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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?. Aleksandar Mijovic King’s College Hospital/National Health Service Blood & Transplant London, UK. Zadar 2011. Immunologic effects. Alloimmunisation Febrile non-haemolytic reactions Platelet refractoriness

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Leukodepletion pathogen inactivation irradiation for some or everyone

Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?

Aleksandar Mijovic

King’s College Hospital/National Health Service Blood & Transplant

London, UK

Zadar 2011


Immunologic effects some, or everyone?

Alloimmunisation

Febrile non-haemolytic reactions

Platelet refractoriness

Rejection of transplanted organ

Graft-vs-host disease

Immune modulation

Increased risk of bacterial infection (?)

Increased recurrence of malignancy (?)

Infectious disease transmission

CMV

HTLV-I

Epstein-Barr virus

vCJD?

Adverse effects of leukocytes in blood components

Modified from: McCullough 2005


vCJD some, or everyone?

  • 4 cases in UK due to transfusion of non-leukodepleted red cells from donors who later developed vCJD.

  • Incubation period 6-8.5 years


Infectivity of experimental tse s in blood intracerebral route brown et al transfusion 1998 38 810
Infectivity of experimental TSE’s in blood -intracerebral route(Brown et al, Transfusion 1998:38;810)


Vcjd what s been done to prevent transmission
vCJD - What’s been done to prevent transmission? route

  • Universal Leukodepletion (1999)

  • Import of plasma from USA

  • Donor selection – ban of donors who received transfusions after 1980

  • Donor testing not yet available

  • Prion-reduction filters (for children and patients with haemoglobinopathies) – 2012?



Effect of leukodepletion on nh ftr yazer et al 2004 pruss et al 2004
Effect of Leukodepletion on NH-FTR routeYazer et al, 2004; Pruss et al, 2004

NH-FTR rate [%]


Effects of Leukodepletion on Platelet Refractoriness route

  • TRAP study, 1997

  • Lymphocytotoxic antibodies

    • 45% controls

    • 17-21% in treated groups

  • Platelet Refractoriness

    • 13% controls

    • 3-5% if platelets filtered or UV light-treated

  • After leukoreduction in Canada:

  • Alloimmunisation reduced from 19% to 7%

  • Immune refractoriness reduced from 14% to 4%

    • Seftel et al 2004


Leukodepletion for cardiac surgery
Leukodepletion for cardiac surgery route

  • Randomised study of: a) Buffy-coat depleted RBC; b) filtered, fresh RBC; c) filtered RBC, post storage

  • Infection rates:

    • 23.0% : 16.9% : 17.9%

  • Mortality:

    • 7.8 % vs 3.6% vs 3.3%

Van de Watering et al 1998


Leukodepletion in hospitalised patients dzik w et al transfusion 2002
Leukodepletion in hospitalised patients routeDzik W et al, Transfusion 2002

  • 2780 pts randomised to receive LD or non-LD blood products.

  • No difference in primary outcomes: 1) In-hospital mortality; 2) Length of hospital stay (LOS); 3) Hospital costs

  • Nor in secondary outcomes: 1) LOS in ICU;

    2) post-operative LOS; 3) antibiotic usage;

    4) re-admission rate


Risk for cmv disease in bmt ljungman et al 1998
Risk for CMV disease in BMT route(Ljungman et al 1998)


PREVENTION OF CMV INFECTION route

  • Use of CMV Neg Blood Products

    • Incidence ofCMV Infection reduced to 0-7% (pneumonia ~ 0%)

    • Leukodepletion

    • Equally effective to donor screening(Bowden et al 1995)

    • Abandonment of CMV screening premature(Nichols et al 2003)


Leukodepletion vs cmv serology to prevent cmv infection
Leukodepletion vs CMV serology to prevent CMV infection route

  • Both are effective

  • Neither is perfect

  • Not possible to decide if one is better than the other

  • Benefit of using both is unknown

Canadian Consensus Conference 2001


Pathogen inactivation in search of zero risk
Pathogen Inactivation: routein search of Zero-risk?




Estimated risk of viral transmission by transfusion in the uk per million donations 2009
Estimated risk of viral transmission by transfusion in the UK [per million donations](2009)

www.hpa.org.uk


414 blood donors in 2005 UK [per million donations]

340 blood donors in 2006

1500 clinical cases with 9 deaths 2006


PATHOGEN INACTIVATION/REDUCTION UK [per million donations]key issues

  • 1. Effective inactivation of a range of agents; no evidence of toxicity. Compare with current alternatives.

  • 2. Underlying residual risk in a given country.

  • 3. ?Threat from new (or newly identified) microbial agents.

  • ?How to measure safety increment from PI.

  • Logistics; process control. Separate PI steps needed for each blood component

  • 6. ?Cost-benefit.


Inactivation of pathogens in platelets by s 59 log

HIV >6.2 UK [per million donations]

HBV >5.5

HCV >4.5

CMV >5.9

West Nile >6.0

HTLV I/II 4.7-5.1

ParvoB19 4.0-4.9

E.Coli >6.4

S.Aureus 6.6

P.Aeruginosa 4.5

B.Cereus >6.0

Yersinia E. >5.9

P.Falciparum 7.0

T.Cruzi >5.3

Inactivation of Pathogens in platelets by S-59 (Log)


Photochemical treatment of platelets eurosprite trial
Photochemical Treatment of Platelets – euroSPRITE trial UK [per million donations]

  • Randomised study (52 v 51 pts) of Amotosalen(S-59) treated BC platelets.

  • Average dose: 3.9 vs 4.3 x 1011 (p<.001)

  • 1-h increment: 27.5 vs 35.8 x 109 /L. Difference 8.3 (95% CI, 0.9 – 15.8) (p=.03)

  • 1-h CCI: 13.1 vs 14.9 x 103 (p=.11)

  • Bleeding/adverse events not different

Van Rhenen et al 2003


Photochemical treatment of platelets sprint trial
Photochemical Treatment of Platelets – SPRINT trial UK [per million donations]

  • Randomised study (318 v 327 pts) of Amotosalen(S-59) treated apheresis platelets.

  • Average dose: 3.7 vs 4.0 x 1011 (p<.001)

  • Grade 2 bleeding: 58.5% vs 57.5% (NInf)

  • Grade ¾ bleeding: 4.1% vs 6.1% (Ninf)

  • 1-h CCI: 11.1 vs 16.0 x 103 (p<.001)

  • Units received: 8.4 vs 6.2 (p<.001)

McCullough et al 2004


Mirasol randomised trial mirasol clinical evaluation group 2010
MIRASOL randomised trial UK [per million donations]Mirasol Clinical Evaluation Group 2010

  • Mirasol: Riboflavin (vitamin B2) + UV light

  • RCT: 56 pts (303 transf.) received PR-platelets, 54 pts (238 transf.) received reference platelets.

  • Primary outcome: 1-hour CCI

  • PR-P vs REF-P: 11725 : 16939 (criteria for non-INF not met).

  • PLT/RC utilisation not significantly different; Safety profile similar.


Plasma spoiled for choice
Plasma - Spoiled for Choice? UK [per million donations]

  • Fresh Frozen Plasma

  • Solvent/Detergent treated plasma

  • Methylene Blue/UV light treated plasma



A.S., 18 y, TTP UK [per million donations]

22 Plasma exchanges

Pulmonary

Embolism

R Fem Vascath

L Fem Vascath

Prednisolone

= SD/Cryopoor plasma exchange


Comparative study of two types of plasma in liver transplantation

COMPARATIVE STUDY OF TWO TYPES OF PLASMA IN LIVER TRANSPLANTATION

RETROSPECTIVE, SINGLE CENTRE STUDY OF ADULT ORTHOTOPIC LIVER TRANSPLANT PATIENTS:

200 S/D FFP OCTAPLAS (1998-2001)

199 SINGLE DONOR FFP (after March 2001)

ENDPOINTS

PRIMARY:

AMOUNT OF BLOOD PRODUCTS USED

ESTIMATED BLOOD LOSS

USE OF OTHER HAEMOSTATIC PRODUCTS

SECONDARY

48HRS MORTALITY


Results
RESULTS TRANSPLANTATION


S/D plasma or FFP ? TRANSPLANTATION

Viral safety

Reduced risk of TRALI

Reduced risk of vCJD?

Increased blood usage in OLT

Increased VTE risk

Cost


Conclusions
Conclusions TRANSPLANTATION

Use S/D PLASMA in:

  • Below age 16

  • Young patient with good immediate and long-term prognosis, anticipated to receive few blood products.

  • Thrombotic Thrombocytopenic Purpura


Acute gvhd

Transfusion related TRANSPLANTATION

onset 2-30 days

pancytopenia/BM aplasia

No response to Th

Mortality >90%

Post BMT/PBPCT

onset 35-70 days

rare BM aplasia

Incidence 20-70%

80-90% respond to Th

mortality 10-15%

Acute GVHD



Transfusion-associated Graft-vs-Host disease: Prevention TRANSPLANTATION

Gamma/ X-ray Irradiation 25Gy

Leukodepletion – does it prevent TA-GVHD?

- No case since 2001 in UK

Pathogen Inactivation for Cellular Components


Indications for irradiation of blood components in the uk
Indications for irradiation of blood components in the UK TRANSPLANTATION

A. Indication by patient condition

  • Intrauterine transfusions

  • Neonatal exchange transfusions

  • Congenital immune deficiencies

  • Allogeneic HSC transplant patients

  • Autologous HSC patients

  • Hodgkin’s disease

  • Purine analogue treatment

  • Aplastic anaemia treated with ATG or Alemtuzumab

    B. Indication by component type

  • Granulocyte transfusions

  • HLA-matched blood components

  • Blood components from relatives


Frequency of homozygous hla donors to recipients heterozygous for the same haplotype 1 x
Frequency of Homozygous HLA donors to recipients heterozygous for the same haplotype[1 : x]


Survey of blood use in france 1997 175 hospitals 3206 transfused patients
Survey of Blood Use in France (1997) heterozygous for the same haplotype175 Hospitals, 3206 Transfused Patients

57% of transfusion recipients were > 65 years

Mathoulin-Pelissier et al, Transfusion 40:1140, 2000


Greying of the population
“Greying” of the Population heterozygous for the same haplotype

  • Life Expectancy in UK (2001)

    • 80 y for Women

    • 75 y for Men

  • In 2007, people ≥ 60 were 21.8% of UK population.

  • The same year, people aged 65+ outnumbered those under 16 y for the first time ever.

  • UN Dept. of Economic & Social Affairs


    Who should we irradiate blood products for
    Who should we irradiate blood products for? heterozygous for the same haplotype

    • According to national guidelines

    • All recipients with malignant disease

    • Recipients > age 65 yr

    • Everyone


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