session 2 - edqm · blood components and cold storage 1942 transfusion in the point-of-wounding...

EDQM SYMPOSIUM

PLASMA FOR DIRECT CLINICAL USE

22-23 SEPTEMBER 2015, STRASBOURG, FRANCE

SLIDES

Session 2

TABLE OF CONTENTS Novel component: liquid plasma thawed or non-frozen Per Johansson, Blood Transfusion Centre (DK) .............................................................................. 1 Novel component: freeze-dried plasma Christophe Martinaud, Hôpitaux des Armées (FR) ......................................................................... 13 Use of plasma in massive haemorrhage Per Johansson, Blood Transfusion Centre (DK) ............................................................................. 33

Novel component: liquid plasma thawed or non-frozen

Pär I. Johansson MD, DMSc, MPA Professor of Transfusion Medicine

Capital Region Blood Bank Rigshospitalet

Denmark &

Department of Surgery Center for Translational Injury Research (CeTIR)

University of Texas Medical School at Houston, TX, USA

Exsanguination accounts for ~30% of the mortality in trauma

Blood products (RBC, Plasma, Platelets) are required immediately

1 EDQM Symposium on "Plasma for Direct Clinical Use", 22-23 Sept. 2015

Liquid plasma is necessary


Quality control study

• Thawed plasma units (pre-stored & not pre-stored)

• Measurements for 72 hours

• FVIII• FV• Fibrinogen

• Based on these data we introduced thawed FFP stored for up to 72 hours to be used in the transfusion packages

• The same patients were allowed to receive a maximum of 2 transfusion packages with stored thawed FFP

Experience with pre-thawed FFP

• Between 2004 – 2009 1.445 patients received 1.965 transfusion packages encompassing 9826 untis of pre-thawed FFP

• Each patient on average received 1.3 transfusion packages

• 91 patients received more than 5 transfusion packages

• The maximum amount of transfusion packages administered per patient was 10

• The discard rate was 1.7%


• Whole blood analysis• Measures the viscoelastic properties of the clot• Global assessment of clot build up and degradation• Rapid tests (15 min.)

Viscoelastical haemostatic assays (VHA)

TEG® ROTEM®


Transfusion packages and TEG

Patients (No.) 10 10 8 5 1

Transfusion package (ªTP; No.) 0 (Before TP) 1 2 4 7

R time (3-8 min) 6.7 (3.7-9.4) 6.0 (4.8-7.6) 6.4 (4.9-7.5) 6.5 (5.0-7.2) 6.8

Angle ( ) (55-78º) 58.9(48.1-71.5) *63.3 (53.1-72.4)

*61.3 (55.2-69.2)

60.8 (55.8-67.3) 60.3

MA (51-69 mm) 48.9 (44.3-63.7) *59.3 (56.5-65.9)

*57.0 (53.4-63.1)

*56.2 (52.2-59.7) *55.3

G (4.6-10.9 d/sc) 4.8 (4.0-8.8) *7.3 (4.6-9.6) *7.1 (5.0-8.8) *7.0 (5.2-8.3) *6.8

Ly30 (0-8%) 0 0 0 0 0

Hypocoagulable patients (No.) 6 0** 0** 0** 0**

Johansson et al. Transf Apher Sci. 2008;39:3-8

Change

• In 2010 the Danish Health and Medicines Authority decided that pre-thawed plasma only could be stored for 24 hours

• This was immediately implemented and resulted in an increase in discard rates from 1.7% to 4.8%


Physician staffed CPH HEMS since 2010

• 2 RBCs O Rh D Negative• Logger from the Blood Bank

HEMS CPH 2011-2013• 35 trauma patients received pre-hospital RBCs• Age mean 44 years• ISS < 15: 9%, ISS 15-25: 18%, ISS > 25: 72%• Transfusions in-hospital

– RBCs 13– FFP 12– PC 4– Waste: 6%

• Mortality 24 h: 29%Thomsen AB, Jørgensen H, Salado J, Johansson PI. Airmed Conf 2014


• Houston, TX, USA• 2 RBCs + 2 thawed FFP (< 5 days)

Life Flight

Odds Ratio p-valueHEMS 0.23 0.033

Arrival base deficit 0.87 0.003Arrival rTEG ACT 1.02 0.035

Arrival SBP 0.93 <0.001Blunt mechanism of injury 0.29 0.050Prehospital crystalloid, mL 0.99 0.637

Multivariate logistic regression for mortality within the first 6 hours

Holcomb JB et al. PREHOSPITAL EMERGENCY CARE 2015


Liquid plasma study in CPH


Liquid plasma

Liquid plasma TEG


Liquid plasma is available in CPH HEMS sinceJanuary 2014

Prehospital Resuscitation On Helicopter Study(PROHS)

1. National HEMS, Rigshospitalet, Copenhagen, Denmark2. Memorial Hermann Hospital/University of Texas Health Science

Center at Houston3. University Hospital Cincinnati4. Mayo Medical Center5. Oregon Health and Science University6. Harborview Medical Center7. University of Maryland Medical Center8. LA County/ University of Southern California Medical Center9. University of Alabama – Birmingham10.University of Arizona

Region Hovedstadens Blodbank


Thank you


Novel component: freeze-dried plasma

EDQM SymposiumPlasma for direct clinical use

Christophe Martinaud (MD,PhD)French Military Blood Institute

Clamart, France

Strasbourg, mardi 22 septembre 2015

OVERVIEW

1. Lyophilized plasma available

2. French LYophilized Plasma (FLYP) history

3. Main characteristics of FLYP

4. Internal & external in vitro quality controls

5. Stability studies

6. Clinical and biological data from 2010

7. Perspectives


OVERVIEW







7. Perspectives

South-Africa = Bioplasma®– pool of unpaid donors– SD treated– universal blood group compatibility– national use– few studies in cardiac surgery

Lyophilized plasma available


South-Africa = Bioplasma®

Germany = LyoPlas N-W®– apheresis plasma– securized by quarantine

Lyophilized plasma available

OVERVIEW







7. Perspectives


World War IIFirst process to separate blood components and

cold storage

1942Transfusion in the point-of-wounding care by J. Juillard

First French use of FDP provided by the US Army.

1949FMBI - lyophilized plasma

production

1946-1954Indochina war:

>30 000 lyophilizedplasma infused

1985Blood contamination scandal

in France: leading to a complete stop in pooled

lyophilized plasma

1991Gulf War, production of

lyophilized plasma obtainedfrom single donor, securised by

quarantine process

1994Pooled FDP is

quarantine for 60 days prior to

delivering

Freeze Dried Plasma: history

2010Pathogen inactivation:

French Lyophilzed Plasma (FLyP)

OVERVIEW







7. Perspectives


Toulon

Clamart

FLyP: an apheresis issued product

Donors are all volunteers and undergo a rigorous medical selection

Amotosalen based pathogen attenuation


11

FLyP: blood donation controls

All blood products– Hemoglobin– ABO Rh Kell– HIV ½ antibodies & PCR– HCV antibodies & PCR– HBV antigen & PCR– HTLV antibodies– Syphilis antibodies

Some blood products– Chagas antibodies– Malaria antibodies

Only for plasma– HLA antibodies– Hemostasis tests– HEV PCR

FLyP: lyophilization - cryodessication


Universal blood group compatibility

pH=8 prior to administration

2-year shelf life at RT

Reconstitution time < 6 min

Therapeutic plasma monitored

by the active hemovigilance & specific traceability

Description of FLyP

Waterdevice

Transfusion device

FLyPPunch


OVERVIEW







7. Perspectives

FLyP: manufacturing process

Mandatory release criteria Additionnal testsNo hemolysins Prothrombin time

Anti-A & anti-B < 1/64 Activated Partial Thromboplastin time

No irregular agglutinins FV, FXI, FXIII

FVIII > 0.5UI/mL Protein C, Protein S, AT, α2-antiplasmin

Fibrinogen > 2g/L Plasma proteins electrophoresis

Residual amotosalen < 2 µM Thrombin Generation

Total proteins > 50g/L Viscoelastometry

Humidity < 2% TAT complex and F1+2

Sterility pH


Parameters Units Solvant-Detergnet-FFP Intercept-FFP Quarantine-

FFP FLYP Reference range

Fibrinogen g/L 2.8 2.7 2.8 2.4 2 - 4

Factor V IU/mL 0.9 1.0 1.0 0.7 0.7 – 1.2

Factor VIII IU/mL 0.7 0.8 1.1 0.7 0.5 – 1.5

Factor XI IU/mL 0.8 0.6 1.0 0.7 0.5 – 1.4

Protein C IU/mL 1.0 0.9 1.2 0.9 0.7 – 1.2

Protein S IU/mL 0.6 1.0 1.4 0.9 0.7 – 1.4

Antithrombin IU/mL 0.9 1.0 1.0 1.0 0.8 – 1.2

α2 antiplasmin IU/mL 0.2 0.8 1.0 0.9 0.8 – 1.2

FLyP: in vitro properties

In vitro properties of FLyP compared with other French plasmas

ANSM 2012

FLyP: in vitro properties

FFP FLyP0

1

2

3

4

5

min

FFP FLyP0

100

200

300

400

Thro

mbi

n nM

FFP FLyP0

500

1000

1500

TF 1pMTF 5pMTF 20pM

nM/m

in

Lag Time Peak Endogenous thrombin Potential

Martinaud et al. Anesthesiology 2012

Thrombin generation Assay

No relevant differences in the thrombin generationEspecially when TF concentration increases


FLyP: in vitro model of fluid resuscitation

Blood Sample40%

LR30%

FFP FLyP LR30%


FFP FLyP LR Baseline0

5

10

15

p=0.16***

p=0.97

Clot initiation time

R (m

in)


40

50

60

70

80 ***p=0.73

***

Clot formation speed

Alph

a An

gle

(deg

rees

)



20

40

60

80 ***p=0.23

***

Clot firmness

Max

imum

Am

plitu

de (m

m)

OVERVIEW







7. Perspectives


After reconstitution

12 different FLYP from the same batch were studied

20°C 4°C

T 0 T + 2H T + 6H T + 24H T 0 T + 2H T + 6H T + 24H

Fibrinogen (g/L) 3,0 2,9 2,9 2,7 3,0 2,9 3,0 2,7

F VIII (UI/ml) 0,6 0,5 0,5 0,4 0,6 0,5 0,5 0,5

F V (%) 64,7 63,0 56,2 40,7 65,2 63,0 57,3 40,2

During 42 months storage

Time (month) 0 27 42 0 27 42 0 27 42 0 27 42

Temperature 4°C

Humidity (%) 0,86 0,61 0,21* 1,21 0,89 0,2* 0,99 0,56 0,25* 1,24 1,23 0,33*

Fibrinogen (g/L) 2,15 2,22 2,27 2,53 2,68 2,79 2,43 2,60 2,64 2,43 2,51 2,49

F VIII (UI/mL) 0,69 0,79 0,6 0,81 0,82 0,78 0,75 0,78 0,74 0,77 0,76 0,74

F V (%) 64 67 67 77 74 76 72 71 71 79 79 84

Total Proteins (g/L) 55,9 58 56,4 51,9 57,4 59 53,0 56 61,3 58,4 62,3 60,6


Stability studies in remote conditions

R1 - [ 28 - 53°C ]Armored vehicle

R2 - [ 4°C ]Tent & refrigerator

R2 - [ 18 - 38°C ]Tent

R1 - [ 0 - 15°C ]Tent & refrigerator

[ 20 - 50°C ]Nurse bag

Stability studies: resultsMali & Rep. of Djibouti

TIME 3 months

Temperature (°C) 4 21 – 23 4 18 – 28 0 – 15 22 – 38 25 – 53

Moisture (%) 0.88 0.63 0.70 0.69 0.60 0.76 0.80

Fibrinogen (g/L) 2.47 2.70 2.67 2.73 2.63 2.40 1.50

F VIII (UI/ml) 0.76 0.66 0.54 0.49 0.69 0.53 0.27

F V (%) 64 55 68 60 59 46 34

Total proteins (g/L) 56.9 55.0 60.4 58.5 55.9 53.7 55.6


OVERVIEW







7. Perspectives


Gender of recipients Other nationalities France Total %

Average age 37 [2 - 79] 47 [9 - 91] 42 [2 - 91]Female 41 37 78 20,2%Male 172 127 299 77,5%

Unknown 7 2 9 2,3%Total with PLYO 220 166 386 100,0%

Blood products transfused

Other nationalities France Total %

FLYP only 220 166 386 100,0%RBC and FLYP 153 135 288 74,6%FWB and FLYP 24 33 57 14,8%

Hemovigilance 2010 – 2014

1868 FLYP transfused / 471 transfusion episodes / 386 recipients

TANSFUSION INDICATION

ALL NATIONALITIES

TRANSFUSION CONTEXT

ALL NATIONALITIES

Hemorrhagic shock 146 32,4% Explosive weapon 78 18,0%

Active bleeding 108 23,9% Blunt trauma 77 17,8%

Risk of bleeding 108 23,9% Penetrating trauma 63 14,5%

Risk of coagulopathy 19 4,2% Obstetric 4 0,9%

Not specified 70 15,5% Not specified 211 48,7%

Total recipient 391 100,0% Total recipient 391 100,0%


Indications and context


PRIOR FLYP AFTER FLYP

Average SD Average SD

PT (%) 46,9 19,4 50,9 18,2

Fibrinogene (g/L) 2,9 2,3 3,1 1,6


Coagulation testing

Outcome All nationalities Clinical tolerance All nationalities

Favorable 197 51,0 % Good 302 78,2%

Not specified 137 35,5% Not specified 80 20,7%

Aggravation 8 2,0% Adverse event 4 1%

Death 44 11,5% Total recipient 386 100,0%

Total recipient 386 100,0%

.


Clinical evolution and tolerance

Only 4 adverse events were reported in 5 yearsFugace erythema

Imputability is not sure


OVERVIEW







7. Perspectives

Perspectives

FLYP will be used in civilian area– In the emergency department (since 2013 in Lille)– In austere settings– In pre-hospital settings at the end of this year


Pre-hospital use

Rational for plasma use asap– Borgman et al. J Trauma 2007– Holcomb et al. PROMMT Study - JAMA 2013– PROPPR study at

http://clinicaltrials.gov/show/NCT01545232.2013

Rational for plasma in pre-hospital– Dretzke J et al. Syst Rev. 2014– Karam O et al. Cochrane Database 2013

Freeze dried plasma (LyoPlas)– Sunde et al. J Trauma Acute Care Surg 2014

France: PREHO – PLYO

Criteria of inclusion– trauma patients with hemorrage – PAS < 90 mmHg AND CF >108 bpm OR PAS < 70

mmHg

Main judgment criteria– PT increasing

Secondary criteria– blood requirement in hospital– survival


Perspectives

FLYP will be used in civilian area– In pre-hospital settings at the end of this year.– In the emergency department (since 2013 in Lille)– In austere settings

Lyophilization process will be proposed to other blood establishments to decrease unit cost

Preparation from whole blood

Novel component: freeze-dried plasma

EDQM SymposiumPlasma for direct clinical use

Christophe Martinaud (MD,PhD)French Military Blood Institute

Clamart, France

Strasbourg, mardi 22 septembre 2015


Prof. Pär I. Johansson MD, DMSc, MPA Capital Region Blood Bank

Rigshospitalet Denmark

& Dept. of Surgery

Center for Translational Injury Research University of Texas Medical School at Houston, TX, USA

Use of plasma in massive haemorrhage

Coagulopathy of massive bleeding

Hardy J-F et al. Can J Anesth 2004.

Coagulopathy secondary to substitution with crystalloidsand colloids

Coagulopathy secondary to haemotherapy

Coagulopathy due to hypothermia and metabolic acidosis

Coagulopathy secondary to trauma, shock

Micro Vascular Bleeding


Erber WN. Transfus Apher Sci. 2002.

Resuscitation - guidelines


Transfusion packages

For massive / life-threatening bleedings

Stored thawed AB RhD negative plasma -immediately available for transfusion

The package consists of 5 RBC, 5 FFP, 2 PC, resulting in a haematocrit ~ 30%, factor concentration >30% and a platelet count ~80 x109/L

The packages are administered consecutively until haemostasis is secured

Johansson et al. Transfusion 2007

Package approach - rAAA

Randomised clinical study was not possible due to the inability to achieve informed consentHemminki et al. BMJ 2006;232:501-2. Lemaire et al. Intensive Care Med 2005;31:476-9.

Patients operated for a ruptured abdominal aortic aneurysm (rAAA).

Prospective intervention (12 months) - retrospective control (24 months) study.

Intervention: 2 PC at start of surgery and 2 PC during reperfusion. FFP was administered in a 1:1 ratio with RBC from start of surgery.

Control group was transfused according to existing guidelines.ASA Task Force on Blood Component Therapy; Anesthesiology 1996;84:73247.

P<0.05ControlIntervention

Johansson et al. Transfusion 2007

p=0.02

Intervention 66%

Control 44%


Damage control resuscitation – A meta-analysis

Johansson et al. JETS 2012

Search for trauma patients receiving 10 RB or more in 24h or less in 2005-2010

Nineteen retrospecitve studies evaluated and 15 studies included (N=3.475)

Highest ratio vs. lowest FFP and/or PLT to RBC ratios evaluated

Holcomb et al. JAMA 2015


Holcomb et al. JAMA 2015

Two hundred sixty-four trauma patients

125 in the TEP group, 141 in the pre-TEP

Demographics and ISS were similar between groups


Is plasma more than just volume and coagulation factors?

More on this later


Monitoring of coagulopathy

Monitoring of coagulopathy has relied on plasma-based coag. tests such as:

PT/INR APTT Fibrinogen conc. D-dimer Platelet count

PT/INR APTT

Whole blood haemostatic assays are required

Whole blood analysis Measures the viscoelastic properties of the clot Global assessment of clot build up and degradation Rapid tests (15 min.)

Viscoelastical haemostatic assays (VHA)

TEG® ROTEM®


VHA principle and clinical relevance

R Angle MA Ly30

Kawasaki et al. 2004

Coag.factors and platelets (PLT)

FibrinolysisFibrinogen, FXIII,PLT

Coag.factors, Fibrinogen, PLT

0

50

100

150

200

250

300

0 20 40 60 80 100

Minutes

nM th

rom

bin

Peak

tt Peak


Hypocoagulable I

Primaryhyperibrinolysis

Hypercoagulable

Reactive fibrinolysis

Hypocoagulable III

Normal

Hypocoagulable ÌI

Heparinization

VHA traces and coagulopathy

Copenhagen Concept

Blood bank-analyze

Blood bank MD on call

OR

Trauma centre

CT/LAB

ICU


Before and after study at Rigshospitalet

MT patients (21% trauma)

Intervention group 442 (2005-2006) vs. historic control 390 (2002-2003)

Intervention group transfused based on TEG

Control group transfused based on ASA 1996 guidelines

Johansson et al. Vox Sang 2009

2005-2006

2002-2003

Number at risk Time in days

2005-2006 442 385 362 352 347 345 345 344 343 343

2002-2003 390 308 281 267 257 255 255 255 255 255

Log-rank, P<0.001


Current guidelines

Endothelial activation and damage

Johansson et al. SJTREM 2009; Johansson & Ostrowski. Medical Hypotheses 2010

Early shock induced coagulopathy reflects systemeic endotheliopathy

Vicious circle


TraumaN ≈ 2300 patients

Coagulopathy is a result of systemic ENDOTHELIOPATHY and this predicts trauma patient outcome

Disrupted vascular integrity

Wataha et al. Transfusioin 2013


Kozar et al. Anesth Analg .2011

Shibani et al. J Trauma .2010


Endothelial “rescue” with plasma improves outcome!!

Thank you!

Plasma and coagulopathy


session 2 - edqm · blood components and cold storage 1942 transfusion in the point-of-wounding...

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