The Need to Consider Renal Health in

Transfusion Care and Research to Inform

Best Practice

Shahid Muhammad

Specialist Biomedical Scientist

Wednesday 01st February 2017

Leadership & Management

Presentation Structure • Introduction

• Objectives - Aims/ Justifications

• What is Chronic Kidney Disease (CKD)

• Clinical Factors and the Decision to Transfuse

• Strategies for Transfusion Therapy

• Assessment of Viral Hepatitis in Renal Patients/ Solid Organ Transplantation

(Table 1)

• Transfusion Risks

• Transfusion Alternatives

• Transfusion Research

• Literature Review - Design/Methods

• Literature Review – Grouping of Terms (Table 2)

• Literature Review – Explicit Number of Papers Identified via PubMed (Table 3)

• Literature Review – No. of Papers Identified via PubMed and EBSOC Host

(Table 4)

• Literature Review - Themes Derived

• Literature Review - Findings

• Concepts of Leadership and Management in Transfusion/ Care Practices

• Further Research & Interventions

• Discussion

• Conclusion

• Summary Points

• Final Message

• References

• An estimated 15 million patients in England have at least one Long-Term Condition (LTC)

or Chronic Illness (CI) (1).

• The numbers of patients with multiple LTCs/ CIs are set to rise from 1.9 million in 2008 to

2.9 million in 2018 (1).

• Already 30% of the population with LTCs/ CIs account for 70% of NHS spending (1).

• Patients with LTCs/ CIs like Chronic Kidney Disease (CKD) who have potential associated

anaemia are prescribed Erythropoiesis-Stimulating Agents (ESAs) like Erythropoietin (or

EPO) – but if in ‘crisis’ may require Red Blood Cell Transfusions (RBTs); and some cannot

receive RBTs or may refuse (because of history of antibodies or co-morbidities – thus

become 'untransfusable' patients) (2).

• There are no universally accepted treatment guidelines for managing transfusion care in

patients with LTCs/ CIs, and practice differs between hospitals, regions, and countries (2).

• There is ever more need to consider the renal health of patients who require ongoing care/

treatment, especially where renal insufficiency is evident/ can compromise the synthesis of

the hormone EPO (2).

• In addition renal health is/ should also be an important consideration for transfusion

research practices.

Introduction

Objectives – Aims/ Justifications Objectives

1) To highlight the need to consider renal health in transfusion care and

research to inform best practice and

2) To provide context of Leadership and Management in transfusion

care/ practices

Aims/ Justifications

1) To understand what further aspects of care are required for patients

with LTCs/ CIs

2) To highlight what specific practices would help in the development of

transfusion care guidelines and

3) To provide a further understanding of treatment alternatives taking

into consideration renal insufficiency from a leadership/ management

stance

• Chronic Kidney Disease (CKD) is an LTC/ CI that can be summated as

the steady and consistent reduction in renal function over time.

• Primarily in the disease development, patients with CKD will have no

identifiable symptoms and it is thus largely a silent disease and this

has been the case for many years – CKD is an under-diagnosed CI

(1,3).

• Even in the absent of indicators, CKD adds significant burden on

cardiovascular health and can cause death acutely or over time owing

to its clinical manifestations (1,3).

• CKD is thus now increasingly being recognized as a global public

health problem and a key determinant of poor health outcomes (4,5).

• With CKD prevalence steadily increasing, scientists with clinical teams

in haematology/ transfusion and biochemistry now need to consider

further, renal health of all patients with LTCs/ CIs where RBT may be

warranted to achieve best practice.

Background

What is Chronic Kidney Disease (CKD)?

Clinical Factors and the Decision to Transfuse • Recommendations regarding optimal Hb levels in patients with LTC/ CIs like

CKD continuously evolve, and results from randomized controlled trials

(RCTs) of corrective strategies continue to be impartial (6).

• Although partial anaemia correction with EPO-stimulating formulations

provide various advantages to normalize Hb levels, there may be higher

probabilities of cardiovascular events and cancer risk (6).

• There is general agreement that RBTs are not typically indicated for Hb levels

of ≥ 100 g/L and transfusion should be considered when Hb is ≤ 70 to 80 g/L

depending on patient characteristics (7).

• As more studies (particularly RCTs) addressing RBTs are published, it will

become increasingly transparent that leaders and managers will need to

assess outcomes that may expose patients to unnecessary risks (7-8).

• The clinical importance of the RBCs storage lesion (i.e. the time-dependent

metabolic, biochemical, and molecular changes that stored cells undergo) is

still lacking. RBCs can be filtered, washed, frozen, or irradiated for specific

conditions/ indications.

Strategies for Transfusion Therapy

• A restrictive transfusion strategy is recommended for patients with

pre-existing CVD (9), and similar transfusion strategies need to be

extended in patients who are at risk of renal insufficiency and the

post renal transplant population.

• In pre-existing CVD patients, transfusion is considered when Hb

levels are ≤ 80 g/L or for symptoms such as chest pain, orthostatic

hypotension, tachycardia unresponsive to fluid resuscitation, or

congestive heart failure (9).

• This weak recommendation is based on moderate-quality evidence

due to limited clinical trial data directly addressing this population of

patients.

• Additional clinical practice guidelines exist but do not factor in

strategies for patients with renal insufficiency, more generally.

Guidelines and Frameworks

• Patients with a CKD as a co-morbidity should have their Hb

assessed (10).

• Having familiarity with the National Institute for Clinical Excellence

(NICE) (10) definitions of renal anaemia (i.e. using a threshold of

110g/L to define anaemia and the need for treatment thereof) used in

CKD and cross-reference with guidelines used by the European Best

Practice Guidelines (11) and Kidney Disease Outcomes Quality

Initiative (KDOQI) (12) is important.

• Leaders and Managers need to continue reviewing guidelines to

ensure that practices are rounded; patients with stage 3b CKD and

have Hb < 110g/L should be tested for anaemia.

• The mean Hb declines as renal function reduces in subsequent

stages of CKD and this is when anaemia then catches up with

additional clinical symptoms.

Assessment of Viral Hepatitis in Renal Patients/ Solid Organ Transplantation (Table 1)

CMV negative

(red cells, platelets and granulocytes)

Gamma Irradiated

(red cells, platelets and granulocytes)

Hepatitis E negative

(all blood components)

Intrauterine transfusions Allogeneic haemopotietic stem cell transplant

recipients from the time of conditioning therapy,

continues while the patient is receiving GvHD

prophylaxis. If chronic GvHD present or taking

immunosuppressants irradiated components

required indefinitely

Patients awaiting solid organ transplant

(SOT) – from 3 months prior to date of

planned elective SOT or from the date of

listing for a solid organ transplant.

Exchange transfusion Allogeneic bone marrow or stem cell donors, 7 days

prior to and during the harvest

Patients who have had SOT – for as long

as the patient is taking

immunosuppressants.

Neonates up to 28 days post expected date of

delivery

Autologous stem cell recipients from conditioning

therapy until 3 months post-transplant (6 months if

total body irradiation is used)

Patients with acute leukaemia – from

diagnosis (unless/until decision made not

to proceed with stem cell transplant).

Pregnant women for planned non-urgent

transfusions

Patients undergoing bone marrow or peripheral

blood stem cell harvesting for future autologous

reinfusion during and for 7 days before harvest

Patients awaiting allogeneic stem cell

transplant – from 3 months prior to the

date of planned transplant and up to 6

months following transplant, or for as long

as the patient is immunosuppressed.

Granulocytes components for CMV

seronegative patients

All donations from HLA matched donors or first or

second degree relatives (even if the recipient is

immunocompetent)

Extra corporeal procedures – e.g.

dialysis, extra-corporeal circulatory

support is included if within above

indications.

Severe T-Lymphocyte immunodeficiency

syndromes

Patients with, or with history of, Hodgkin Lymphoma

Patients treated with, or with history of treatment

with, purine analogue drugs

(Fludarabine, Cladribine, Deoxycoformicin,

Bendamustine and Clofarabine)

Patients treated with, or with history of treatment

with,Alemtuzumab and/or Rabbit Anti Thymocyte

Globulin (ATG)

Intra-uterine transfusions (IUT)

Exchange transfusion in neonates

Top-up transfusion in neonates (if there has been

an IUT, exchange transfusion or if the donor is a

first or second degree relative) until 6 months after

the expected delivery date.

Platelets transfused in utero to treat alloimmune

thrombocytopaenia and top up platelet transfusions

until 6 months after the expected date of delivery

Granulocyte transfusion

Table adapted from (13)

Transfusion Risks

• Results of a study by (Wardrop et al. 2013) elaborating on research

by (15) exploring Aprotinin (a powerful anti-fibrinolytic) in patients

undergoing heart surgery (14).

• In this observational study, 4374 patients undergoing Coronary Artery

Bypass Graft (CABG) surgery, showed doubling of the risk of renal

failure requiring HD, having an MI, or heart failure (P <0.001) and a

181% increase in the risk of stroke or encephalopathy (P=0.001)

when Aprotinin was used compared with the lysine analogues to

prevent bleeding (14).

• Evidence available for the use of anti-fibrinolytics in haematology

patients is still limited and how they may potentially have an impact

on renal function over time has not been explored (14-15).

Transfusion Alternatives

• PBM represents an international initiative in best practice of transfusion

medicine and this policy has incorporated the key objectives of the PBM

conference: ‘The Future of Blood Transfusion’, June 2012, hosted by the

Department of Health (DH), the National Blood Transfusion Committee

(NBTC) and the NHS Blood and Transplant (NHSBT) (13).

• Autologous blood donation and EPO-based pharmacological stimulating

agents are efficacious in the pre-operative period. Intraoperatively, acute

normo-volaemic haemodilution, cell salvage, anti-fibrinolytics, specific

anaesthetic and surgical techniques, coagulation monitoring, acceptance of

minimal Hb values and artificial oxygen carriers can reduce the need for RBTs

(16).

• Alternatives to RBTs should be given strong consideration, however focused

evaluations of specific LTC/ CI patient populations and alternatives will help to

clarify best use of treatment options (17) taking into account renal function

(18-22).

Transfusion Research

• NHSBT is going to try to provide, as much as is possible,

‘bespoke’ RBTs for those who have already produced

antibodies, and to prevent those who have not from producing

antibodies in the first instance (23).

• Patients who have an LTC/ CI with potentially compromised

renal function, discussions and decisions need to be had as

to whether to transfuse or not should be envisaged with

alternative treatment modalities providing similar efficacy.

• Leaders and Managers should become more aware specific

disease states in different ethnicities to help inform routine

practices.

Literature Review - Design/ Methods

Four hundred and fifty (450) abstracts were identified between

1977-2015 (or over 38 years).

Two-hundred and seventy four (274) papers were cross-

examined using a Critical Appraisal Skills Programme (CASP

2015) and after removal of duplications, eighty-two (82) papers

were evaluated to:

1. Understand what aspects of care are required more

consideration for patients with LTCs/ CIs.

2. Understand what specific practices would help in the

development of transfusion care guidelines and

3. Provide an understanding of present indications for RBTs.

Blood Renal Leadership/ Management

Blood Transfusion Disease Leadership

Red Blood Cells Chronic Management

Blood Replacement Illness Framework

Erythropoietin Renal Guidelines

Haemoglobin Long-Term Best Practice

Anaemia Surgery Research

Haemorrhage Healthcare

Intervention Medication

Pharmacotherapy Condition

Literature Review –

General Grouping of Terms through PubMed & EBSCO Host

Database (Table 2)

Literature Review –

Explicit Number of Papers Identified through Pubmed (Table 3) Blood Renal Leadership/ Management

Basic search

A combination of Blood terms

(as listed in table 2)

This retrieved 48 articles

(1977-2015)

Basic search

A combination of renal terms inserted

(as listed in table 2)

This retrieved 24 articles

(1989-2015)

Basic search

A combination of challenges terms inserted (as

listed in table 2)

This retrieved 291 papers

(1977-2015)

Advanced search

Inserting all the words

(see table 2)

Selecting, title/ abstract, and OR search

option

This retrieved 28 articles

(1977-2015)

Advanced search

Inserting all the words

(see table 2)

Selecting, title/ abstract, and OR search option

This revealed 24 articles

(1989-2015)

Advanced search

Inserting all the words

(see table 2)

Selecting, title/ abstract, and OR search option

This revealed 388 papers

(1977-2015)

Refined search

Highlighted:

Adults

OR Search

English

Humans

Title/Abstracts

Medline and PubMed Central subsets

were also marked

This retrieved 20 articles

(1977-2015)

Refined search

Highlighted:

Adults

OR Search

English

Humans

Title/Abstracts

Medline and PubMed Central subsets were also

marked

This retrieved 22 articles

(1989-2015)

Refined search

Highlighted:

Adults

OR Search

English

Humans

Title/Abstracts

Medline and PubMed Central subsets were also

marked

This retrieved 98 abstracts

(1989-2015)

Literature Review – Number of Papers Identified through

both PubMed and EBSCO Host (Table 4)

Theme Papers

Theme 1

Lack of Renal Health in Transfusion Care Strategies

for Patients with LTCs/ CIs

(Carpenter 1990;Collins et al. 2014;Corry et al. 1980;Corwin et al. 1987;Corwin

2011;Corwin and Bonventre 1986;Drueke et al. 2006;Eschbach, Jr. et al.

1967;Eschbach et al. 1970;Eschbach et al. 1987;Eschbach 1994;Eschbach

2000;Eschbach 2002;Eschbach and Adamson 1985;Karkouti 2012;Macdougall and

Obrador 2013;Napolitano et al. 1999;Opelz et al. 1997;Opelz and Terasaki

1978;Whitman et al. 2013)

Theme 2

Managing Anaemia in the Chronically Ill’/

‘Untransfusable’ Patient

(Bargman 1991;Beliaev et al. 2012;Charles et al. 2006;Corwin et al.

1995;Gilbertson et al. 2013;Hebert et al. 1995;Hebert 1998;Heh-Foster et al.

2014;Karkouti et al. 2005;Karkouti et al. 2006;Karkouti et al. 2007;Karkouti et al.

2015;Karkouti and Dattilo 2006; Melmed et al. 2009;Napolitano 2004;Napolitano

2005;Shander 2004;Sherman et al. 1988;Surgenor et al. 2001)

Theme 3

Alternatives and Indications to RBTs

(Ball and Winstead 2008;Bargman 1991;Charles et al. 2006;Corwin et al.

1995;Corwin et al. 2014;Corwin and Napolitano 2014;Drews 2003;Hebert et al.

1999;Karkouti et al. 2003;Ladas et al. 2004;Lorentzen et al. 2013;Macdougall and

Obrador 2013;Madjdpour et al. 2006;Napolitano 2005;Spahn 1999;Spahn

2004;Spahn and Casutt 2000;Spence and Atabek 1994;Whitman et al. 2013)

Theme 4

The Importance of Research in Leadership and

Management to Inform Best Practice

(Blajchman and Hebert 2001;Carson 2005;Carson and Armas-Loughran

2003;Carson and Patel 2014;Corwin 1999;Corwin et al. 2003;Corwin 2005;Corwin

and Carson 2007;Goodnough and Shander 2007; Eschbach, J.W. & Adamson,

J.W. 1989;Hardy 2003;Hebert and Fergusson 2002;Karkouti et al. 2003;Klein et

al.2007;Klein et al.2015; Murphy et al. 2001; Murphy and Goodnough

2015;Napolitano et al. 1999;Napolitano 2005;Napolitano and Corwin

2004a;Napolitano and Corwin 2004b;Spahn 2004;Spahn and Casutt 2000;Spahn

and Marcucci 2004)

Literature Review - Themes Derived The themes this work uncovered include:

1) ‘Lack of Renal Health in Transfusion Care Strategies for

Patients with Chronic Illnesses’.

(20 papers)

2) ‘Managing Anaemia in the Chronically Ill’/ ‘Untransfusable’

Patient’.

(24 papers)

3) ‘Alternatives and Indications to RBTs’

(19 papers)

4) ‘The Importance of Research in Leadership and

Management to Inform Best Practice’.

(19 papers)

Literature Review - Findings Four issues were swiftly recognized

1) There were only three papers that explored RBTs and considered

renal insufficiency before 1978.

2) There have not been formal care plans to safeguard RBT requests

in the LTCs/ CI patient population for the longer term (until more

recently).

3) The alternatives and indications for RBTs in patients with a LTC/ CI

are still somewhat inconsistent universally and this makes

practices difficult to standardize.

4) There has been limited emphasis on the importance of research in

leadership and management to inform best practices.

Concepts of Leadership and Management in Transfusion/

Care Practices

• No universally accepted definitions or theories of leadership or management

actually exists.

• Scientists looking to develop their aptitudes in a specific area of practice,

there now needs to be more clarity of definitions and differentiate between

biomedical leaders and biomedical managers.

• Leadership (perhaps more so than management) is also knowing when and

how patients may benefit with alternative treatments or treatment pathways;

this also means there needs to be good examples in practice so colleagues

can gain first hand of what works and what doesn’t and this all links to

evidence-based practice.

• Scientists are needed who consider renal health more intricately in

transfusion care through research to inform best practice.

• There is still quite a gap in research and this mainly focuses on patient

management in the short-term. The question is then what should be

done better?

• This is a question that can only really be answered by conducting more

longitudinal studies that look to compare different forms of treatment

alternatives over time.

• Future research must also consult renal guidelines and the Renal

Registry (RR)/ Renal Association (RA) would be a first port of call for

Biomedical Scientists to gain more knowledge relating to what formally

constitutes renal insufficiency.

Further Research & Interventions

Discussion

• Obviously if a patient with an LTC/ CI requires an RBT and there is

no other way to treat them, then that pathway should be taken.

• However, in practice, scientists should be having tighter discussions

with medical colleagues so that they too are aware of advantages

and disadvantages in the more intricate ‘nature’ of RBTs, being more

on the forefront of practice.

• Scientists are ‘in the game’ of saving and sustaining lives – they

should not be supporting care where lives are potentially being

further compromised.

Leadership, Management and Research relating to renal health in transfusion practices are

intricate.

Biomedical Scientists with transfusion care expertise are needed where an in-depth insight on

the importance of understanding renal health and sensitivity of laboratory tests are concerned.

If transfusion services are to be effective, scientists need to Take Ownership to ensure safe

and quality assured practices. This will help to bridge gaps in transfusion practices and the

future care of patients with LTCs/ CIs.

National Blood Transfusion Committee (2014) informs: ‘Transfuse one dose of blood

component at a time, (e.g. one unit of RBTs or platelets, in non-bleeding patients and

reassess patient clinically and with further blood count to determine if further transfusion is

needed)’ and so nationally centres are now moving toward a single unit transfusion policy in 1)

keeping with PBM and 2) to reduce inappropriate RBTs (24).

Research integrated with practice is important to achieve best care/ practice, especially in

those who have/ at risk of renal insufficiency.

Conclusion – Taking Ownership!

• Frameworks/ guidelines for scientists proceeding with a RBT request, especially with regard to patients with an

LTC/ CI, are getting better.

• Literature and research practices in transfusion care need to factor in renal health more substantially so that

discourse can be re-iterated as to whether a patient ‘really needs’ to be transfused. This also means that other

forms of replacement therapies and treatments should be tried and tested.

• More research is needed to help inform whether patients who are suspect for renal insufficiency should be

provided alternative forms of therapy that may 1) support them in the longer term and 2) identify any particular

predisposition/s before a RBT is considered because a number of suspect renal insufficient patients who

receive long-term transfusions will develop allo-and/ or autoantibodies. This is going to be an issue in an ageing

population.

• Again, longitudinal studies are required to better appreciate whether there is any advantage of RBTs vs.

different EPO formulations in clinical practice with a view to assess a strategy for phenotyping and matching

patients with suspect renal insufficiency.

• A cross-sectional study would initially be helpful to understand/ appreciate how transfusion research practices

could be improved with awareness and educating medical/ clinical teams, especially those supporting the care

of patients with LTCs/ CIs, ‘untransfusable’ patients and indeed those who refuse treatment.

• There is still a need to consider renal health in transfusion care and research practices to ensure effective and

best practices are achieved across health spheres for patients with LTCs/ CIs.

• The complexity of care plans should highlight the importance of better integration across laboratory practices

and medicine in order to achieve formal consensus and help form robust guidelines.

Summary Points

Final Message………….. “Biomedical science professionals are encouraged, and have a

professional responsibility, to offer advice and expertise to

individuals, teams, committees or working groups where their

input can contribute positively to a service or project outcome”

Ref: Institute of Biomedical Sciences, Good Professional Practice - Benchmark Series (IBMS, 2015)

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Questions – Thank you