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n3:pmcid: PMC0
bibo:doi: 10.1007%2Fs12016-016-8540-0
n6:contains: _:vb51138866 _:vb51138857 _:vb51138924 _:vb51138902 _:vb51138887 _:vb51138947 _:vb51138956

Subject Item: _:vb51138857
rdf:type: n6:Section
dc:title: introduction
n6:contains: _:vb51138858 _:vb51138859 _:vb51138860 _:vb51138861 _:vb51138862 _:vb51138863 _:vb51138864 _:vb51138865

Subject Item: _:vb51138858
rdf:type: n3:Context
rdf:value: Histamine is the main suspect mediator in allergic reactions, since angioedema can be seen in anaphylaxis [>>1<<] or as a concurrent symptom of the mast-cell-driven diseases like chronic spontaneous urticaria [2].
n3:mentions: n2:8400230

Subject Item: _:vb51138859
rdf:type: n3:Context
rdf:value: Histamine is the main suspect mediator in allergic reactions, since angioedema can be seen in anaphylaxis [1] or as a concurrent symptom of the mast-cell-driven diseases like chronic spontaneous urticaria [>>2<<]. For angioedema with unknown aetiology (idiopathic angioedema), histamine receptor antagonists are clinically applied on a trial-and-error basis, sometimes with higher than recommended doses [2, 3]. Approximately one in six patients with
n3:mentions: n2:24785199

Subject Item: _:vb51138860
rdf:type: n3:Context
rdf:value: For angioedema with unknown aetiology (idiopathic angioedema), histamine receptor antagonists are clinically applied on a trial-and-error basis, sometimes with higher than recommended doses [>>2<<, 3]. Approximately one in six patients with idiopathic angioedema remains unresponsive to antihistamines [4, 5]. In such cases, the involvement of other mediators should be considered.
n3:mentions: n2:24785199

Subject Item: _:vb51138861
rdf:type: n3:Context
rdf:value: For angioedema with unknown aetiology (idiopathic angioedema), histamine receptor antagonists are clinically applied on a trial-and-error basis, sometimes with higher than recommended doses [2, >>3<<]. Approximately one in six patients with idiopathic angioedema remains unresponsive to antihistamines [4, 5]. In such cases, the involvement of other mediators should be considered.
n3:mentions: n2:24673465

Subject Item: _:vb51138862
rdf:type: n3:Context
rdf:value: Approximately one in six patients with idiopathic angioedema remains unresponsive to antihistamines [>>4<<, 5]. In such cases, the involvement of other mediators should be considered.
n3:mentions: n2:25196353

Subject Item: _:vb51138863
rdf:type: n3:Context
rdf:value: Approximately one in six patients with idiopathic angioedema remains unresponsive to antihistamines [4, >>5<<]. In such cases, the involvement of other mediators should be considered.
n3:mentions: n2:17060655

Subject Item: _:vb51138864
rdf:type: n3:Context
rdf:value: This vasoactive peptide was first identified as a mediator for angioedema in patients with hereditary angioedema (HAE) [>>6<<–8]. Bradykinin is the end-product of the contact activation system. This enzymatic cascade circulates in the plasma and consists of factor XII (FXII), plasma prekallikrein (PPK) and high molecular weight kininogen (HK). This system is
n3:mentions: n2:6222104 n2:9734886 n2:10589018

Subject Item: _:vb51138865
rdf:type: n3:Context
rdf:value: Several studies suggested potential natural activators of FXII [>>9<<–13], but thus far none of these have been definitively established to induce activation of the contact system during angioedema in vivo.
n3:mentions: n2:18725990 n2:21349432 n2:20005807 n2:19372258 n2:20796202

Subject Item: _:vb51138866
rdf:type: n6:Section
dc:title: blood coagulation
n6:contains: _:vb51138876 _:vb51138877 _:vb51138878 _:vb51138879 _:vb51138872 _:vb51138873 _:vb51138874 _:vb51138875 _:vb51138868 _:vb51138869 _:vb51138870 _:vb51138871 _:vb51138867 _:vb51138884 _:vb51138885 _:vb51138886 _:vb51138880 _:vb51138881 _:vb51138882 _:vb51138883

Subject Item: _:vb51138867
rdf:type: n3:Context
rdf:value: Cells that surround the vessel wall express TF so that only when the endothelial layer is compromised will locally active coagulation take place [>>48<<, 49]. After binding to TF, activated factor VII (FVII) of the extrinsic pathway activates factor X (FX), and to a lesser extent factor IX (FIX) [50]. Activated FX next triggers the formation of a small amount of active factor II
n3:mentions: n2:19372318

Subject Item: _:vb51138868
rdf:type: n3:Context
rdf:value: Cells that surround the vessel wall express TF so that only when the endothelial layer is compromised will locally active coagulation take place [48, >>49<<]. After binding to TF, activated factor VII (FVII) of the extrinsic pathway activates factor X (FX), and to a lesser extent factor IX (FIX) [50]. Activated FX next triggers the formation of a small amount of active factor II (thrombin).
n3:mentions: n2:2237820

Subject Item: _:vb51138869
rdf:type: n3:Context
rdf:value: After binding to TF, activated factor VII (FVII) of the extrinsic pathway activates factor X (FX), and to a lesser extent factor IX (FIX) [>>50<<]. Activated FX next triggers the formation of a small amount of active factor II (thrombin). Thrombin accelerates coagulation via positive feedback mechanisms. Factor VIII (FVIII), activated by thrombin, forms a complex together with FIX
n3:mentions: n2:22652793

Subject Item: _:vb51138870
rdf:type: n3:Context
rdf:value: Furthermore, FXI of the intrinsic pathway is also activated by thrombin [>>51<<], and additional FIX is being amplified by thrombin activation.
n3:mentions: n2:20439754

Subject Item: _:vb51138871
rdf:type: n3:Context
rdf:value: The initiator of this cascade of events, TF, is of vital importance since TF deficiency is lethal and incompatible with normal embryonic development or may cause early death in the perinatal period [>>52<<].
n3:mentions: n2:8779717

Subject Item: _:vb51138872
rdf:type: n3:Context
rdf:value: Mysteriously, FXII deficiency is a seemingly asymptomatic condition in both mice and human (Hageman’s disease), as it is not associated with a bleeding tendency, unlike deficiencies of other coagulation factors [>>53<<]. The same holds for the other components of the contact system cascade; their deficiency does not result in bleeding [54].
n3:mentions: n2:14367514

Subject Item: _:vb51138873
rdf:type: n3:Context
rdf:value: The same holds for the other components of the contact system cascade; their deficiency does not result in bleeding [>>54<<]. This makes the relevance of FXII and the contact system for physiological hemostasis debatable. This logic raises a pertinent question: should FXII be regarded as a coagulation factor, as far as angioedema is concerned? It has been
n3:mentions: n2:12780784

Subject Item: _:vb51138874
rdf:type: n3:Context
rdf:value: It has been demonstrated that the bradykinin-producing contact system machinery can be fully activated in plasma without evidence of coagulation [>>10<<, 11, 55]. This might be explained by the physical properties of FXII(a): in a sequence of cleavage events, FXIIa is progressively fragmented. The fragment that remains after multiple cleavages (βFXIIa or FXIIf) has lost its potential for
n3:mentions: n2:21349432

Subject Item: _:vb51138875
rdf:type: n3:Context
rdf:value: It has been demonstrated that the bradykinin-producing contact system machinery can be fully activated in plasma without evidence of coagulation [10, >>11<<, 55]. This might be explained by the physical properties of FXII(a): in a sequence of cleavage events, FXIIa is progressively fragmented. The fragment that remains after multiple cleavages (βFXIIa or FXIIf) has lost its potential for
n3:mentions: n2:18725990

Subject Item: _:vb51138876
rdf:type: n3:Context
rdf:value: It has been demonstrated that the bradykinin-producing contact system machinery can be fully activated in plasma without evidence of coagulation [10, 11, >>55<<]. This might be explained by the physical properties of FXII(a): in a sequence of cleavage events, FXIIa is progressively fragmented. The fragment that remains after multiple cleavages (βFXIIa or FXIIf) has lost its potential for
n3:mentions: n2:23349032

Subject Item: _:vb51138877
rdf:type: n3:Context
rdf:value: Murine models of FXII deficiency indicate that the basal production of bradykinin in plasma is approximately 50 % dependent on FXII [>>56<<]. This suggests the presence of a second pathway generating bradykinin in vivo. Several alternative, FXII-independent routes for initiation of bradykinin generation have been identified. The endothelial cell-derived factors heat shock
n3:mentions: n2:16732380

Subject Item: _:vb51138878
rdf:type: n3:Context
rdf:value: The endothelial cell-derived factors heat shock protein 90 (HSP90) and prolylcarboxypeptidase may facilitate FXII-independent PPK activation on the endothelial cell surface [>>57<<]. Moreover, bradykinin can be directly released from HK by other enzymes than PK; this was recently demonstrated for Mannose Binding Serine Protease 1 [58]. The relevance of these FXII-independent pathways of bradykinin generation needs
n3:mentions: n2:23672780

Subject Item: _:vb51138879
rdf:type: n3:Context
rdf:value: Moreover, bradykinin can be directly released from HK by other enzymes than PK; this was recently demonstrated for Mannose Binding Serine Protease 1 [>>58<<]. The relevance of these FXII-independent pathways of bradykinin generation needs to be established. It is imaginable that during endothelial cell activation or damage, small amounts of PPK are activated by these mechanisms, which boost
n3:mentions: n2:21625439

Subject Item: _:vb51138880
rdf:type: n3:Context
rdf:value: described, (mostly) located in the proline-rich region of FXII (according to mature amino acid sequence: Thr309Arg, Thr309Lys, Ala324Pro, 72-bp deletion at c971_1018þ24 and an 18-bp duplication c894_911, and c1681-1G/A in intron 13) [>>16<<–20, 59]. Additionally, isolated cases of normal C1-INH with FXII mutation have been successfully treated with the bradykinin-receptor antagonist—icatibant.
n3:mentions: n2:26392288 n2:17186468 n2:21849258 n2:16638441 n2:25524745

Subject Item: _:vb51138881
rdf:type: n3:Context
rdf:value: (mostly) located in the proline-rich region of FXII (according to mature amino acid sequence: Thr309Arg, Thr309Lys, Ala324Pro, 72-bp deletion at c971_1018þ24 and an 18-bp duplication c894_911, and c1681-1G/A in intron 13) [16–20, >>59<<]. Additionally, isolated cases of normal C1-INH with FXII mutation have been successfully treated with the bradykinin-receptor antagonist—icatibant.
n3:mentions: n2:23994767

Subject Item: _:vb51138882
rdf:type: n3:Context
rdf:value: Plasmin, the central enzyme of the fibrinolytic system, cleaves the fibrin lattice into smaller fibrin degradation products (FDPs) including D-dimers, which are regarded as a valuable biomarker for thrombosis [>>60<<]. Plasmin is generated from its zymogenic precursor plasminogen by either tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA) [61]. Fibrin provides a platform for its own degradation by binding and potentiating
n3:mentions: n2:25934358

Subject Item: _:vb51138883
rdf:type: n3:Context
rdf:value: Plasmin is generated from its zymogenic precursor plasminogen by either tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA) [>>61<<]. Fibrin provides a platform for its own degradation by binding and potentiating both tPA and plasminogen. The fibrinolytic system is amenable to inhibition at several stages: plasmin is directly inhibited by α2-antiplasmin, while
n3:mentions: n2:15842654

Subject Item: _:vb51138884
rdf:type: n3:Context
rdf:value: The fibrinolytic system is amenable to inhibition at several stages: plasmin is directly inhibited by α2-antiplasmin, while specific inhibitors of plasminogen activators (PAI-1 and PAI-2) control tPA and uPA [>>61<<, 62]. Activation of plasminogen on the fibrin lattice is indirectly prevented by thrombin-activatable fibrinolysis inhibitor, via removal of C-terminal lysines that are needed for the binding of tPA and plasminogen to fibrin.
n3:mentions: n2:15842654

Subject Item: _:vb51138885
rdf:type: n3:Context
rdf:value: The fibrinolytic system is amenable to inhibition at several stages: plasmin is directly inhibited by α2-antiplasmin, while specific inhibitors of plasminogen activators (PAI-1 and PAI-2) control tPA and uPA [61, >>62<<]. Activation of plasminogen on the fibrin lattice is indirectly prevented by thrombin-activatable fibrinolysis inhibitor, via removal of C-terminal lysines that are needed for the binding of tPA and plasminogen to fibrin. Intriguingly,
n3:mentions: n2:23504606

Subject Item: _:vb51138886
rdf:type: n3:Context
rdf:value: Intriguingly, plasminogen activation on the endothelium can take place in the absence of fibrin when the uPA receptor is expressed [>>63<<]. This, amongst others, occurs during tissue injury and hypoxia and makes it attractive to speculate that plasmin may have additional functions beyond fibrinolysis.
n3:mentions: n2:1829461

Subject Item: _:vb51138887
rdf:type: n6:Section
dc:title: bradykinin-mediated angioedema
n6:contains: _:vb51138896 _:vb51138897 _:vb51138898 _:vb51138899 _:vb51138900 _:vb51138901 _:vb51138888 _:vb51138889 _:vb51138890 _:vb51138891 _:vb51138892 _:vb51138893 _:vb51138894 _:vb51138895

Subject Item: _:vb51138888
rdf:type: n3:Context
rdf:value: Most HAE patients have SERPING1 gene mutations (encoding for C1-inhibitor (C1-INH) production) [>>14<<, 15] while a small minority have mutations in the F12 gene, with normal C1-INH activity [16–20].
n3:mentions: n2:20889195

Subject Item: _:vb51138889
rdf:type: n3:Context
rdf:value: Most HAE patients have SERPING1 gene mutations (encoding for C1-inhibitor (C1-INH) production) [14, >>15<<] while a small minority have mutations in the F12 gene, with normal C1-INH activity [16–20].
n3:mentions: n2:18758157

Subject Item: _:vb51138890
rdf:type: n3:Context
rdf:value: Most HAE patients have SERPING1 gene mutations (encoding for C1-inhibitor (C1-INH) production) [14, 15] while a small minority have mutations in the F12 gene, with normal C1-INH activity [>>16<<–20].
n3:mentions: n2:26392288 n2:17186468 n2:21849258 n2:25524745 n2:16638441

Subject Item: _:vb51138891
rdf:type: n3:Context
rdf:value: Attacks can be life-threatening when swelling compromises the airways, and extremely painful when located in the intestine [>>21<<, 22]. Therapy targeting the contact system has been successful in HAE, strongly supporting the concept that angioedema is mediated via bradykinin production [23–25]. Evidence for bradykinin involvement in angioedema is not limited to HAE.
n3:mentions: n2:22305226

Subject Item: _:vb51138892
rdf:type: n3:Context
rdf:value: Attacks can be life-threatening when swelling compromises the airways, and extremely painful when located in the intestine [21, >>22<<]. Therapy targeting the contact system has been successful in HAE, strongly supporting the concept that angioedema is mediated via bradykinin production [23–25]. Evidence for bradykinin involvement in angioedema is not limited to HAE.
n3:mentions: n2:25527240

Subject Item: _:vb51138893
rdf:type: n3:Context
rdf:value: Therapy targeting the contact system has been successful in HAE, strongly supporting the concept that angioedema is mediated via bradykinin production [>>23<<–25]. Evidence for bradykinin involvement in angioedema is not limited to HAE. First, a comparable phenotype can be observed in patients that have acquired C1-INH deficiency due to underlying auto-immune or lymphoproliferative disease [26,
n3:mentions: n2:20818887 n2:20818888 n2:19264579

Subject Item: _:vb51138894
rdf:type: n3:Context
rdf:value: First, a comparable phenotype can be observed in patients that have acquired C1-INH deficiency due to underlying auto-immune or lymphoproliferative disease [>>26<<, 27]. Second, anti-hypertensive drugs that inhibit bradykinin breakdown, such as angiotensin-converting enzyme (ACE), dipeptidyl peptidase IV (DPPIV) or neprilysin (NEP), can induce angioedema. During clinical trials of NEP inhibitors
n3:mentions: n2:26068904

Subject Item: _:vb51138895
rdf:type: n3:Context
rdf:value: First, a comparable phenotype can be observed in patients that have acquired C1-INH deficiency due to underlying auto-immune or lymphoproliferative disease [26, >>27<<]. Second, anti-hypertensive drugs that inhibit bradykinin breakdown, such as angiotensin-converting enzyme (ACE), dipeptidyl peptidase IV (DPPIV) or neprilysin (NEP), can induce angioedema. During clinical trials of NEP inhibitors [28],
n3:mentions: n2:15047756

Subject Item: _:vb51138896
rdf:type: n3:Context
rdf:value: During clinical trials of NEP inhibitors [>>28<<], up to 2.17 % of patients and 0.2–0.65 % of patients prescribed ACE inhibitors developed angioedema [29, 30].
n3:mentions: n2:25176015

Subject Item: _:vb51138897
rdf:type: n3:Context
rdf:value: During clinical trials of NEP inhibitors [28], up to 2.17 % of patients and 0.2–0.65 % of patients prescribed ACE inhibitors developed angioedema [>>29<<, 30].
n3:mentions: n2:18413488

Subject Item: _:vb51138898
rdf:type: n3:Context
rdf:value: During clinical trials of NEP inhibitors [28], up to 2.17 % of patients and 0.2–0.65 % of patients prescribed ACE inhibitors developed angioedema [29, >>30<<].
n3:mentions: n2:16043683

Subject Item: _:vb51138899
rdf:type: n3:Context
rdf:value: Evidently, contact activation is closely linked to the coagulation system [>>31<<–33]. Activation of coagulation and fibrinolysis during HAE attacks has been repeatedly reported [34–47].
n3:mentions: n2:10469157 n2:1833421

Subject Item: _:vb51138900
rdf:type: n3:Context
rdf:value: Activation of coagulation and fibrinolysis during HAE attacks has been repeatedly reported [>>34<<–47]. Yet, HAE patients present with swellings but not with thrombotic tendency [37]. Combined genetic and clinical findings suggest that a subset of coagulation factors are actively involved in angioedema attacks.
n3:mentions: n2:25640891 n2:22171564 n2:7172497 n2:19474702 n2:3146615 n2:20143645 n2:8711433 n2:25952149 n2:26452350 n2:9129025 n2:22288590 n2:8426080 n2:8426075

Subject Item: _:vb51138901
rdf:type: n3:Context
rdf:value: Yet, HAE patients present with swellings but not with thrombotic tendency [>>37<<]. Combined genetic and clinical findings suggest that a subset of coagulation factors are actively involved in angioedema attacks.
n3:mentions: n2:25640891

Subject Item: _:vb51138902
rdf:type: n6:Section
dc:title: a functional link between plasminogen activation and contact system activation
n6:contains: _:vb51138920 _:vb51138921 _:vb51138922 _:vb51138923 _:vb51138916 _:vb51138917 _:vb51138918 _:vb51138919 _:vb51138912 _:vb51138913 _:vb51138914 _:vb51138915 _:vb51138908 _:vb51138909 _:vb51138910 _:vb51138911 _:vb51138904 _:vb51138905 _:vb51138906 _:vb51138907 _:vb51138903

Subject Item: _:vb51138903
rdf:type: n3:Context
rdf:value: Besides that, FXII is also capable of activation of plasminogen [>>33<<, 64, 65]. Compared to tPA and uPA, FXIIa is a relatively weak plasminogen activator.
n3:mentions: n2:10469157

Subject Item: _:vb51138904
rdf:type: n3:Context
rdf:value: Besides that, FXII is also capable of activation of plasminogen [33, >>64<<, 65]. Compared to tPA and uPA, FXIIa is a relatively weak plasminogen activator.
n3:mentions: n2:659637

Subject Item: _:vb51138905
rdf:type: n3:Context
rdf:value: Besides that, FXII is also capable of activation of plasminogen [33, 64, >>65<<]. Compared to tPA and uPA, FXIIa is a relatively weak plasminogen activator.
n3:mentions: n2:8585009

Subject Item: _:vb51138906
rdf:type: n3:Context
rdf:value: However, population studies have proposed that FXIIa may protect against cardiovascular disease via plasminogen activation [>>66<<, 67]. This may be attributable to additional interactions between the contact system and the fibrinolytic system: FXIIa can enzymatically inactivate PAI-1 [68], whereas PK stimulates uPA activation on the endothelium [65].
n3:mentions: n2:8325306

Subject Item: _:vb51138907
rdf:type: n3:Context
rdf:value: However, population studies have proposed that FXIIa may protect against cardiovascular disease via plasminogen activation [66, >>67<<]. This may be attributable to additional interactions between the contact system and the fibrinolytic system: FXIIa can enzymatically inactivate PAI-1 [68], whereas PK stimulates uPA activation on the endothelium [65].
n3:mentions: n2:17723129

Subject Item: _:vb51138908
rdf:type: n3:Context
rdf:value: This may be attributable to additional interactions between the contact system and the fibrinolytic system: FXIIa can enzymatically inactivate PAI-1 [>>68<<], whereas PK stimulates uPA activation on the endothelium [65].
n3:mentions: n2:19500599

Subject Item: _:vb51138909
rdf:type: n3:Context
rdf:value: This may be attributable to additional interactions between the contact system and the fibrinolytic system: FXIIa can enzymatically inactivate PAI-1 [68], whereas PK stimulates uPA activation on the endothelium [>>65<<].
n3:mentions: n2:8585009

Subject Item: _:vb51138910
rdf:type: n3:Context
rdf:value: It has been demonstrated that plasmin can induce FXII activation in vitro [>>69<<]. In line with this finding, patients with myocardial infarction treated with therapeutic plasminogen-activating agents, such as streptokinase or recombinant tPA (r-tPA), showed increased plasma levels of cleaved HK (a surrogate marker
n3:mentions: n2:7805216

Subject Item: _:vb51138911
rdf:type: n3:Context
rdf:value: patients with myocardial infarction treated with therapeutic plasminogen-activating agents, such as streptokinase or recombinant tPA (r-tPA), showed increased plasma levels of cleaved HK (a surrogate marker for bradykinin release) [>>69<<] and elevated plasma levels of FXIIa [70]. Other clinical observations also support the importance of plasmin as a natural FXII activator.
n3:mentions: n2:7805216

Subject Item: _:vb51138912
rdf:type: n3:Context
rdf:value: treated with therapeutic plasminogen-activating agents, such as streptokinase or recombinant tPA (r-tPA), showed increased plasma levels of cleaved HK (a surrogate marker for bradykinin release) [69] and elevated plasma levels of FXIIa [>>70<<]. Other clinical observations also support the importance of plasmin as a natural FXII activator.
n3:mentions: n2:17111198

Subject Item: _:vb51138913
rdf:type: n3:Context
rdf:value: Neurologists repeatedly reported angioedema, which is presumably mediated via bradykinin, as a side effect of plasminogen activators given to patients with ischaemic stroke [>>71<<–82]. Up to 8 % of stroke patients receiving r-tPA develop angioedema, often located in the oral cavity and lingual region and contralateral to the infarction site [83]. Similar observations were made with other thrombolytic agents [84–86].
n3:mentions: n2:25802571 n2:24350070 n2:22791493 n2:22399862 n2:25053461 n2:24247033 n2:25434502 n2:25671036 n2:24909847 n2:24974191 n2:24620962 n2:25440357

Subject Item: _:vb51138914
rdf:type: n3:Context
rdf:value: Up to 8 % of stroke patients receiving r-tPA develop angioedema, often located in the oral cavity and lingual region and contralateral to the infarction site [>>83<<]. Similar observations were made with other thrombolytic agents [84–86]. A study with 42 post-r-tPA angioedema cases reported that five patients required emergency intubation or cricothyroidotomy due to laryngeal swelling, with fatal
n3:mentions: n2:25016564

Subject Item: _:vb51138915
rdf:type: n3:Context
rdf:value: Similar observations were made with other thrombolytic agents [>>84<<–86]. A study with 42 post-r-tPA angioedema cases reported that five patients required emergency intubation or cricothyroidotomy due to laryngeal swelling, with fatal outcome in two cases.
n3:mentions: n2:16113853 n2:7937456

Subject Item: _:vb51138916
rdf:type: n3:Context
rdf:value: Notably, concurrent use of ACE inhibitors is also reported in patients who developed angioedema during r-tPA treatment [>>78<<, 79, 83]. Evidence for plasmin-dependent bradykinin generation as a cause of angioedema during treatment with fibrinolytic agents is accumulating. However, the majority of these adverse reactions are still treated as a histamine-driven
n3:mentions: n2:24909847

Subject Item: _:vb51138917
rdf:type: n3:Context
rdf:value: Notably, concurrent use of ACE inhibitors is also reported in patients who developed angioedema during r-tPA treatment [78, >>79<<, 83]. Evidence for plasmin-dependent bradykinin generation as a cause of angioedema during treatment with fibrinolytic agents is accumulating. However, the majority of these adverse reactions are still treated as a histamine-driven
n3:mentions: n2:24620962

Subject Item: _:vb51138918
rdf:type: n3:Context
rdf:value: Notably, concurrent use of ACE inhibitors is also reported in patients who developed angioedema during r-tPA treatment [78, 79, >>83<<]. Evidence for plasmin-dependent bradykinin generation as a cause of angioedema during treatment with fibrinolytic agents is accumulating. However, the majority of these adverse reactions are still treated as a histamine-driven
n3:mentions: n2:25016564

Subject Item: _:vb51138919
rdf:type: n3:Context
rdf:value: This is in good correspondence with the normal clotting times that were reported in FXII-HAE patients [>>18<<]. These patients’ plasma also did not become unusually active upon cleavage by plasma kallikrein. Detailed biochemical studies showed that these mutations introduce new cleavage sites in the FXII molecule. The mutated sites are
n3:mentions: n2:21849258

Subject Item: _:vb51138920
rdf:type: n3:Context
rdf:value: Anti-fibrinolytic therapy, mainly tranexamic acid, has been used as prophylactic therapy for HAE attacks since the 1970s [>>4<<, 88, 89]. Tranexamic acid is a lysine derivate (analogue) that binds to lysine-binding sites of plasminogen and thereby prevents its binding to fibrin and subsequent activation by tPA or uPA [90]. Moreover, HAE patients with normal C1-INH
n3:mentions: n2:25196353

Subject Item: _:vb51138921
rdf:type: n3:Context
rdf:value: Anti-fibrinolytic therapy, mainly tranexamic acid, has been used as prophylactic therapy for HAE attacks since the 1970s [4, >>88<<, 89]. Tranexamic acid is a lysine derivate (analogue) that binds to lysine-binding sites of plasminogen and thereby prevents its binding to fibrin and subsequent activation by tPA or uPA [90]. Moreover, HAE patients with normal C1-INH
n3:mentions: n2:4551861

Subject Item: _:vb51138922
rdf:type: n3:Context
rdf:value: Anti-fibrinolytic therapy, mainly tranexamic acid, has been used as prophylactic therapy for HAE attacks since the 1970s [4, 88, >>89<<]. Tranexamic acid is a lysine derivate (analogue) that binds to lysine-binding sites of plasminogen and thereby prevents its binding to fibrin and subsequent activation by tPA or uPA [90]. Moreover, HAE patients with normal C1-INH levels
n3:mentions: n2:4562897

Subject Item: _:vb51138923
rdf:type: n3:Context
rdf:value: Tranexamic acid is a lysine derivate (analogue) that binds to lysine-binding sites of plasminogen and thereby prevents its binding to fibrin and subsequent activation by tPA or uPA [>>90<<]. Moreover, HAE patients with normal C1-INH levels (i.e. FXII-HAE) have decreased levels of PAI-2 during remission compared to patients with HAE due to C1-INH deficiency [36]. This suggests that their angioedema episodes might have
n3:mentions: n2:25559460

Subject Item: _:vb51138924
rdf:type: n6:Section
dc:title: biomarkers of contact activation, fibrinolytic activity and coagulation in angioedema
n6:contains: _:vb51138932 _:vb51138933 _:vb51138934 _:vb51138935 _:vb51138928 _:vb51138929 _:vb51138930 _:vb51138931 _:vb51138940 _:vb51138941 _:vb51138942 _:vb51138943 _:vb51138936 _:vb51138937 _:vb51138938 _:vb51138939 _:vb51138925 _:vb51138926 _:vb51138927 _:vb51138944 _:vb51138945 _:vb51138946

Subject Item: _:vb51138925
rdf:type: n3:Context
rdf:value: Bradykinin is only present in the circulation for a few seconds after it is released from HK, due to rapid degradation by kininases [>>91<<] which complicates its detection.
n3:mentions: n2:10871321

Subject Item: _:vb51138926
rdf:type: n3:Context
rdf:value: Circulating cleaved HK seems to be among the most suitable biomarkers for contact activation since cleaved HK levels have been shown to correlate with attack frequency [>>92<<]. Currently, cleaved HK can be detected by immunoblotting [92]. This assay often shows profound cleavage of HK in citrated plasma from patients with C1-INH deficiency.
n3:mentions: n2:24552232

Subject Item: _:vb51138927
rdf:type: n3:Context
rdf:value: Currently, cleaved HK can be detected by immunoblotting [>>92<<]. This assay often shows profound cleavage of HK in citrated plasma from patients with C1-INH deficiency.
n3:mentions: n2:24552232

Subject Item: _:vb51138928
rdf:type: n3:Context
rdf:value: There is a large base of evidence that contact activation during angioedema attacks is accompanied by changes in the fibrinolytic and coagulation systems that could serve as disease biomarkers [>>34<<–47, 93–95].
n3:mentions: n2:22171564 n2:25640891 n2:7172497 n2:3146615 n2:19474702 n2:20143645 n2:25952149 n2:26452350 n2:9129025 n2:22288590 n2:8711433 n2:8426080 n2:8426075

Subject Item: _:vb51138929
rdf:type: n3:Context
rdf:value: There is a large base of evidence that contact activation during angioedema attacks is accompanied by changes in the fibrinolytic and coagulation systems that could serve as disease biomarkers [34–47, >>93<<–95]. The understanding that the contact system and fibrinolytic system are functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP)
n3:mentions: n2:2935973 n2:6517610 n2:19076541

Subject Item: _:vb51138930
rdf:type: n3:Context
rdf:value: system are functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [>>34<<–36, 39, 40, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema.
n3:mentions: n2:25952149 n2:26452350

Subject Item: _:vb51138931
rdf:type: n3:Context
rdf:value: are functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34–36, >>39<<, 40, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema.
n3:mentions: n2:22288590

Subject Item: _:vb51138932
rdf:type: n3:Context
rdf:value: functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34–36, 39, >>40<<, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema.
n3:mentions: n2:22171564

Subject Item: _:vb51138933
rdf:type: n3:Context
rdf:value: linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34–36, 39, 40, >>43<<, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema.
n3:mentions: n2:8711433

Subject Item: _:vb51138934
rdf:type: n3:Context
rdf:value: linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor α2-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34–36, 39, 40, 43, >>44<<]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema.
n3:mentions: n2:8426080

Subject Item: _:vb51138935
rdf:type: n3:Context
rdf:value: D-dimer levels are elevated during remission periods and markedly increase during attacks [>>34<<, 37, 39, 40, 93].
n3:mentions: n2:26452350

Subject Item: _:vb51138936
rdf:type: n3:Context
rdf:value: D-dimer levels are elevated during remission periods and markedly increase during attacks [34, >>37<<, 39, 40, 93].
n3:mentions: n2:25640891

Subject Item: _:vb51138937
rdf:type: n3:Context
rdf:value: D-dimer levels are elevated during remission periods and markedly increase during attacks [34, 37, >>39<<, 40, 93]. Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, 43, 93].
n3:mentions: n2:22288590

Subject Item: _:vb51138938
rdf:type: n3:Context
rdf:value: D-dimer levels are elevated during remission periods and markedly increase during attacks [34, 37, 39, >>40<<, 93]. Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, 43, 93].
n3:mentions: n2:22171564

Subject Item: _:vb51138939
rdf:type: n3:Context
rdf:value: D-dimer levels are elevated during remission periods and markedly increase during attacks [34, 37, 39, 40, >>93<<]. Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, 43, 93].
n3:mentions: n2:19076541

Subject Item: _:vb51138940
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [>>34<<, 39, 40, 42, 43, 93].
n3:mentions: n2:26452350

Subject Item: _:vb51138941
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, >>39<<, 40, 42, 43, 93].
n3:mentions: n2:22288590

Subject Item: _:vb51138942
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, >>40<<, 42, 43, 93].
n3:mentions: n2:22171564

Subject Item: _:vb51138943
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, >>42<<, 43, 93].
n3:mentions: n2:9129025

Subject Item: _:vb51138944
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, >>43<<, 93].
n3:mentions: n2:8711433

Subject Item: _:vb51138945
rdf:type: n3:Context
rdf:value: Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, 43, >>93<<].
n3:mentions: n2:19076541

Subject Item: _:vb51138946
rdf:type: n3:Context
rdf:value: Evidence for extrinsic pathway coagulation was demonstrated by a significant increase of FVIIa during angioedema attacks in 14 patients, by Cugno et al. [>>42<<]. It would be attractive to hypothesize that increased coagulation parameters in HAE are secondary to massive vascular leakage (Fig. 2). Even though biomarkers for coagulation, such as D-dimer, will not directly reflect bradykinin
n3:mentions: n2:9129025

Subject Item: _:vb51138947
rdf:type: n6:Section
dc:title: neutrophil activation and contact system activation are functionally linked
n6:contains: _:vb51138952 _:vb51138953 _:vb51138954 _:vb51138955 _:vb51138948 _:vb51138949 _:vb51138950 _:vb51138951

Subject Item: _:vb51138948
rdf:type: n3:Context
rdf:value: Recent work shows that HAE attacks are associated with increasing neutrophil counts and neutrophil elastase levels [>>96<<]. Neutrophils are important cells for the innate immunity. They migrate out of the bloodstream within hours after a pathogen is detected.
n3:mentions: n2:26654922

Subject Item: _:vb51138949
rdf:type: n3:Context
rdf:value: Migration of neutrophils to sites of inflammation is orchestrated by several mechanisms, such as chemotaxis by interleukins and complement factors and interaction of neutrophils with endothelial cell receptors [>>97<<]. It can be envisioned that neutrophils interact with the contact system to boost neutrophil extravasation by bradykinin-mediated vasodilatation. First of all, neutrophil elastase, released by active neutrophils, inactivates C1-INH
n3:mentions: n2:24940954

Subject Item: _:vb51138950
rdf:type: n3:Context
rdf:value: First of all, neutrophil elastase, released by active neutrophils, inactivates C1-INH thereby allowing contact activation to take place [>>98<<]. Second, in vitro studies show that the bradykinin B1 receptor (BKB1R) regulates neutrophil trafficking [99, 100]. Third, both kallikrein and FXIIa can induce neutrophil degranulation [101]. Finally, neutrophil extracellular traps (NETs)
n3:mentions: n2:6980881

Subject Item: _:vb51138951
rdf:type: n3:Context
rdf:value: Second, in vitro studies show that the bradykinin B1 receptor (BKB1R) regulates neutrophil trafficking [>>99<<, 100]. Third, both kallikrein and FXIIa can induce neutrophil degranulation [101]. Finally, neutrophil extracellular traps (NETs) have been shown to activate FXII. NETs exist of DNA, and the negative charge of DNA is believed to induce
n3:mentions: n2:14742641

Subject Item: _:vb51138952
rdf:type: n3:Context
rdf:value: Second, in vitro studies show that the bradykinin B1 receptor (BKB1R) regulates neutrophil trafficking [99, >>100<<]. Third, both kallikrein and FXIIa can induce neutrophil degranulation [101]. Finally, neutrophil extracellular traps (NETs) have been shown to activate FXII. NETs exist of DNA, and the negative charge of DNA is believed to induce
n3:mentions: n2:11258678

Subject Item: _:vb51138953
rdf:type: n3:Context
rdf:value: Third, both kallikrein and FXIIa can induce neutrophil degranulation [>>101<<]. Finally, neutrophil extracellular traps (NETs) have been shown to activate FXII.
n3:mentions: n2:3486686

Subject Item: _:vb51138954
rdf:type: n3:Context
rdf:value: NETs exist of DNA, and the negative charge of DNA is believed to induce auto-activation of FXII [>>102<<]. At the very least, NETs can sequester FXII and present it for activating cleavage. NETs are a binding site for antimicrobial proteins such as histones, neutrophil elastase and cathepsins [99]. To what extent the proteins loaded on NETs
n3:mentions: n2:20375580

Subject Item: _:vb51138955
rdf:type: n3:Context
rdf:value: NETs are a binding site for antimicrobial proteins such as histones, neutrophil elastase and cathepsins [>>99<<]. To what extent the proteins loaded on NETs contribute to neutrophil-induced FXII activation is not yet elucidated. The negative charge of NETs, in combination with potential FXII-activating enzymes, would make neutrophils a plausible
n3:mentions: n2:14742641

Subject Item: _:vb51138956
rdf:type: n6:Section
dc:title: mast cell activation is linked to bradykinin generation
n6:contains: _:vb51138964 _:vb51138965 _:vb51138966 _:vb51138967 _:vb51138960 _:vb51138961 _:vb51138962 _:vb51138963 _:vb51138968 _:vb51138969 _:vb51138957 _:vb51138958 _:vb51138959

Subject Item: _:vb51138957
rdf:type: n3:Context
rdf:value: Indeed, anti-histamine therapy reduces the occurrence of angioedema in urticaria patients [>>2<<]. It should be noted that plasma bradykinin levels were not found elevated in four patients with an acute attack of anti-histamine-sensitive angioedema [103]. Yet, evidence accumulates that angioedema in allergic reactions is also
n3:mentions: n2:24785199

Subject Item: _:vb51138958
rdf:type: n3:Context
rdf:value: It should be noted that plasma bradykinin levels were not found elevated in four patients with an acute attack of anti-histamine-sensitive angioedema [>>103<<]. Yet, evidence accumulates that angioedema in allergic reactions is also accompanied by bradykinin release. FXIIa-C1-INH complexes and kallikrein-C1-INH complexes were increased up to tenfold, within minutes after experimental insect
n3:mentions: n2:12192030

Subject Item: _:vb51138959
rdf:type: n3:Context
rdf:value: FXIIa-C1-INH complexes and kallikrein-C1-INH complexes were increased up to tenfold, within minutes after experimental insect stings in six allergic patients who developed shock or angioedema [>>1<<]. In contrast, patients who only developed urticarial rash in reaction to the venom showed a non-significant increase in C1-INH complexes. In line with these results, it was shown that in the patients with angioedema or shock, a third up
n3:mentions: n2:8400230

Subject Item: _:vb51138960
rdf:type: n3:Context
rdf:value: In line with these results, it was shown that in the patients with angioedema or shock, a third up to half of the total pool of plasma HK was cleaved within minutes [>>1<<]. These results were confirmed in another study where HK was analysed in patients with an anaphylactic reaction (mainly induced by food allergens) [104]. In this study, even patients with a mild reaction (i.e. gastro-intestinal
n3:mentions: n2:8400230

Subject Item: _:vb51138961
rdf:type: n3:Context
rdf:value: These results were confirmed in another study where HK was analysed in patients with an anaphylactic reaction (mainly induced by food allergens) [>>104<<]. In this study, even patients with a mild reaction (i.e. gastro-intestinal complaints) showed 60 % cleavage of their HK pool. Evidence of the clinical relevance of bradykinin during anaphylaxis with hypotension was further demonstrated
n3:mentions: n2:25240785

Subject Item: _:vb51138962
rdf:type: n3:Context
rdf:value: Hypotension after IgE-mediated, antigen-induced anaphylaxis was reduced in FXII-deficient mice compared to wild-type mice [>>104<<]. The same protection toward IgE-mediated hypotension was reported in BKB2R knockout mice and HK- and PPK-deficient mice [105]. Although direct release of bradykinin from HK by tryptase could also contribute to these findings, it would be
n3:mentions: n2:25240785

Subject Item: _:vb51138963
rdf:type: n3:Context
rdf:value: The same protection toward IgE-mediated hypotension was reported in BKB2R knockout mice and HK- and PPK-deficient mice [>>105<<]. Although direct release of bradykinin from HK by tryptase could also contribute to these findings, it would be reasonable to propose that bradykinin production during anaphylaxis is for a major part FXII-driven.
n3:mentions: n2:3282517

Subject Item: _:vb51138964
rdf:type: n3:Context
rdf:value: Moreover, mast cell degranulation may trigger FXII activation via the release of heparin, which activates FXII in vitro and induces FXII-dependent hypotension in mice models [>>10<<]. Heparin-induced vascular leakage in mice was diminished by BKB2R antagonist (icatibant) and exaggerated in C1-INH-deficient mice [10].
n3:mentions: n2:21349432

Subject Item: _:vb51138965
rdf:type: n3:Context
rdf:value: Heparin-induced vascular leakage in mice was diminished by BKB2R antagonist (icatibant) and exaggerated in C1-INH-deficient mice [>>10<<]. Heparin is a negatively charged compound, capable of inducing FXII auto-activation. However, like the NETs of neutrophils, heparin binds a large variety of proteins [106]. Contrary to this, a study of 14 HAE patients showed that
n3:mentions: n2:21349432

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rdf:value: However, like the NETs of neutrophils, heparin binds a large variety of proteins [>>106<<]. Contrary to this, a study of 14 HAE patients showed that tryptase levels do not increase during HAE attacks [107]. It might be helpful to keep in mind that in HAE patients that also suffer from allergies, attacks may be aggravated by an
n3:mentions: n2:26289657

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rdf:value: Current studies were unable so far to demonstrate bradykinin or an increased HK cleaving in such patients [>>103<<, 104, 108].
n3:mentions: n2:12192030

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rdf:value: Current studies were unable so far to demonstrate bradykinin or an increased HK cleaving in such patients [103, >>104<<, 108]. Considering the strong evidence of interaction between mast cells and bradykinin production, patients with idiopathic angioedema and recurrent swellings who fail to respond to high-dose anti-histamine treatment might benefit from
n3:mentions: n2:25240785

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rdf:value: Current studies were unable so far to demonstrate bradykinin or an increased HK cleaving in such patients [103, 104, >>108<<]. Considering the strong evidence of interaction between mast cells and bradykinin production, patients with idiopathic angioedema and recurrent swellings who fail to respond to high-dose anti-histamine treatment might benefit from
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