1. Octaplas is plasma derived from pooling donations which undergoes pathogen inactivation, filtration, and pooling. This decreases the risk of transfusion complications compared to single donor fresh frozen plasma. 2. Studies show Octaplas causes less damage to the endothelial glycocalyx and reduces bleeding and transfusion requirements compared to fresh frozen plasma in emergency surgeries. 3. Octaplas provides more consistent coagulation factor levels than single donor plasma and its use may decrease the need for additional coagulation factor concentrates like fibrinogen and prothrombin complex concentrate.

1. Massive transfusion: the right
place of FFP and Octaplas
János Fazakas MD , PhD
Semmelweis University
Department of Transplantation and Surgery, Budapest

2. Safety issues first !
HCV
HBV
HIV
WNV
HCVparvo
B19
CJD HEV
± ?
TRALI, TRIM,
TACO…
Complication

3. The Terrible T‘s (Benson, 2012)
TRALI
TACO
TRIM
8 % pts with TRALI,
7,5% pts with TACO,
43,4 % pts with respiratory
symptoms difficult to recognize,
(Gajic et al, 2007)
2008, TAD
(Transfusion
associated
dyspnea)
- FFP related to increased risk of pneumonia and sepsis (Sarani, 2008)
- 3,2% pts with ТACO, extra cost more than 14 000 USD per pt
- Up to 8% in some populations(Benson, 2012)

4. br j haemat 2015 apr 28. doi: 10.1111/bjh.13459
No evidence of circulatory overload
(BNP)
No preexisting ALI before transfusion
During or within 6 hours of transfusion
No alternative risk factor for ALI present*
ALI: Acute onset; Hypoxemia:PaO2/FiO2 ≤ 300
mmHg
Bilateral infiltrates on chest radiograph
TRALI: transfusion related acute lung injury
• Reported incidence from 1: 100 000
to 8% or more (Gajic, Benson)
• 1 in 1120 to 1 in 5000 (Silleman)
• for all blood components and up to
1: 432 per unit of platelets.
• Difference in design: from self -
reporting to prospective trials
• Difficulties in recognition: may
change to secondary outcomes like
pneumonia or Multiple Organ Failure

5. br j haemat 2015 apr 28. doi: 10.1111/bjh.13459
∑
The threshold is formed by the level of lung neutrophils
and the ability of the mediators in the transfusion produ
The “first hit” consists of patient factors.
The “second hit” is the transfusion of a blood.
the absence of a “first hit” as long as
the second hit is strong enough to overcome the
threshold
TRALI is a clinical diagnosis !
• there is no pathognomonic diagnostic test
non–Ab model: cytokines, lipids1 2 3Two hit model Threshold model
Or
Or

6. Anti-HLA in
Multiparous women
WBCs
Cytokines
Lipids
It is not possible
to exclude any of
these in single
bag technologies
Dilution
Filtration
Chromatography
TRALI: causes, ways to overcome and results
OctaplasLG
Pay attention
non–Ab model: cytokines, lipids3

7. TRIM: transfusion related immune modulation
• Acquired immune deficiency with elevated risk of infections and tumor
• Related to WBCs ↔Reason for leukodepletion
• Which influence of current level of residual WBCs on immunity?
• Transfusion of allogenic blood products is still associated with higher
risk of nosocomial infections

8. FFP and risk of infections
A significant association was found between transfusion of fresh frozen
plasma and ventilator-associated pneumonia with shock (RR 5.42,
2.73–10.74), ventilator associated pneumonia without shock (RR 1.97,
1.03–3.78), bloodstream infection with shock (RR 3.35, 1.69–6.64), and
undifferentiated septic shock (RR 3.22, 1.84–5.61).
Is it TRIM? Or TRALI with secondary outcomes? Both of them?
Something else?

9. Allergic and other reactions
• Netherlands (Saadah,2018): after switch to SD plasma reduced risk of
 allergic reactions (OR = 0.19 [0.11 to 0.34; P < 0.01])
 Febrile Non-Hemolytic Transfusion Reactions (FNHTR) (OR = 0.38
[0.18 to 0.79; P < 0.01])
• Finland (Krusius, 2009): switch to Octaplas decreased the rate of serious
adverse reactions by 84% (p=0.0005)
• Sweden (Vaara, 2010): after hospital switch to Octaplas 0 reactions vs 19
Filtration and dilution play a role!

10. WHO IS THE KEY PLAYER ?
EC activation EC-PLT, Inflammation EC-Leuc, Hyperpermeability leakage, tissue hypoxia, CF reduction

11. Pati et al. Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and
resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw J Trauma
(2010) 69(Suppl 1):S55–63
Peng et al. Fresh frozen plasma lessens pulmonary endothelial inflammation and hyper-permeability after hemorrhagic
shock and is associated with loss of syndecan 1 Shock (2013) 40(3):195–202
Torres et al. Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function
after hemorrhagic shock in rats J Trauma Acute Care Surg (2013) 75(5):759–66
Kozar et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock Anesth Analg (2011)
112(6):1289–95
Wu et al. Loss of syndecan-1 abrogates the pulmonary protective phenotype induced by plasma after hemorrhagic
shock Shock (2017) 48(3):340–5.
Banet al. Plasma-mediated gut protection after hemorrhagic shock is lessened in syndecan-1-/- mice. Shock (2015)
44(5):452–7.
Key question is which plasma component may exert a beneficial effect on the glycocalyx
Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a
combat support hospital J Trauma (2007) 63(4):805–13.
• FFP correct, pH-metabolic acidosis, base excess, and lactate significantly better than LR and HES
• FFP prevent/correct shock-induced pulmonary hyper-permeability, reduce TNFalfa

12. Plasma-first resuscitation to treat haemorrhagic shock during
emergency ground transportation in an urban area: a
randomised trialMoore et al. Lancet 2018; 392: 283–91

13. … in case of massive bleeding: we need all of them !
Hemodynamic stability Hemostasis stability
... cristalloids and colloids + coagulation factor conc.
… whole blood concept: RBC + FFP +  PLT
Massive bleeding – what and when?
FFP

14. „1 + 1 + 1…= ? ” into each other hemodilution !
Sihler KC. Chest 2010; 137(1):20ö-220.
RBC + FFP + Thr ≠ whole blood
Into each other dilution …

15. FFP as a pig in a poke
12 radom units of single donor FFP
89 90 90 90
73
88
81
71 68
80 78
85
55
64
87
73
89
69
106
121
110 110
138
134
167
145
149
125 125
159
137
159
110
116 118
135
0
20
40
60
80
100
120
140
160
180
PT
aPTT
TT
RT
FI
FII
FV
FVII
FVIII
FIX
FX
FXI
FXII
FXIII
VWF:RCo
ATIII
PC
PS
%
or how many factors there's ...

16. Small dosis of fibrinogen and PCC to the FFP = fix it

17. Blood loss > BV
Rebalance… Replace… Measure…
Adapted from Prof Görlinger
pH>7.2 se Ca> 1 mmol/L Hgb >70-100g/L T > 35°C
5 - 10U FFP → POCTs / conventional parameters
Fibrinogen
FXIII
Thrombocyte
AT-III
PCC
Fibrinogen 1g  2U FFP
PCC 500 IU 2U FFP
FXIII 20IU/kg  5U FFP
Thr 1U/10kg
AT-III 500IU 5U FFP
Not one after the other,
but at the same time !!!

18. POC: TEG and ROTEM
EXTEM CT > 80s
TEG R > 10 min
Norma
lPathologic EXTEM,
TEG
Norm
al
Pathologic EXTEM,
TEG
K > 4 min
Alfa angle < 74°
Pathologic FIBTEM
Normál EXTEM, APTEM,
TEG
Pathologic EXTEM, TEGMA
MCF
Norm
al
Pathologic EXTEM,
TEG
Normol FIBTEM
K > 4 min
Alfa angle < 74°
MA, MCF
continuously
decrease
TEG/TEM „slides back”
Factors replacement ?
TEG/TEM „became thiner”
„ substrate: platelets  ”
TEG/TEM „became
thiner”
„ substrate: fibrinogen  ”
TEG/TEM „the end … run
out”
Fibrinolysis ?
5 - 10U FFP → POCTs / conventional parameters

19. Regular TEG/ROTEM measurements: the „MET concept”
1.
2.
3.
Measure!
Evaluate!
Recheckthenewbalance!
Every 5 U of improved FFP
Treat!
Fibrinogen 1g  2U FFP
PCC 500IU 2U FFP
Change the ratio

20. Octaplas ?
The difference…?

21. Octaplas – factor content
12 consecutive Octaplas batches
98 96 98
93 96 95 96
83
75
90
96
92
88
97
83
96 95
86
105 105 102 104 104 104
108 108
115
110
103
105 106
103
120
103 102
111
0
20
40
60
80
100
120
140
160
180
PT
aPTT
TT
RT
FI
FII
FV
FVII
FVIII
FIX
FX
FXI
FXII
FXIII
VWF:RCo
ATIII
PC
PS
%
12 consecutive Octaplas batches
Bio-pharmaceutical range: ± 20%
Pharmaceutical range: ± 5%
630 to 1520 single-donor units of the same blood group which reduces the variability
in coagulation and inhibiting factors that is typically seen in single-donor FFP units

22. POPULATION
CRITICALLY ILL
CHILDREN
PRIMARY OUTCOME
Coagulation effect
(INR) and Safety
profile (mortality)
INTERVENTION:
FFP OR OCTAPLAS
LOCATION
101 PICUs in 21
countries
FINDINGS
LESS

23. POPULATION
< 10 KG, < 2 Y,
CARDIAC SURGERY
PRIMARY OUTCOME
Coagulation effect: INR
Safety profile: infection
INTERVENTION:
PERIOPERATIVE FFP OR
OCTAPLAS
LOCATION
University Hospital
Southampton NHS
Comparison of the Coagulation Effect Achieved by OctaplasLG Versus
Fresh Frozen Plasma in Pediatric Cardiac Surgical Patients
FINDINGS
Clin Appl Thromb Hemost. 2018 Nov;24(8):1327-1332
3x

24. POPULATION
Emergency surgery
for thoracic aorta
dissection, adults
PRIMARY OUTCOME
Biomarkers of
Endotheliopathy
Bleeding, Transfusion
Prohemostatics, Organ
Failure, Safety
INTERVENTION:
PERIOPERATIVE FFP OR
OCTAPLAS
LOCATION
Rigshospitalet,
Copenhagen University,
Denmark
FINDINGS
glycocalyx and endothelium injury,
bleeding, transfusions,
prohemostatics, time on ventilators
were significantly reduced

25. Octaplas LG group:
1. LESS damage to the endothelial glycocalyx (syndecan-1)
2. LESS endothelial tight junction injury (sVE-cadherin)
3. LESS microthrombotic endothelial adhesion (sE selectin)
4. MORE anticoagulation regulation in glycocaliyx (TM)
Capillary leakage
Hypotension
Tissue oxygen delivery
Endothelial leucocyte
adhesion Clotting/Regulation
FINDINGS

26. Octaplas LG group:
1. LESS days on ventilator (1 day vs 2 days) *
2. LESS bleeding during surgery: 2150 vs 2750 * (21%)
3. LESS 24-hour RBC transfusion: 3975 mL vs 6220 ml * (35%)
4. LESS platelet transfusion: 1400 mL vs 2450 mL * (>1 l)
5. LESS Fibrinogen-PCC-rhFVIIa: 7 pts vs 13 (1/2x)
6. LESS 30-day mortality: 20.7% vs 25% (5%)
BENEFIT = REDUCED COST
FINDINGS

27. •2:00 in the morning
• KTX, POD2, coughing followed by hemorrhage,
• The patient is in shock…
!Blood loss > 1x BV … 5 l
graft rupture

29. 2 l
2 l

30. Hypothermia
Acidosis
Hypoxia
 Ca+2
2:46-3:21 in the morning
Anemia

32. 2000 ml Ringer
1000 ml Gelofusine
RBC (4) FFP (5)
Octaplas (3)
Fibrinogen 6g
PCC 3000 IU
ICU: no vasopressor,
only mechanical ventilation
3 g
1500
3 g
1500
1h 10 min

33. Discharge on second POD
Hypoperfusion
period  1:20 h

34. You are not alone in the hospital !
iv lines: 1000 ml/ min
Fast infusion system
Key member of the
team:
„Team leader” + „Phone”
RBC, Octaplas or FFP
Coagulation factor conc.
Lab. Assays /40 min
VET /40 min

35. Summary
Industrially produced plasma – OctaplasLG - decreases
risk of post-transfusion complications
 Directly – due to inactivation, filtration, and pooling
 Directly by healing of endothelopathy
 Undirectly – due to efficient hemostasis and less
requirements for other blood products od factor
concentrates: fibrinogen, PCC