Probing interactions between the coagulants thrombin, Factor XIII, and fibrin(ogen)

Maurer, Muriel C.; Trumbo, Toni A.; Isetti, Giulia; Turner, Brian T.

doi:10.1016/j.abb.2005.11.009

Cited by 13 publications

(8 citation statements)

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“…Because R95-allele possesses increased subunit dissociation independently from L34-allele (28), the two variants may have additive effects on FXIII activation. Thus, a synergistic interaction might account for effects on MI occurrence referring to the hypotheses mentioned above (38)(39)(40). In our survey, we didn't find any significant effects on survival by R95-allele by itself or in combination with L34-allele, reserving the worst clinical outcome mainly to the VV34-genotype irrespective to the coexistence of the R95-allele.…”

Section: Discussionmentioning

confidence: 37%

“…(38). To date, it has been hypothesized that fibrinogen levels (38), the early and wasteful activation of FXIII L34-zymogen, with consequent premature depletion from the circulation (39), and its lesser reliance on fibrin during clot formation (40), might be responsible for the cardio-protective effects of the L34-allele. As the FXIIIB-H95R variant is concerned, published data on the association with MI or thrombotic disease are very few and more controversial, yielding protection against MI (29,30) and risk for venous thrombosis in similar setting of populations (28).…”

Section: Discussionmentioning

confidence: 99%

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Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

Gemmati

Federici

Campo

et al. 2007

Mol Med

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It has been demonstrated recently that coagulation factor XIII (FXIII) plays an extraordinary role in myocardial healing after infarction, improving survival in a mouse model. Common FXIII gene variants (i.e. FXIIIA-V34L and FXIIIB-H95R) significantly influence the molecular activity. To evaluate whether there is a relationship between the two FXIII gene variants and survival in patients after myocardial infarction (MI), V34L and H95R were PCR-genotyped in a cohort of 560 MI cases and follow-up was monitored. Cases with ST-segment elevation MI (STEMI) were 416 (74.3%) and 374 of these were treated with primary percutaneous coronary intervention (PCI) (89.9%). The remaining 144 patients showed non-ST-segment elevation MI (NSTEMI) at enrollment. The combined endpoint was the occurrence of death, re-infarction, and heart failure. Kaplan-Meier analysis at one year yielded an overall rate for adverse events of 24.5% with a lower incidence in the L34-carriers (28.8% vs 17.1%; log-rank, P = 0.00025), similar to that of the 416 STEMI (23.8%) being (28.0% and 16.9%; VV34-and L34-carriers respectively; log-rank, P = 0.001). Primary PCI-group had a slight lower incidence (22.9%) of adverse events (26.8% and 17.1%; VV34-and L34-carriers respectively; log-rank, P = 0.009). During hospitalization, 506 patients received PCI (374 primary PCI and 132 elective PCI). Significance was conserved also in the overall PCIgroup (28.6% and 17.8%; VV34-and L34-carriers respectively; log-rank, P = 0.001). Similar findings were observed at 30 days follow-up. Cases carrying both FXIII variants had improved survival rate (log-rank, P = 0.019). On the other hand, minor bleeding complications were found increased in L34-carriers (P = 0.0001) whereas major bleeding complications were not. Finally, more direct evidence on the role of FXIII molecule on survival might come from the fact that despite significant FXIII antigen reductions observed in cases after MI, regardless the FXIII genotype considered, L34-carriers kept almost normal FXIII activity (VV34-vs L34-carriers; P < 0.001). We conclude that FXIII L34-allele improves survival after MI in all the groups analyzed, possibly through its higher activity associated with assumable positive effects on myocardial healing and recovered functions. Genetically determined higher FXIII activity might influence post-MI outcome. This paves the way for using FXIII molecules to improve myocardial healing, recovery of functions, and survival after infarction.

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Section: Discussionmentioning

confidence: 37%

Section: Discussionmentioning

confidence: 99%

Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

Gemmati

Federici

Campo

et al. 2007

Mol Med

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“…In particular, the G-to-T transversion at nucleotide 185 of FXIII gene underlying the replacement of a valine by a leucine at codon 34 (Val34Leu) in the catalytic A subunit of factor XIII, is considered the main functional locus of this coagulation factor [ 71 ]. In fact, the mutant 34Leu form of this activation-peptide generates an anti-thrombophilic status by means of direct or indirect effects on: (1) factor XIII transglutaminase activity [ 72 , 73 ]; (2) thrombin-related activation of factor XIII [ 73 , 74 ]; (3) tridimensional structure of the cross-linked fibrin-clot [ 71 , 75 , 76 , 77 , 78 , 79 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration

Parmeggiani

Costagliola

Semeraro

et al. 2015

IJMS

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Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

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“…To date, it has been hypothesized that some conditions might be implicated to attain the anti-thrombotic effects of T185-allele, i.e. the elevation of fibrinogen concentrations in addition to the early and wasteful activation of FXIII Leu34zymogen, consequently accompanied by its premature depletion from the circulation and its lesser reliance on fibrin during the clot formation [149][150][151][152].…”

Section: Anti-thrombophilic Effects Of Factor Xiii-a G185t Gene Polym...mentioning

confidence: 99%

“…progression and persistence of the hemodynamic occlusion inside CNV), the common variant G185T of FXIII-A gene results in an earlier and wasteful conversion of the zymogen to activated enzyme with a consequent premature depletion from blood circulation. This fact, together with its associated lesser reliance on fibrin during clot formation [150,151], seem to be responsible for the clinical effects of FXIII T185-allele in patients with either hemorrhagic or thromboembolic diseases [140,159], as well as for the minor CNV respon-siveness to PDT-V in the carriers of this mutated allele [16,17,70]. The G185T polymorphism does not significantly influence transglutaminase activity of FXIII, but it promotes an early fibrin crosslinking that inhibits the lateral aggregation of the fibrin fibers.…”

Section: Anti-thrombophilic Effects Of Factor Xiii-a G185t Gene Polym...mentioning

confidence: 99%

Pharmacogenetic Aspects in Therapeutic Management of Subfoveal Choroidal Neovascularisation: Role of Factor XIII-A 185 T-Allele

Parmeggiani

Costagliola²,

Incorvaia³

et al. 2011

CDT

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In Western Countries, the occurrence of choroidal neovascularization (CNV) secondary to different forms of macular degeneration represents a common cause of blindness. Particularly, age-related macular degeneration (AMD) and pathologic myopia (PM) are the most frequent diseases related to CNV development. At present, the combined employment of drugs acting against vascular endothelial growth factor (anti-VEGF) and photodynamic therapy with verteporfin (PDT-V) is a promising therapeutic strategy for neovascular macular degenerations. However, this approach inevitably leads to an increase in health-resource utilization. In several clusters of patients treated for CNV, correlations among common gene polymorphisms implicated in coagulation- or complement-cascade and different levels of, respectively, post-PDT-V or post-anti-VEGF benefit have been reported. Factor XIII-A G185T substitution (rs5985), a frequent anti-thrombophilic genetic variant of Caucasian ethnic groups, unequivocally influences a worsening of the CNV responsiveness to PDT-V in patients affected by either AMD- or PM-related CNV. These coherent pharmacogenetic findings point out the opportunities to: i. optimize the eligibility criteria of PDT-V and, ii. customize the interventional strategy against CNV, for finally minimizing the socio-economic burden of neovascular macular degenerations.

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Probing interactions between the coagulants thrombin, Factor XIII, and fibrin(ogen)

Cited by 13 publications

References 50 publications

Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration

Pharmacogenetic Aspects in Therapeutic Management of Subfoveal Choroidal Neovascularisation: Role of Factor XIII-A 185 T-Allele

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