EVIDENCE-BASED TRANSFUSION OF BLOOD AND BLOOD COMPONENTS first do no harm

Transfusion from dog to man Scultetus 1693

Dr Derek Norfolk NHSBT and Leeds Teaching Hospitals

BLOOD SAVES LIVES

Nearly 3m units of red cells, 250,00 platelet donations and 400,000 FFP units transfused each year in UK Many modern therapies impossible without transfusion BUT: Falling donor base in most developed countries Cost rising 10% a year (Red cells 132 a unit, Platelets 210 a dose) Poor evidence base for use Increasing concern about safety

MAGNITUDE OF RISK (red cells, platelets, plasma)

UK 2009
HIV less than 1 in 10,000,000 donations Hepatitis C less than 1 in 30,000,000 Hepatitis B less than 1 in 1,000,000 Fatal haemolytic transfusion reactions (mainly ABO incompatible red cells, due to human error) 1 in 600,000 to 1 in 1,000,000 Transfusion-related acute lung injury (TRALI) - 1 in 5,000 plasma-rich components transfused Bacterial contamination of platelets - 1 in 2000 units at 5 days - fatal in 1 in 25-80,000

BSE and vCJD

mmm interesting. interesting.. Id say we taste a little like chicken

Gary Larson

v-CJD AND TRANSFUSION

~ 170 vCJD cases in UK since 1994 Now 3 probable transfusion-transmitted cases (2 from same donor) 2 other pre-clinical cases diagnosed post mortem in patients who received blood from donors who later developed vCJD Estimate 1 in 4,000-10,000 of population may be carriers UK transfusion policy now dominated by vCJD risk reduction

v-CJD AND TRANSFUSION

Now beef is safe (?), transfusion, surgical instruments/endoscopes may be main risk British donors now banned in most First World countries All plasma products in UK (except FFP for adults) imported from USA All UK blood and platelets filtered to remove white cells (costs 85m per year) April 2004 UK banned all donors who had received a blood transfusion since 1980 (donor pool reduced by 5%)

v-CJD AND TRANSFUSION

Prion filtration of all components from 2010 (very expensive) A blood test for v-CJD prions in donors expected within 2 years focus groups suggest up to 40% of donors might choose to stop donating rather than be tested - could lose 20,000 false positive donors every year even if test 99% sensitive and specific (no confirmatory test) Appropriate use of blood essential

Transfusion-related immunomodulation (TRIM) Reduced survival in ICU patients (TRICC Study, 1999) Increased cancer relapse after surgery Increased postoperative infection Plasma/platelet infusion increasingly linked to ARDS and mortality in critical care patients

What is the evidence base for transfusion?

BLOOD FRACTIONATION
WHOLE DONOR BLOOD

**

**
RED CELLS PLATELETS PLASMA FFP

ALBUMIN IMMUNOGLOBULINS CLOTTING FACTORS

RED CELLS

Stored at 4oC red cells in optimal additive solution (SAG-M) Shelf-life 35 days from donation

Red Cells
What do red cells actually do? Carry oxygen to the tissues bound to Hb return CO2 to the lungs But its a bit more sophisticated than that. Intact red cells: alter their Hb affinity to optimise oxygen delivery (2,3 DPG) regulate interactions between haem and blood vessel walls to optimise oxygen delivery to tissues (nitric oxide)

Interactions with vessel wall

Intact red cells dilate pre-capillary arterioles to increase blood flow to hypoxic tissues (probably by release of nitric oxide bound to Hb thiol groups) Stored red cells: - quickly lose capacity to release NO - 2,3 DPG rapidly depleted, takes up to 72 hours to regenerate - increasing release of red cell microvesicles that may scavenge NO and impair microvascular flow

Increasing evidence transfusion of red cells in critically ill patients may be harmful
Fine balance between increased O2 delivery and impairment of microcirculation May cause impaired or aberrant immune responses Very different situation to transfusing a clinically stable patient

RED CELL TRANSFUSION

Only absolute indication is to increase oxygen delivery to vital organs in anaemic patients Each organ system has different demand for O2 and different critical point for hypoxia We dont yet have any simple way of measuring oxygen delivery to tissues so the haemoglobin (Hb) concentration is used as an imperfect surrogate measure

What factors affect the transfusion trigger

Severity of anaemia Rate of fall of haemoglobin Is the blood volume normal (as in most medical anaemias) or reduced (ie is the patient bleeding?) Is heart and lung function OK? (cardiorespiratory reserve) Other co-morbidities

What evidence is there?

Jehovas Witnesses: - can tolerate many major surgical procedures without transfusion if plasma volume maintained - mortality increased with Hb levels below 4 or 5 g/dl if they need critical care or have significant heart disease Data from animal studies:

Acute normovolaemic anaemia in rats, dogs and baboons

Healthy animals respond to progressive anaemia with increasing cardiac output, shift in O2 dissociation curve and increasing whole body oxygen extraction ratio Heart function maintained down to haematocrit 8.6% (Hb ~3 g/dl) in healthy animals but failed at 17% (~6g/dl) in animals with coronary artery stenosis

So, what is the current consensus about red cell transfusion triggers?

RED CELL TRANSFUSION

Should be avoided in patients with chronic anaemias due to iron or vitamin deficiencies (the treatment is iron or other haematinic) Post-surgical anaemia (keep a comfortable margin above any critical point for vital organs): - healthy, no heart disease - 7g/dl - ischaemic heart disease ~ 9 or 10g/dl Critical care - 7g/dl Transfusion-dependent patients: - MDS ~ whatever maintains quality of life - Thalassaemia ~ keep above 10g/dl to supress own red cell production

PLATELETS

Stored at 20oC 5 day shelf life from donation The evidence base is even more flimsy - no good clinical trials Mostly used to prevent (prophylaxis) rather than treat bleeding Big users are: Haemato-oncology (72% given prophylactically) Cardiac surgery Trauma and critical care More than 200 for an adult dose/40m a year in England

RISKS OF PLATELET TRANSFUSION (rich in plasma proteins, release inflammatory mediators and cytokines) Febrile reactions Allergic reactions/TRALI/increased morbity in critical care patients HLA-alloimmunisation and platelet refractoriness (less common since leucodepletion) Bacterial transmission (from donor arm) can be fatal (1 in 2000 units at 5days carry bacteria, fatal in 1 in 25-80,000)

PLATELET TRANSFUSION
(normal range 150-400x109/l) Consensus Guidelines Marrow failure/post-chemotherapy Transfusion trigger <10x109/l if stable 20x109/l if infected or on antibiotics Trauma and massive transfusion - keep above 50x109/l (higher may be better) Surgical procedures - 50x109/l safe for most biopsies, lumbar puncture and operations (100x109/l for brain surgery) DIC - only if bleeding

PLATELET TRANSFUSION
Prophylactic or Therapeutic? Evidence base for giving routine platelet prophylaxis is poor Uncontrolled studies suggest transfusing only those with clinically significant bleeding is safe and markedly reduces exposure Large multicentre RCT of prophylactic v therapeutic platelets in Haemato-oncology is ongoing in UK (TOPPS Trial) - no difference in major bleeds in first 200 patients

FRESH FROZEN PLASMA (FFP)

Stored at 30OC for up to 12 months Thawed immediately before use (takes 20-30 min) Contains clotting factors in same concentration as donor blood

FRESH FROZEN PLASMA

Highest death rate per transfusion of any blood product (mainly severe allergic reactions/anaphylaxis/TRALI) Audits show at least 30% is given for no scientifically valid reason and mostly in non-bleeding patients 50% of doses given are subtherapeutic (2 units is homeopathic in an adult)

WHAT IS THE DOSE OF FFP?

Minimum of 15-20ml/kg ie 4-6 units in an adult patient (10001800ml) High volume is often a problem in practice Recent research suggests minimum of 30ml/kg to raise clotting factors reliably above 30% Must repeat clotting tests after transfusion to determine frequency and adequacy of dosing (rarely done!)

INDICATIONS FOR FFP

(BCSH Guidelines 2004)
Bleeding due to multiple factor deficiencies: DIC with bleeding (NB not indicated in absence of bleeding) Massive transfusion/surgical bleeding (with abnormal clotting tests due to dilution or consumption of clotting factors) Clotting factor deficiencies where no concentrate exists (eg Factor V) Plasma exchange in TTP

FFP UNPROVEN OR CONTRAINDICATED Prophylaxis for bedside procedures - liver, renal biopsy, central line, LP etc with mildly deranged clotting (INR<2.0) - not a single published study shows correlation of PT/APTT with bleeding or a reduced bleeding risk after FFP transfused Reversal of warfarin FFP is only partially effective (better at reducing PT than stopping bleeding). Should use Prothrombin Complex + vitamin K in rare situations where immediate reversal is needed (BCSH Guidelines)

Can FFP properly correct warfarin?

courtesy of Dr Mike Makris, Sheffield

Effect of transfusing 4 units of FFP (~ 800ml) in 11 cases with bleeding and raised INR INR improves, but Factor levels are still subtherapeutic

FFP (n=11) Pre INR

Factor II FactorVII Factor IX Factor X

Post 2.0 17 19 19 20

8.95 3 5 10 6

Median clotting factor levels in u/dl Normal ranges 50-150u/dl

Emergency reversal of oral anticoagulation: FFP vs Prothrombin Complex Concentrate

FFP (800 ml)

80

PCC (25 -50 U FIX / kg)

80 70 60 50 40 30 20 10

iu/dl

70 60 50 40 30 20 10 0 FII FVII FIX FX

0 FII FVII FIX FX

Thrombogram remains abnormal

Thrombogram normalises

Makris M et al. Thromb Haemost 1997

Warfarin reversal options depend on urgency and severity of bleeding (see BNF and BCSH Guidelines)
Elective surgery avoid warfarin for 4 days Within 24hr oral vitamin K 0.5 - 1.0 mg Within 6hr intravenous vitamin K (1-5mg) Immediate Prothrombin complex concentrate (2550 iu/Kg plus IV vitamin K (5mg)

FFP has no role in warfarin reversal in the modern hospital

Blood transfusion is like marriage; it should not be entered upon lightly, unadvisedly or wantonly, or more often than is absolutely necessary.
Rosemary Beal 1976 (Adelaide)

Key sources of information:

www.transfusionguidelines.org.uk - Handbook of Transfusion Medicine, Better Blood Transfusion Toolkit www.bcshguidelines.com - all the current national guidelines www.sign.ac.uk - Scottish multidisciplinary guidelines