Activated factor 12 (FXIIa) predicts recurrent coronary events after an acute myocardial infarction

Grundt, Heidi; Nilsen, Dennis W; Hetland, Øyvind; Valente, E.; Fagertun, Hans

doi:10.1016/j.ahj.2003.07.012

Cited by 56 publications

(52 citation statements)

References 22 publications

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“…Data from the studies from Doggen et al and Endler et al seem at odds with work showing that elevated plasma fXIIa is associated with an increased risk of coronary events. 47,48 It is difficult to draw unifying conclusions from this data, but there seems to be grounds for concern that fXII may not contribute to thrombosis in humans and rodents in the same manner, or to the same extent.…”

Section: Discussionmentioning

confidence: 97%

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Matafonov

Leung

Gailani

et al. 2014

Blood

200

167

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• Factor XII can contribute to thrombus formation in human and nonhuman primate blood.• An antibody that blocks factor XII activation (15H8) produces an antithrombotic effect in a primate thrombosis model.The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks.Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in

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Section: Discussionmentioning

confidence: 97%

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Matafonov

Leung

Gailani

et al. 2014

Blood

200

167

View full text Add to dashboard Cite

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“…However, mortality for patients with 1% to 10% of normal factor XII level (severe deficiency) was similar to mortality for the population median, suggesting a fundamental difference between severe and moderate factor XII deficiency. Elevated levels of activated factor XII (factor XIIa) have been associated with increased risk for coronary heart disease 60 and were a prognostic risk factor for recurrent coronary events, 61 supporting the premise that factor XIIa may contribute to thrombus formation. It is not known whether factor XIIa contributed to thrombotic events in these patients, or was generated as a consequence of the thrombosis or tissue ischemia.…”

Section: Intrinsic Pathway Proteins and Thromboembolic Disease In Humansmentioning

confidence: 94%

Intrinsic Pathway of Coagulation and Arterial Thrombosis

Gailani

Renné

2007

ATVB

247

172

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Abstract-Formation of a fibrin clot is mediated by a group of tightly regulated plasma proteases and cofactors. While this system is essential for minimizing blood loss from an injured blood vessel (hemostasis), it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels (thrombosis). Many antithrombotic drugs target key elements of the plasma coagulation mechanism such as thrombin and factor Xa, based on the premise that plasma elements contributing to thrombosis are primarily those involved in hemostasis. Recent studies with genetically altered mice raise questions about this paradigm. Deficiencies of the intrinsic pathway proteases factor XII and factor XI are not associated with abnormal hemostasis in mice, but impair formation of occlusive thrombi in arterial injury models, indicating that pathways not essential for hemostasis participate in arterial thrombosis. If factor XII or factor XI make similar contributions to thrombosis in humans, these proteases could be ideal targets for drugs to treat or prevent thromboembolic disease with minimal risk of therapy-associated bleeding. (Arterioscler Thromb Vasc

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“…16 Clinical studies point to a contribution of FXII in arterial thrombosis in humans, but the data are ambiguous. 20,[38][39][40][41][42] Both low and high levels of FXII, FXIIa, or FXIIa-C1 esterase inhibitor have been associated with an increased risk of thrombosis. Some of the inconsistencies in clinical studies may be related to differences in assay methodologies because different aspects of the contact pathway were determined.…”

mentioning

confidence: 99%

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Konings

Govers‐Riemslag

Philippou

et al. 2011

Blood

122

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Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombindeficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and ␣-FXIIa, but not ␤-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that IntroductionBlood coagulation culminates in the formation of fibrin, which binds platelets and forms a clot. Fibrin is formed from fibrinogen via cleavage of 2 fibrinopeptides from the A␣-and B␤-chains N-termini, located in the E-region, by thrombin. 1 Fibrinopeptide cleavage exposes binding sites for complementary sites in the D-region, triggering polymerization and the production of protofibrils. Protofibrils aggregate laterally to form fibers, which branch out and form a 3-dimensional network. 2 There is increasing evidence that the structure of fibrin regulates thrombosis. Dense fibrin clots with small pores and increased fiber density are more resistant to lysis. 3 Structural characteristics affect the mechanical properties of fibrin. 4 Both venous and arterial thrombosis has been associated with the formation of an altered fibrin network. [5][6][7][8][9][10] The role of factor (F)XII in hemostasis has long been contested because deficiency in FXII, unlike deficiencies of other coagulation factors, does not lead to bleeding diathesis in humans 11 or in mice. 12 However, recent in vivo data show that FXII deficiency or inhibition in rodent models reduces thrombus formation while maintaining normal hemostasis. [12][13][14][15] These findings indicate the existence of FXII-related mechanisms that are preferentially involved in thrombosis but not hemostasis.Contact activation is triggered by the binding of FXII (80 kDa) to a negatively charged surface and involves the formation of ␣-FXIIa via autocatalysis. Bound ␣-FXIIa converts prekallikrein into kallikrein. Kallikrein can further convert ␣-FXIIa to ␤-FXIIa by an additional cleavage at R334-N335. ␣-FXIIa consists of a heavy and light chain that are disulphide linked (80 kDa), whereas ␤-FXIIa (28 kDa) lacks the heavy chain and loses its capacity to bind to negatively charged surfaces. 16 The N-terminal region of FXII (␣-FXIIa heavy chain) shows strong homology with tissuetype plasminogen activator (tPA), with the presence of fibr...

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Activated factor 12 (FXIIa) predicts recurrent coronary events after an acute myocardial infarction

Cited by 56 publications

References 22 publications

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Intrinsic Pathway of Coagulation and Arterial Thrombosis

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

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