑CO, ↑RR
Selective shunting of blood to vital organs eg skin to kidneys
Glossitis: red, beefy tongue
Angular stomatitis: sores in corner of mouth
Cheilosis: scaling, fissuring: dryness, lip scaling
Koilonychia: spoon-shaped, concave nails.
Brittle hair + nails. Hair loss
Oesophageal stricture + dysphagia
Gastric atrophy, gastritis, absent/↓ acid secretion in stomach
Blue sclerae
Obsessive consumption of ice.
Pica = abnormal craving, for non food substances eg dirt, ice, paint or clay
RLS
Post cricoid webs
Complications of iron deficiency anaemia?
High ouput HF
Angina
Cardioresp failure
Impaired growth/ development
Infections.
Diagnosis of iron deficiency anaemia?
↓ RBCC, low/normal reticulocytes, ↓ Hb, haematocrit. 🡩RDW (>14.6%)
Hypochromic-microcytic erythrocytes
↓MCV, MCH, MCHC
Blood smear: central pallor, target cells. Poikilocytosis (abnormally shaped), pencil cells.
↓iron, ferritin, transferrin saturation ↑total iron binding capacity + transferring receptors.
Older pt: malig til proven otherwise
Endoscopy to rule out malig in males + post menopausal females
Management of iron deficiency anaemia?
Ferrous sulfate, furmarate or gluconate. SE = constipation, black stools. Nausea, diarrhoea, faecal impaction. Continue for 3mnth after def corrected to replenish stores.
Ascorbic acid: aid dietary absorption
Parenteral iron: dextrate/sucrose, severe persistent anaemia, intolerance of PO iron, malabsorption
↑ dietary iron: heam > meat absorbed better than non haem eg eggs, legumes, nuts. Dark leafy vegetables.
Blood transfusion
Levothyroxine, Ca/ bisphosphonates, Quinolones, tetracyclines.
Summary of lead poisoning anaemia?
Lead exposure, toxicity, interferes with enzymatic steps in haem pathway, ↓Hb synthesis, impairs Na/K ATPase in erythrocytes > haemolysis.
RF: water contaminated with industrial waste/ from lead pipes. Leaded paint. Older homes. Breathing industrial emissions (smelters, refineries, battery manufacturing, recycling), food/beverages from lead glazed ceramics.
Small hypochromic RBCs
Dyspnoea
Activity intolerance
Lead toxicity: abdo pain, headache, difficulty concentrating, muscle/joint, confusion, ataxia. Peripheral neuropathy (mainly motor), constipation, blue lines on gum margin.
Ix - ↑ serum blood lead level Basophilic stippling Clover leaf morphology ↓/normal MCV ↓ mean MCH Haemolysis: ↑ indirect bilirubin, LDH, ↓ haptoglobin ↑urinary coproporphyrin
Tx - Eliminate exposure Chelation therapy: dimercaptosuccinic acid (DMSA, aka succimer), CaNa2EDTA D-penicillamine EDTA Dimercaprol
What is thalassaemia?
People with thalassaemia produce either no or too little haemoglobin
AR, microcytic hypochromic, rigid less deformable membranes > extravascular haemolysis, phagocytosis by reticuloendothelial macrophages.
Deficient α/β chains > imbalanced, aggregate + precipitate > unstable Hb tetramer.
What is alpha thalassaemia?
deficiency of alpha chains in haemoglobin
2 separate alpha-globulin genes on each Chr 16
If 1 or 2 alpha globulin alleles are affected then the blood picture would be hypochromic and microcytic, but the Hb level would be typically normal
If are 3 alpha globulin alleles are affected results in a hypochromic microcytic anaemia with splenomegaly. This is known as Hb H disease
If all 4 alpha globulin alleles are affected (i.e. homozygote) then death in utero (hydrops fetalis, Bart’s hydrops)
Minima: carrier, no Sx 1 gene missing
Minor: trait, mild anaemia, 2 genes missing.
HbH disease: 3 genes missing, mild anaemia.
Major: 4 genes missing, hydrops fetalis, Hb Barts (γ tetramer), incompatible with extrauterine life.
What is beta thalassaemia?
Absence of beta globulin chains
Point mutation in Chr11
Minor: 1 gene, trait. Asymptomatic carrier /mild hypo chromic, microcytic anaemia, ↑HbA2 (2 α + 2 delta). No haemolysis
Intermedia: 2 genes. Moderate anaemia Sx, may be transfusion dependent in later life. Haemolysis: splenomeg + gall stones.
Major: no β globin trains produced, transfusion dependent, Cooley’s anaemia. Presents once fully switched from fetal Hb few mnths of life, FTT + hepatosplenomegaly. Microcytic anaemia, HbA2 and HbF raised, HbA absent
Management of thalassaemia
Beta- thalassaemia major - repeated transfusion - leads to iron overload (organ failure) so iron chelation therapy (desferritoxamine) is important
Folic acid
Splenectomy
Blood transfusions >9g.dL
Allogenic haematopoietic cell transplantation
Features of thalassaemia?
Pallor, fatigue, activity intolerance
Tachycardia, ↓BP, arrhythmias
Chronic haemolysis: jaundice, dark urine, hepatosplenomeg
Failure to gain weight
Large head, frontal + parietal bossing, chipmunk facies, misaligned teeth.
Diagnosis of thalassaemia?
β thalassaemia major: microcytic anaemia, ↑reticulocytes. ↑HbA2 + HbF. Absent HbA. Extramedullary haematopoiesis: hepatomeg, bone expansion, XR > hair on end of bones as marrow expands into cortical bone.
↑reticulocytes
↑WBC > generalised haematopoietic hyperactivity, all ↓ as spleen enlarges.
MCHC ↑ related to erythrocyte dehydration
↓MCV ↑RCDW
Blood smear: poikilocytosis (teardrop shaped cells), anisocytosis, erythroblasts (nucleated RBCs), target cells. Inclusions (precipitated globin chains), basophilic stippling
Haemolysis: ↑LDH, UBR, ↓haptoglobin
↑iron, transferrin saturation, ferritin.
β thalassaemia minor: microcytosis often disproportionate to anaemia
α thalassaemia: Heinz bodies. Target cells
What is sideroblastic anaemia?
condition where iron available but red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion.
This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired.
Congenital cause: delta-aminolevulinate synthase-2 deficiency
Acquired causes myelodysplasia alcohol lead anti-TB medications
Features of sideroblastic anaemia?
Syndromic: exocrine pancreatic insuff, hepatic/ renal failure, sensorineural deafness, myopathy
Fatigue, dyspnoea, palpitations, pallor
Mild jaundice if haemolysis significant
Investigations for sideroblastic anaemia?
full blood count
- hypochromic microcytic anaemia (more so in congenital)
- low reticulocyte count
iron studies (haemochromatosis)
- high ferritin
- high iron
- high transferrin saturation
blood film
- basophilic stippling of red blood cells, anisocytosis, poikilocytosis, hypochromic, iron containing inclusions (Pappenheimer bodies),
bone marrow
- Prussian blue staining will show ringed sideroblasts
Management of sideroblastic anaemia?
supportive
treat any underlying cause
Via B6 pyridoxine may help
Chelation - deforxamine
Complications of sideroblastic anaemia?
Iron overload > haemochromatosis
Anaemia induced acceleration of erythropoiesis > erythroid hyperplasia of BM
↑risk of infection
Acute leukaemia
Causes of normocytic anaemia
Insuff production of erythrocytes:
Anaemia of chronic disease
CKD
Anaplastic anaemia
Haemolytic anaemia
Causes of anaemia of chronic disease?
Infection, RA, malig, CKD, IBD, TB, endocarditis, hypopit/thyroid/adrenal
↓iron release from BM to developing erythroblasts, inadequate EPO response to anaemia, ↓RBC survival
Inhibition of erythropoiesis, ↓erythrocyte lifespan
Features of anaemia of chronic disease?
Hypoxia, pallor, fatigue, dyspnoea, activity intolerance
Sx of underlying condition
Investigations of anaemia of chronic disease?
↓Hb, iron, (TIBC), transferring sat, reticulocyte count.
↑/normal ferritin as acute phase protein.
↑ESR/CRP/IL6
↓EPO
Normochromic normocytic or hypochromic microcytic
BM: ↑iron in macrophages, erythroid precursors.
Management of anaemia of chronic disease?
Treat cause
Renal failure: recombinant EPO
Supplemental iron: IV iron due to systemic inflam
Transfusion
What is aplastic anaemia?
Characterised by pancytopenia (low RBC, WBC and plts) and a hypoplastic bone marrow
due to BM hypoplasia/aplasia
↓reduction in no of pluripotent SC, inefficiency with remaining ones.
Peak incidence of acquired = 30 years old
Features of aplastic anaemia?
normochromic, normocytic anaemia
leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
Fanconi - ↑risk of AML, neurological Sx, short stature, Café Au Lait spots. Hearing loss
Dyskeratosis congenita: osteoporosis, premature hair loss/ premature greying, hyperhidrosis, dysphagia due to oesophageal stricture, extensive dental carries or tooth loss.
Schwachman-Diamond: steatorrhea, skeletal dysplasia
GATA2: monocytopenia, non TB mycobacterial infection, pulmonary alveolar proteinosis, congen lymphoedema, Emberger syndrome. Hearing loss, persistent warts.
Causes of aplastic anaemia?
idiopathic
congenital: Fanconi anaemia, dyskeratosis congenita
drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
toxins: benzene
infections: parvovirus, hepatitis
radiation
Investigations for aplastic anaemia?
Prolonged bleeding time
↓Hb, haematocrit, neutrophils, plts reticulocytes.
Normal erythrocyte morphology
BM: hypocellular, ↑fat spaces, some lymphocytes, plasma cells, stromal elements eg blastoid cells, no ↑ in blasts/ dysplasia.
Leukopenia with lymphocytes relatively spared.
Management of aplastic anaemia?
Antimicrobials for infections
Stem cell transplant
Transfusions: plts, RBCs. ↑risk of alloimmunisation, graft rejection after BM transplant.
GFs: granulocyte colony stimulating factor for freq/ severe infections, thrombopoietin receptor agonists with immunosuppressive therapy.
IS therapy: lymphocyte immunoglobulin, anti-thymocyte globulin, methylprednisolone, ciclosporin.
What is haemolytic anaemia?
↑destruction of red cells + ↓circulating lifespan. BM unable to compensate for loss.
Extravascular: within reticuloendothelial system, removed from circulation as are defective.
Intravascular: within BVs eg trauma, complement fixation or extrinsic factors
Causes of haemolytic anaemia?
RBC membrane defect: hereditary spherocytosis, hereditary elliptocytosis
Thalassaemia, sickle cell
RBC met defects: G6PD def, pyruvate kinase def
AI, transfusion reactions, drug induced
Paroxysmal nocturnal haemoglobinuria, microangiopathic, march haemoglobinuria
Infections (e.g. malaria, babesiosis, bartonellosis, leishmaniasis, clostridium perfingens, Haem influenzae B), drugs/ chemicals (cephalosporins, penicillin, quinine derivatives, NSAIDs, naphthalene or fava beans), hypersplenism, trauma, exceptional exertion (circulatory trauma), liver disease.
Lymphoprolif disorders
Mechanical prosthetic heart valves
Features of haemolytic anaemia?
Jaundice
Hepatosplenomeg
Pallor, fatigue, activity intolerance, SOB, dizziness
Orthostasis
IV: haemoglobinuria, iron def
EV: jaundice, splenomeg, gallstone formation.
Episodic dark urine
Investigation for haemolytic anaemia?
↓haptoglobin
Polychromasia: purplish appearance of RBC due to reticulocytes.
↑UBR, urinary urobilinogen, reticulocytes, LDH
Normocytic normochromic anaemia
Marrow hyperplasia
↑MCHC
Blood film: polychromasia, macrocytosis, spherocytes, elliptocytes, fragmented cells or sickle cells. Bite or spur cells. Schistocytes (helmet cells) in IV haemolysis
G6PD: Heinz bodies
Pyruvate kinase def: burr cells, echinocytes
Urine: Perl’s reaction (detects high levels of hemosiderin due to Hb), Schumm’s test can also show high Hb levels.
What is AI haemolytic anaemia?
Autoantibodies against antigens on RBC surface
Divided into warm and cold, types, according to at what temperature the antibodies best cause haemolysis.
It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infection or drugs.
Investigations for AI haemolytic anaemia?
general features of haemolytic anaemia - anaemia - reticulocytosis - low haptoglobin - raised lactate dehydrogenase (LDH) and indirect bilirubin
blood film: spherocytes and reticulocytes
specific features of autoimmune haemolytic anaemia
- positive direct antiglobulin test (Coombs’ test).
Summary of warm AIHA?
Warm is the most common type of AIHA. In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen.
Causes of warm AIHA
- idiopathic
- autoimmune disease: e.g. systemic lupus erythematosus*
- neoplasia (lymphoma, chronic lymphocytic leukaemia)
- drugs: e.g. methyldopa
Management
- treatment of any underlying disorder
- steroids (+/- rituximab) are generally used first-line
Summary of cold AIHA?
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud’s and acrocynaosis. Patients respond less well to steroids
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
often no Tx required
Summary of paroxysmal AIHA?
children Donath-Landsteiner, viral/ bacterial infections, dark urine in morning.
jaundice, haemoglobinuria, anaemia after infection, pain in legs + back following cold exposure.
What is G6PD deficiency?
is the commonest red blood cell enzyme defect.
It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion.
Many drugs (antimalarials (primaquine), ciprofloxacin, sulph-group drugs. (sulphonamides, sulphasalazine, sulfonylureas) can precipitate a crisis as well as infections and broad (fava) beans
G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone
this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress
Features of G6PD deficiency?
neonatal jaundice is often seen
intravascular haemolysis
gallstones are common
splenomegaly may be present
Heinz bodies on blood films.
Bite and blister cells may also be seen
Diagnosis of G6PD deficiency?
Damage to Hb within cells > Heinz bodies. Splenic macrophages attempt to remove Heinz bodies > bite, blister cells
↓Hb, haptoglobin
Neg coombs
↑BR, LDH
Reticulocytosis
G6PD enzyme assay
levels should be checked around 3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results
Newborn screening
Fluorescent spot test: glucose 6 phosphate + NADP added to haemolysate of RBCs > fluorescence of NADPH
Methaemoglobin reduction test: methylene blue measures transfer of hydrogen ions from NADPH to methaemoglobin > indirectly estimates NADPH generation by G6PD.
Management of G6PD deficiency?
Folic acid supplements
Eliminate triggers
Phototherapy
Haemolytic ep: hydration, transfusions
Splenectomy not beneficial
Summary of haemolytic disease of newborn?
Fetomaternal haem > exposes maternal circulation to antigens on RBCs > formation of maternal IgG against fetal RBCs > cross placenta > agglutination, haemolysis.
Causes of maternal sensitisation: delivery, abortion, maternal trauma, CVS, amniocentesis, antenatal haem, idiopathic
RF: blood group incompatibility.
ABO incompatibility: mild to mod hyperbilirubinemia within 1st 24hrs of life, mild to mod anaemia.
Rh incompatibility: kernicterus, hyperbilirubinaemia. Sx anaemia: pallor, lethargy, ↑HR/RR. Hydrops fetalis.
IUGR
Complications: Anaemia Hyperbilirubinemia Kernicterus Growth restriction Hydrops fetalis Erythroblastosis fetalis ↑immature RBCs in fetal circulation
Ix:
Doppler USS: restriction, hydrops.
Antenatal: pos indirect antiglobulin test (IAT, indirect Coombs, IgG), Kleihauer-Betke (pos if fetomaternal haem), percut umbilical blood sampling (measures Hb, haematocrit, identifies fetal blood type). Spectrophotometric amniotic fluid analysis: ↑BR if haemolysis has occurred.
Postnatal: blood typing pos direct antiglobulin (DAT, direct Coombs test, maternal Ig on RBC), ↑BR, ↓Hb, haematocrit, RBCs, reticulocytes.
Blood smear: haemolysis, polychromasia, microspherocytosis.
Haematopoietic agents: epoetin alfa/ darbepoetin, iron supplements. Iron supplements RBC transfusion Exchange transfusion Phototherapy IV immunoglobulin: ↓haemolysis
What is hereditary spherocytosis?
most common hereditary haemolytic anaemia in people of northern European descent
autosomal dominant defect of red blood cell cytoskeleton
the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
red blood cell survival reduced as destroyed by the spleen
mutation in spectrin, ^ Na permeability
Presentation of hereditary spherocytosis?
often asymptomatic
failure to thrive
jaundice, gallstones
anaemia Sx
splenomegaly
MCHC elevated
complications:
- aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
- megaloblastic anaemia - folate deficiency
- neonatal incterus, hydrops fetalis, fetal death
Diagnosis of hereditary spherocytosis?
patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests
↓Hb, haptoglobin
↑reticulocytes, RDW, BR, LDH, MCHC
Spherocytes (round, lack central pallor) schistocytes (RBC fragment)
Osmotic fragility test
if the diagnosis is equivocal the BJH recommend the EMA binding test and the cryohaemolysis test
for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
Management of hereditary spherocytosis
acute haemolytic crisis:
- treatment is generally supportive
- transfusion if necessary
longer term treatment:
- folate replacement
- splenectomy - wait until after childhood as can prevent response to fatal infections, life long penicillin prophylaxis
- phototherapy
What is paroxysmal nocturnal haemoglobinuria
is an acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
X linked. Nocturnal haemolysis, haemolytic anaemia, BM failure, thrombosis
PIGA gene mutation, required for synthesis of GPI on cell surface, anchors glycoproteins on surface protecting cell from lysis. Def = complement mediated IV haemolysis.
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
Features of paroxysmal nocturnal haemoglobinuria
- haemolytic anaemia
- variable Sx according to degree of GPI loss
- red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
- intermittent episodes of haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day) with haemolysis during night
- thrombosis e.g. Budd-Chiari syndrome
- aplastic anaemia may develop in some patients
- Haemolysis in ↑ complement: infections, surgery, blood transfusion, strenuous exercise, XS alcohol.
Diagnosis and management of paroxysmal nocturnal haemoglobinuria
Diagnosis:
- normal RBC morphology
- Occasional poikilocytosis + anisocytosis
- Normochromic
- Normal/↓: hb, reticulocytes
- ↑BR, LDH, ↓haptoglobin
- flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
- Ham’s test: acid-induced haemolysis (normal red cells would not)
Management:
- blood product replacement
- anticoagulation
- eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
- stem cell transplantation
What is pyruvate kinase deficiency?
Chronic premature haemolysis, hyperreactive erythropoiesis
AR mutation of PK-LR
Haemolysis primarily extravascular, IV variable
Block in glycolysis, accumulation of 2,3-BPG shifts oxyhaemoglobin dissociation curve to right improved O2 delivery to tissues > better tolerance of haemolytic anaemia.
ATP def
↓RBC ↑reticulocytes, serum glycolytic 2,3-BPG Haemoglobinuria, hemosiderinuria ↓PK enzymatic activity, PK-LR gene mutation ↑BR, LDH, ↓haptoglobin Burr cells: echinocytes
Splenectomy
Allogeneic haematopoietic cell transplantation
Chelation therapy: ↓iron related organ damage.
Phototherapy
Exchange transfusion
What is sickle cell anaemia?
is an autosomal recessive condition that results for synthesis of an abnormal haemoglobin chain termed HbS
It is more common in people of African descent as the heterozygous condition offers some protection against malaria
Around 10% of UK Afro-Caribbean’s are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic
haemoglobin
normal haemoglobin: HbAA
sickle cell trait: HbAS
homozygous sickle cell disease: HbSS. Some patients inherit one HbS and another abnormal haemoglobin (HbC) resulting in a milder form of sickle cell disease (HbSC)
RBCs containing HbS polymerise, deform into sickle/ crescent shaped forms when deoxygenated. Sickle cells less deformable, ↓lifespan due to haemolysis, can obstruct small vessels
Features of sickle cell anaemia?
Symptoms in homozygotes don’t tend to develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.
Mild to mod anaemia, stable Hb of 60-80, but acute falls due to splenic sequestration
Persistent pain in chest/ skeleton
gallstones
Dactylitis: swollen dorsa of hands + foot
FTT
Jaundice
Tachycardia
Renal papillary necrosis
Thrombotic crisis
Sequestration crisis: sickling within organs such as spleen or lungs, pooling of blood with worsening anaemia. ↑reticulocytes
Aplastic crisis: sudden ↓in Hb ↓reticulocytes, parvovirus
Haemolytic crisis: ↓Hb ↑reticulocytes
Acute chest syndrome: infection, fat from necrotic marrow or acute sequestration. Vicious cycle > block vessels, preventing other RBCs becoming oxygenated > hypoxic vasoconstriction > harder to further oxygenate blood. SOB, CP, pul infiltrates, hypoxia > death within hrs.
Investigations of sickle cell anaemia?
definitive diagnosis of sickle cell disease is by haemoglobin electrophoresis
↓Hb, haematocrit, RBCC
↑reticulocytes, WBCC
Target cells
Normochromic normocytic
Howell Jolly bodies: hyposplenia, purple, perph in RBC.
↑UBR, LDH, ↓haptoglobin
Hb electrophoresis: fetal Hb predominante in new borns, older infants ↑HbS.
DNA based assays
Cellulose acetate electrophoresis: sickle cell anaemia 75-95% HbS, HbA absent, sickle cell trait 40% HbS, <2% HbF, 60% HbA.
Hb solubility testing
Peripheral blood smear: nucleated RBCs, sickle shaped cells
Complications of sickle cell disease?
Anaemia: aplastic crisis
Stroke, TIA, seizures
Pain: vaso-oclusion, tissue ischaemia infarction, dactylitis (acute pain in small bones of hands/feet esp kids)
↑risk of infection: due to hyposplenism from multiple eps of splenic sequestration + ↓perfusion.
MI, dysrhythmias, HF, cardiomeg, VTE leg uclers, sudden death
Priapism, ED, preg complications eg IUGR, fetal death, LBW, preeclampsia
Osteoporosis, bone infarction, AVN of bone, expansion of medullary cavity, enlarged cheeks, hair on end of bone
Prolif retinopathy, retinal detachment
Management of sickle cell anaemia?
Prophylaxis of infection, with penicillin, influenza/ pneumonia vaccines (every 5 yrs), stay hydrated, don’t get too cold, don’t drink alcohol, don’t smoke.
Crisis: O2 (↓sickling), fluids, analgesia, blood transfusion, Abx if infection.
Hydroxyurea: hydroxycarbamide decrease cell deformability, decrease RBC endothelial adhesion, ^HbF levels, ↓sickling.
L-glutamine:↓ sickling
Crizanlizumab
Voxelotor
What is macrocytic anaemia?
divided into causes associated with a megaloblastic bone marrow and those with a normoblastic bone marrow
megaloblastic causes: vitamin B12 deficiency folate deficiency (causes - atrophic gastritis (2' to H. Pylori), gastrectomy, phenytoin, methotrexate, pregnancy, alcohol excess)
normoblastic causes: alcohol liver disease hypothyroidism pregnancy reticulocytosis myelodysplasia drugs: cytotoxics
Features of microcytic anaemia?
Fatigue, dyspnoea Weight loss, pallor Impaired conc/memory Diarrhoea Oncychoschizia (brittle nails) Anaemia Sx ↑Haemolysis: jaundice, splenomegaly, lemon tinge Neuronal demyelination: numbness, tingling, subacute combined degen of SC (progressive weakness, ataxia + paraesthesia), memory loss, poor concentration, depression, irritability Glossitis > sore tongue + mouth
↑risk of gastric Ca
Neural tube defects
Investigations of microcytic anaemia?
Megaloblastic: erythroblasts within BM, large, immature nucleus ↑nuclear: cytoplasmic ratio as can’t mature.
↑MCV, MCH
Normal MCHC
Hypersegmented neutrophils, 6+ lobes in nucleus.
Poikilocytosis
Macroovalcoytes (large oval cells/ macrophages)
↓reticulocyte count, Hb + haematocrit
Pernicious anaemia: anti IF antibody, antigastric parietal cell.
Management of megaloblastic anaemia?
B12: 3 injections per wk, for 2 wks, followed by 3 monthly injections
Must replace B12 before folate to avoid precipitating subacute combined degen of cord
5mg folic acid daily for 4 months
Summary of pernicious anaemia?
autoimmune disorder affecting the gastric mucosa that results in vitamin B12 deficiency
antibodies to intrinsic factor +/- gastric parietal cells
intrinsic factor antibodies → bind to intrinsic factor blocking the vitamin B12 binding site
gastric parietal cell antibodies → reduced acid production and atrophic gastritis. Reduced intrinsic factor production → reduced vitamin B12 absorption
vitamin B12 is important in both the production of blood cells and the myelination of nerves → megaloblastic anaemia and neuropathy
more common in females (F:M = 1.6:1) and typically develops in middle to old age
associated with other autoimmune disorders: thyroid disease, type 1 diabetes mellitus, Addison’s, rheumatoid and vitiligo
more common if blood group A
other features:
- mild jaundice - combined with pallor - ‘yellow tinge’
- glossitis - sore tongue
Ix - microcytic anaemia, hypersegmented polymorphs on blood film, low WCC and platelets, vit B12 and folate levels, anti intrinsic factor antibodies, anti gastric parental cell antibodies
^ risk of gastric ca
Tx - vit B12 replacement IM, folic acid supplementation
Summary of diamond blackfan anaemia?
an inherited blood disorder that affects the ability of the bone marrow to produce red blood cells. In some cases there is also short stature
Inheritance is typically autosomal dominant , but can rarely be X-linked
AD ribosomopathy, BM failure/ aplasia, impaired haematopoiesis, macrocytic normochromic.
Anaemia often at birth
LBW, growth restriction
Craniofacial: low set ears, micrognathia, high arched/ cleft palate, broad nasal bridge.
Short webbed neck
Ophthalmological: congen glaucoma, cataracts, strabismus
Thumbs: duplex/bifid, flat thenar eminence
Absent/ horseshoe kidney
VSD/ASD, coarctation of aorta
Predisposition to: leukaemia, myelodysplastic syndrome, solid tumours.
Usually diagnosed within 1 mnth of life
Renal imaging/ echo
↓RBCC, hb, haematocrit, reticulocytes
↑MCV, MCH, WBC, plt
Bone marrow aspirate normal, except few/no erythroid precursors
↑EPO, fetal Hb due to stress haematopoiesis
↑eADA
25% spont remission Allogenic haematopoietic stem cell transplant Monitor for malig development Transfusions Steroids
Summary of Fanconi anaemia?
Autosomal recessive/X linked
Macrocytic normochromic anaemia
Aplastic anaemia
Features - haematological: aplastic anaemia increased risk of acute myeloid leukaemia - neurological - skeletal abnormalities: short stature thumb/radius abnormalities - cafe au lait spots
Usually diagnosed within 1st 8 yrs of life.
Androgen therapy: oxymetholone.
SC transplant
GF: G-CSF, GM-CSF, thrombopoietin mimetics eg romiplostim
Plt transfusion if <10,000, severe bleeding/ bruising
Leukoreduced irradiated RBCs
What is disseminated intravascular coagulation?
a serious disorder in which the proteins that control blood clotting become overactive.
In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein (tissue factor =TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage.
Upon activation, TF binds with coagulation factors that then triggers the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation
Causes of disseminated intravascular coagulation?
sepsis
trauma
obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)
malignancy
Typical blood picture of DIC?
↓ platelets ↓ fibrinogen ↑ PT & APTT ↑ fibrinogen degradation products schistocytes due to microangiopathic haemolytic anaemia
(low P+F, high PT, APTT, and FDP)
PT - extrinsic pathway
aPPT - intrinsic pathway
Features of DIC?
Acute: bleeding, ecchymoses, petechiae, purpura, blood oozing from gingival/ oral mucosa, sites of trauma, catheters, IV lines. Haematuria.
Chronic: thromboembolism, tissue hypoxia, infarction
Complications of DIC?
Widespread thrombosis, ischaemia, necrosis of brain, heart, kidneys, liver, lungs, adrenals, spleen > organ dysfunction
ARDS
PE
Waterhouse Frederiksen syndrome
Microangiopathic haemolytic anaemia
Life threatening bleeding
Management of DIC?
O2 IV fluids
Replace clotting factors, FFP, cryoprecipitate, fibrinogen
Plt transfusion <30,000
What is haemophilia
an X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition.
Haemophilia A is due to a deficiency of factor VIII. X linked recessive
Haemophilia B (Christmas disease) there is a lack of factor IX, X-linked
Features of haemophilia?
Asymptomatic/ spont bleeding
Fatigue: iron def anaemia if sig bleeding
Pallor, ↑HR, RR, ↓BP.
haemoarthroses
haematomas
prolonged bleeding after surgery or trauma
haematuria
menorrhagia
Ix of haemophilia?
prolonged APTT (as only intrinsic pathway affected)
bleeding time, thrombin time, prothrombin time normal
normal plt count
XR - acute joint bleeding, or bone changes of chronic arthropathy
CT/MRI - bleeding
Management of haemophilia?
Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment.
F8 infusions 2X daily 12hr ½ life. If severe. Can be frozen + administered at home.
Avoid sports, trauma, meds that promote bleeding.
Mild haem A: desmopressin, stimulates vWF release, promotes stabilisation of residual F8.
Antifibrinolytic: aminocaproic/ tranexamic acid
RFs for haemophilia?
peritoneal dialysis, genetics, FH, M>F, F carriers only way can occur in F is if 1X Chr, Turner’s
What is Von Willebrand’s disease?
the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
Role of von Willebrand factor
- large glycoprotein which forms massive multimers up to 1,000,000 Da in size
- promotes platelet adhesion to damaged endothelium
- carrier molecule for factor VIII
Types
- type 1: partial reduction in vWF (80% of patients), most common, AD, quatitative def
- type 2*: abnormal form of vWF, qualitative
- type 3**: total lack of vWF (autosomal recessive)
Investigation for Von Willebrand’s disease?
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
PTT prolonged, PT normal, prolonged bleeding time.
Abnormal PFA-100
↓F8 + vWF
defective platelet aggregation with ristocetin
Management of Von Willebrand’s disease?
tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
factor VIII/vWF concentrate - after major injury, during operation
Plt transfusion
RF for Von Willebrands disease?
FH, consanguineous relationship, lymphoprolif disorders, AS, myeloprolif disorders, hypothyroid
Features of Von Willebrands disease?
Typically asymptomatic
Surgery/ trauma provoke clinical manifestation
Spont mucosal, cutaneous bleeding (epistaxis, easy bruising, bleeding from wounds, bleeding gums)
Menorrhagia, PPH
GI bleed
Internal/ joint bleeding
Haemarthrosis
What is immune thrombocytopenia?
Immune (or idiopathic) thrombocytopenic purpura (ITP) is an immune-mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex
Children with ITP usually have an acute thrombocytopenia that may follow infection or vaccination. In contract, adults tend to have a more chronic condition.
Presentation of ITP
may be detected incidentally following routine bloods
symptomatic patients may present with
- petichae, purpura
- bleeding (e.g. epistaxis)
- catastrophic bleeding (e.g. intracranial) is not a common presentation
Management of ITP
first-line treatment for ITP is oral prednisolone
pooled normal human immunoglobulin (IVIG) may also be used
- it raises the platelet count quicker than steroids, therefore may be used if active bleeding or an urgent invasive procedure is required
splenectomy is now less commonly used
Mycophenolate, thrombopoietin receptor agonist, rituximab, fostamatinib.
Children:
- usually, no treatment is required
- ITP resolves in around 80% of children with 6 months, with or without treatment
- advice to avoid activities that may result in trauma (e.g. team sports)
- other options may be indicated if the platelet count is very low (e.g. < 10 * 109/L) or there is significant bleeding. Options include:
- oral/IV corticosteroid
- IV immunoglobulins
- platelet transfusions can be used in an emergency (e.g. active bleeding) but are only a temporary measure as they are soon destroyed by the circulating antibodies
What is Evan’s syndrome?
ITP in association with autoimmune haemolytic anaemia (AIHA)
Investigations of ITP
Adults: plt auto-Ig, thrombocytopenia, diagnosis of exclusion.
↓Plt.
Normal: Hb, LDH, BR, haptoglobin, reticulocytes, schistocytes.
Children:
full blood count
- should demonstrate an isolated thrombocytopenia
blood film
bone marrow examinations is only required if there are atypical features e.g.
- lymph node enlargement/splenomegaly, high/low white cells
- failure to resolve/respond to treatment
Causes of ITP?
Kids: viral infection VZV, measles, glandular fever, vaccination. More common
Adult: AI disease, after infection eg HIV
Evan’s syndrome: ITP in association with AI haemolytic anaemia.
Drugs: quinidine, phenytoin, valproic acid, rifampin, trimeth, sulfonamide.
Features of ITP?
Kids: acute onset, 2-6y/o, mucocutaneous bleeding, spont nose bleeds, bleed after a cut, petechial/purpuric rash. Life threatening haem rare normally only in response to trauma. Often resolves spont over 1-2 wks, chronic if >1 yr.
Adult: less acute, young-middle aged women. Major haem rarely seen, easy bruising, purpura, epistaxis, menorrhagia. RR course.
What is heparin induced thrombocytopenia?
occurs when heparin dependent IgG antibodies bind to heparin/platelet factor 4 complexes to activate platelets and produce a hypercoagulable state.
a prothrombotic disorder caused by antibodies to complexes of platelet factor 4 (PF4) and heparin
RFs for heparin induced thrombocytopenia?
RF: unfractionated > LMWH, F>M
Heparin: activates antithrombin 3, complex that inhibits thrombin, 10, 9, 12.
LMWH: activates antithrombin 3, forms complex that inhibits factor 10.
Features of heparin induced thrombocytopenia?
Usually not sufficient enough to cause sig bleeding.
Skin necrosis at injection site
Acute systemic reaction after IV heparin bolus: fever with chills, ↑HR, BP, RR.
Limb ischaemia, organ infarction.
Complications of heparin induced thrombocytopenia?
VTE
Occlusion of LL arteries by plt rich white clots > limb ischaemia, necrosis, gangrene, loss of limbs
Skin necrosis
Organ infarction: kidney, MI cerebrovasculat
Adrenal haem
Heparin induced anaphylactoid
Ix for heparin induced thrombocytopenia?
HIT immunoassay: ELISA for anti-PF4.
Colorimetric change > optical density, HIT antibody conc, ↑OD = ↑ antibody titre
Functional assay: serotonin release assay > serotonin release from plts. Ability of HIT Ig to activate test plts.
Heparin induced plt aggregation assay
4Ts: thrombocytopaenia ↓plt, timing, fall in plts 5-10 days after heparin, thrombosis, no oTher explanation.
Schistocytes.
Normal: Hb, LDH, BR, haptoglobin, reticulocytes, schistocytes
Tx for heparin induced thrombocytopenia?
Immediate discontinuation of heparin
Non-heparin coag eg fondaparinux, argatroban, danaparoid
Transition to warfarin
Thormboembolectomy
Heparin overdose: protamine sulphate
What is thrombotic thrombocytopenic purpura?
Def ADAMTS13 protease > can’t break down vWF > XS accumulation > ↑ propensity for plts to attach/ accumulate > plt rich thrombi
Consumptive thrombocytopenia
Overlap with HUS
RF for thrombotic thrombocytopenic purpura?
F, African, SLE, sepsis, liver disease, pancreatitis cardiac surgery ↓ADAMTS13 pregnancy (↓ADAMTS13, ↑vWF 2nd -3rd trim). Post infection, ciclosporin, oral contraceptive pill, penicillin, acyclovir, clopidogrel, tumours, SLE, HIV.
Features of thrombotic thrombocytopenic purpura?
Pentad: thrombocytopenia, MAHA, renal dysfunction, neurologic impairment, fever
Rare - typically adult females
Mucocut bleeding: petechiae, purpura, epistaxis, gingival bleeding
IV haemolysis: dark urine
Light headed, abdo pain, easy bruising
N/V
Fluctuation neuro signs > microemboli
Complications of thrombotic thrombocytopenic purpura?
Tissue ischaemia
Organ dysfunction
Microangiopathic haemolytic anaemia
Renal insuff
Focal neurological/ mental status anomalies
Arrhythmias
Overlaps with HUS
Ix of thrombotic thrombocytopenic purpura?
MAHA: schistocytes ↓plt, hb, haematocrit ↑reticulocyte Spherocytes ↑LDH, BR, ↓haptoglobin ↑Cr ADAMTS13 assay: measures degradation of vWF by ADAMTS13
Management of TTP?
GC
Plasma exchange: source of ADAMTS-13, remove auto-Ig.
Causes of TTP?
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
What is polycythaemia vera?
a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets.
It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with polycythaemia vera and this has resulted in significant changes to the diagnostic criteria. The incidence of polycythaemia vera peaks in the sixth decade
↑RBCs independent of EPO. ↑blood viscosity
Abnormal blood flow, defective plt function > vein thrombosis, infarcts bleeding.
Features of polycythaemia vera?
hyperviscosity
pruritus, typically after a hot bath (due to ^ basophils, causing histamine release)
splenomegaly
haemorrhage (secondary to abnormal platelet function) - Bleeding gums, epistaxis, GI bleed, ecchymosis
plethoric appearance
hypertension in a third of patients
Erythromelalgia: hyperaemic + inflamed extremities due to microvascular exclusion
low ESR
facial redness
angina, intermittent claudication
Ix for polycythaemia vera?
Excl 2° polycythaemia: ↑EPO
full blood count/film (raised RBC, haematocrit; Hb, neutrophils, basophils, platelets, LDH, uric acid, raised in half of patients)
JAK2 mutation
serum ferritin
renal and liver function tests
If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests:
- red cell mass
- arterial oxygen saturation
- abdominal ultrasound
- serum erythropoietin level
- bone marrow aspirate and trephine
- cytogenetic analysis
- erythroid burst-forming unit (BFU-E) culture
Also low ESR and raised leukocyte alkaline phosphatase
↓EPO, ESR
Bone marrow aspiration: hypercellularity with trilineage growth (panmyelosis), erythroid, granulocytic + megakaryocytic prolif with pleomorphic, mature megakaryocytes.
JAK 2 mutation
↓MCV, ferritin, Fe def.
↑leukocyte ALP
Management of polycythaemia vera?
aspirin
- reduces the risk of thrombotic events
venesection
- first-line treatment to keep the haemoglobin in the normal range
chemotherapy - decrease RBC production
- hydroxyurea - slight increased risk of secondary leukaemia
- phosphorus-32 therapy
IFNα: ↑RBC destruction, peginterferon α 2a.
Prognosis of polycythaemia vera?
thrombotic events are a significant cause of morbidity and mortality
5-15% of patients progress to myelofibrosis
5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment)
Causes of polycythaemia vera?
Reactive: dehydration + stress.
1°: XS prolif of progenitor cells, XS RBC often neutrophilia + plts. JAK2 mutation. EPO receptor mutation
2°: inappropriate activation of erythropoiesis > high altitude, smoking, chronic lung disease, CVD, OSA, renal disease, HCC, adrenal tumours, cerebellar haemangioma, hypernephroma, uterine fibroids.
Complications of polycythaemia vera?
Abnormal blood flow
Hyperuricaemia: ↑cell turnover. Gout
Spent phase: myelofibrosis (>AML), extramedul haematopoiesis in liver, spleen.
HTN
Budd-Chiari, DVT
MI
Stroke
What is essential thrombocytosis?
Thrombocytosis is an abnormally high platelet count, usually > 400 * 109/l.
Overproduction of megakaryocytes in BM
↑Plt, abnormally shaped ↓Plt survival.
JAK2, MPL, calreticulin
Cause: reactive (acute phase protein), malig, part of myeloprolif disorder > PV, hyposplenism, CML, myelofibrosis
Features of essential thrombocytosis?
platelet count > 600 * 109/l
asymptomatic
both thrombosis (venous or arterial) and haemorrhage can be seen
a characteristic symptom is a burning sensation in the hands
Thrombosis: ischaemia, stroke, erythromelalgia
Headache, dizziness, fatigue, vision loss, abdo pain, nausea
Paradoxical bleed: epistaxis, bleeding gums, ecchymoses
Splenomegaly
a JAK2 mutation is found in around 50% of patients
Management of essential thrombocytosis?
high risk:
- hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
- interferon-α is also used in younger patients
low-dose aspirin may be used to reduce the thrombotic risk if low risk
severe - plt pheresis, removal of plts from blood d
Ix for essential thrombocytosis?
↑Plt, anisocytosis (RBC unequal size)
↑bleeding time
BM aspiration: normal cellularity
Hx of thrombosis, bleeding, vasomotor Sx, 1st trimester fetal loss
What is myelodysplastic syndrome?
Abnormal ineffective haematopoiesis > peripheral cytopenia
BM failure of all myeloid lines, blast accumulation <20%
Idiopathic
Toxins, IS agents, chemo, radiation
Genetic
> 70y/o
acquired neoplastic disorder of hematopoietic stem cells
pre-leukaemia, may progress to AML
more common with age
presents with bone marrow failure (anaemia, neutropaenia, thrombocytopenia)
Features of myelodysplastic syndrome?
Anaemia
Neutropenia
Thrombocytopaenia
Pre-leukaemia
Complications of myelodysplastic syndrome?
AML/CML
Most succumb to bleeding/ infections before AML
Ix of myelodysplastic syndrome?
↓RBC, WBC, pLT Normal/ ↑MCV, ↑RDW ↓reticulocytes ↑blasts Bilobed neutrophils, ring sideroblasts, megaloblastoid maturation, nuclear budding abnormalities, pawn ball megakaryocytes
Tx of myelodysplastic syndrome?
TNF inhibs: lenalidomide, thalidomide
Allogenic haematopoietic stem cell transplant
What is myelofibrosis?
- a myeloproliferative disorder
- thought to be caused by hyperplasia of abnormal megakaryocytes
- the resultant release of platelet derived growth factor is thought to stimulate fibroblasts
- haematopoiesis develops in the liver and spleen
- ↓all cell types
- JAK2, MPL, calreticulin
- Late in course of PV/ET
Features of myelofibrosis?
e.g. elderly person with symptoms of anaemia e.g. fatigue (the most common presenting symptom)
massive splenomegaly
hypermetabolic symptoms: weight loss, night sweats etc
Asymptomatic
Thrombosis, ischaemia
Headache, dizziness, fatigue
Numbness in extremities
Erythromelalgia
Vision loss, abdo pain, nausea
Bleeding: epistaxis, bleeding gums, bruises
Splenomegaly
VTE due to initial XS plt
Anaemia
Susceptibility to infection
Ix of myelofibrosis?
anaemia and low plts
high WBC and platelet count early in the disease
progress to pancytopenia
‘tear-drop’ poikilocytes on blood film
unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
Biopsy - hypocellularity, fibrosis
high urate and LDH (reflect increased cell turnover)
What is anti phospholipid syndrome?
Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)
A key point for the exam is to appreciate that antiphospholipid syndrome causes a paradoxical rise in the APTT
Features of anti phospholipid syndrome?
venous/arterial thrombosis recurrent fetal loss livedo reticularis thrombocytopenia prolonged APTT other features: pre-eclampsia, pulmonary hypertension
Associations other than SLE
other autoimmune disorders
lymphoproliferative disorders
phenothiazines (rare)
Management of anti phospholipid syndrome?
primary thromboprophylaxis
- low-dose aspirin
secondary thromboprophylaxis
- initial venous thromboembolic events: lifelong warfarin with a target INR of 2-3
- recurrent venous thromboembolic events: lifelong warfarin; if occurred whilst taking warfarin then consider adding low-dose aspirin, increase target INR to 3-4
- arterial thrombosis should be treated with lifelong warfarin with target INR 2-3
Ix of anti phospholipid syndrome?
> 1 AP Ig. Lupus anticoag AKA lupus Ig, anticardiolipin Ig, anti-β2 glycoprotein I, antiphospholipid Ig
Prolonged PT, PTT
False pos in veneral disease lab for syphilis
Thrombocytopenia
Pos coombs test
Summary of antithrombin 3 deficiency?
AT3 normally inactivates thrombin, factor 5
AD mutation
Liver disease, warfarin, nephrotic syndrome, renal failure, depletion in acute thrombosis/ DIC
Features - DVT/PE
Complications - VTE heparin resistance
Ix - ↓antithrombin 3 activity
No ↑ in aPTT following heparin
Tx - Anticoag
Summary of Factor 5 Leiden?
Most common inherited thrombophilia
Activated protein C resistance
Mutant coag factor 5, lacks Arg506 cleavage site > resitant to degradation by activated protein C > unreg activation of coag cascage > hypercoag state > VTE
Protein C resistance
RF: pregnancy, oral hormonal contraceptives
Ix - ↓antithrombin 3 activity
No ↑ in aPTT following heparin
Heterozygotes have a 4-5 fold risk of venous thrombosis. Homozygotes have a 10 fold risk of venous thrombosis but the prevalence is much lower at 0.05%
VTE
DVT
Possible fetal loss
> 2 thrombolic events > life long anticoag
Summary of protein C deficiency?
Unreg activation of coag cascade
Protein C usually vit K dependent inhibitor of factors 5 + 8
AD inherited
Causes: acute thrombois, DIC, liver disease, warfarin.
Sx: VTE Homozygotes: neonatal purpura fulminans T1: ↓levels T2: normal levels, ↓ function
Complications
Warfarin induced thrombotic skin necrosis
Ix:
↓protein C
Tx:
- Prophylactic protein C concentrate
- Anticoags
- Warfarin induced skin necrosis: stop warfarin, start vit K, heparin, protein C/ FFP
Summary of protein S deficiency?
Cofactor of protein C
↓protein C activity > enhanced coag cascade
AD PROS1 mutation
Causes: pregnancy, oral hormonal contraceptive DIC, acute thrombosis, HIV, nephrotic syndrome, liver disease
Sx:
VTE
Homozygotes: neonatal purpura fulminans.
T1: ↓protein S
T2: ↓function
T3: ↓free protein S + function, normal total protein S.
Ix:
Protein S assay
Tx:
Prophylactic anticoag in high risk situations eg post partum, preop
Summary of hereditary angioedema?
AD, ↓plasma C1 inhibitor, uncontrolled release of bradykinin > oedema
Sx:
attacks may be proceeded by painful macular rash
painless, non-pruritic swelling of subcutaneous/submucosal tissues
may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
urticaria is not usually a feature
Ix:
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
Tx
acute
- HAE does not respond to adrenaline, antihistamines, or glucocorticoids
- IV C1-inhibitor concentrate, fresh frozen plasma (FFP) if this is not available
prophylaxis: anabolic steroid Danazol may help
Summary of acute intermittent porphyria
AD, defect in porphobilinogen deaminase
Toxic accumulatio of delta aminolaevulinic acid + porphobilinogen
Sx: Abdo pain, vomiting Neuropsychiatric Sx Motor neuropathy Depression HTN tachycardia 20-40 y/o F
Ix:
Urine turns deep red on standing
↑urinary porphobilinogen (more between attacks than acute attacks)
Assay of red cells for porphobilinogen deaminase
↑delta aminolaevulinic acid + porphobilinogen
Tx:
Avoid triggers
Acute attacks: IV haematin/ haem arginate. IV glucose
What are packed red cells + when to use?
chronic anaemia, centrifuging of whole blood.
Each unit 250-350 mls, ↑Hb by 10. Stat in emergency, usually 90-120 mins or 2-3hrs if comorbidities
Irradiated products (depleted of T lymphocytes) for graft vs host disease
Washes Red cell concentrates prevent anaphylaxis
What is plt rich plasma + when to use?
bleeding in thrombocytopenia, prophylactically in marrow failure. Obtained by low speed centrifugation
Plt transfusions have highest risk of bacterial contamination
<10X109 if no active bleeding
Plt don’t have to be ABO compatible.
What is prothrombin complex concentrate + when to use?
reversal of anticoag in pts with severe bleeding or head injury. F2, 7, 9, 10 – 1972.
What is FFP + when to use?
from single unit of blood, contains clotting factors, albumin + immunuglobulin.
Correct clotting def, pts with hepatic failure who are to undergo surgery
Pt or PTT >1.5
What is cryoprecipitate + when to use?
formed from FFP, contains F8, fibrinogen. C vWF.
Useful in DIC, liver failure, major haem. 15-30mL
Threshold and target for RBC?
RBC transfusion threshold: <70g/L or <80g/L in ACS
RBC target: 70-90 or 80-100 in ACS.
RBC stored at 4°C
In non urgent scenario: unit
of RBC transfused over 90-120 mins.
Threshold and target for plt’s?
Plt transfusion < 30X109 sig bleeding
Plt transfusion <100X109 for severe bleeding or bleeding at critical sites eg CNS
Summary of non haemolytic febrile transfusion reaction
Ig reacting with white cell fragments in blood product + cytokines that have leaked from blood during storage
Fever + chills
More common in plt transfusion
Slow or stop transfusion
Paracetamol
Monitor
Summary of minor allergic reaction > transfusion
Caused by foreign plasma proteins
Pruritis
Urticaria
Temp stop transfusion
Antihistamine
Monitor
Summary of Anaphylaxis in blood transfusion
Pts with IgA def who have anti IgA Ig
Mins after starting
Hypotension
Dyspnoea, wheeze, stridor
Angioedema
Stop transfusion
IM adrenaline
O2 fluids
Summary of acute haemolytic reaction
ABO incompatible blood massive haemolysis
RBC destruction by IgM
Begin few minutes after transfusion is started
Fever
Abdo pain
Hypotension, agitation
Mins after transfusion started
DIC
Renal failure
Send blood for direct coombs test
Repeat typing + cross match
Stop transfusion
Fluid resus
Summary of transfusion associated circ overload
Causes:
Rate of transfusion
Pre-existing HF
Pul oedema
HTN
Acute/worsening oedema within 6hrs of transfusion
Tx:
Slow or stop transfusion
Furosemide
O2
Summary of transfusion related acute lung injury
Non cardiogenic pul oedema, ↑vascular permeability caused by host neutrophils that become activated by substances in donated blood
Within 6 hours of transfusion
Hypoxia Pul infiltrates on CXR Fever Hypotension Within 6 hrs of transfusion
ARDS
Stop transfusion
O2
Supportive care
Summary of post transfusion purpura?
Rare
7-10 days post transfusion containing plt
