_:b604479553 . _:b604479554 . . . _:b51138943 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, >>42<<, 43, 93]." . _:b604479470 "3"^^ . _:b604479555 . _:b604479564 . _:b604479565 . _:b604479566 . _:b604479567 . _:b604479465 "3"^^ . . _:b604479560 . _:b604479561 . _:b604479562 . _:b604479563 . _:b604479464 "3"^^ . _:b604479572 . _:b604479573 . _:b604479574 . _:b604479575 . _:b604479467 "3"^^ . _:b604479568 . _:b604479569 . _:b604479570 . _:b604479571 . _:b604479466 "3"^^ . _:b604479580 . _:b51138880 . _:b604479581 . _:b604479582 . _:b604479477 "2"^^ . _:b604479583 . _:b604479576 . _:b604479577 . _:b604479578 . _:b604479476 "2"^^ . _:b604479579 . _:b604479524 . _:b604479525 . _:b604479526 . _:b604479479 "2"^^ . _:b604479527 . _:b604479520 . _:b604479521 . _:b604479522 . _:b604479478 "2"^^ . _:b604479523 . _:b604479532 . _:b604479533 . _:b604479534 . _:b604479473 "2"^^ . _:b604479535 . _:b604479492 . _:b604479528 . _:b604479529 . _:b604479530 . _:b604479472 "2"^^ . _:b604479531 . _:b51138940 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [>>34<<, 39, 40, 42, 43, 93]." . _:b604479540 . _:b51138890 . _:b604479541 . _:b604479542 . _:b604479475 "2"^^ . _:b604479543 . _:b604479536 . _:b604479537 . . _:b51138875 . _:b604479474 "2"^^ . _:b604479538 . _:b604479539 . . _:b604479548 . _:b51138885 "The fibrinolytic system is amenable to inhibition at several stages: plasmin is directly inhibited by \u03B12-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," . _:b604479549 . _:b604479550 . _:b604479485 "2"^^ . . _:b604479551 . _:b604479544 . . _:b604479545 . _:b604479443 . _:b604479484 "2"^^ . _:b604479546 . _:b604479547 . _:b604479492 . _:b604479493 . . _:b604479487 "2"^^ . _:b604479494 . _:b51138908 . _:b604479495 . . . _:b604479562 . _:b604479488 . _:b604479573 . _:b604479489 . _:b604479490 . _:b604479486 "2"^^ . _:b604479491 . _:b604479556 . _:b604479500 . _:b604479501 . _:b604479502 . _:b604479481 "2"^^ . _:b604479503 . . _:b604479496 . _:b604479497 . _:b51138865 . _:b604479480 "2"^^ . _:b604479498 . _:b604479499 . . _:b604479508 . _:b604479509 . _:b604479519 . _:b604479483 "2"^^ . _:b604479510 . _:b604479511 . _:b604479504 . _:b604479505 . _:b604479506 . _:b604479482 "2"^^ . _:b604479507 . _:b604479516 . _:b51138891 "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\u201325]. Evidence for bradykinin involvement in angioedema is not limited to HAE." . . _:b604479517 . _:b604479518 . _:b604479519 . _:b604479512 . _:b51138939 "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]." . _:b604479513 . _:b604479514 . _:b51138879 . _:b604479515 . . . . . _:b51138928 . _:b604479469 . . _:b51138863 . . . _:b51138877 "Murine models of FXII deficiency indicate that the basal production of bradykinin in plasma is approximately 50\u00A0% 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" . _:b51138913 . _:b51138932 . _:b604479493 . . . _:b51138938 . _:b51138901 . _:b604479553 . _:b51138911 . _:b51138900 . _:b604479507 . _:b51138910 . _:b51138942 . . . _:b51138882 "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" . _:b604479452 . . _:b604479589 . _:b51138886 . _:b51138945 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, 43, >>93<<]." . _:b51138946 . . _:b604479484 . . _:b604479474 . . . _:b604479545 . . _:b51138899 . _:b51138900 . . _:b51138903 . _:b604479450 . _:b604479427 . _:b51138936 . . _:b51138941 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, >>39<<, 40, 42, 43, 93]." . . _:b51138880 . _:b51138956 "mast cell activation is linked to bradykinin generation" . . . _:b51138867 "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" . _:b604479587 . _:b604479548 . _:b51138966 . . _:b51138928 . _:b51138965 . _:b51138890 . _:b51138964 . _:b51138905 . _:b604479542 . _:b604479445 . _:b51138889 "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\u201320]." . _:b51138909 . . _:b51138929 . _:b51138872 . . . . . _:b604479567 . . _:b51138914 "Up to 8\u00A0% 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\u201386]. A study with 42 post-r-tPA angioedema cases reported that five patients required emergency intubation or cricothyroidotomy due to laryngeal swelling, with fatal" . _:b51138925 "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." . . _:b604479569 . . _:b604479501 . "PMC0" . _:b51138957 . _:b51138860 . _:b604479473 . _:b51138861 . _:b51138866 "blood coagulation" . _:b51138862 . _:b604479493 . . . . _:b51138863 . _:b604479492 . . _:b604479495 . _:b51138857 . _:b604479494 . _:b51138882 . _:b51138858 . _:b51138883 . _:b604479489 . _:b51138859 . _:b604479488 . . _:b51138868 . _:b604479491 . . _:b51138869 . _:b604479490 . _:b51138870 . _:b604479501 . _:b51138928 . _:b51138884 . _:b51138871 . _:b604479500 . _:b51138915 . _:b51138864 . _:b604479503 . _:b51138865 . . _:b604479502 . _:b51138866 . _:b604479523 . _:b604479497 . "10.1007%2Fs12016-016-8540-0" . _:b51138867 . _:b604479496 . _:b51138876 . . _:b604479499 . _:b51138877 . _:b604479534 . . _:b604479498 . _:b51138878 . _:b604479509 . _:b51138879 . _:b604479508 . _:b51138872 . _:b604479487 . _:b604479511 . _:b604479430 . . _:b51138873 . _:b604479510 . _:b51138874 . _:b604479505 . _:b604479462 . _:b51138875 . . _:b604479504 . _:b51138884 . _:b51138878 . _:b604479507 . _:b51138885 . _:b604479506 . _:b51138886 . . _:b604479517 . _:b51138887 . _:b604479516 . _:b51138880 . _:b604479519 . . _:b51138881 . _:b604479518 . _:b51138870 "Furthermore, FXI of the intrinsic pathway is also activated by thrombin [>>51<<], and additional FIX is being amplified by thrombin activation." . _:b51138882 . _:b604479513 . _:b51138883 . . . _:b604479512 . _:b51138892 . _:b604479515 . _:b51138893 . _:b604479514 . . _:b51138894 . _:b604479479 . . _:b604479525 . _:b51138895 . _:b604479524 . _:b51138886 "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." . _:b604479584 . _:b51138888 . _:b604479527 . _:b51138889 . _:b604479526 . _:b51138890 . _:b51138900 . _:b604479521 . . _:b51138891 . _:b604479520 . _:b51138900 . _:b604479544 . _:b604479523 . _:b51138910 "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" . _:b51138901 . _:b604479522 . _:b51138894 "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" . . _:b51138946 "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.\u00A02). Even though biomarkers for coagulation, such as D-dimer, will not directly reflect bradykinin" . _:b51138902 . _:b604479533 . _:b51138903 . _:b604479532 . . _:b51138896 . _:b604479535 . . _:b51138897 . _:b51138888 . _:b604479534 . _:b604479448 . _:b51138898 . _:b604479465 . _:b604479529 . _:b51138899 . _:b604479528 . _:b51138909 "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<<]." . _:b51138908 . _:b604479531 . _:b51138909 . _:b604479530 . _:b51138910 . _:b604479541 . _:b51138911 . _:b604479540 . _:b51138877 . _:b51138904 . _:b51138917 "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" . _:b604479543 . _:b51138874 "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 (\u03B2FXIIa or FXIIf) has lost its potential for" . _:b51138905 . _:b51138913 . _:b604479542 . . _:b604479506 . _:b51138906 . _:b604479537 . _:b51138915 "Similar observations were made with other thrombolytic agents [>>84<<\u201386]. 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." . _:b51138907 . _:b604479486 . _:b604479536 . _:b51138916 . _:b604479539 . _:b51138864 . _:b51138917 . _:b604479538 . _:b51138903 "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." . _:b51138918 . _:b604479549 . _:b51138919 . . _:b604479548 . _:b51138912 . . _:b604479551 . _:b51138913 . _:b604479533 . . _:b604479550 . _:b51138914 . . _:b604479545 . _:b51138915 . . _:b604479544 . _:b604479471 . _:b51138924 . _:b604479547 . _:b51138925 . _:b604479546 . _:b51138926 . _:b604479557 . _:b51138927 . _:b604479556 . _:b51138920 . _:b604479559 . _:b604479552 . _:b51138921 . _:b51138933 "linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor \u03B12-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34\u201336, 39, 40, >>43<<, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema." . _:b604479558 . _:b51138922 . _:b604479553 . _:b51138923 . _:b604479552 . . _:b51138932 . _:b604479555 . _:b51138933 . _:b604479554 . . _:b51138932 "functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor \u03B12-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34\u201336, 39, >>40<<, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema." . _:b51138934 . _:b604479518 . _:b604479565 . _:b51138935 . _:b604479564 . _:b604479515 . _:b51138928 . _:b51138879 "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" . . _:b604479567 . _:b51138929 . _:b604479566 . _:b51138930 . _:b604479561 . _:b51138928 "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<<\u201347, 93\u201395]." . _:b51138931 . . _:b604479560 . _:b51138940 . _:b604479563 . . _:b51138941 . _:b51138913 . . _:b604479562 . _:b51138942 . _:b604479573 . _:b51138943 . _:b604479447 . _:b604479572 . _:b51138936 . _:b604479575 . _:b51138937 . _:b51138956 _:b51138964 . _:b51138967 "Current studies were unable so far to demonstrate bradykinin or an increased HK cleaving in such patients [>>103<<, 104, 108]." . _:b604479574 . _:b51138956 _:b51138965 . _:b51138938 . _:b51138956 _:b51138966 . _:b51138956 _:b51138967 . _:b51138956 _:b51138960 . _:b604479569 . _:b51138956 _:b51138961 . _:b51138913 . _:b51138939 . _:b51138956 _:b51138962 . _:b51138956 _:b51138963 . . _:b604479568 . _:b51138948 . _:b51138956 _:b51138968 . _:b604479571 . _:b51138956 _:b51138969 . _:b51138967 . _:b51138949 . . . _:b51138919 "This is in good correspondence with the normal clotting times that were reported in FXII-HAE patients [>>18<<]. These patients\u2019 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" . _:b604479570 . _:b51138950 . _:b604479581 . _:b51138951 . _:b604479580 . _:b51138956 _:b51138957 . _:b51138944 . _:b51138956 _:b51138958 . _:b51138956 _:b51138959 . _:b604479583 . _:b51138880 "described, (mostly) located in the proline-rich region of FXII (according to mature amino acid sequence: Thr309Arg, Thr309Lys, Ala324Pro, 72-bp deletion at c971_1018\u00FE24 and an 18-bp duplication c894_911, and c1681-1G/A in intron 13) [>>16<<\u201320, 59]. Additionally, isolated cases of normal C1-INH with FXII mutation have been successfully treated with the bradykinin-receptor antagonist\u2014icatibant." . _:b51138945 . _:b604479550 . _:b51138947 _:b51138952 . _:b604479582 . _:b51138947 _:b51138953 . _:b51138946 . . _:b51138947 _:b51138954 . _:b51138947 _:b51138955 . _:b604479577 . _:b51138947 . _:b604479439 . _:b51138913 . _:b604479576 . _:b51138956 . _:b51138947 _:b51138948 . _:b604479579 . _:b51138947 _:b51138949 . _:b51138957 . _:b604479456 . _:b51138947 _:b51138950 . _:b51138947 _:b51138951 . _:b604479578 . _:b51138958 . _:b604479589 . _:b51138959 . _:b604479588 . _:b51138952 . _:b51138953 . _:b604479590 . _:b51138954 . _:b604479585 . _:b51138897 . _:b51138955 . _:b51138900 . _:b51138859 "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" . _:b604479584 . _:b51138964 . _:b604479587 . _:b51138883 "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 \u03B12-antiplasmin, while" . _:b51138965 . _:b51138936 "D-dimer levels are elevated during remission periods and markedly increase during attacks [34, >>37<<, 39, 40, 93]." . . _:b604479586 . _:b604479470 . _:b51138966 . _:b51138861 "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." . _:b51138967 . . _:b51138908 "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]." . . _:b51138960 . _:b51138953 "Third, both kallikrein and FXIIa can induce neutrophil degranulation [>>101<<]. Finally, neutrophil extracellular traps (NETs) have been shown to activate FXII." . _:b604479497 . . _:b51138961 . _:b51138962 . . _:b51138963 . . _:b51138958 . . . . _:b604479576 . . . _:b51138907 "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]." . _:b604479538 . _:b51138968 . . . _:b51138969 . _:b51138927 "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." . . . _:b51138924 "biomarkers of contact activation, fibrinolytic activity and coagulation in angioedema" . _:b604479460 . _:b604479483 . . . _:b604479478 . . . _:b51138960 "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" . . . . . _:b51138896 . . . . _:b51138888 "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\u201320]." . _:b51138928 . . . _:b51138905 "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." . . _:b604479477 . _:b51138875 "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 (\u03B2FXIIa or FXIIf) has lost its potential for" . _:b604479539 . . _:b604479493 "2"^^ . _:b604479527 . _:b51138865 . _:b604479590 . _:b604479492 "2"^^ . _:b604479575 . _:b51138922 . _:b51138928 . _:b604479495 "2"^^ . . _:b604479494 "2"^^ . _:b51138924 _:b51138932 . _:b604479489 "2"^^ . _:b51138924 _:b51138933 . _:b51138924 _:b51138934 . _:b604479568 . _:b51138924 _:b51138935 . _:b51138924 _:b51138928 . _:b604479488 "2"^^ . _:b51138924 _:b51138929 . _:b51138924 _:b51138930 . _:b51138924 _:b51138931 . _:b51138924 _:b51138940 . _:b604479491 "2"^^ . _:b51138924 _:b51138941 . . _:b51138924 _:b51138942 . _:b51138924 _:b51138943 . _:b51138924 _:b51138936 . _:b604479490 "2"^^ . _:b51138942 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, >>40<<, 42, 43, 93]." . _:b51138924 _:b51138937 . _:b51138924 _:b51138938 . _:b51138924 _:b51138939 . _:b51138904 . _:b604479501 "2"^^ . . _:b51138878 "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" . _:b604479500 "2"^^ . . _:b604479454 . . _:b604479485 . _:b604479558 . _:b604479463 . . _:b604479503 "2"^^ . _:b604479502 . _:b51138924 _:b51138925 . _:b51138924 _:b51138926 . _:b604479566 . _:b51138924 _:b51138927 . _:b604479502 "2"^^ . . _:b51138874 . _:b604479497 "2"^^ . _:b604479496 "2"^^ . _:b51138866 . _:b604479449 . _:b604479499 "2"^^ . _:b51138880 . _:b51138913 . _:b604479498 "2"^^ . _:b604479572 . _:b604479561 . . _:b604479509 "2"^^ . . _:b604479508 "2"^^ . _:b51138934 "linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor \u03B12-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34\u201336, 39, 40, 43, >>44<<]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema." . _:b604479431 . _:b604479511 "2"^^ . _:b604479496 . _:b604479510 "2"^^ . _:b51138857 . _:b604479505 "2"^^ . . _:b604479504 "2"^^ . . . _:b604479507 "2"^^ . . . . _:b604479506 "2"^^ . _:b51138944 . _:b51138920 "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" . _:b51138920 . _:b604479517 "2"^^ . _:b51138890 . _:b604479516 "2"^^ . _:b604479489 . _:b604479519 "2"^^ . . _:b604479518 "2"^^ . _:b604479513 "2"^^ . _:b51138900 . _:b51138926 . _:b604479512 "2"^^ . _:b51138927 . _:b604479577 . _:b604479491 . _:b604479515 "2"^^ . _:b604479570 . _:b604479514 "2"^^ . _:b51138864 . _:b604479525 "2"^^ . . . _:b604479524 "2"^^ . . _:b604479512 . _:b604479527 "2"^^ . _:b604479466 . _:b51138924 . _:b51138921 . _:b604479526 "2"^^ . _:b51138913 . . _:b604479521 "2"^^ . _:b51138902 . _:b604479520 "2"^^ . _:b604479549 . _:b51138949 . _:b51138887 _:b51138896 . _:b604479523 "2"^^ . _:b51138887 _:b51138897 . _:b51138887 _:b51138898 . _:b51138887 _:b51138899 . _:b51138887 _:b51138900 . _:b604479522 "2"^^ . . _:b51138887 _:b51138901 . . _:b51138887 _:b51138888 . _:b604479533 "2"^^ . _:b51138887 _:b51138889 . _:b51138887 _:b51138890 . _:b51138887 _:b51138891 . _:b51138887 _:b51138892 . _:b604479532 "2"^^ . _:b51138887 . _:b51138887 _:b51138893 . _:b51138887 _:b51138894 . _:b51138887 _:b51138895 . _:b604479535 "2"^^ . _:b51138900 "Activation of coagulation and fibrinolysis during HAE attacks has been repeatedly reported [>>34<<\u201347]. 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." . . _:b604479534 "2"^^ . _:b604479529 "2"^^ . _:b604479528 "2"^^ . _:b51138919 . _:b604479531 "2"^^ . . . _:b604479530 "2"^^ . . _:b51138862 "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." . . _:b604479541 "2"^^ . _:b51138912 "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." . _:b604479540 "2"^^ . _:b51138924 _:b51138944 . _:b51138902 _:b51138920 . _:b51138924 _:b51138945 . _:b51138902 _:b51138921 . _:b51138902 _:b51138922 . _:b51138924 _:b51138946 . _:b51138902 _:b51138923 . _:b604479543 "2"^^ . _:b51138902 _:b51138916 . _:b51138902 _:b51138917 . _:b51138902 _:b51138918 . _:b51138902 _:b51138919 . _:b604479542 "2"^^ . _:b51138902 _:b51138912 . _:b51138902 _:b51138913 . _:b51138902 _:b51138914 . . _:b51138902 _:b51138915 . _:b604479537 "2"^^ . _:b51138902 _:b51138908 . _:b604479551 . _:b51138902 _:b51138909 . _:b51138902 _:b51138910 . _:b51138902 _:b51138911 . _:b604479536 "2"^^ . _:b51138902 _:b51138904 . _:b51138902 _:b51138905 . _:b51138902 _:b51138906 . _:b51138902 _:b51138907 . . _:b604479539 "2"^^ . . _:b604479455 . _:b51138902 _:b51138903 . _:b604479538 "2"^^ . _:b51138892 . _:b604479549 "2"^^ . _:b604479548 "2"^^ . _:b604479516 . . . _:b604479551 "2"^^ . _:b51138947 . _:b51138956 . _:b51138929 . _:b604479550 "2"^^ . _:b604479545 "2"^^ . . . _:b604479544 "2"^^ . _:b604479525 . _:b604479509 . _:b604479547 "2"^^ . _:b604479546 "2"^^ . _:b604479557 "2"^^ . _:b51138866 _:b51138876 . . _:b51138866 _:b51138877 . _:b51138866 _:b51138878 . _:b51138866 _:b51138879 . _:b604479556 "2"^^ . _:b51138866 _:b51138872 . _:b51138866 _:b51138873 . _:b51138866 _:b51138874 . . _:b51138906 "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]." . _:b51138866 _:b51138875 . _:b604479559 "2"^^ . _:b51138866 _:b51138868 . _:b51138866 _:b51138869 . _:b51138860 "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." . _:b51138866 _:b51138870 . _:b51138866 _:b51138871 . _:b604479558 "2"^^ . _:b51138866 _:b51138867 . _:b604479553 "2"^^ . _:b51138863 "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." . _:b604479552 "2"^^ . . _:b604479555 "2"^^ . . _:b51138892 "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\u201325]. Evidence for bradykinin involvement in angioedema is not limited to HAE." . _:b604479554 "2"^^ . _:b604479565 "2"^^ . . _:b51138876 "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 (\u03B2FXIIa or FXIIf) has lost its potential for" . _:b604479564 "2"^^ . _:b604479567 "2"^^ . _:b604479566 "2"^^ . _:b604479561 "2"^^ . . _:b604479560 "2"^^ . _:b604479563 "2"^^ . . . _:b604479562 "2"^^ . . _:b604479573 "2"^^ . _:b604479572 "2"^^ . _:b604479575 "2"^^ . _:b604479574 "2"^^ . _:b604479569 "2"^^ . _:b604479568 "2"^^ . _:b51138921 "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" . _:b604479571 "2"^^ . _:b51138866 _:b51138884 . _:b51138913 . _:b51138866 _:b51138885 . _:b51138866 _:b51138886 . _:b51138857 _:b51138858 . _:b51138857 _:b51138859 . _:b604479570 "2"^^ . _:b51138950 . _:b51138857 _:b51138860 . _:b51138866 _:b51138880 . _:b51138866 _:b51138881 . _:b51138857 _:b51138861 . _:b51138866 _:b51138882 . _:b51138857 _:b51138862 . _:b51138866 _:b51138883 . _:b51138857 _:b51138863 . _:b604479581 "2"^^ . _:b51138857 _:b51138864 . _:b51138857 _:b51138865 . _:b604479436 . _:b604479580 "2"^^ . _:b604479432 . _:b604479583 "2"^^ . . . _:b604479582 "2"^^ . _:b604479577 "2"^^ . . _:b51138913 . . _:b604479576 "2"^^ . _:b51138869 . _:b604479579 "2"^^ . _:b51138862 . . _:b604479513 . _:b604479433 . _:b604479578 "2"^^ . _:b51138889 . _:b51138916 . _:b604479589 "2"^^ . . _:b51138959 "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" . _:b604479588 "2"^^ . _:b51138872 "Mysteriously, FXII deficiency is a seemingly asymptomatic condition in both mice and human (Hageman\u2019s disease), as it is not associated with a\u00A0bleeding 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]." . _:b51138929 "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\u201347, >>93<<\u201395]. 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 \u03B12-antiplasmin (PAP)" . . _:b604479446 . _:b604479590 "2"^^ . _:b604479585 "2"^^ . _:b51138857 "introduction" . _:b604479584 "2"^^ . . _:b604479587 "2"^^ . . _:b604479586 "2"^^ . . . _:b604479586 . _:b604479546 . _:b51138912 . . _:b604479429 . _:b604479428 . _:b604479517 . _:b604479431 . . _:b604479495 . . _:b604479430 . _:b604479560 . . _:b604479425 . _:b604479505 . _:b51138935 "D-dimer levels are elevated during remission periods and markedly increase during attacks [>>34<<, 37, 39, 40, 93]." . _:b604479520 . _:b604479427 . _:b604479426 . _:b604479437 . _:b604479436 . _:b604479439 . _:b604479540 . _:b604479438 . _:b51138884 "The fibrinolytic system is amenable to inhibition at several stages: plasmin is directly inhibited by \u03B12-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." . _:b604479433 . _:b51138954 . _:b51138957 "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" . _:b604479432 . . _:b51138895 "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]," . _:b604479435 . _:b51138964 "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]." . _:b604479434 . _:b51138876 . _:b51138881 "(mostly) located in the proline-rich region of FXII (according to mature amino acid sequence: Thr309Arg, Thr309Lys, Ala324Pro, 72-bp deletion at c971_1018\u00FE24 and an 18-bp duplication c894_911, and c1681-1G/A in intron 13) [16\u201320, >>59<<]. Additionally, isolated cases of normal C1-INH with FXII mutation have been successfully treated with the bradykinin-receptor antagonist\u2014icatibant." . _:b604479547 . _:b604479445 . _:b604479442 . _:b604479444 . _:b51138969 . . . _:b604479447 . _:b604479526 . _:b604479446 . _:b604479563 . _:b604479441 . . _:b51138925 . _:b604479440 . _:b604479443 . _:b604479442 . _:b51138867 . _:b604479453 . _:b604479510 . _:b604479452 . _:b51138865 . _:b604479455 . _:b604479454 . _:b604479529 . _:b604479449 . . _:b604479448 . _:b51138928 . _:b604479451 . _:b604479580 . _:b604479450 . _:b604479461 . _:b51138865 . _:b604479460 . _:b51138864 . . _:b604479463 . _:b604479462 . _:b51138916 "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" . _:b604479457 . . _:b604479456 . _:b51138929 . _:b604479459 . _:b604479459 . _:b604479458 . . . _:b604479469 . _:b604479467 . _:b604479468 . _:b604479471 . _:b51138873 "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" . _:b604479470 . _:b604479465 . . . . _:b604479444 . _:b604479464 . . _:b51138958 "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" . _:b604479467 . _:b604479582 . _:b604479466 . _:b51138939 . _:b604479574 . _:b604479477 . _:b604479476 . _:b604479479 . . _:b604479458 . _:b604479478 . _:b604479481 . _:b604479473 . . . _:b604479472 . _:b51138885 . _:b604479475 . _:b604479474 . _:b604479429 . _:b604479485 . . _:b604479484 . . _:b51138900 . _:b604479487 . _:b51138961 . _:b51138911 "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." . _:b604479437 . _:b604479486 . _:b51138962 . . _:b604479537 . _:b604479481 . _:b604479480 . . _:b604479483 . . _:b51138898 . _:b604479482 . . . _:b51138890 . . _:b51138968 . . . _:b51138893 . _:b51138893 . . _:b51138880 . _:b604479521 . _:b51138893 . . _:b51138880 . . _:b51138966 "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" . . _:b51138864 "This vasoactive peptide was first identified as a mediator for angioedema in patients with hereditary angioedema (HAE) [>>6<<\u20138]. 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" . . _:b604479434 . _:b51138893 "Therapy targeting the contact system has been successful in HAE, strongly supporting the concept that angioedema is mediated via bradykinin production [>>23<<\u201325]. 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," . . _:b604479438 . _:b51138890 . . . _:b604479554 . . _:b604479564 . _:b51138962 "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" . _:b604479555 . _:b51138945 . _:b51138928 . . _:b51138930 . _:b604479425 . _:b51138959 . _:b604479426 . _:b51138913 . _:b51138969 "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" . . . _:b604479559 . _:b51138871 "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<<]." . _:b604479490 . . _:b51138947 "neutrophil activation and contact system activation are functionally linked" . _:b604479503 . _:b51138940 . _:b51138960 . . . _:b604479461 . _:b51138935 . _:b51138951 "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" . _:b51138923 . _:b51138963 . _:b51138930 . . _:b604479500 . _:b51138928 . . _:b51138952 . _:b604479528 . _:b51138900 . _:b51138900 . _:b51138858 "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]." . _:b51138904 "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." . . _:b51138928 . _:b51138917 . . . _:b604479530 . _:b604479498 . _:b51138913 . . . _:b51138902 "a functional link between plasminogen activation and contact system activation" . _:b51138897 "During clinical trials of NEP inhibitors [28], up to 2.17\u00A0% of patients and 0.2\u20130.65\u00A0% of patients prescribed ACE inhibitors developed angioedema [>>29<<, 30]." . _:b51138943 . _:b51138937 "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]." . _:b51138896 "During clinical trials of NEP inhibitors [>>28<<], up to 2.17\u00A0% of patients and 0.2\u20130.65\u00A0% of patients prescribed ACE inhibitors developed angioedema [29, 30]." . _:b604479524 . _:b604479464 . . _:b51138931 . . _:b51138928 . _:b604479557 . _:b51138918 "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" . _:b51138938 "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]." . _:b51138930 "system are functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor \u03B12-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [>>34<<\u201336, 39, 40, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema." . _:b51138923 "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" . _:b51138952 "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" . . _:b51138900 . . . _:b51138937 . _:b604479581 . . . . _:b51138949 "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" . _:b51138941 . _:b604479472 . _:b604479504 . _:b51138868 . _:b51138933 . _:b51138891 . . _:b51138928 . _:b51138868 "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)." . _:b51138900 . _:b604479579 . _:b51138901 "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." . _:b604479488 . _:b51138899 . . _:b51138871 . _:b604479457 . _:b51138934 . _:b51138968 "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" . . _:b51138913 . _:b51138948 . _:b51138928 . _:b604479543 . . _:b51138914 . . _:b604479532 . _:b51138928 . _:b604479583 . _:b604479460 . _:b604479461 . _:b604479462 . _:b604479463 . _:b51138918 . _:b604479456 . _:b51138948 "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." . _:b51138915 . _:b604479457 . _:b604479458 . _:b604479459 . _:b604479468 . _:b604479469 . _:b604479470 . _:b604479471 . _:b604479464 . _:b604479465 . _:b604479466 . _:b604479467 . _:b51138870 . _:b604479476 . _:b604479477 . _:b604479478 . _:b604479479 . _:b604479472 . _:b604479473 . _:b604479474 . _:b51138900 . _:b604479475 . . _:b604479484 . _:b604479485 . _:b604479486 . _:b604479514 . _:b604479487 . _:b604479480 . _:b604479481 . _:b604479482 . _:b604479483 . _:b604479428 . . _:b604479429 . _:b604479430 . _:b604479431 . _:b604479425 . _:b604479426 . _:b604479427 . _:b604479436 . _:b604479531 . _:b604479437 . _:b604479438 . _:b604479439 . _:b604479432 . _:b604479433 . _:b604479434 . _:b604479435 . _:b604479444 . _:b604479445 . . _:b604479446 . _:b604479447 . _:b604479440 . _:b604479441 . _:b51138881 . _:b604479442 . . _:b604479443 . _:b604479452 . _:b604479453 . _:b604479454 . _:b51138913 "Neurologists repeatedly reported angioedema, which is presumably mediated via bradykinin, as a side effect of plasminogen activators given to patients with ischaemic stroke [>>71<<\u201382]. Up to 8\u00A0% 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\u201386]." . _:b604479455 . _:b604479448 . _:b604479449 . _:b604479450 . _:b604479451 . . _:b51138898 "During clinical trials of NEP inhibitors [28], up to 2.17\u00A0% of patients and 0.2\u20130.65\u00A0% of patients prescribed ACE inhibitors developed angioedema [29, >>30<<]." . . _:b604479571 . . . _:b604479435 . _:b604479541 . _:b51138900 . . _:b51138873 . . _:b51138953 . . _:b604479428 . _:b51138900 . . _:b604479482 . . _:b51138931 "are functionally linked sheds a new light on the repeatedly reported occurrence of increased levels of complexes of plasmin and its main inhibitor \u03B12-antiplasmin (PAP) and decreased levels of PAI-1 measured during HAE attacks [34\u201336, >>39<<, 40, 43, 44]. Fibrinolytic biomarkers may also be helpful in identifying bradykinin-mediated angioedema." . . _:b51138899 "Evidently, contact activation is closely linked to the coagulation system [>>31<<\u201333]. Activation of coagulation and fibrinolysis during HAE attacks has been repeatedly reported [34\u201347]." . _:b51138926 "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." . _:b604479511 . . . . . . _:b51138954 "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\u00A0cleavage. NETs are a binding site for antimicrobial proteins such as histones, neutrophil elastase and cathepsins [99]. To what extent the proteins loaded on NETs" . . _:b51138890 "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<<\u201320]." . _:b604479451 . . _:b51138950 "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)" . . . _:b604479476 . _:b604479522 . _:b604479585 . _:b51138951 . . _:b51138906 . _:b51138963 "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." . . _:b604479428 "6"^^ . _:b604479565 . _:b604479440 . _:b604479431 "5"^^ . _:b51138955 . _:b604479429 "6"^^ . _:b604479430 "5"^^ . _:b604479588 . _:b604479426 "8"^^ . _:b604479427 "7"^^ . _:b604479536 . _:b604479425 "8"^^ . _:b51138861 . . _:b604479437 "4"^^ . _:b604479436 "4"^^ . . . _:b604479439 "4"^^ . . _:b604479494 . _:b51138922 "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" . _:b604479438 "4"^^ . . _:b604479480 . _:b604479433 "4"^^ . . . _:b604479432 "5"^^ . . _:b51138858 . _:b604479435 "4"^^ . _:b604479434 "4"^^ . _:b604479499 . _:b604479445 "3"^^ . _:b604479535 . _:b51138907 . _:b604479444 "3"^^ . . _:b51138865 . . _:b604479447 "3"^^ . . . _:b604479446 "3"^^ . . _:b604479441 "3"^^ . . . _:b51138955 "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" . _:b604479440 "4"^^ . _:b604479443 "3"^^ . _:b604479442 "3"^^ . _:b51138865 "Several studies suggested potential natural activators of FXII [>>9<<\u201313], but thus far none of these have been definitively established to induce activation of the contact system during angioedema in vivo." . _:b604479453 "3"^^ . . _:b604479452 "3"^^ . . _:b604479455 "3"^^ . _:b604479454 "3"^^ . _:b51138961 "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\u00A0% cleavage of their HK pool. Evidence of the clinical relevance of bradykinin during anaphylaxis with hypotension was further demonstrated" . _:b604479449 "3"^^ . _:b51138894 . _:b51138869 "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\u00A0(FVIII), activated by thrombin, forms a complex together with FIX" . _:b604479448 "3"^^ . . _:b604479508 . _:b604479578 . . _:b604479451 "3"^^ . _:b604479453 . _:b604479450 "3"^^ . _:b604479461 "3"^^ . _:b51138887 "bradykinin-mediated angioedema" . _:b604479460 "3"^^ . _:b604479588 . _:b604479589 . _:b604479590 . . _:b604479463 "3"^^ . _:b604479584 . . _:b604479585 . _:b604479586 . _:b604479587 . _:b604479462 "3"^^ . _:b51138965 "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" . _:b51138944 "Also, thrombin-anti-thrombin complexes and prothrombin fragments F1+F2 increase during attacks [34, 39, 40, 42, >>43<<, 93]." . _:b604479457 "3"^^ . _:b51138859 . _:b604479456 "3"^^ . _:b604479475 . _:b604479459 "3"^^ . _:b604479458 "3"^^ . _:b604479469 "3"^^ . _:b604479468 . _:b51138895 . _:b604479468 "3"^^ . _:b604479556 . _:b604479557 . _:b604479558 . _:b604479471 "2"^^ . _:b51138860 . _:b604479441 . _:b604479559 . _:b604479552 .