Solid organ transplantation and

its transfusion aspects

Jnos Fazakas MD , PhD

Semmelweis University
Department of Transplantation and Surgery, Budapest

1. ABO compatible grafts (donor organ)

SOT = ABO even above HLA
Liver, kidney, and heart ABO incompatible transplants done at some centers

BMT = HLA above ABO

2. RBC Transfused: Should be of donors type

Transfusion requirements are modest in most cases (1-4 U RBC)
except in liver transplantation

3. Platelet/Plasma: Should be compatible with both recipient

and donors organ
4. Passenger Donor Lymphocytes with/in the transplanted
organs

O group donor graft to non O group recipients: donor lymphocytes Ig production

CNI: Cya or tacrolimus allows more Ig production
Recipient: antibodies in 1-2 weeks may do some hemolysis . 1 months
plasma exchange, 1-2 x BV/PV steroids

transfusion washed, leukoreduced with O RBCs and recipients type of plasma/platelet

5. CMV negative patients receiving seronegative organs

receive CMV safe blood products: leukoreduced, or from CMV
seronegative donors

6. Transfusion-associated graft vs. host disease is rare

therefore routine irradiation is not considered necessary at most
centers. (only 4 published cases!)

6. Alloimmunization to HLA antigen is serious concern

difficulties in finding compatible organs: kidney, lung and heart
transplants (HLA type I T lymphocytes matching !), but not liver
Blood products should be leukoreduced for heart, lung and kidney
transplant recipients

Transfusion and organ transplantation

Liver Transplantation (underlying coagulopathy)

RBCs, coagulation factors and platelets

Start: 10 U RBC, 20 U FFP, 8 U PLT (?)

Large amount of products may be needed on short notice
the key : close communication with the blood bank
In group AB and B, group O RBCs may be used to conserve the more
uncommon RBC types; in group A and O patients, use ABO-identical RBCs

the anhepatic phase:

Coagulation factors: no synthesis, but consumption, tPA - fibrinolysis

intraoperative RBC salvage to reduce allogeneic RBC exposure

nearly bloodless liver Tx have been reported

Kidney Transplantation
EPO further reduced transfusion needs of patients with ESRD
renal transplant patients transfusion early before surgery ?
TRIM, SeK+ (1 U 0.5 gr K)
it is not a bleeding surgical procedure

Heart Transplantation
VAD HTx could be more bleedy
Cardiopulmonary bypass (CPB) affects platelet function and number
Multiplate impedance aggregometry

Platelet transfusion is necessary in case of substantial bleeding

1 / 25 years

* FFP and platelets, in the immediate post-transplant period following an ABOincompatible (ABOi) solid organ transplant!
* the transfusion risks associated with passenger lymphocyte syndrome (PLS)!
communication between the clinical team and the transfusion laboratory

Use of X-irradiation as an alternative to gamma irradiation (25 Gy but no > 50 Gy)

 Irradiation to prevent TA-GvHD is not recommended on a routine basis for all

cases
the leuko-reduced products had decreased the Alloimmunization
ABO and HLA matching has decreased considerably with the use of modern
immunosuppressant drugs
ABO incompatible Tx: isoagglutinin elimination techniques with immunoadsorption
and anti-CD20 antibodies (rituximab)
Preop.: EPO; Intraop.: cell saver; Postop.: cell salvage

Global
RECIPIENT

Hemostasis view

Vascular bed specific

GRAFT

FIBRINOLYSIS

COAGULATION

95 %

5%
Initiation

Kallikrein,
Bradikinin

Amplification

Propagation

XIIa

Plasminogen
Endothel
tPA

AGGREGATION
vWF, thrombocyte receptors

ADAMTS13, NO, PGI2

ANTIAGGREGATION

XIIIa

T + TM
Exstrinsic
kinase

APC
(fast)
Plasmin

AT-III
(slow)
ANTICOAGULATION

ANTIFIBRINOLYSIS

Hemostasis rebalance in liver disease

Rebalance Rebalance Rebalance Rebalance

Production
Clearence
Reserve Capacity
platelets, vitamin K-dependent factors
(II, VII, IX, X), V,
dysfibrinogen,
protein C and S, AT-III,
platelet dysfunction
Plasminogen, 2-AP,
RES dysfunction
ADAMTS13

Decreased
to about 25-70%

Low level balance

high risk of bleeding and thrombosis

LPS, TF,
vWF, F VIII
tPA, PAI-1

Increased up
to 200%

Saner, FH. Digestion 2013; 88:135144.

Schaden, E. Curr Opin Crit Care 2013,19:000000..
Northup, PG. Clinical Gastroenterology and Hepatology 2013; 11: 1064-1074.

Hemostasis rebalance in liver disease

Rebalance Rebalance Rebalance Rebalance

Production
Clearence
Balance
Promoting
thrombosis
platelets, vitamin
K-dependent factorsDelicate rebalance
(II, VII, IX, X), V,
protein C and S, AT-III,
Plasminogen, 2-AP,
ADAMTS13

dysfibrinogen,
platelet dysfunction
RES dysfunction

Promoting bleeding
LPS, TF,
vWF, F VIII
tPA, PAI-1

Increased up
to 200%

Decreased
to about 25-70%
Low level balance
high risk of bleeding and thrombosis

Saner, FH. Digestion 2013; 88:135144.

Schaden, E. Curr Opin Crit Care 2013,19:000000..
Northup, PG. Clinical Gastroenterology and Hepatology 2013; 11: 1064-1074.

Vascular bed specific hemostasis

PRO

ANTI

vWF ++++
TF +
TR ++
PAI-1 ++++

tPA
+
TFPI
+++
Heparan +++
TM
++

Differential expression
of hemostatic factors
on different endothelial cells

EC

Organ-specific responses by
endothelial cells

Every organ define its hemostasis

according to its function
Crit Care Med 2001; 29 [Suppl.]:S28 S35

vWF

++

tPA

TF

TFPI

+++

++

Heparan

PAI-1

TM

High flow anticoagulation effect

Primary hemostasis dependent endothelium

vWF

++

TF
T
PAI-1

+
+
+

tPA

++++

vWF

absent

tPA

TFPI
Heparan

+++
+++

TF

++

TFPI
+++
Heparan +++

TM

+++

PAI-1

TM

Environmental relationship
innate immune response
prothrombotic effect
Specific anticoagulation and profibrinolysis

++++

Low flow prothrombotic effect

Secondary hemostasis dependent endothelium
Specifically anticoagulation effect

vWF

++

tPA

TF

TFPI

+++

++

Heparan

PAI-1

TM

High flow anticoagulation effect

Primary hemostasis dependent endothelium

vWF

++

TF
T
PAI-1

+
+
+

tPA

++++

vWF

absent

tPA

TFPI
Heparan

+++
+++

TF

++

TFPI
+++
Heparan +++

TM

+++

PAI-1

TM

Environmental relationship
innate immune response
prothrombotic effect
Specific anticoagulation and profibrinolysis

++++

Low flow prothrombotic effect

Secondary hemostasis dependent endothelium
Specifically anticoagulation effect

Graft = vascular bed specific

Vascular bed specific organ hemostasis

Primary
vWF +++
hemostasis
TF +

Primary
TR ++
PAI-1 ++
hemostasis

high flow = anticoagulation

Kidney medulla:
Semin Immunopathol (2012) 34:167179

Secondary
tPA
+
hemostasis
TFPI +

Secondary
PC +
hemostasis
TM +

Fibrinolysis

Low flow = IRI = TF =

procoagulation=
microthrombosis

vWF ,
TFPI , PC , TM
Circ Res. 2012;111:110-130

Ivan-Zietek et al.

38 BD 60% stroke - 40% mv accident:

AT, PC, P, PAP, F1-2, TAT, D dimer

Graft = vascular bed specific hemostasis

Vascular bed specific organ hemostasis

Primary
vWF absent
hemostasis
TF +

TR ++
PAI-1 +

low flow = 4 - 8 mmHg

Liver:

tPA

TFPI +++

Secondary

Heparan +++
hemostasis
TM
++++

Fibrinolysis

vWF absent, TFPI ,

Heparan , TM

Semin Immunopathol (2012) 34:167179

Circ Res. 2012;111:110-130

Kashiwadate et al. Transplantation Proceedings, 44, 369372 (2012)

Sinusoidal space was measured in histological findings

Liver transplantation
hepatectomy anhepatic phase reperfusion neohepatic phase
hypovolemic

,, Tsunami
Volume
overload

Dilution
No
clearance
Consumption
No synthesis
Bleeding
,,350-500
ml
blood
pH
, TC

=Consumption
1 U RBC

Kidney transplantation
CV patient KVA or DAT HD anticoagulation (LMWH or citrate)

Factor consumption
dilution

,,blood flow: 1-1.5 l/min

= 1/2 U RBC

Global hemostasis
rebalanced hemostasis
Recipient

DBD

Vascular bed-specific hemostasis

DBD = damaged glycocalix + EC weak control /flow + EC/

Bloodless SOT

zero tolerance
for blood loss
Hemodynamic management: avoid dilution
Hemostasis management: individualized pyramid of hemostasis

Hemodynamic management
Replace what is missing
Pressure gradient = flow = anticoagulation

NV = 100% BV

volume
space

Hemodynamic management
Replace what is missing
Pressure gradient = flow = anticoagulation

Narcosis induction
Induction
NV = 100%
= 75-90%
BV BV

volume
space

norepinephrin
vasodilatation

Hemodynamic management
Replace what is missing

Pressure gradient = flow = anticoagulation

space

Anhepatic phase

NV = 100% BV

volume
volume

Preload; ITBI 20-30%

norepinephrin
space

Congestion
volume

space

volume
space

Hemodynamic management
Replace what is missing

Pressure gradient = flow = anticoagulation

NV = 100% BV

volume

old style

space

Volume + norepinephrin
,, Tsunami
Reperfusion
volume

new style

norepinephrin

space

Hemodynamic management
Vascular space / blood volume distribution

Replace what is missing !

TXA

PT < 1.5x
APTI < 1.5x

Fibr. < 1,5-2 g/L

(delivery < 3-3.5 g/L)

FV < 30 %

Thr < 50-80 G/L

FVII < 30 % FXIII < 60 %

Order of priority

firmness
initiation
amplification
initiation
substrate
fibrinolysis
diagnosis
homeostasis
Adapted from
Prof Grlinger

FXIII
FVIIa
thrombocyte

> 20 IU/kg
off label
Thr(U) = 1U/10kg

PCC

PCC(IU)=(PTc-PTb)kg
FFP(ml)=(PTc-PTb)1.5mlkg

fibrinogen
Tranexam acid
fibrinogen, thrombocyte - INR, APTI,
- TEG, ROTEM, TAG
pH>7.2 se Ca> 1 mmol/l Hgb >100g/l T > 35C

surgical hemostasis control of hemorrhage (FXIV)

Fibr(g)=(Fc-Fb)0.06gkg

Individualize the management of hemostasis

Calculate the patient

blood and plasma volume

Individualized
therapy

Define the trough levels

Focus on the
weakest link

Calculate the minimum

reserve capacity
Preserve the reserve capacity
Do not be iatrogenic!
(avoid dilution)
Pay attention
Consumption, bleeding, dilution

Weakest link?

Calculate the patient

blood and plasma volume

Blood volume (BV) = BW kg 70-90 ml/kg

Plasma volume (PT) = BW kg 70-90 ml/kg x (1-Hct/100)

calculate

50 kg; 3500ml BV; 2100ml PV

Individualized
therapy

START

Define the trough levels

End point - trough level: .

Minimal
factor level ?

STOP

Weakest link

Calculate the minimum

reserve capacity

50 kg; 3500ml BV; 2100ml PV

Htc
Starting point: 35%
Reduction point: 25%

3.5 l x (35%-25%)
30%

1166 ml blood loos

calculate
Fibrinogen
Starting point: 3 g/L
Reduction point: 1.5 g/L

3.5 l or (2.1 l) x (3 -1.5)

2.75

? ml blood loss
? ml plasma loss

3.5L or (2.1L) x (60%-40%)

2.25

? ml blood loss
? ml plasma loss

Prothrombin
Starting point: 60%
Reduction point: 40%

Individualized
therapy

Calculate the reserve

capacity of the hemostasis
BV = VT [Hct (k) - Hct (r)]/ Hct (mean)
Blood volume (VT) = BW kg 70-90 ml/kg

PV = PT [Factor (k) - Factor (r)]/ Factor (m)

Plasma volume (PT) = BW kg 70-90 ml/kg x (1-Hct/100)

Thr

Focus on the weakest

link ??

4880ml

AT III.
FVII

Fibrinogen
XIII.

2930ml
1615ml

2690ml

2333ml

PCC

FXIII

1166ml

Individualized pyramid
Fibrinogen

FVII

AT-III

put them in the increasing order

1050ml

1400ml

RBC

RBC

1400ml

1750ml

PCC

Original Grlinger pyramid

1550ml

2580ml

Thr

840ml

Focus on the reserve capacity

dont be iatrogenic!

Volume replacement

Dilution

Factor dilution = bleeding risk!

How much volume could

be replaced without
coagulopathy?

Jehovah witness liver transplantation

no blood products, no factor concentrates used
Intrinsic pathway

Extrinsic pathway

XII

III
XI

VII

IX
IX
INDIVIDUALIZED
X
Xa

II
.
V.

XIII

After
PYRAMID12
OFh
GRLINGER

Va

VIII

II.

HEMOSTATIC THERAPY

VIII

COUNT
XIII

II
.
V.

Tenase

II.
XIII

After
24 h

Stabilization

After
12 h

Before
OLtx

Amplifikation

End of the
OLtx

End of the
OLtx

Initiation

Before
OLtx

After
24 h

Lysis

focus on the
weakest link

XIII

Individualized hemostasis treatment: normovolemia

100 %

?
60 %
Platelets
Pro-Anticoagulant
factors

Consumption
Reperfusion

Fibrinogen
Dilution: Iatrogenic

30 %

Maintain normovolemia:

volume replacement / hour: UO + perspiration

blood loss < predicted by the pyramid
spleen auto-transfuse the graft ?
cell saver could be applied

Maintain perfusion pressure-flow

Vasopressors: NA

ALF

0%

Postoperative 12 24 hours
POSTOPERATIVE PERIOD
START

Hourly measured

COA
PiCCO

HEMODINAMIC
MEASUREMENTS, BG
4 hourly

Termodilution technique
(PiCCO) (macro-micro)

LAB
VITAL
11

COAG
VITAL
0G
BG

VITAL
1

COAG
VITAL
10

COA

PiCCO
VITAL
BG

COAG
VITAL
8

Hemostasis parameters
2 - 4 hourly
ACT/LW, INR/APTI
TEG, Multiplate-TAG

COAG
VITAL
4
RX/US
VITAL
7

Semmelweis University
Department of Transplantation and Surgery
ICU

Vital parameters
Volume balance

RX/U
VITAL
2
G

10

PiCCO
VITAL
BG
9

RADIOLOLOGY EXAM
US 1212-24 hourly

PiCCO
COAG
VITAL
6
BG

LAB
VITAL
5
LABORATORY PARAMETERS
6-12 hourly
Blood count, coagulation
faktors, LFT, RFT, albumin

Individualized hemostasis treatment: normovolemia

100 %

Individualized pyramid
of Grlinger

60 %

Anticoagulation therapy: dose

Platelets
Pro-Anticoagulant
factors

Consumption
Reperfusion

Fibrinogen

Anticoagulation therapy: dose adjusted

30 %
Normovolemia

ALF

0%

Postoperative period: first 12 24 hours

Intraoperative RBC, FFP, Platelets

Liver transplants 2014.07.01-2015.09.30 (n=113)

47.1 % NO RBC

82.4 % NO FFP

81.4 % NO CELL SAVER

80.4 % NO Platelets

Hungary OLTx 1995.01.05-2015.09.30

Intraoperative RBC transfusion and mortality (2015.11.10-ig)

Intraoperative RBC Patients Mortality Mortality Survival Survival

transfusion
(n)
(n)
(%)
(n)
(%)
NO RBC

105

6,7%

98

93,3%

1-5 U RBC

285

45

15,8%

240

84,2%

6-10 U RBC

192

65

33,9%

127

66,1%

11-20 U RBC

117

48

41%

69

59,0%

> 20 U RBC

38

26

68,4%

12

31,6%

Individualized management of hemostasis

Construct the patient own hemostasis pyramid !
Focus on the weakest link !

Mild bloody SOT

(1/2 blood volume loss)

Hemodynamic management: avoid dilution

Hemostasis management: Fibrinogen + PCC

Cirrhotic liver removed = 300 - 400 ml

More bleeding as was predicted

by the individualized pyramid
400 C 2000 ml C

Graft preservation solution flushed out = 200 - 300 ml

Hepatic artery / Portal vein anastomosis = 100 ml

TXA

PT < 1.5x
APTI < 1.5x

Fibr. < 2-2.5 g/L

(delivery < 3-3.5 g/L)

FV < 30 %

Thr < 50-80 G/L

FVII < 30 % FXIII < 60 %

Order of priority

firmness
initiation
amplification
initiation
substrate
fibrinolysis
diagnosis
homeostasis
Adapted from
Prof Grlinger

FXIII
BV:30% 70%

FVIIa
BV:
50%
50%
BV:
60%

thrombocyte

> 20 IU/kg
off label
Thr(U) = 1U/10kg

40%
BV:
70%
PCC
30%
BV:80%
fibrinogen
20%
BV:
90%

PCC(IU)=(PTc-PTb)kg
FFP(ml)=(PTc-PTb)1.5mlkg

10%
BV: 100%

Tranexam acid
fibrinogen, thrombocyte - INR, APTI,
- TEG, ROTEM, TAG
pH>7.2 se Ca> 1 mmol/l Hgb >100g/l T > 35C
surgical hemostasis control of hemorrhage (FXIV)

Fibr(g)=(Fc-Fb)0.06gkg

SOT and massive transfusion

(1-2-3-4..x blood volume loss)

Hemodynamic management: avoid dilution

Hemostasis management: improved FFP concept - FFP + Fibrinogen + PCC

Massive bleeding ?

time

and /or
Stainsby D, et al. Br J Haematol 2006, 135:634-641.

volume

Massive bleeding what and when?

Only fibrinogen + PCC + colloids and crystalloids are it enough?

T1/2 48-123 h

2
10

T1/

2 38

T1/2 18-30 h

9
T1/2 3-4 h

Sorensen B, et al. Critical Care 2011 15:201.

After a loss of 100% of blood volume

Into each other dilution

firmness
initiation
amplification
initiation
substrate
fibrinolysis
diagnosis
homeostasis

pH>7.2 se Ca> 1 mmol/L Hgb >100g/L T > 35C

surgical hemostasis control of hemorrhage
(FXIV)
AdaPVed from Prof
Grlinger

RBC + FFP + Thr whole blood

Into each other dilution

1 + 1 + 1= ?

into each other hemodilution !

Sihler KC. Chest 2010; 137(1):20-220.

FFP as a pig in a poke

or how many factors there's ...

12 radom units of single donor FFP

180
167
160

159

159
149

145
140

138

137

134
125

121

120

135

125
118

116

106

110

110

90

90

110

100
90

89

88
81

80
73

71

89

87

85

80

78
73

68

69

64

60
55
40

PV 100% ?
20

PS

PC

ATIII

VWF:RCo

FXIII

FXII

FXI

FX

FIX

FVIII

FVII

FV

FII

FI

RT

TT

aPTT

PT

Octaplas
The difference: I do know how many factors there's ...

12 consecutive Octaplas batches

180

160

140

120

120

115
105

105
98

96

100

102
98

104

104

104

93

96

95

110

108

108
96

92

90

103
96

103
97

102
95

88

83

80

111

106

105

103
96

86

83
75

60

40

Bio-pharmaceutical range: 20%

Pharmaceutical range:
5%

20

PS

PC

ATIII

VWF:RCo

FXIII

FXII

FXI

FX

FIX

FVIII

FVII

FV

FII

FI

RT

TT

aPTT

PT

THE PRINCIPLE OF ENRICHED PLASMA

vascular bleeding
+ 1250 IU FXIII + 100 g FVIIa + 500 IU ATIII
volumen

2 E FFP enriched by: + 1 gr fibrinogen + 500 IU PCC

anticoag

balanced

procoag

CRISTALOIDS ARENT USEFUL FFP 93% = WATER !

Minerva Anestesiol 2012;78:358-68

The principle of improved FFP

Rebalance

Replace

Blood loss

2x

Measure

AT-III

AT-III 500IU 5U FFP

Thr 1U/10kg

Thrombocyte

FXIII 20IU/kg 5U FFP

FXIII
PCC

PCC

Fibrinogen
diagnosis
homeostasis

500 IU

2U FFP but 5 U Octaplas

Fibrinogen

1g

2U FFP

After 5-10U FFP POCTs / conventional parameters

pH>7.2

se Ca> 1 mmol/L

Hgb >70-100g/L

T > 35C
Adapted from Prof Grlinger

The principle of improved FFP

Rebalance

Replace

Measure

TXA
FVIIa

Blood loss

3x

AT-III

100-500 g

AT-III 500IU 5U FFP

Thrombocyte
FXIII
PCC
Fibrinogen

diagnosis
homeostasis

10U FFP

Thr 1U/10kg
FXIII 20IU/kg 5U FFP
PCC

500IU

Fibrinogen

2U FFP

1g

2U FFP

After 5-10U FFP POCTs / conventional parameters

pH>7.2

se Ca> 1 mmol/L

Hgb >70-100g/L

T > 35C
Adapted from Prof Grlinger

POC: TEG and ROTEM

Normal
Pathologic EXTEM, TEG

TEG/TEM slides back

Factors replacement ?

EXTEM CT > 80s

TEG R > 10 min

Normal

K > 4 min
Alfa angle < 74
Normol FIBTEM

TEG/TEM became thiner

substrate: platelets

Pathologic EXTEM, TEG

Normal

K > 4 min
Alfa angle < 74

TEG/TEM became thiner

substrate: fibrinogen
Pathologic FIBTEM
Pathologic EXTEM, TEG

Norml EXTEM, APTEM, TEG

MA, MCF
continuously
decrease

MA
MCF

Pathologic EXTEM, TEG

TEG/TEM the end run out

Fibrinolysis ?

C yours factor concentrates run out ?

Targeted replacement of factor concentrates

or give FFP but remove water C (CVVH)

400 ml

30 ml/kg FFP

400 ml

5. capitol:

Topical

versus

systemic hemostasis

C TOPICAL C

Weakest organ:
The liver graft

Most at risk organ: the others

The solution:
topical administration of fibrinogen

Recipient on dual antiplatelet therapy : failed local hemostasis

The weakest organ: the kidney + the most at risk organ: the heart

Topical application of fibrinogen powder and Tachosil

Graftectomy failed local hemostasis

(antiplatelet therapy.)

bleeding & hematoma

Topical application of fibrinogen - PCC powder

KTx 2003, AMI 2012 BMS stent

Clopidogrel 1x150mg!, ASA 1x100mg po
Enoxoparin 40mg sc
Pneumonia, Tracheostomy
Tracheal bleeding ?
Hgb
Htc
Prothrombin
AT-III
INR
V
VII
X
aPTI
Fibrinogen
Thr
D-dimer
ACT 105

106 g/L
31 %
56%
102,9%
1,4
72%
84%
118%
36,6 s
7,4 g/L
226 G/L
> 4850 ug/L

100 ug Novoseven nebulisation

Hgb
Htk
Prothrombin
AT-III
INR
V
VII
X
aPTI
Fibrinogn
Thr
D-dimer
ACT 105s;

106 g/L
31 %
56%
102,9%
1,4
72%
84%
118%
36,6 s
7,4 g/L
226 G/L
> 4850 ug/L

The concept
Medical history,
Clinical picture

Conventional lab parameters

POC: ROTEM/TEG, Multiplate
Invidualiazed pyramid of Grlinger

Dont harm, dont treat numbers

ReplaceC only what is missing

Improved FFP: fibrinogen-PCC-ATIII-FXIII

Most at risk organ

The weakest organ

Topical to/or Systemic

Minimal Models for Quantum Decoherence in

Coupled Biomolecules

Energy transfer!.
Reaction time, dynamics,
coherent, incoherent, localized

Why should medical doctors be interested in

quantum biology/pathophysiology?
Quantum mechanics plays a
critical role in much of biology!
Retinal, responsible for vision
Ultrafast vision receptor

Green Fluorescent Protein used in diagnosis

Highly efficient marker plastic surgery

Classical or Quantum
What decides?

Tunneling in enzymes
RBC, PLT, Coagulation
factors!the future ?

Thank You !
jancsidora@gmail.com

Replace only what is missing

Blood loss < predicted by the

- 3/4 vrcserig = FAKTOROK
- 3/4 Blood volume loss = FACTOR CONC.
> 3-4 x vrcsere: FAKTOROK + FFP
Massive transfusion = FACTOR CONC. + FFP