Key Points

  • High-molecular-weight kininogen deficiency in mice protects against APAP-induced hepatotoxicity.

  • Plasmin-mediated cleavage of high molecular weight kininogen enhances APAP-induced hepatotoxicity independently of bradykinin signaling.

Abstract

Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor–dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (factor XII [FXII] and prekallikrein) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high-molecular-weight kininogen-deficient (HK−/−) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK−/− mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, enzyme-linked immunosorbent assay, and mass spectrometry analysis showed that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin-mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.

REFERENCES

1.
Stravitz
RT
,
Kramer
DJ
.
Management of acute liver failure
.
Nat Rev Gastroenterol Hepatol
.
2009
;
6
(
9
):
542
-
553
.
2.
Budnitz
DS
,
Lovegrove
MC
,
Crosby
AE
.
Emergency department visits for overdoses of acetaminophen-containing products
.
Am J Prev Med
.
2011
;
40
(
6
):
585
-
592
.
3.
Jollow
DJ
,
Mitchell
JR
,
Potter
WZ
,
Davis
DC
,
Gillette
JR
,
Brodie
BB
.
Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo
.
J Pharmacol Exp Ther
.
1973
;
187
(
1
):
195
-
202
.
4.
Mitchell
JR
,
Jollow
DJ
,
Potter
WZ
,
Davis
DC
,
Gillette
JR
,
Brodie
BB
.
Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism
.
J Pharmacol Exp Ther
.
1973
;
187
(
1
):
185
-
194
.
5.
Mitchell
JR
,
Jollow
DJ
,
Potter
WZ
,
Gillette
JR
,
Brodie
BB
.
Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione
.
J Pharmacol Exp Ther
.
1973
;
187
(
1
):
211
-
217
.
6.
Potter
WZ
,
Davis
DC
,
Mitchell
JR
,
Jollow
DJ
,
Gillette
JR
,
Brodie
BB
.
Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro
.
J Pharmacol Exp Ther
.
1973
;
187
(
1
):
203
-
210
.
7.
Nelson
SD
.
Molecular mechanisms of the hepatotoxicity caused by acetaminophen
.
Semin Liver Dis
.
1990
;
10
(
4
):
267
-
278
.
8.
Jaeschke
H
,
Bajt
ML
.
Intracellular signaling mechanisms of acetaminophen-induced liver cell death
.
Toxicol Sci
.
2006
;
89
(
1
):
31
-
41
.
9.
Jaeschke
H
,
Knight
TR
,
Bajt
ML
.
The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity
.
Toxicol Lett
.
2003
;
144
(
3
):
279
-
288
.
10.
Jaeschke
H
,
Xie
Y
,
McGill
MR
.
Acetaminophen-induced liver injury: from animal models to humans
.
J Clin Transl Hepatol
.
2014
;
2
(
3
):
153
-
161
.
11.
Ganey
PE
,
Luyendyk
JP
,
Newport
SW
, et al
.
Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice
.
Hepatology
.
2007
;
46
(
4
):
1177
-
1186
.
12.
Sullivan
BP
,
Kassel
KM
,
Jone
A
,
Flick
MJ
,
Luyendyk
JP
.
Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury
.
Am J Pathol
.
2012
;
180
(
6
):
2321
-
2329
.
13.
Miyakawa
K
,
Joshi
N
,
Sullivan
BP
, et al
.
Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice
.
Blood
.
2015
;
126
(
15
):
1835
-
1843
.
14.
Kopec
AK
,
Joshi
N
,
Cline-Fedewa
H
, et al
.
Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMβ2 integrin-dependent upregulation of Mmp12
.
J Hepatol
.
2017
;
66
(
4
):
787
-
797
.
15.
Ilich
A
,
Bokarev
I
,
Key
NS
.
Global assays of fibrinolysis
.
Int J Lab Hematol
.
2017
;
39
(
5
):
441
-
447
.
16.
Gao
S
,
Silasi-Mansat
R
,
Behar
AR
,
Lupu
F
,
Griffin
CT
.
Excessive plasmin compromises hepatic sinusoidal vascular integrity after acetaminophen overdose
.
Hepatology
.
2018
;
68
(
5
):
1991
-
2003
.
17.
Kleniewski
J
,
Blankenship
DT
,
Cardin
AD
,
Donaldson
V
.
Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin
.
J Lab Clin Med
.
1992
;
120
(
1
):
129
-
139
.
18.
Kleniewski
J
,
Donaldson
VH
,
Wagner
CJ
.
Plasmin induced changes in high molecular weight kininogen (HMW-K)
.
Adv Exp Med Biol
.
1983
;
156
:
165
-
173
.
19.
Cap
AP
.
Plasmin: a driver of hemovascular dysfunction
.
Blood
.
2016
;
128
(
20
):
2375
-
2376
.
20.
Renné
T
,
Gailani
D
,
Meijers
JC
,
Müller-Esterl
W
.
Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein
.
J Biol Chem
.
2002
;
277
(
7
):
4892
-
4899
.
21.
Ratnoff
OD
,
Saito
H
.
Interactions among Hageman factor, plasma prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent
.
Proc Natl Acad Sci U S A
.
1979
;
76
(
2
):
958
-
961
.
22.
Maas
C
,
Renné
T
.
Coagulation factor XII in thrombosis and inflammation
.
Blood
.
2018
;
131
(
17
):
1903
-
1909
.
23.
Hall
JM
.
Bradykinin receptors
.
Gen Pharmacol
.
1997
;
28
(
1
):
1
-
6
.
24.
Kayashima
Y
,
Smithies
O
,
Kakoki
M
.
The kallikrein-kinin system and oxidative stress
.
Curr Opin Nephrol Hypertens
.
2012
;
21
(
1
):
92
-
96
.
25.
Maas
C
.
Plasminflammation—an emerging pathway to bradykinin production
.
Front Immunol
.
2019
;
10
:
2046
.
26.
Cugno
M
,
Hack
CE
,
de Boer
JP
,
Eerenberg
AJ
,
Agostoni
A
,
Cicardi
M
.
Generation of plasmin during acute attacks of hereditary angioedema
.
J Lab Clin Med
.
1993
;
121
(
1
):
38
-
43
.
27.
Ritchie
BC
.
Protease inhibitors in the treatment of hereditary angioedema
.
Transfus Apheresis Sci
.
2003
;
29
(
3
):
259
-
267
.
28.
Kantelip
B
,
Champiat
B
,
Mignot
P
,
Fonck
Y
,
Molina
C
.
Intravascular bronchioloalveolar tumor or I.V.B.A.T. Apropos of a case and review of the literature [in French]
.
Rev Pneumol Clin
.
1985
;
41
(
4
):
273
-
282
.
29.
Rathbun
KM
.
Angioedema after thrombolysis with tissue plasminogen activator: an airway emergency
.
Oxf Med Case Rep
.
2019
;
2019
(
1
):
omy112
.
30.
Lisman
T
,
Arefaine
B
,
Adelmeijer
J
, et al
.
Global hemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease
.
J Thromb Haemost
.
2021
;
19
(
1
):
85
-
95
.
31.
Pernambuco
JR
,
Hughes
RD
,
Langley
PG
,
Izumi
S
,
Williams
R
.
Hepatocyte growth factor and plasminogen activation in fulminant hepatic failure
.
Blood Coagul Fibrinolysis
.
1994
;
5
(
4
):
511
-
515
.
32.
Pernambuco
JR
,
Langley
PG
,
Hughes
RD
,
Izumi
S
,
Williams
R
.
Activation of the fibrinolytic system in patients with fulminant liver failure
.
Hepatology
.
1993
;
18
(
6
):
1350
-
1356
.
33.
Takahashi
H
,
Tatewaki
W
,
Wada
K
,
Yoshikawa
A
,
Shibata
A
.
Thrombin and plasmin generation in patients with liver disease
.
Am J Hematol
.
1989
;
32
(
1
):
30
-
35
.
34.
Stravitz
RT
,
Ellerbe
C
,
Durkalski
V
, et al;
Acute Liver Failure Study Group
.
Bleeding complications in acute liver failure
.
Hepatology
.
2018
;
67
(
5
):
1931
-
1942
.
35.
Reuben
A
,
Tillman
H
,
Fontana
RJ
, et al
.
Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study
.
Ann Intern Med
.
2016
;
164
(
11
):
724
-
732
.
36.
Ganger
DR
,
Rule
J
,
Rakela
J
, et al;
Acute Liver Failure Study Group
.
Acute liver failure of indeterminate etiology: a comprehensive systematic approach by an expert committee to establish causality
.
Am J Gastroenterol
.
2018
;
113
(
9
):
1319
-
1328
.
37.
Pauer
HU
,
Renné
T
,
Hemmerlein
B
, et al
.
Targeted deletion of murine coagulation factor XII gene—a model for contact phase activation in vivo
.
Thromb Haemost
.
2004
;
92
(
3
):
503
-
508
.
38.
Gailani
D
,
Lasky
NM
,
Broze
GJ
Jr
.
A murine model of factor XI deficiency
.
Blood Coagul Fibrinolysis
.
1997
;
8
(
2
):
134
-
144
.
39.
Stavrou
EX
,
Fang
C
,
Merkulova
A
, et al
.
Reduced thrombosis in Klkb1-/- mice is mediated by increased Mas receptor, prostacyclin, Sirt1, and KLF4 and decreased tissue factor
.
Blood
.
2015
;
125
(
4
):
710
-
719
.
40.
Merkulov
S
,
Zhang
WM
,
Komar
AA
, et al
.
Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis
.
Blood
.
2008
;
111
(
3
):
1274
-
1281
.
41.
Bugge
TH
,
Flick
MJ
,
Daugherty
CC
,
Degen
JL
.
Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction
.
Genes Dev
.
1995
;
9
(
7
):
794
-
807
.
42.
Institute of Laboratory Animal Resources
.
Committee on Care and Use of Laboratory Animals
.
Guide for the Care and Use of Laboratory Animals
. NIH publication.
Bethesda, MD
:
US Department of Health and Human Services, Public Health Service
.
43.
Buntrock
RE
.
Sax’s dangerous properties of industrial materials
.
Choice Curr RevAcad Libraries
.
2013
;
51
(
1
):
109
.
44.
Yamamoto-Imoto
H
,
Zamolodchikov
D
,
Chen
ZL
, et al
.
A novel detection method of cleaved plasma high-molecular-weight kininogen reveals its correlation with Alzheimer’s pathology and cognitive impairment
.
Alzheimers Dement (Amst)
.
2018
;
10
(
1
):
480
-
489
.
45.
Henderson
MW
,
Noubouossie
DF
,
Ilich
A
, et al
.
Protease: serpin complexes to assess contact system and intrinsic pathway activation
.
Res Pract Thromb Haemost
.
2020
;
4
(
5
):
789
-
798
.
46.
Ilich
A
,
Noubouossie
DF
,
Henderson
M
, et al
.
Development and application of global assays of hyper- and hypofibrinolysis
.
Res Pract Thromb Haemost
.
2019
;
4
(
1
):
46
-
53
.
47.
Arnold
K
,
Xu
Y
,
Sparkenbaugh
EM
, et al
.
Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure
.
Sci Transl Med
.
2020
;
12
(
535
):
eaav8075
.
48.
Renné
T
,
Schmaier
AH
,
Nickel
KF
,
Blombäck
M
,
Maas
C
.
In vivo roles of factor XII
.
Blood
.
2012
;
120
(
22
):
4296
-
4303
.
49.
Gailani
D
,
Broze
GJ
Jr.
Factor XI activation in a revised model of blood coagulation
.
Science
.
1991
;
253
(
5022
):
909
-
912
.
50.
Saito
H
,
Ratnoff
OD
,
Waldmann
R
,
Abraham
JP
.
Fitzgerald Trait: deficiency of a hitherto unrecognized agent, Fitzgerald Factor, participating in surface-mediated reactions of clotting, fibrinolysis, generation of kinins, and the property of diluted plasma enhancing vascular permeability (PF/Dil)
.
J Clin Invest
.
1975
;
55
(
5
):
1082
-
1089
.
51.
Sainz
IM
,
Pixley
RA
,
Colman
RW
.
Fifty years of research on the plasma kallikrein-kinin system: from protein structure and function to cell biology and in-vivo pathophysiology
.
Thromb Haemost
.
2007
;
98
(
1
):
77
-
83
.
52.
Kaplan
AP
,
Austen
KF
.
A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin
.
J Exp Med
.
1971
;
133
(
4
):
696
-
712
.
53.
Hebbes
TR
,
Turner
CH
,
Thorne
AW
,
Crane-Robinson
C
.
A “minimal epitope” anti-protein antibody that recognises a single modified amino acid
.
Mol Immunol
.
1989
;
26
(
9
):
865
-
873
.
54.
Back
N
,
Guth
PS
,
Munson
AE
.
On the relationship between plasmin and kinin
.
Ann N Y Acad Sci
.
1963
;
104
(
1
):
53
-
68
.
55.
Marcos-Contreras
OA
,
Martinez de Lizarrondo
S
,
Bardou
I
, et al
.
Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism
.
Blood
.
2016
;
128
(
20
):
2423
-
2434
.
56.
Yang
A
,
Xie
Z
,
Wang
B
,
Colman
RW
,
Dai
J
,
Wu
Y
.
An essential role of high-molecular-weight kininogen in endotoxemia [published correction appears in J Exp Med. 2019;216(1):244]
.
J Exp Med
.
2017
;
214
(
9
):
2649
-
2670
.
57.
Lisman
T
,
Bakhtiari
K
,
Adelmeijer
J
,
Meijers
JC
,
Porte
RJ
,
Stravitz
RT
.
Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure
.
J Thromb Haemost
.
2012
;
10
(
7
):
1312
-
1319
.
58.
Groeneveld
D
,
Cline-Fedewa
H
,
Baker
KS
, et al
.
Von Willebrand factor delays liver repair after acetaminophen-induced acute liver injury in mice
.
J Hepatol
.
2020
;
72
(
1
):
146
-
155
.
59.
Kopec
AK
,
Luyendyk
JP
.
Coagulation in liver toxicity and disease: role of hepatocyte tissue factor
.
Thromb Res
.
2014
;
133
(
suppl 1
):
S57
-
S59
.
60.
Schmaier
AH
,
McCrae
KR
.
The plasma kallikrein-kinin system: its evolution from contact activation
.
J Thromb Haemost
.
2007
;
5
(
12
):
2323
-
2329
.
61.
Shariat-Madar
Z
,
Mahdi
F
,
Schmaier
AH
.
Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator
.
J Biol Chem
.
2002
;
277
(
20
):
17962
-
17969
.
62.
Higashiyama
S
,
Ishiguro
H
,
Ohkubo
I
,
Fujimoto
S
,
Matsuda
T
,
Sasaki
M
.
Kinin release from kininogens by calpains
.
Life Sci
.
1986
;
39
(
18
):
1639
-
1644
.
63.
Dobó
J
,
Major
B
,
Kékesi
KA
, et al
.
Cleavage of kininogen and subsequent bradykinin release by the complement component: mannose-binding lectin-associated serine protease (MASP)-1
.
PLoS One
.
2011
;
6
(
5
):
e20036
.
64.
Kleniewski
J
,
Donaldson
V
.
Granulocyte elastase cleaves human high molecular weight kininogen and destroys its clot-promoting activity
.
J Exp Med
.
1988
;
167
(
6
):
1895
-
1907
.
65.
Raum
D
,
Marcus
D
,
Alper
CA
,
Levey
R
,
Taylor
PD
,
Starzl
TE
.
Synthesis of human plasminogen by the liver
.
Science
.
1980
;
208
(
4447
):
1036
-
1037
.
66.
Tomiya
T
,
Hayashi
S
,
Ogata
I
,
Fujiwara
K
.
Plasma alpha 2-plasmin inhibitor-plasmin complex and FDP-D-dimer in fulminant hepatic failure
.
Thromb Res
.
1989
;
53
(
3
):
253
-
260
.
67.
Pant
A
,
Kopec
AK
,
Baker
KS
,
Cline-Fedewa
H
,
Lawrence
DA
,
Luyendyk
JP
.
Plasminogen activator inhibitor-1 reduces tissue-type plasminogen activator-dependent fibrinolysis and intrahepatic hemorrhage in experimental acetaminophen overdose
.
Am J Pathol
.
2018
;
188
(
5
):
1204
-
1212
.
68.
Roth
K
,
Strickland
J
,
Joshi
N
, et al
.
Dichotomous role of plasmin in regulation of macrophage function after acetaminophen overdose
.
Am J Pathol
.
2019
;
189
(
10
):
1986
-
2001
.
69.
Bekheet
SH
,
Awadalla
EA
,
Salman
MM
,
Hassan
MK
.
Bradykinin potentiating factor isolated from Buthus occitanus venom has a protective effect against cadmium-induced rat liver and kidney damage
.
Tissue Cell
.
2011
;
43
(
6
):
337
-
343
.
70.
Doria
C
,
Elia
ES
,
Kang
Y
, et al
.
Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity
.
Liver Transpl
.
2008
;
14
(
5
):
684
-
687
.
71.
Betto
MR
,
Lazarotto
LF
,
Watanabe
TT
,
Driemeier
D
,
Leite
CE
,
Campos
MM
.
Effects of treatment with enalapril on hepatotoxicity induced by acetaminophen in mice
.
Naunyn Schmiedebergs Arch Pharmacol
.
2012
;
385
(
9
):
933
-
943
.
72.
Khan
MM
,
Bradford
HN
,
Isordia-Salas
I
, et al
.
High-molecular-weight kininogen fragments stimulate the secretion of cytokines and chemokines through uPAR, Mac-1, and gC1qR in monocytes
.
Arterioscler Thromb Vasc Biol
.
2006
;
26
(
10
):
2260
-
2266
.
73.
Wachtfogel
YT
,
DeLa Cadena
RA
,
Kunapuli
SP
, et al
.
High molecular weight kininogen binds to Mac-1 on neutrophils by its heavy chain (domain 3) and its light chain (domain 5)
.
J Biol Chem
.
1994
;
269
(
30
):
19307
-
19312
.
74.
Colman
RW
,
Jameson
BA
,
Lin
Y
,
Johnson
D
,
Mousa
SA
.
Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis
.
Blood
.
2000
;
95
(
2
):
543
-
550
.
75.
McCrae
KR
,
Doñate
F
,
Merkulov
S
,
Sun
D
,
Qi
X
,
Shaw
DE
.
Inhibition of angiogenesis by cleaved high molecular weight kininogen (HKa) and HKa domain 5
.
Curr Cancer Drug Targets
.
2005
;
5
(
7
):
519
-
528
.
76.
Zhang
JC
,
Claffey
K
,
Sakthivel
R
, et al
.
Two-chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5
.
FASEB J
.
2000
;
14
(
15
):
2589
-
2600
.
77.
Colman
RW
.
Inhibitory and antiadhesive properties of human kininogens
.
Immunopharmacology
.
1996
;
32
(
1-3
):
9
-
18
.
78.
Hatoh
T
,
Maeda
T
,
Takeuchi
K
, et al
.
Domain 5 of high molecular weight kininogen inhibits collagen-mediated cancer cell adhesion and invasion in association with α-actinin-4
.
Biochem Biophys Res Commun
.
2012
;
427
(
3
):
497
-
502
.
79.
Kawasaki
M
,
Maeda
T
,
Hanasawa
K
,
Ohkubo
I
,
Tani
T
.
Effect of His-Gly-Lys motif derived from domain 5 of high molecular weight kininogen on suppression of cancer metastasis both in vitro and in vivo
.
J Biol Chem
.
2003
;
278
(
49
):
49301
-
49307
.
80.
Liu
Y
,
Pixley
R
,
Fusaro
M
, et al
.
Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway
.
Oncogene
.
2009
;
28
(
30
):
2756
-
2765
.
81.
Sonesson
A
,
Nordahl
EA
,
Malmsten
M
,
Schmidtchen
A
.
Antifungal activities of peptides derived from domain 5 of high-molecular-weight kininogen
.
Int J Pept
.
2011
;
2011
:
761037
.
82.
Nordahl
EA
,
Rydengård
V
,
Mörgelin
M
,
Schmidtchen
A
.
Domain 5 of high molecular weight kininogen is antibacterial
.
J Biol Chem
.
2005
;
280
(
41
):
34832
-
34839
.
83.
Bradford
HN
,
Schmaier
AH
,
Colman
RW
.
Kinetics of inhibition of platelet calpain II by human kininogens
.
Biochem J
.
1990
;
270
(
1
):
83
-
90
.
84.
Schmaier
AH
,
Bradford
H
,
Silver
LD
, et al
.
High molecular weight kininogen is an inhibitor of platelet calpain
.
J Clin Invest
.
1986
;
77
(
5
):
1565
-
1573
.
85.
Colman
RW
,
Bradford
HN
,
Warner
AH
.
High molecular weight kininogen, the extracellular inhibitor of thiol proteases, is deficient in hamsters with muscular dystrophy
.
Thromb Res
.
1989
;
54
(
2
):
115
-
123
.
86.
Higashiyama
S
,
Ohkubo
I
,
Ishiguro
H
,
Kunimatsu
M
,
Sawaki
K
,
Sasaki
M
.
Human high molecular weight kininogen as a thiol proteinase inhibitor: presence of the entire inhibition capacity in the native form of heavy chain
.
Biochemistry
.
1986
;
25
(
7
):
1669
-
1675
.
87.
Kollarik
M
,
Undem
BJ
.
Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice
.
J Physiol
.
2004
;
555
(
pt 1
):
115
-
123
.
88.
Eberhardt
MJ
,
Schillers
F
,
Eberhardt
EM
, et al
.
Reactive metabolites of acetaminophen activate and sensitize the capsaicin receptor TRPV1
.
Sci Rep
.
2017
;
7
(
1
):
12775
.
89.
Luyendyk
JP
,
Schoenecker
JG
,
Flick
MJ
.
The multifaceted role of fibrinogen in tissue injury and inflammation
.
Blood
.
2019
;
133
(
6
):
511
-
520
.
90.
Lisman
T
,
Stravitz
RT
.
Rebalanced hemostasis in patients with acute liver failure
.
Semin Thromb Hemost
.
2015
;
41
(
5
):
468
-
473
.
91.
Leebeek
FW
,
Rijken
DC
.
The fibrinolytic status in liver diseases
.
Semin Thromb Hemost
.
2015
;
41
(
5
):
474
-
480
.
92.
Kodali
S
,
Holmes
CE
,
Tipirneni
E
,
Cahill
CR
,
Goodwin
AJ
,
Cushman
M
.
Successful management of refractory bleeding in liver failure with tranexamic acid: case report and literature review
.
Res Pract Thromb Haemost
.
2019
;
3
(
3
):
424
-
428
.
93.
Barratt-Due
A
,
Johansen
HT
,
Sokolov
A
, et al
.
The role of bradykinin and the effect of the bradykinin receptor antagonist icatibant in porcine sepsis
.
Shock
.
2011
;
36
(
5
):
517
-
523
.
94.
Fontana
RJ
.
Acute liver failure including acetaminophen overdose
.
Med Clin North Am
.
2008
;
92
(
4
):
761
-
794, viii
.
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