Haematology in Primary Care Dr Josh Wright Consultant Haematologist Sheffield Teaching Hospitals

Referral Hit Parade Raised Hb Leucocytosis- neutrophilia/lymphocytosis Thrombocytosis/thrombocytopenia Paraproteins macrocytosis Low B12 Anaemia in the elderly Microcytosis/ iron deficiency/alpha thal

Common haematological issues in primary care Lecture Workshop Interpreting the blood count Common referral issues White cell problems Platelet problems Paraproteins Red cell issues Erythrocytosis Haematinics inc low B12 Haemoglobinpathy inc alpha thal Anaemia in the elderly Any cases brought for discussion

Full blood count Normal range Adult male Adult female Range Hb 131-166 Hct 0.38-0.48 RBC count 3.6-4.8 MCV 80-98 MCH 27-34.2 WBC x109/l 3.5-9.5 Neutrophils 1.7-6.5 Lymphocytes 1.0-3.0 Platelets 140-370 Range Hb 110-147 Hct 0.32-0.42 WBC 3.5-9.5 Neutrophils 1.7-6.5 Lymphocytes 1.0-3.0 Platelets 140-370

What is the definition of normal?

White Blood Count Lymphocytosis History Male age 58 years Hypertension, Type II DM Smokes 10 cigs Drugs Simvastatin, Amlodopine Exam BMI 38 Bp 140/85 FBC September 2011 October 2011 November 2011 Hb 139 141 140 WBC Lymphocytes Neutrophils 6.7 3.9 2.8 6.9 4.1 4.2 2.5 Platelets 249 310 270

Lymphocytosis Does the patient have haematological cancer? Should I refer to haematology? Should I continue to monitor the lymphocyte count? Are there any other tests I should do?

Lymphocytosis Primary Reactive Chronic Lymphoid malignancies Chronic Lymphocytic Leukaemia Lymphoma Monclonal B Lymphocytosis Reactive Viral (EBV, CMV, HSV, VZV) Stress Lymphocytosis Drug induced Septic shock Myocardial infarct Trauma Other co-morbidities Chronic Cigarette smoking Autoimmune disorder Chronic inflammation Sarcoid Raised BMI/metabolic syndrome Lymphocytosis

Malignant Lymphocytosis ? FBC Lymphocyte count more than 10x109/L Lymphocyte count less than 10x109/L anaemia or thrombocytopenia recurrent infection? adenopathy, spleen, liver? Abnormal blood film? Yes No Refer to haematologist Repeat FBC, review 1yrly

The Neutrophil Count

White Blood Count Neutrophil Leucocytosis History Male age 68 years Osteoarthritis, CABG 2001 Non smoker (stopped 2001) Type 2 DM Drugs Simvastatin, Aspirin, Gliclazide Exam Unremarkable FBC July 2009 December 2010 May 2011 Hb 163 165 WBC Lymphocytes Neutrophils 15.7 2.4 13.0 17.0 2.0 13.5 14.0 2.1 11.9 Platelets 430 420 400

Neutrophil leucocytosis Acute neutrophilia Reactive Infection/Inflammation neoplasia Bleeding Pain Smoking Drugs (glucocorticoids) Chronic neutrophilia Drugs BMI/metabolic syn Haematologic Eg CML 1/100000

(Neutrophil) Leucocytosis Important points Urgent referral >50 Blood film features of CML or CMML (film comment) Consider if Chronic neutrophilia>20 Chronic monocytosis >1 Chronic eosinophila>2 History & Exam infection, inflammation, autoimmune, neoplasia rash, arthritis, weight loss CRP, U&E, LFT, TFT Ca Auto Ab Micro culture FBC, ESR CXR Urine Reactive screen negative Haematology referral

Neutropenia Caucasian female aged 36yrs, no significant medical history, no regular medication FH rheumatoid arthritis Hb 126 g/l WCC 3.1 Neutrophils 0.4 Platelets 180

Neutropenia (Neutrophils<1.7) What do I need to know? Is the patient unwell? (Viral assoc transient) Any previous counts? Any other cytopenia? Is the patient on chemotherapy? Other drugs How severe is it? Mild (1.0-1.7), functionally normal Moderate (0.5-1.0) Severe (<0.5)-RISK OF INFECTION

Neutropenia What are the common causes? Infection Drugs (chemotherapy!) Autoimmune Hereditary Racial (African origin 1.0-1.3)

Neutropenia pathway Neutropenia <1.0 Consider repeat particularly if recent infection Patient on chemotherapy No Moderate or Severe <0.5 Unwell ? Yes No Discuss with haematologist and refer B12, Folate, LFT, GGT, autoAb Haematology advice/referral

Thrombocytosis Male 65yrs, mild hypertension on ramipril. Hb 160, Hct 0.50, WCC 11.0 plts 450 Refer or not?

Thrombocytosis Maybe reactive to inflammation, infection other malignancy, iron deficiency or bleeding In MPD very high counts >1500 assoc with vascular events and bleeding Urgent referral >1000 600-1000 if assoc with CVA, TIA, VTE Consider if >600 consistently >450 with vascular event High wcc or Hb

Thrombocytopenia >100 functionally normal <20 bleeding risk rises but most symptom free Causes Immune Drugs eg quinine Bone marrow failure syndromes eg MDS ALCOHOL Liver disease Pregnancy

Thrombocytopenia Refer <50 50-100 if other cytopenia or planned surgery/dental work Investigations Blood film- platelet clumping Repeat sample Renal & liver function Clotting screen Autoantibodies

?Myeloma Hb 110 WCC & plts normal U&E normal Total Protein 66 (60-74) IgG * IgA 0.7 (0.8-4.0) IgM 0.5 (0.5-2.0) MIg 7.0 IgG Kappa monoclone History 68yr female, Back pain 4 months ESR 70 X Ray normal Should I refer to haematology? Reminder…….Monoclonal or polyclonal?

Paraproteins Refer if IgM usually assoc with lymphoma IgG>15g, IgA>10g IgD or E Lower levels if assoc with CRAB IgM usually assoc with lymphoma Any other features? Paraprotein>10g ?Hyperviscosity C- Hypercalacemia R- unexplained renal failure A-anaemia/cytopenia B-bone pain/fracture

Paraproteinaemia Most will be MGUS Present 3% over 70 and 5% over 80 1% risk of progression to MM per annum A few secondary to auto-immune disease & rarely other malignancies If criteria for referral not met then monitor on a 6-12 monthly basis.

Common Red cell Problems Macrocytosis Erythrocytosis Haematinic assessment Anaemia in the elderly Haemoglobinopathies including alpha thal carriage

Macrocytosis Approx 8% population Commonest causes alcohol & hypothyroidism B12/ folate deficiency Drugs (including those used for HIV) Reticulocytosis Paraprotein Myelodysplasia (elderly population & associated with cytopenias)

Isolated macrocytosis Raised MCV >100 Monitor if screening normal Check B12, Folate,, LFT, GGT, TFT, Igs, No Are there cytopenias? Isolated macrocytosis Yes Refer to Haematology

Erythrocytosis??

Erythrocytosis Apparent True Physiological True none physiological Dehydration Diuretics Alcohol Raised BMI True Physiological Hypoxia eg COPD, sleep apnoea High altitude Smoking True none physiological Primary polycythaemia Certain rare tumours Anabolic steroid usage URGENT REFERRAL Hct >60 males or 0.56 females

Erythrocytosis Incidence of polycythaemia rubra vera ~5/100 000 Male Female Hct >0.52 for at least 2 months Hct >0.48 for at least 2 months Refer to Haematology Incidence of polycythaemia rubra vera ~5/100 000 Incidence of apparent polycythaemia~ HIGH!

Haematinics There is no entirely reliable blood test for iron status There is no entirely reliable blood test for folate There is no entirely reliable blood test for B12

Ferritin is the test of choice Inaccurate in the presence of inflammation A trial of iron remains a valid approach ALCOHOL/FATTY LIVER & FERRITIN Serum folate is a good reflection of what you have just eaten I’m not sure what B12 is a good reflection of! Interpret borderline values with caution Schilling test no longer available

Reduced serum B12 B12< 100 True deficiency highly likely parenteral replacement B12 100-145 replace especially if raised MCV, cytopenia, neuropathy B12>140 deficiency unlikely B12 is an unreliable test Always reduced in pregnancy Uncomplicated B12/folate deficiency does not require OP referral.

Anaemia in the elderly Frequency of anaemia increases with age Incidence 10-40% Many have diagnosable/treatable cause 25% no identified cause Investigations FBC & film Reticulocytosis Renal/ liver function Immunoglobulins Haematinics Coeliac screen Dietary history GI investigations Bone marrow

Anaemia in the elderly CAUSE OF ANEMIA PERCENTAGE OF CASES Anemia of chronic disease 30 to 45 Iron deficiency 15 to 30 Posthemorrhagic 5 to 10 Vitamin B12 and folate deficiency Chronic leukemia or lymphoma 5 Myelodysplastic syndrome No identifiable cause 15 to 25

The lost 25%? MULTIFACTORIAL Decline in erythropoetin Decline in androgens Increased inflammatory cytokines even in absence of a recognised disease Age associated decline in stem cell function Early MDS without other cytopenias or BM changes

Indications for haematology referral Pancytopenia Monoclonal gammopathy Suspicion of myelodysplastic syndrome Blood smear showing immature white cells or nucleated red cells Indeterminate status of iron stores Unexplained progressive or unresponsive anemia

What are haemoglobinopathies? Commonest single gene disorders worldwide Autosomal recessive Disease states homozygous or combined heterozygotes Defects of quality or quantity of haemoglobin Quality Variant Hbs eg sickle Quantity Under production eg thals

National Screening Plan NHS Plan commits to “a new national linked antenatal & neonatal screening programme for haemoglobinopathy & sickle cell disease by 2004” Universal neonatal Antenatal ?selective ?universal

The haemoglobinopathy screen MCV, MCH Hb A2 HPLC ZPP/ferritin Sickle solubility test, electrophoresis, molecular analysis

Case study 32 year old female of Pakistani origin attends c/o fatigue Hb 11.9, MCV 71, MCH 23 Ferritin 109 Hb A2 normal, no evidence of b thal

b thalassaemia

a thalassaemia

thalassaemia heterozygotes a0 a+ UK Africans 25% India 5-58% PNG 20-80% Thailand 3-17% Maori 5-10% Cypriot 2% India rare African rare Hong Kong 5% China 3-9% Phillipines 10%

Summary points Other than for individuals of E. Med or SE Asian origin a thal trait is insignificant Microcytosis is commonly due to thal trait A national antenatal/neonatal screening programme is now in place