Anaemia

Nov 2010

Overview

Iron deficiency anaemiaMacrocytic anaemiaHaemolytic anaemia

Recognition and management of bleeding disorders

Case history (1)

45yr old female3 month history of fatigue and shortness of breath on exertionO/E pallor ++FBC – Hb 6.2g/dl

Case history (1)

What further results are important in the full blood count?What further details are important in the clinical history and examination?What further investigations should be carried out?How should the patient be managed?

Full Blood Count

Hb 6.2 g/dl (12-16)WCC 7.0 x 109/l (4-11)Platelets 300 x 109/l (140-440)MCV 60fl (76-96)MCH 24 pg (27-32)

WCC differential –NBlood Film

Some causes of microcytic anaemia…..

AcquiredIron deficiencyAnaemia of chronic diseaseMyelodysplastic syndromesLead poisoning

More causes of microcytic anaemia…..

InheritedThalassaemiaSickle cell trait

What further details are important in the clinical history?

Dietary intake of ironSymptoms of malabsorption / weight lossOvert GI blood lossMenorrhagiaPregnancyOral iron therapyBleeding history/ family history of bleeding disorder

Iron Requirements

Males 0.5-1mg per dayMenstruating females 1-2mg per dayPregnant females 1.5-2.5mg per dayChildren 1mg per day

An adequate diet contains 15mg of iron, 10% of which is absorbed.

Dietary iron

Red meat , liver, beansAbsorbed in the duodenum and jejunumAbsorption enhanced by ascorbic acid, citrus fruitsAbsorption reduced by phytates, alkalis, tea, tetracyclines

Causes of iron deficiency anaemia

Inadequate intake

Failure of absorption

Increased blood loss

Increased requirements

Dietary ironIron supplementsGastrointestinal symptomsHx of Coeliac diseaseOvert blood loss from bowel or change of bowel habitMenorrhagiaPregnancy

Common causes of gastrointestinal bleeding

Oesophagus

Stomach

Small bowel

Hiatus herniaVaricesGastritis Ulcer CarcinomaUlcerMeckels diverticulumCarcinoma

Common causes of gastrointestinal bleeding

Colon

Rectum

Ulcerative colitisCarcinoma Diverticulitis

HaemorrhoidsUlcerationCarcinoma

Iron loss in pregnancy

Obligatory iron loss 150-200 mgFetal iron 200-370 mgIron in placenta and cord 30-170 mgIron in blood lost at delivery 90-310 mg

Total iron loss 470-1050mg

What further investigations should be carried out?

Serum ferritin +/- serum ironB12 / folateFaecal Occult Blood+/- Coeliac screen+/- Gastroscopy and/or colonoscopy+/- Gynaecology referral

Causes of raised ferritin levels

Acute inflammationAcute liver diseaseLymphomasSolid tumoursHaemochromatosis

How should the patient be managed?

Treat the underlying causeOral iron supplements

correct anaemiareplenish iron stores

IV ironmalabsorptionintolerance

Is there a role for blood transfusion?

Failure to respond to oral iron

Is the diagnosis correct?Is the patient taking the iron?Is there evidence of malabsorption?Is there evidence of persistent blood loss?

Case (2)

45yr old female3 month history of fatigue and palpitationsO/E pallor ++FBC – Hb 5.3 g/dl

Case 2

What further results are important in the full blood count?What further details are important in the clinical history and examination?What further investigations should be carried out?How should the patient be managed?

Full Blood Count

Hb 6.2 g/dl (12-16)WCC 7.0 x 109/l (4-11)Platelets 120 x 109/l (140-440)MCV 120fl (76-96)MCH 28pg (27-32)

WCC differential –NBlood Film

Some causes of macrocytosis…...

Megaloblastic anaemiaVitamin B12 deficiencyFolate deficiencyMyelodysplasia

More causes of macrocytosis….

Liver diseaseAlcohol excessHypothyroidismCytotoxic drugs

What further details are important in the clinical history?

DietSymptoms of malabsorption / weight lossFamily history of anaemia or autoimmune disordersThyroid diseaseAlcohol intake

What further investigations should be performed?

Blood filmB12, Folate, FerritinLiver function testsThyroid function tests

Coeliac screenIntrinsic factor and parietal cell antibodies?Bone marrow – only if above normal

Vitamin B12

Sources – liver meat fish and dairy productsDaily intake 3-30 microgramAdult daily requirement 1-2 microgramBody stores 3-5 mg in the liver (2-4 yr supply)Important for pyrimidine synthesis in the production of DNA

Vitamin B12 absorption

B12 attaches to intrinsic factor (IF) in the stomachIF – a glycoprotein secreted by the parietal cellsB12/IF passes to the terminal ileum where absorption takes place

Causes of B12 deficiency

Strict vegetarianismMalabsorption

Pernicious anaemiaGastrectomyCoeliac diseaseDisease involving the terminal ileum

ResectionCrohn’s disease

Pernicious anaemia

Autoimmune diseaseGastric atrophyAnti parietal cell antibodies 90%Anti intrinsic factor antibodies 70%

Often associated with other autoimmune disorders

B12 deficiency – clinical features

Related to anaemiaNeurological

Peripheral neuropathyLoss of vibration and position senseDemyelination of the cordIrreversible

Management

Lifelong replacement with B12 usually requiredIM Hydroxocobalamin 1000 microgram every 3 months

Folate

Dietary sources- eggs, green vegetables, liver, nutsAbsorbed in the jejumunDaily intake 600-700microgramDaily requirement 100 microgramStored in the liver (4-6 months supply)Important in DNA synthesis

Causes of folate deficiency

Dietary – infancy and old ageMalabsorption – coeliac diseaseIncreased utilisation – pregancy, lactation, haemolytic anaemiaAntifolate drugs – methotrexate, anticonvulsants

Management of folate deficiency

Treat underlying causeCorrect folate levels : oral folic acid 5-15mg dailyProphylactic folate to at risk groups eg pregnancy, congenital haemolytic anaemias

Haemolytic Anaemias

Haemolytic anaemia

Normal red cell life span 100-120 days

A haemolytic anaemia occurs if that life span is shortened

CongenitalAcquired

Mrs C

31 year old femaleHistory of recent “viral illness”C/O increasing tirednessNoticed to look jaundiced by her family

Mrs C

What laboratory investigations should be carried out?

How should the patient be managed?

Mrs C –laboratory results

FBC – Hb 7.7 g/dl Blood film – polychromasiaRaised reticulocyte countRaised bilirubinRaised lactate dehydrogenase (LDH)

Haemolytic Anaemia

How would you investigate the patient?

What are the causes of acquired haemolytic anaemia?

Idiopathic Secondary

A u to im m u ne A llo im m u ne D rug ind uced

Im m une N on Im m une

Acquired Haem olytic anaem ia

Autoimmune haemolytic anaemia

Warm AntibodyIdiopathicSecondary

CLLConnective tissue disordersLymphomasDrugs eg Methyldopa

Cold AntibodyIdiopathicSecondary

MycoplasmaInfectious mononucleosisLymphoma

Alloimmune Haemolytic Anaemia

Haemolytic transfusion reactions eg ABO mismatch

Haemolytic disease of the newborn eg Rhesus incompatibility

Non immune haemolytic anaemia

Red cell fragmentation

Infections

Chemical/ Physical

DIC, Cardiac valvesHUS, TTPMarch haemoglobinuria

Malaria, Clostridium

Drugs, chemicalsVenomsBurns

Clinical features of haemolytic anaemias

Symptoms related to anaemiaJaundiceIncreased incidence of pigmented gallstonesSplenomegalyLeg ulcers- sickle cell, hereditary spherocytosis

Warm autoimmune haemolytic anaemia

Antibody usually IgG – maximum activity @370

Any age, either sexSplenomegaly commonBlood film – microspherocytes, polychromasiaDirect Coombs test (DCT) positive

Warm autoimmune haemolytic anaemia

ManagementTreat the underlying causeCorticosteroidsSplenectomy Other immunosuppressants eg azathioprine, cyclosporinBlood transfusion – if life threatening

Cold autoimmune haemolytic anaemia

Antibody usually IgM – maximum activity @40

Raynauds PhenomenonPositive DCT – complementCold agglutinins – agglutination on blood film

Cold autoimmune haemolytic anaemia

ManagementTreat the underlying causeKeep the patient warmConsider immunosuppression

Haemolytic anaemia and infections

Direct damage to cells eg malariaToxin production eg clostridiumOxidant stress in G6PD deficiencyDIC eg meningococcusAutoantibody formation eg infectious mononucleosis

Inherited haemolytic anaemias

Red cell membrane defects

Disorders of red cell metabolism

Abnormal haemoglobins

Peter M

10 yr oldLife long history of recurrent anaemia and jaundiceFather gives similar history and required cholecystectomy when he was 20yr

Peter M – Laboratory investigations

Hb 9.2g/dlBlood film – microspherocytes, polychromasiaElevated bilirubinDCT negativeOsmotic fragility testing- increased haemolysisHereditary Spherocytosis

Hereditary Spherocytosis

Autosomal dominantVariable severityDefect in a red cell membrane proteinCells destroyed prematurely in the spleenSplenomegaly is common

Hereditary Spherocytosis

Splenectomy for severe casesIncreases the red cell survivalDefer until >6yrs

Folic acid

Abnormalities of Red Cell Metabolism

Glucose-6-phosphate dehydrogenase deficiencyPyruvate Kinase deficiency

Inherited haemolytic Inherited haemolytic anaemiasanaemias

Red cell membrane defects

Disorders of red cell metabolism

Abnormal haemoglobins

Abnormal Haemoglobins

Disorders of globin chain synthesis – the thalassaemias

Structural defects of haemoglobin eg sickle cell disease

Sickle cell disease - Pathogenesis

Chronic haemolytic anaemia caused by a point mutation in the globin gene Causes insolubility of Hb in the deoxygenated stateInsoluble chains crystallise in the red cells causing sicklingVascular occlusion

Sickle cell disease – clinical features

Vaso-occlusive crisesCommon precipitants are infection, dehydrationBone pain StrokeVisceral infarction – spleen, kidneysDactilytis - children

Sickle cell disease – clinical features

Sequestration crisesSickling with pooling of red cells in liver or spleen – severe anaemia, rapid enlarging liver or spleenAcute chest syndrome – chest pain, hypoxia, diffuse shadowing on CXR

Sickle cell disease – laboratory features

Hb 7-9 g/dlSickle cells on blood filmAbnormal haemoglobin electrophoresis

Sickle cell disease – management

GeneralAvoid known precipitantsFolic acidVaccinate, prophylactic penicillin (reduced splenic function)

Sickle cell disease – management

Vaso-occlusive crisesHydrationAnalgesia – opioidsAntibiotics if infection

Sickle cell disease – management

TransfusionFor severe anaemiaRed cell exchange

Severe crisesLung sequestrationStokeHepatic sequestration

Other sickling disorders

Sickle cell traitBenign conditionUsually asymptomaticAdvice re carrier state

The Thalassaemias

2 globin genes4 globin genes

Autosomal recessive disordersCharacterised by ineffective haemopoiesis

The Thalassaemias

ThalassaemiaSeverity depends on the number of genes deletedTrait – 1 or 2genes deleted, mild anaemia, hypochromic microcytic filmHb H disease – 3 genes deleted , splenomegaly, Hb 6-10g/dl, hypochromic microcyticHyrdrops fetalis – 4 gene deletion, death in utero

The Thalassaemias

ThalassaemiaTrait – mild hypochromic microcytic anaemia, advice re carrier state thal major

Severe anaemia @ 3-6 months whem switch is made from fetal HbHepatosplenomegalyExpansion of bones

The Thalassaemias

Laboratory featuresSevere anaemiaHypochrominc microcytic cells, target cellsBM erythroid hyperplasiaDNA analysis

The Thalassaemias

ManagementRegular transfusionIron chelationBone marrow transplantation

Reduced life expectancy

BLEEDING DISORDERSRecognition and continuing

care

TISSUE FACTOR

+TFVIITISSUE FACTOR

COMPLEXXI

IXX

VIII

V

PROTHROMBINTHROMBIN

VII VIIa

FIBRINOGEN

Va

VIIIa

XIa

IXaXa

TRIGGER

FIBRIN

Vesselinjury

PlateletRelease rxn

PlateletAggregation

Vasoconstriction CoagulationCascade

StableHaemostatic Plug

Recognition of Bleeding Disorders

The Bleeding History

Personal historyEpistaxisBleeding post surgeryBleeding post dental extractionMenorrhagiaHistory of anaemiaEasy bruising

Family history NB

The Bleeding history

Coag. DeficienciesProlonged bleeding after trauma and surgery (>24 hrs).Haemarthroses Muscle bleeding.

Platelet defects and VWD:Bruising.Petechiae or purpura.Epistaxis.Menorrhagia Prolonged post-trauma bleeding

Investigations

Investigation of bleeding disorders

FBC - platelet countProthrombin time (PT) - factors V, VII, XActivated partial thromboplastin time (APTT)- factors VIII, IX, XI, XIIFibrinogen

Investigation of bleeding disorders

Von Willebrand FactorSpecific clotting factor assaysPlatelet function testing

Treatment of bleeding disorders- general principles

Avoid IM injections and NSAIDsAvoid delay in treating the patient. Treat on suspicion of a bleedListen to the patient - he/she has lifelong experienceRecord any treatment given including batch numbers to ensure full traceability of factor concentratesSeek help early

Treatment of bleeding disorders- general principles

VaccinationAgainst Hepatitis A and BGive by SC routeChidhood vaccinationsCheck antibody levels annually

Haemophilia

Haemophilia A VIII deficiency sex-linked, 1/3rd carriers <50% VIIIC.1:20,000 births

Haemophilia B IX deficiencysex-linked, 1/3rd carriers <50% IX.1:100,000

These are clinically indistinguishable

Haemophilia

Mild haemophilia ( 5 - 20 %): – bleed only with trauma and surgery.

Severe haemophilia( < 1%) : – Haemarthroses 2-8 times/month.– Muscle bleeds.– Intracerebral bleeding– Prolonged bleeding with trauma and

surgery.

HAEMOPHILIA - HAEMARTHROSIS

Haemophilia Care

Treatment of acute bleedsManagement of HIV and Hep C infectionManagement of arthropathyDental review / dental hygieneAnnual clinic reviewVaccination

Haemophilia treatment

A bleed or potential bleed requires immediate treatmentIf in doubt manage as a bleed Identify site of suspected bleed and assess for compression of vital structuresAvoid unnecessary investigations - eg Xrays, coagulation profiles – unless clinically indicated

Haemophilia treatment

FACTOR VIII and IX

Previously plasma derived

Now all recombinant in Ireland

Delivered directly to patients homes

Haemophilia - treatment

Moderate and severe bleeds need admission

Daily factor concentrateImmobilisationAnalgesiaPhysiotherapy

Von Willebrand Disease

19265yr old girl – died at 13yr during 4th menstrual period4 siblings died from gastrointestinal haemorrhageBoth parents had significant bleeding historyVWF – identified 1950s, purified 1972, sequenced 1985

Von Willebrand Disease

Up to 1% of the population125 / million have a clinically significant bleeding disorderAutosomal inheritance

Von Willebrand factor

Large glycoprotein produced by endothelial cells and megakaryocytes Mediates platelet to endothelial adhesion Mediates platelet to platelet interactionCarrier protein for Factor VIII

Von Willebrand Disease

MILD/MODERATE BLEEDING TENDANCY

mucocutaneous bleedingeasy bruisingepistaxismenorrhagiarecurrent iron deficiencyfamily history

VWD diagnosis

Coag screen often normal

VWF - quantiative assays

VWF Ricof - functional assay

VWD - diagnosis

Levels increased by menstrual cycle, OCP, pregnancy, smoking, stress, inflammatory disorders

Repeat sampling recommendedequivocal resultsminor abnormalitiesstrong personal or family history

VWD Treatment

Avoid NSAIDsAvoid IM injectionsVaccinate against Hepatitis A and BTreat anaemiaDental hygiene

Very few patients require treatment with clotting factor concentrate

VWD TREATMENT -Specific measures

Clotting factor concentrates

DDAVP

Cyclokapron

DDAVP

Promotes release of VWF and factor VIII from endothelial cells0.3ug/kg in 100mls N/Saline over 30 minsAverage response is a threefold rise in VWF and FVIIITreatment of choice in responsive patients for spontaneous bleeding , trauma or minor surgeryIntra nasal DDAVP

VWD TREATMENT -Specific measures

Cyclokapron Antifibrinolytic agentStabilises clotGiven orallyProvides adequate cover for minor procedures or dental work