Anaemia - an important health care issue

Borås, May, 2007 PD Dr. T. Brinkmann



Anaemia

Disease State Management


PD Dr. Thomas BRINKMANNEurClinChem

European Scientific Group Manager Associate Professor of Clinical Biochemistry Diagnostics and Life Science Medical Faculty Europe, Middle East, Africa and India Ruhr University of Bochum Beckman Coulter Eurocenter Bochum, Germany Nyon, Switzerland


Beckman Coulter EurocenterNyon, Switzerland


NYON


Europe - Beckman Coulter’s Definition


Anaemia is an important health issue

AnaemiaIron DeficiencyAnaemia of CancerAnaemia of Renal FailureAnaemia in elderly people and chronic diseases

How to detect anaemia?

Anaemia Disease State Management

Anaemia in Chronic Diseases (+IDA)Haematological Malignancies (EPO)

Summary

Objective


Anaemia – is an important public health issue


Anaemia: Definition

• Definition:Anaemia is a symptom of disease that requires investigation to determine the underlying etiology.

It is defined as a decrease in red blood cell mass but in practice it is defined by haemoglobin concentrations below:

– males 13.0 g/dL (WHO)– females 12.0 g/dL (WHO)


Anaemia

• Prevalence– Widespread public health problem with major consequences for

human health and socio-economic development– WHO estimates 2 billion people are affected worldwide– >50% due to iron deficiency

• Effects on health– Increased maternal and child mortality– Decreased cognitive and physical development in children– Decreased productivity in adults– Increased risk of postoperative morbidity and mortality


Anaemia

• Causes– Nutritional deficiencies

• Iron, B12, Folate, Vitamin A

– Infectious diseases• Malaria, helminth infections (hookworm and schistosomiasis), HIV

– Thalassaemias, sickle cell, haemolytic anaemia, leukaemia

– Cancer, chronic renal disease, diabetes, heart disease, rheumatoid arthritis, gastrointestinal disease

– Chemotherapy, radiotherapy


Anaemia: Symptoms

Signs depends on the severity of anaemia

Two general reasons for anaemia– decreased red cell production– increased red cell destruction


Anaemia in the world

Data from World Health Organisation


Anaemia in the worldAnaemia in the world

Data from World Health Organisation


Anaemia in Iron Deficiency


Iron Deficiency Anaemia

• The most frequent cause of anaemiaThe most frequent cause of anaemia

• Causes of iron deficiencyCauses of iron deficiency– Diet low iron: only 1 mg absorbed for 10-20 mg ingestedDiet low iron: only 1 mg absorbed for 10-20 mg ingested

– Body changes that increase requirement: growth in children, pregnancy, Body changes that increase requirement: growth in children, pregnancy,

lactationlactation

– Gastrointestinal tract abnormalities (post surgery)Gastrointestinal tract abnormalities (post surgery)

– Blood loss: gastrointestinal bleeding, menstruation, injuryBlood loss: gastrointestinal bleeding, menstruation, injury



Prevalence of iron deficiency in Europe

Public Health Nutrition, 2001

n Age % of

population Children France 38 2- 24 months 4.2 44 2- 6 years 2.0

Adolescent girl Ireland 86 14.5- 18.4 years 7.0 25 14- 18 years

Menstruating women Sweden 372 38 years 6.6 122 38 years 7.4 Denmark 595 30- 50 years 2.8 Ireland 192 18- 44 years 13.5 UK 125 16- 50 years 9 France 476 17- 42 years 1.3 203 16- 53 years 2.9 6648 30- 50 years 4.4 Spain 322 15- 50 years 5.3 Pregnant Women

Holland 796 6-28 Denmark 107 18 France 332 9 359 10 191 30 Germany 378 13.6



• Anaemia in childrenAnaemia in children– Range from 4 to 7%

– Impaired cognitive performance, motor development, coordination, language development

• Anaemia in pregnant womenAnaemia in pregnant women– Range from 6 to 30%

– Risk factor for premature delivery, low birth weight, possible inferior neonatal health


Anaemia of Cancer


Anaemia of Cancer

• Many factors contribute to anaemia in cancer:Many factors contribute to anaemia in cancer:

– BleedingBleeding– HaemolysisHaemolysis– Marrow infiltration by tumor cellsMarrow infiltration by tumor cells– Nutritional deficienciesNutritional deficiencies– Cytokine-mediated anaemiaCytokine-mediated anaemia– ChemotherapyChemotherapy– Radio-induced myelosuppressionRadio-induced myelosuppression


Anaemia of Cancer

0

20

40

60

80

100

HaematologicalMalignacy

Solid Tumor HaematologicalMalignacy

Solid Tumor

At diagnosisDuring the course of the treatment

From European Cancer Anaemia Survey, Abstract in Blood 2002


Anaemia of Renal Failure


Anaemia of Renal Failure

• Anaemia of chronic renal Anaemia of chronic renal disease is caused by the disease is caused by the inadaequate production of inadaequate production of Eythropoetin hormone due to Eythropoetin hormone due to reduced mass of functioning reduced mass of functioning kidney tissuekidney tissue

• Prevalence of anaemia is Prevalence of anaemia is correlated to the level of correlated to the level of kidney destructionkidney destruction


Anaemia of Renal Disease

• Chronic Renal Insufficiency– Progressive destruction of renal mass– Evaluated and staged with rate of glomerular filtration (not only,

Creatinin clearance: 15-80 mL/min)

• Anaemia in Chronic Renal Insufficiency:– Increased risk of mortality and cardiac complications

• For every 1g decrease in Hb concentration, there is a 6% increase in the risk of left ventricular hypertrophy

– Third National Health and Nutrition Examination Survey in US( Hb < 12 g / dL)

• 1,200,000 women• 300,000 men ( J Am Soc Nephrol, 2002)


Anaemia of Renal Disease

• Chronic renal failure:

– Very low glomerular filtration rate ( <10 -15 mL/min)

– Treatment: kidney transplantation or dialysis

– Anaemia is corrected by substitutive rhEpo but Hb monitoring is required

– In US:• 1,200 people per million population

– In Europe:• 700 people per million population

( Nephrol Dial Transplant, 2002)


Anaemia in elderly peopleand chronic diseases


Prevalence and causes of anaemia in elderly

Prevalence : men 11.0%, women 10.2%

Anaemia of chronic disease


Anaemia of Chronic Disease

The most frequent cause of anaemia in elderly peopleThe most frequent cause of anaemia in elderly people

• Chronic diseasesChronic diseases– Chronic infections: tuberculosis, hepatitis, lung abscessChronic infections: tuberculosis, hepatitis, lung abscess– Non infectious inflammatory diseases:Non infectious inflammatory diseases:

Rheumatoid arthritis, temporal arthritis, systemic lupusRheumatoid arthritis, temporal arthritis, systemic lupus– Neoplastic disorders, lung and breast cancer, HodgkinNeoplastic disorders, lung and breast cancer, Hodgkin– Chronic disorders: COPD, diabetes, congestive heart failureChronic disorders: COPD, diabetes, congestive heart failure

• MechanismMechanism– Iron is sequestrated in macrophagesIron is sequestrated in macrophages– Cytokines secreted due to chronic diseaseCytokines secreted due to chronic disease– Cytokines block iron release from macrophagesCytokines block iron release from macrophages– Iron unavailable for precursor cells in bone marrowIron unavailable for precursor cells in bone marrow

– Underproduction of red blood cellsUnderproduction of red blood cells


Anaemia of Chronic Disease

• Estimated prevalence of anaemia associated with chronic disease

New England Journal of MedicineMarch 2005


Anaemia

• Iron deficiency anaemia

• Anaemia of cancer

• Anaemia in pregnancy

• Anaemia of renal disease

• Anaemia in elderly

• Anaemia in chronic disease


How to detect anaemia ?


Beckman Coulter Anaemia Menu

Complete Blood Count

Reticulocyte Count

Hb electrophoresis

Haptoglobin

Serum Iron

Total Iron Binding Capacity

Unbound Iron Binding Capacity

Transferrin

Transferrin saturation

Ferritin

Folate

RBC Folate

Vitamin B12

EPO

Anti-Intrinsic Factor

Soluble Transferrin Receptor

Remisol Data Management Software

Haematology

Haematology

Special Chemistry

Special Chemistry

General Chemistry

General Chemistry

General Chemistry

General Chemistry

General Chemistry

Immunoassay

Immunoassay

Immunoassay

Immunoassay

Immunoassay

Immunoassay

Immunoassay

Data Management


Anaemia and Beckman Coulter

• Anaemia is a significant health concernAnaemia is a significant health concern

• Occurs in a multitude of disease states with many different causesOccurs in a multitude of disease states with many different causes

• With unmatched expertise in chemistry, haematology, immunoassay With unmatched expertise in chemistry, haematology, immunoassay and data management, Beckman Coulter is uniquely positioned to and data management, Beckman Coulter is uniquely positioned to find comprehensive solutions for anaemia disease managementfind comprehensive solutions for anaemia disease management

HAEMATOLOGY CLINICAL CHEMISTRY IMMUNODIAGNOSTICS

REMISOL DATA MANAGEMENT


Our Solution


Our Solution

The family of UniCel systems is designed for flexible multi-platform configuration and

connectivity, enabling labs to consolidate and optimize workload and labor resources and

hence to reduce costs


UniCel DxI ® Access Immunoassay Systems

UniCel DxC Synchron Clinical Systems

UniCel DxH Coulter Cellular Analysis Systems

UniCel DxA Automation Systems

UniCel DxE Information Systems

UniCel DSM Disease Management Solutions

UniCel = Unified WorkcellDx = Diagnostics Excellence


Input OutputLab processes

Patient sample

Productivity

Result

Diagnostics Companies: Current Focus

ResultResult


Beckman Coulter Contributionto Disease State Management


Patient sample

ClinChemPhysician

Patient

Productivity Efficiency

Result


Circle of Life


Chemistry

Immunoassay Hematology

Data Management

Automation

Anaemia with UniCel Disease Management

Instruments, Software and Reagentsprovide a unique solution for disease

management


Disease State Management: The Product

Expert system

Remisol


Combining Hardware, Reagents and InformationExample: Pernicious Anaemia

• Prevalence– Major cause of vitamin B12 deficiency in developed countries. – Underdiagnosed.

• Chronic and autoimmune illness with malabsorption of B12 due to Intrinsic Factor deficiency

– Destruction of parietal cells from the gastric mucosa leading to failure of IF production.– Occurrence of autoantibodies to gastric parietal cells or to IF.– End-stage of autoimmune destruction of gastric mucosa.

• Clinical signs– Silent until the end-stage.– First: megaloblastic anaemia– Weakness, weight loss, non specific GI symptoms, neurological symptoms ( senile dementia...)– Associated with other autoimmune diseases: hypothyroidism, Graves' disease, thyroiditis, Addison's disease– Associated with a higher risk to develop gastric cancer


Case Study

• A woman consults GP for weakness and palor

• GP suspects anaemia – Prescription for a CBC– Anaemia confirmed with normal/high MCV

• B12 and Folate are tested

• Use of an expert system


Common medical practice according to Philippe Day, UK

Macrocytic Anaemia

B12

assay

Anti-IF Manual Assay

Schilling test

IV B12 supplementation

during 1-2 months

Macrocytic Anaemia

B12

assay

Reflex Access anti- IF Assay

Low

Low

B12 supplementation

(IV or oral)

Use of Acess anti-IF Assay

If anti-IF is negative considder Gastrin test to check other gastrointestinal disorders


Contribute to Enhance Value Delivered by Laboratory to Doctor








UniCel Disease Management

Diagnostic Value Cost

Time to Diagnosis

Test Invasiveness

Schilling test good high within a week high

Gastroscopy good high within a week high

Anti-IF good low same day none


Pernicious AnaemiaDisease Management Benefits

– For the lab: better service to clinician and cost reduction

• Reduced time to diagnosis• Automated methods/reflex testing

– For the clinician: better patient management

• Reduced time to diagnosis• Adapted B12 therapy• Adequate surveillance of the patient (gastric cancer)

– For the patient:• Reduced time to diagnosis and treatment• Better peace of mind• Less « medication »



Patient sample

ClinChemPhysician

Patient

Productivity Efficiency

Result


Differentiate

Anaemia of Chronic Disease (ACD)

from

Iron Deficiency Anaemia (IDA)


Differentiate ACD from ACD with IDA

• Prevalence ACD27% of anaemias 17% of the elderly (outpatient) and 35% (acute ward)? ACD with IDA (not easy to separate)

• Clinical signsAsthenia, fatigue or depression, fever and the symptoms of the underline disease


Common practice

• Anaemia of Chronic DiseaseTreat the inflammation In case of anaemia with low Iron and Tf Sat%, normal or high Ferritin, with history of chronic infection of inflammation, confirmed with positive CRP, we suspect an

ANAEMIA OF CHRONIC DISEASE

• ACD + IDA (mixed form)Treat the underlined disease (inflammation) and wait for the outcome

Insufficient Iron therapy (too low, too short)IDA often misdiagnosed and mistreated

Impact for the patient: Individual remains anaemic for a long timeQoL remains low


Proposed practice

Include sTfR

Weiss et al. N Engl J Med 2005;352:1011-23.


- Indicator of iron availabilty during erythropoesis- No acute phase parameter- Not influenced by liver metabolism- Not influenced by malignant diseases

sTfrlg(Ferritin)Ferritin Index

The smaller the Ferritin Index,

the more Iron in the deposits

Borås, May, 2007 PD Dr. T. BrinkmannIDA = Iron Defiency Anemia ACD = Anemia of Chronic Disease

Punnonen K et al, Blood 1997


Punnonen K et al, Blood 1997

Ferritin Index Improved discrimination

ACD

versus

ACD + IDA


UniCel Disease

Management

Benefits Patient

Benefits Hospital Administration

Benefits Laboratory

Disease Management Benefits


Benefits Patients

• Prevention of secondary diseases (e.g. heart diseases, renal diseases)

• Improve QoL• Reduction of morbidity• Adequate treatment• Adequate selection of patients for EPO therapy• Earlier diagnosis and intervention• Shorter stay in hospital• Improve quality of care


UniCel Disease

Management

Benefits Patient


Benefits Laboratory



Benefits laboratory

• Which tests can be addedSoluble Transferrin receptor in combination of Ferritin and MCH (CHr), LHD% (%Hypo), IRF in three days will suspect that the patient respond or not with the treatment.

• Soluble Transferrin Receptor in combination with Ferritin will reduce the time for diagnosis and address directly the treatment, EPO, etc. and in case of Mixed ACD-ID it will reduce the time for the correction of the anaemia because only with iron the patient will remain anaemic for a minimum of 3 months with all its effects.

• Secondary diagnosisEasy detection of unknown disease (TBC) that will appear after the diagnosis of ACD

• REFERENCES1) Weiss G. and Goodnough L.T.: Anaemia of Chronic Disease.

N. Engl. J. Med. 2005;352:1011-23.2) Beguin Y., Clemons G.K., Pootrakul P. and Fillet G.: Quantitative Assessment of Erythropoiesis and Functional Classification of Anaemia Based on Measurements of

Serum Transferrin Receptor and Erythropoietin. Blood 1993;81:1067-76.

3) Metzgeroth G. and Hastka J. Diagnostic work-up of Iron deficiency. J. Lab. Med. 2004;28:391-9.

4) Zini G., Machin S., Briggs C. et al.: Multicenter Evaluation of Coulter MCH and the new derived LHD% parameters versus CHr and %Hypo for the assessment of Iron metabolism Disturbances. Poster 199, ISLH Meeting 2006.

5) IRF: «The IRF can also be used as an early indicator of response to erythropoietin therapy in patients with chronic renal failure and other diseases».


UniCel Disease

Management

Benefits Patient


Benefits Laboratory




• Shorter stay • Less medication and the right one

Less controls and analysis• Less visits with the specialists• Saving transfusions

• REFERENCESO’Broin S., Kelieher B., Balfe A. , Mc Mahon: Evaluation of serum transferrin receptor assay in a centralised iron screening service. Clin. Lab. Haem. 2005;27:190-4.


Anaemia in

Haematological Malignancies

EPO Therapy


Lab2%

Other21%

Pharmaceuticals11%

Hospital Services

33%

Professional Services

33%

Our Troubled Present: The EPO Example

Source: Kronberg ConferenceAdvaMed

Source: NCHS, CMS, G2 Strategic Lab Outlook 2000, “Creating Incentives for Genomic Research to Improve Therapies” Evans et al, Nature Vol 10, #12

Desired Response

$97B

Non- Response

$54B

Adverse Response

$12B


Example of a Disease: Anaemia in Haematological Malignancies Prevalence

Disease

ANAEMIA at diagnosis during therapy all severe

<8.5 g/dL

Non-Hodgkin-Lymphoma

MultipleMyeloma

60%

30%

25%

5-10%

90%

60%

High anaemia frequency in multiple myeloma due to- renal impairment by disease- bone marrow transplant


Prediction of Response in Haematological Malignancies

Borås, May, 2007 PD Dr. T. Brinkmann Y. Beguin, 1998

Prediction of Response in Haematological Malignancies

EPO before therapy[mU/ml]

sTfR increase 2 weeks after therapy

Responsen

17

7

24

100

< 100

< 100

-

< 25 %

25 %

18 %

29 %

96 %


EPO Treatment in Anaemia of Cancer

• Anaemia treatment with rHuEPO

• High cost

• 50% response rate

• Need to predict response rate to treatment

• IVD EPO helps to predict response


Common Practice

• Transfusion of erythrocyte units instead of EPO therapy?


Prediction of Response: Proposal

EPO serum concentration as predictive marker of response

Haemoglobin▼9.0 – 11 g/dL

Control EPO concentration

EPO

Continue

therapy

Hb remains low

Hb increases

Control o/p EPO Control o/p EPO

Control o/p EPO

Radiation Chemotherapy


UniCel Disease

Management

Benefits Patient


Benefits Laboratory



Benefits

• Benefits to the Patient– Improve quality of life– Prevent transfusions


UniCel Disease

Management

Benefits Patient


Benefits Laboratory



Benefits

• Benefits to the Laboratory– EPO testing– Increase value of information output


UniCel Disease

Management

Benefits Patient


Benefits Laboratory



Benefits

• Benefits to Hospital Administration– Hugh cost savings by selecting patients

receiving EPO therapy


Summary


• Beckman Coulter is fully engaged in implementing its strategy - Simplify, automate, innovate laboratory processes– Simplify, automate, innovate disease management processes

• The focus is on fulfilling unmet needs– Family of compatible immunoassay and workstation systems

• Closed tube sampling, broad menu, optimal CC/IA balance– Anaemia– Prostate disease– Reproductive endocrinology and high risk pregnancy– Cardiovascular

• The strategy will contribute to– Streamline processes from blood draw to results reports– Enhance value of information delivered by the Laboratory– Help physicians through decision-making processes


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Anaemia - an important health care issue

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