The Principles of Transfusion Medicine - “The 4 Agendas”

Igazi Foundation Education Day16th November 2013

Dr Paddy Knox

HIV & Hepatitis;

Transfusion Reactions

SAFETYDoH and Medical

Aid Funders

FUNDING

CONSUMER

??? Benefits of transfusion

DONOR PATIENT

EFFICACYBloodless Surgery, Jehovah Witness; Future

of Blood Transfusion

SAFETY

Transfusion Transmitted Infections HIV HEPATITIS

HBV & HCV MALARIA

ADVERSE REACTIONS Haemovigilance Report Incorrect Blood to Incorrect Patient Acute Transfusion Reactions,TRALI

Transfusion Transmitted Infections

Malaria

Trypanosoma Cruzii

PROTOZOA

Syphilis

Yersinia enterocolitica

Pseudomonas

Serratia

StaphylococcusStreptococcus

BACTERIA

VIRUSESHIV 1/2

Hepatitis B

Hepatitis C

Parvovirus B19

Prions

Hepatitis G

Cytomegalovirus

HTLV 1/2

ViralRNA/DNADetection(11days)

Viral Antigen Detection(16days)

AntibodyTesting

(22-42days)

SurrogateMarker

Serum ALT T-cell count

Anti-HIV Anti-HBV Anti-HCV Anti-HTLV

HIV p24 Ag HBsAg HCV Ag

NAT• HIV-1/2• HCV• HBV

NAT is the only direct test for the infectious agent.

Shorter window period to detection

Progress in Detection of Transfusion-Transmitted Pathogens

Earlier Viral Detection = Safer Blood Supply

PathogenInactivation

Inactivates viral and bacterial RNA/DNA

Reported HIV Transmissions 2001 - 2005

Between 2001 and 2005, 4 341 343 units of blood products were transfused in South Africa. 8 cases of HIV transfusion related infections were reported to the Haemovigilance programme.2001 - 2 cases

2002 - 2 cases2003 - 2 cases 2004 - 1 case2005 - 1 possible HIV Transmission,

7 cases: 2001 and 2004 All involved donors were traced, they were repeat donors who were in the window period of their infections. Since introduction of NAT in 2005, there have been no reported cases of HIV transmission.

Patients in South Africa have access to a quality blood service.

5-6 -5 -4 -3 -2 -1 0 1 2 3 4 6

10-1210-1110-1010-9 10-8 10-7 10-6 10-5 10-4 10-3 10-2 10-1 1PROBABILITY

RISK DECREASING RISK INCREASING

Annual risk of a person > 16 yrs ofexposure to at least 1 incidence of crime

Risk of serious ADR occurring

Annual risk of being infected by HIV

Death due to ADR

Annual risk of serious injury in road traffic accident

Annual risk of dying of cancer

Annual risk of being killed in road traffic accident

Estimated risk of receiving a window period donation

Risk of transfusion reaction

Hazards of Transfusion

Delayed2-14days

Immunological

Immediate< 24hr

Non Haemolytic

Intravascular Extravascular

Haemolytic

Immunological Infection Physical

Overview of Results

46%

28%

17%

7% 2%

AcuteTransfusionReactionMisdirectedUnits

DelayedTnsfusionReactionTransfuionTransmittedinfectionsUnclassified

46% Acute Haemolytic

28% Misdirected

17% Delayed

7% TTIs

SUMMARY OF ADVERSE EVENTS

TTI, 1

PTP, 0TAGVHD, 0

UNCLASSIFIABLE, 5

DEATH FROM LACK OF BLOOD, 1

TRALI, 3

NEAR MISSES, 5

DHTR (from IBT), 2

ATR, 75

IBCT, 28

South AfricanHaemovigilance Report 2006South AfricanHaemovigilance Report 2006

8 Steps for a Blood TransfusionStep 1: Prescription, consent and request for blood and

blood productsStep 2: Patient identification, blood sampling and

labellingStep 3: Blood grouping and compatibility testingStep 4: Transport of blood units to the hospital wardStep 5: Handling of blood units in the clinical areaStep 6: Administration of blood to the patientStep 7: Care, monitoring and follow up of the transfused

patient; recordingStep 8: Management of adverse transfusion reactions

Efficacy of Blood Products Transfusion Trigger

RCC Platelets Plasma

Time Related Issues 2,3 DPG Storage lesions Citrate toxicity

Cold Chain Management Immuno-modulation

Indications for leucodepletion Infection Increase recurrence CA

Carson JL, Noveck H, Berlin JA, et al. Transfusion 2002;42:812-818

Mortality rate stratified by postoperative Hb level (n=300)

Postoperative Hb (g/dL)

Study population 30-day in hospital mortality

1.1 – 2.0 7 7 (100%)

2.1 – 3.0 24 13 (54.2%)

3.1 – 4.0 28 7 (25%)

4.1 – 5.0 32 11 (34%)

5.1 – 6.0 54 5 (9.3%)

6.0 – 7.0 56 5 (8.9%)

7.1 – 8.0 96 0 (0%)

NEJM 1999 Hebert, Wells & TRICC Investigators

Transfusion Requirements in Critical Care (TRICC)

Multicenter Randomised, control study in 838 patientsHb <9g/dl within 72 hrs of admission

418 Restrictive transfusion Transfuse if Hb <7g/dlMaintain Hb 7 – 9g/dl

420 Liberal TransfusionTransfused if Hb <10g/dlMaintained Hb 10 – 12g/dl

NEJM 1999 Hebert, Wells & TRICC Investigators

Transfusion Requirements in Critical Care (TRICC) On average RCC administered

2.6 units in Restrictive group 5.6 units in Liberal group

33% of restrictive group received no blood vs 100% got blood liberal group

Non significant trend towards decrease in restrictive group 30 day & 60 day mortality Multi-organ failure

Subgroup analysis significant difference in restrictive group

<55yrs APPACHE II score < 20

No significant difference between groups Sepsis Cardiovasacular disease

Fewer cardiac complications including myocardial infarct & pulmonary oedema in restrictive group

1.Lancet 1996 Carsons, Duff & Am J Crit Care Hebert, Wells 2.JAMA

1998 Carsons & Duff

Transfusion Requirements in Critical Care (TRICC)

TRICC study did not show more adverse outcomes in cardiac cases, with transfusion trigger of Hb 7g/dl

2 large cohort studies found an increase in mortality rates amongst patients with ischaemia1

A large retrospective study of elderly patients who had hip surgery found that an Hb 8g/dl did not influence 30 or 90 day mortality2

When thinking of RBC transfusion – good rule of thumb

Hb < 4,5g/dl – patient’s life may be in danger in the short term.

Hb < 7g/dl Why not transfuse?

Hb > 7g/dl Why transfuse?

Hb 7 – 10 g/dl cardiac and respiratory reserve plays a major role in deciding whether or not to carry out a transfusion.

Hb > 10g/dl transfusion rarely necessary.

Management of citrate toxicity If the transfusion rate of whole blood is more rapid than one unit

every five minutes it is recommended that:10ml of 10% calcium gluconate be administered IV for every two units of citrated blood transfused

The flow rate of citrate determines its toxicity

In dogs, 0.06 mmol citrate / kg / min, for 20 minutes, is lethal Flow rate of 0.04 mmol / kg / min well tolerated

Calcium must never be added directly to unit of blood

Red cell concentrate (packed cells) do not contain citrate

Calcium is not routinely administered in plasma exchange procedures (in the management of TTP) one unit of FFP is administered approximately every 10 minutes

2,3-Diphosphoglycerate (2,3-DPG)

After transfusion, levels of 2,3-DPG are regenerated, in-vivo Approximately 50% is regenerated within 7 hours

It generally considered that low 2,3 DPG levels in stored blood are not usually clinically significant

In clinical situations of hypoxia and lactic acid production, and with decreasing pH, the oxygen dissociation curve is also shifted to the right, increasing oxygen delivery (countering the effect of a low 2,3,-DPG)

Lower 2,3-DPG red cell concentrations during the first 24 hours of

intensive care are not associated with higher ICU mortality

In the setting of massive transfusion, preferably transfuse red cells that have been stored for less than 7 days

Platelets

Pooled Whole Blood or Apheresis platelets

Dose is > 3 x1011 platelets (~ 5 WB platelets)

StorageRoom temperature (20 - 240C)

Agitation

Air permeable bags (after 1982)

5 day storage due to risk of contamination

What determines the need to transfuse Platelets? Patient’s clinical status Co-existing clinical conditions Bleeding risk Platelet count

Dictum: Patients are transfused therapeutically to stop

bleeding or prophylactically to prevent it.

The decision to transfuse Prophylactic 5x10~9/l:

Stable patients 10x10~9/l:

Recent haemorrhage Fever (>38C)

20x10~9/l: Sepsis Drugs that inhibit plt

production or function Abnormal coagulation Neonates Anaemia Anatomic lesion

Therapeutic Stop aspirin prior to

surgery >50x10~9/l:

Massive transfusions Actively bleeding Most surgery

>100x10~9/l: Major surgery

Cardiovascular surgery

Neurological surgery

Opthalmic surgery

PlasmaMay be usedMultifactor clotting deficiencies

DIC, massive transfusion, liver disease

Replace a single inherited clotting deficiencyTTP

Plasma exchange / Plasma infusion

Reversal of WarfarinOnly partial effectUse only when active bleeding

Bleeding due to Haemorrhagic Disease of the NewbornPlus Vit K

Neonates with coagulapathy and bleeding or needing a surgical procedure

Plasma may not be used

As a volume expander

For plasma exchange other than TTP

For nutritional support or protein losing conditions

Risks:

TRALI

Pulmonary Oedema

Anaphylactic shock

Allergic Reaction

vCJD

Plasma Options

Freeze Dried Plasma (Bioplasma)

Pooled product

Viral InactivationHIV,HCV,HBV

Reconstitute with sterile water

Can be kept at room temperature

80% Coagulation factor

FFP (Donor Plasma)

Single donor

Risk of TTIs low, due to donor retest program

Requires thawing 15mins

Requires freezer storage

Coagulation factors reflex that of donor

Both products have same clinical affect

The Consumer

Pediatrics 10%

Surgical 21%

Medical 27%

Casualty 4%

Obs & Gyn 26%

0

5

10

15

20

25

30

Trauma Obstetrics Other

Usage of red cells by diagnosis and genderMaleFemale

%

Blood Usage in the Border Area

Alternatives to allogenic transfusion

Autologous Pre-operative haemodilution

Inexpensive Risk of error

Pre-operative banking Up to 4 weeks prior, @ intervals of 7 –

10days Last donation 72 hrs before operation Cannot be done in emergency Additional cost

Alternatives to allogenic transfusion

Directed Donation Usually family or friends No evidence to show directed units safer Additional cost Require minimum of 2 days If a family member, the unit needs to be

irradiated

Alternatives to allogenic transfusion

Cell Salvage Very useful in specific surgery

Cardio-thoracic Some orthopaedics

Need to require approx 2.5 units to make it worthwhile

Erythropoetin Expensive Urology, orthopaedic

Alternatives to allogenic transfusion No such thing as a blood substitute

Search for a safe alternative oxygen carrier For immediate use in trauma especially war front

& problem X-match An ideal product:

that doesn’t require refrigeration Not require cross match Be stored @ room temperature for weeks Have no side effects Be pathogen free Survive in the circulation for weeks Transport & deliver O2

2 approaches to O2 carrier Hb base products

Human Hb (Polyheme, Hemospan, hemolink)

Bovine Hb (Biopure) Recombinant Hb (Optro)

Perflurocarbon Oxygent (USA trials) Oxycyte Pertoran (Russia)

Hemopure is a haemoglobin based oxygen carrier (HBOC) which

contains 13g/dL of polymerized haemoglobin of bovine origin

in a modified Lactated Ringer’s Solution. It is 250ml of a clear deep purple solution which:

Requires no reconstitution before use Does not require cross-matching with patient’s blood Is room temperature stable (2-30° C) Has a shelf life of 3 years Not remain in the circulation for more than a couple of days Been used in 290 patients in SA Not registered in USA

On Cellular Level Convert blood groups

Strip the A or B antigen off RBC = Group O This has been done in labs Cost Need to do it on a large scale

Stem Cells Make red blood cells from human embryonic stem

cells The researchers said the cells they made behaved

like natural red blood cells in lab tests, and that their process could be used in large-scale production. The results suggest that embryonic stem cells could someday supply type O-negative "universal donor" red cells for transfusion

FUNDING

RAND

Voluntary Non Remunerated Blood Donor (VNRBD)

Protects the Recipient Lowest TTI

incidence & prevalence

Repeat donors safer Protection of donor

Against exploitation Ethics

Ethically immoral to pay for body parts

Why are the Costs Associated with Blood Products deemed to be so high?

Testing – 30% Serology & NAT ABO grouping

Blood Bank & Blood Collection - 30% Other Costs – 30%

IT, HR, Quality, Admin Cost Recovery

Vein to Vein Cost of RCC – more than actual cost to user Pricing takes into account procurement of plasma &

platelet

SAFETY - Regulatory requirements

Defer Test Issue

• Donor deferral

• Regular donors

• Education

• Safe blood

• Low risk communities

• Tests as per regulations and standards

• Quality system

• Staff training

• SANAS

• Appropriate use of blood

• Blood user education

• Lookback programme

• Haemovigilance

• Quality system

In the 21st Century

There is no substitute for bloodThere is no such thing as zero risk bloodHowever risk management & advance

technology makes it as safe as possible

SAFE Blood is a scarce resource which needs to be managed with care