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www.cambridgehaematology.com Haematology in Primary Care: The Full Blood Count Charles Crawley George Follows C ambridge H aematology P artners
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www.cambridgehaematology.com The FBC
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www.cambridgehaematology.com Haemoglobin Low haemoglobin defines anaemia –Males 13-18g/l –Females 11.5-16g/l –Variations: Children –Neonates – 14-24g/l –2 months – 8.9-13.2g/l –9-12ys - 11.5-15.4g/l Pregnancy –3 rd Trimester – 9.8-13.7g/l Age –5-7 th decade – falls in men rises in women Exercise –Increases Hb Altitude Smoking
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www.cambridgehaematology.com MCV Mean Cell Volume: average size of RBC –Normal adult : 76 (80) - 100 fL MCV < 76 fL (microcytic) MCV > 100 fL (macrocytic) MCV 80 - 100fL (normocytic)
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www.cambridgehaematology.com Practical Classification of Anaemia Microcytic (<76fL) Normocytic Normocytic Macrocytic (>100) Macrocytic (>100) Iron deficiency ThalassaemiaHaemoglobinopathies Anaemia of chronic disease LeadHyperthyroidism Blood loss Haemolytic - RBC membrane - Enzyme defects - Extrinsic Stem cell defects Megaloblastic Megaloblastic Excess alcohol Excess alcohol Hypothyroid Hypothyroid Liver disease Liver disease Reticulocytosis Reticulocytosis Drug therapy Drug therapy Marrow failure Marrow failure Reticulocyte count : In the investigation of anaemia Reduced: Failure of erythropoiesis Increased:Appropriate BM erythroid response
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www.cambridgehaematology.com 35 year Male Hx:Lethargy, SOB Sx:Pale FBC:Hb6.4 g/dL MCV 71 fL RDW0.19 WCC5.2 Platelets375 Film: Severe hypochromasia and microcytosis
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www.cambridgehaematology.com Commonest Causes Iron Deficiency FemaleMale 1 – 5 yr NutritionNutrition 5 – 15 yr Increased utilisation/ growth 15 – 40 yr MenstruationPregnancy Coeliac disease (Malabsorption) > 40 yr Gastrointestinal Blood loss
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www.cambridgehaematology.com Blood Film
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www.cambridgehaematology.com Differential Diagnosis Causes of microcytic hypochromic anaemia –Iron deficiency Blood loss Malabsorption - Coeliac disease; gastrectomy Increased utilisation - parasites Dietary deficiency - rare –Haemoglobinopathy –Anaemia of chronic disease
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www.cambridgehaematology.com Fe Deficiency vs Anaemia of Chronic Disease Variable Fe deficiency Chronic disease Serum Iron Transferrin or Normal Transferrin Saturation Ferritin or Normal or normal CRPNormal GIT studies: endoscopy etc
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www.cambridgehaematology.com 26 year Female Hx:Antenatal visit; First trimester FBC:Hb11.0 g/dL MCV73 fL MCH27 pg RDW0.14 WCC8.5 x 10 9 /L Platelets 164 x 10 9 /L Film: Microcytic RBC
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www.cambridgehaematology.com Fe Deficiency vs Hbinopathy Check iron status: Ferritin Family history / ethnicity: –Thalassaemia / haemoglobinopathy –Need to determine risk to fetus of severe thalassaemic syndrome (in 1 st rimester): Homozygous thalassaemia (α or β) Homozygous Hb S (sickle cell disease) Severe compound heterozygous states –E.g.: HbS/β; HbE/β; HbSC –Determine need to check partner
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www.cambridgehaematology.com Red Cell Distribution Width (RDW) The degree of variation in size of RBC: N <14 Increased RDW corresponds with anisocytosis: –Iron deficiency (increased RDW is the earliest lab feature: anisocytosis precedes the anaemia) –Megaloblastic anaemia (can be very high >20) –Anaemia with bone marrow erythroid response (i.e. reticulocytosis) RDW useful in DDx of microcytic anaemias. –Most cases of iron deficiency: raised RDW –Most cases thalassaemia trait: normal RDW
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www.cambridgehaematology.com MCH Mean Cell Haemoglobin (27-32 pg) –The mean haemoglobin per red blood cell MCH usually rises or falls as the MCV is increased or decreased. MCH < 25 pg used as a guide to the presence of thalassaemia or haemoglobinopathy. –MCH usually markedly reduced in thalassaemia (e.g. beta thalassaemia trait MCH 19 pg)
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www.cambridgehaematology.com Haemoglobin Studies 1. Normal adult 2. HPFH (heterozygote) 3. Hb S--HPFH 4. Hb C--HPFH 5. Normal newborn A/F/S/C control
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www.cambridgehaematology.com 73 year male Hx:Tiredness FBC:Hb4.0 g/dL MCV102 fL RDW0.24 WCC / PltNormal Film:Macrocytes, fragmented red cells, occasional NRBC
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www.cambridgehaematology.com Blood Film 73 yr old male
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www.cambridgehaematology.com Severe Macrocytic Anaemia Megaloblastic anaemia Liver disease: end-stage failure Red cell aplasia: –Parvovirus; thymoma, other malignancy Bone marrow failure or infiltration: –Myelodysplasi –Multiple myeloma
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www.cambridgehaematology.com Investigations 1.Serum vitamin B12 Red cell folate (serum folate) 2.Reticulocyte count (BM erythroid function) 3.Liver function 4.Parvovirus serology 5.Bone marrow examination
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www.cambridgehaematology.com Don’t Forget the Alcohol
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www.cambridgehaematology.com Other Causes of Macrocytic Anaemia Severe liver disease Excess alcohol Haemorrhage / haemolysis: reticulocytosis Drug therapy: esp. cytotoxics Hypothyroidism Myelodysplasia Marrow infiltration –Bone marrow examination may be indicated
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www.cambridgehaematology.com Myelodysplasia (MDS) Clonal disorder Ineffective haematopoiesis Incidence increases with age –Age 50yrs - 1 per 100,000 –Age 70yrs – 25 per 100,000 RBC, WCC, and platelets affected
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www.cambridgehaematology.com Myelodysplasia Bone Marrow Peripheral Blood
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www.cambridgehaematology.com Myelodysplasia Prognosis –Number of cytopenias –BM Blast percentage –Cytogenetics –Age Survival –Varies 11.7 yrs – 0.4yrs Management –Supportive –Stem cell transplantation –New drugs
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www.cambridgehaematology.com Normocytic Anaemia Multiple aetiologies Primary marrow production defect –Myelodysplasia –Marrow infiltration –Haematinic deficiencies Reduced red cell survival –Blood loss –Intrinsic defects (eg. Enzyme; membrane) –Extrinsic defects (eg. Plasma problems)
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www.cambridgehaematology.com Approach to Normocytic Anaemia History: –Acute blood loss ; jaundice; dark urine Exclude treatable causes: –Check ferritin, folate, vitamin B12 –Renal and hepatic function –Acute phase reactants Consider haemolysis The blood film may have the answer !
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www.cambridgehaematology.com 78 year male Hx:Chest pain PMHx:Myocardial infarct FBC:Hb7.2 g/dL MCV97 fL WCC4.5 x 10 9 /L Platelets320 x 10 9 /L Reticulocytes: 320 (10-100)
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www.cambridgehaematology.com Blood Film
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www.cambridgehaematology.com Blood Film RBC:Spherocytes Polychromasia Nucleated red cells Spherocytic haemolytic anaemia: Auto-immune haemolytic anaemia Hereditary spherocytosis
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www.cambridgehaematology.com Other Investigations Biochemistry: –Bilirubin100 μmol/L (<20) –Other LFTNormal –LDH1,500 U/L (120-240) –Haptoglobin<0.1 Haematology: –Reticulocyte count –Direct anti-globulin (Coombs) test: Positive Enzymes, Hereditary spherocytosis screen
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www.cambridgehaematology.com Haemolytic Anaemia Primary Red Cell Problem: –Red cell membrane: Hereditary spherocytosis –Enzyme defect: G6PD deficiency –Haemoglobin defect: thalassaemia –Abnormal red cells: dyserythropoiesis (MDS) Secondary Red Cell Destruction –Autoimmune –Severe hepatic dysfunction –Red cell fragmentation: DIC; HUS; TTP –Infections: malaria; clostridium
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www.cambridgehaematology.com Blood Film Glucose-6-phosphate dehydrogenase deficiency blister or helmet cells
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www.cambridgehaematology.com Normocytic Anaemia Blood film may have the answer: –Normal red cell morphology –Dimorphic (high RDW): 2x RBC populations –Marked anisocytosis: marrow dysfunction/MDS –Is there polychromasia? Yes: Anaemia with marrow response No:Impaired marrow response –Anaemia of Chronic Disease –BM failure –Red cell aplasia: Parvovirus; aplastic anaemia
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www.cambridgehaematology.com Polycythaemia Pseudopolycythaemia Primary –Polycythemia vera Secondary –Hypoxia Altitude Cardiac/Pulmonary disease Cirrhosis Abnormal Haemoglobins Chronic CO exposure –Inappropriate erythropoietin Renal lesions Tumours Drug
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www.cambridgehaematology.com Clinical Features Hyperviscosity –Headaches –Blurred vision –Breathlessness –Confusion –(Plethora) Thrombosis –Venous + arterial –Bleeding Other –Pruritis –Gout
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www.cambridgehaematology.com Polycythaemia investigations FBC + Film CXR Cardiac assessment Red Cell mass Blood gasses Major advance – JAK 2 mutation screens
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www.cambridgehaematology.com JAK2 Presence of the V617F mutation indicates that the patient has an acquired, clonal hematological disorder and not a reactive or secondary process. Absence of the JAK2 V617F mutation does not exclude a MPD as up to 50% of patients with ET and IMF will have wildtype JAK2. The V617F mutation does not help in sub- classifying the type of MPD of a given patient
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www.cambridgehaematology.com Pathogenesis: Deregulated Tyrosine Kinases in MPD CML BCR-ABL CMML TEL-PDGFRB CEL FIP1L1-PDGFRA SM KIT D816V PV JAK2 V617F ET JAK2 V617F IMF JAK2 V617F
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www.cambridgehaematology.com Questions so far?
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www.cambridgehaematology.com Platelets Too many (thrombocytosis) Too few (thrombocytopenia) Dysfunctional –When should we worry?
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www.cambridgehaematology.com Thrombocytosis > 450 x 10 9 /l Causes –Reactive (almost anything!) Common – bleeding, infection, malignancy Tend to be less than 1000 x 10 9 /l –Primary bone marrow disorder Myeloproliferative disorders (up to 3000+) (essential thrombocythaemia, myelofibrosis, polycythaemia, chronic myeloid leukaemia)
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www.cambridgehaematology.com History, examination should guide investigations and referrals Should the patient be on aspirin? –Only firm evidence is MPDs –Reactive often given if > 1000, but little evidence for this Thrombocytosis
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www.cambridgehaematology.com Essential Thrombocythaemia (ET) –Long term management balancing thrombotic vs bleeding risk –Aspirin for intermediate risk –Cytoreduction + aspirin for higher risk (beware the pseudohyperkalaemia!!) Thrombocytosis
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www.cambridgehaematology.com Thrombocytopenia Is it real??? –Poor sample –Clumped in EDTA – blood film **If at all possible confirm with a repeat sample
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www.cambridgehaematology.com Pancytopeniavs Isolated low platelets Pancytopenia – –always serious (marrow failure) Isolated – may be relatively unimportant Thrombocytopenia
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www.cambridgehaematology.com Decreased production –Rare in isolation –Viral infections Increased consumption –Autoimmune – ITP –Drugs –Pregnancy –Large spleen / portal hypertension –Infections (HIV) –RARE but serious TTP – HUS - DIC Thrombocytopenia
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www.cambridgehaematology.com Investigations depend on clinical suspicion –Platelet volume may be helpful (small - think marrow) 10.5 –BM often not required Thrombocytopenia
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www.cambridgehaematology.com Thrombocytopenia (not joint bleeds!)
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www.cambridgehaematology.com How real is the bleeding risk? –Cause of low platelets –Wet vs dry purpura –Platelet transfusions often not useful Thrombocytopenia
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www.cambridgehaematology.com ITP – a few useful reminders Children –Acute, post viral, –spontaneous resolution (often no therapy) Adult –More insidious onset –Chronic = common –Many (not all!) cases do require treatment –Steroids – splenectomy –Novel therapies
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www.cambridgehaematology.com Platelet Dysfunction Range of rare inherited causes –Family history –Refer the child that bleeds abnormally! Don’t forget the acquired dysfunction –Renal failure –Liver disease –ASPIRIN
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www.cambridgehaematology.com Questions and break!
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www.cambridgehaematology.com White Cells
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www.cambridgehaematology.com White Cells
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www.cambridgehaematology.com White Cells Important (and commonly problematic!) –Neutrophils –Lymphocytes Important (less commonly problematic) –Monocytes –eosinophils Less important –basophils
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www.cambridgehaematology.com Neutrophils
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Neutrophilia Often result ‘expected’ –History –Examination –primary haematological cause NOT common
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www.cambridgehaematology.com Neutrophilia Infection Inflammation / necrosis Cancer – any sort reported Bone marrow disease (MPDs, CML) Drugs (steroids!!, growth factors) Not always pathological Pregnancy, smoking, normal variant!
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www.cambridgehaematology.com Neutropenia (<1.5 x 10 9 /l) Isolated neutropenia vsPancytopenia
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www.cambridgehaematology.com How worried should I be? Pancytopenia is ALWAYS worrying Many cases of isolated neutropenia are less serious What should I do with a neutropenic patient? How common is neutropenic sepsis?
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www.cambridgehaematology.com Pancytopenia Marrow Failure –Drugs (chemotherapy) –Infiltration (cancer, MF,lymphoma etc.) –Myelodysplasia / leukaemia / myeloma –Aplastic anaemia / PNH –Don’t forget B12 / folate (anorexia) Peripheral consumption –hypersplenism
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www.cambridgehaematology.com Pancytopenia Referral usually required Bone marrow biopsy usually required
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www.cambridgehaematology.com Isolated Neutropenia Not always easy to identify a cause! Always think drugs (idiopathic vs dose) Viral infection Auto-immune disease Marrow causes (sepsis / very ill elderly) Don’t forget –Racial variation –cyclical neutropenia (clinical and lab details) –If child, think congenital
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www.cambridgehaematology.com Investigations will depend on clinical presentation –Chance finding vs ill patient –Viral serology may be indicated (hepatitis, EBV etc – Think HIV!) –Autoimmune (SLE, sjorgrens, RA – Felty’s) –Serial blood counts –Referral may be required Isolated Neutropenia
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www.cambridgehaematology.com When to refer urgently –Cause of neutropenia –Is the patient acutely ill? Neutropenic fever vs sepsis –Incidence etc –Antibiotic policies etc. –Prophylactic antibiotics - controversial Isolated Neutropenia
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www.cambridgehaematology.com Lymphocytes Lineage B vs T vs NK OriginRole
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www.cambridgehaematology.com Causes –Reactive (CMV, EBV, hepatitis, toxo, adenov) Pertussiss Inflammatory reaction (not common) –Lymphoproliferative disorder Acute and chronic leukaemias lymphomas Lymphocytosis
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www.cambridgehaematology.com Priorities for investigation –Clinical picture –If other FBC abnormalities, speak to a haematologist –If in doubt, ask for an opinion on a blood film –Monospot test vs viral serology –Flow cytometry –Molecular tests Lymphocytosis
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www.cambridgehaematology.com Lymphocytosis (>4 x 10 9 /l) Blasts vs more mature cells Clinical picture very important –Young sick child vs older well patient vs
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www.cambridgehaematology.com Young patient with clinical picture of infectious mononucleosis –Monospot useful –Film useful (rule out ALL) –Flow cytometry less helpful –Serology as second line investigation –ID referral occasionally required –(worth thinking about acute HIV) Lymphocytosis
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www.cambridgehaematology.com Acute lymphoblastic leukaemia –Children >> adults –Often presents very acutely –Range of clinical features –Laboratory features typical –Referral mandatory Lymphocytosis
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www.cambridgehaematology.com Older patient with lymphocytosis –Blood film required (CLL vs LGL) –Flow cytometry usually required –? Refer Clinical picture Underlying diagnosis Lymphocytosis
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www.cambridgehaematology.com CLL –Relatively common (300 + / year) –New entity of Monoclonal B Lymphocytosis (MBL) –Age –Clinical presentation Asymptomatic stage A VS Symptomatic stage C Lymphocytosis
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www.cambridgehaematology.com CLL –History Night sweats, weight loss, INFECTIONS –Examination Lymphadenopathy, hepato-splenomegaly –Investigation Flow cytometry Lymphocytosis
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www.cambridgehaematology.com Flow cytometry Lymphocytosis T cells Leukaemic B cells
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www.cambridgehaematology.com Lymphocytosis Should I refer CLL? –Long stage A phase in many patients –Patients and the ‘leukaemia’ word! –Rough guide Symptomatic Unusual / lymphoma phenotype Lymphadenopathy / splenomegaly Lymphocyte doubling time < 12 months with lymphocytes > 30 x 10 9 /l Hb < 10 g/dl (or haemolysing) Platelets < 100x 10 9 /l
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www.cambridgehaematology.com CLL – beware –Not always benign –Infections (hypogamma) –Haemolysis –ITP Lymphocytosis
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www.cambridgehaematology.com Rarer lymphoproliferative disorders –LGL –PLL –Leukaemic phase of most lymphomas –Hairy cell leukaemia Lymphocytosis
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www.cambridgehaematology.com Lymphopenia (<1.0 x 10 9 /l) Many cases reflect normal variants How hard should you chase a cause? More common causes –HIV / hepatitis / Hodgkin’s (steroids) Rarer causes –Autoimmune disease / sarcoidosis
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www.cambridgehaematology.com Investigations –Clinical picture –Lymphocyte subset analysis –RARE – bone marrow Lymphopenia
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www.cambridgehaematology.com Enlarged LN ? cause Clinical context is critical –? Symptom profile –(?spleen) Please do first line investigations –FBC may save a LN biopsy Neck nodes – ENT fast track referral Axillary and groin nodes –Much depends on the clinical context –Haematology review first? –Biopsy first? –CT first?
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www.cambridgehaematology.com Eosinophils High –Allergic disorders –Drug Hypersensitivity –Skin Diseases –Parasitic infections –Myeloproliferative disorders –Connective tissue disorders Churg Strauss
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www.cambridgehaematology.com Monocytes High –Range of infectious and inflammatory stimuli –Primary BM conditions CMML (overlap between myelodysplasia and myeloproliferative disorder) CML Clinical picture and blood film important If no clear cause consider haematology referral
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Questions? C ambridge H aematology P artners www.cambridgehaematology.com charles.crawley@cambridgehaematology.com george.follows@cambridgehaematology.com
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