The role of fibrinogen plasma levels, the –455G>A fibrinogen and the factor XIII A subunit (FXIII-A) Val34Leu polymorphism in cancer-associated venous thrombosis

SummaryVenous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the –455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen –455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839–1.310 p=0.68), nor the –455G>A SNP (HR=0.77, 95%CI 0.491–1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646–1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen –455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen –455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.

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Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency

Blood ◽

10.1182/blood-2011-10-386045 ◽

2012 ◽

Vol 119 (22) ◽

pp. 5111-5117 ◽

Cited By ~ 69

Author(s):

Aida Inbal ◽

Johannes Oldenburg ◽

Manuel Carcao ◽

Anders Rosholm ◽

Ramin Tehranchi ◽

...

Keyword(s):

Factor Xiii ◽

Autosomal Recessive Disorder ◽

Allergic Reactions ◽

Open Label ◽

Impaired Wound Healing ◽

Bleeding Rate ◽

Life Threatening ◽

A Subunit ◽

Bleeding Episodes ◽

Congenital Factor

Congenital factor XIII (FXIII) deficiency is a rare, autosomal-recessive disorder, with most patients having an A-subunit (FXIII-A) deficiency. Patients experience life-threatening bleeds, impaired wound healing, and spontaneous abortions. In many countries, only plasma or cryoprecipitate treatments are available, but these carry a risk for allergic reactions and infection with blood-borne pathogens. The present study was a multinational, open-label, single-arm, phase 3 prophylaxis trial evaluating the efficacy and safety of a novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency. Forty-one patients ≥ 6 years of age (mean, 26.4; range, 7-60) with congenital FXIII-A subunit deficiency were enrolled. Throughout the rFXIII prophylaxis, only 5 bleeding episodes (all trauma induced) in 4 patients were treated with FXIII-containing products. The crude mean bleeding rate was significantly lower than the historic bleeding rate (0.138 vs 2.91 bleeds/patient/year, respectively) for on-demand treatment. Transient, non-neutralizing, low-titer anti-rFXIII Abs developed in 4 patients, none of whom experienced allergic reactions, any bleeds requiring treatment, or changes in FXIII pharmacokinetics during the trial or follow-up. These non-neutralizing Abs declined below detection limits in all 4 patients despite further exposure to rFXIII or other FXIII-containing products. We conclude that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. This study is registered at http://www..clinicaltrials.gov as number NCT00713648.

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Joint Linkage and Association of Six Single-Nucleotide Polymorphisms in the Factor XIII-A Subunit Gene Point to V34L As the Main Functional Locus

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.0000231538.60223.92 ◽

2006 ◽

Vol 26 (8) ◽

pp. 1914-1919 ◽

Cited By ~ 16

Author(s):

Marlies de Lange ◽

Toby Andrew ◽

Harold Snieder ◽

Dongliang Ge ◽

T. Simon Futers ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Factor Xiii ◽

Nucleotide Polymorphisms ◽

Subunit Gene ◽

Single Nucleotide ◽

Functional Locus ◽

A Subunit

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Plasma levels of the A subunit of factor XIII in patients undergoing off-pump coronary artery bypass surgery

Polish Archives of Internal Medicine ◽

10.20452/pamw.4076 ◽

2017 ◽

Vol 127 (7-8) ◽

pp. 550-553 ◽

Cited By ~ 2

Author(s):

Artur Słomka ◽

Piotr Korbal ◽

Aleksandra Piekuś ◽

Wojciech Pawliszak ◽

Lech Anisimowicz ◽

...

Keyword(s):

Coronary Artery ◽

Coronary Artery Bypass ◽

Plasma Levels ◽

Factor Xiii ◽

Coronary Artery Bypass Surgery ◽

Bypass Surgery ◽

Artery Bypass ◽

Off Pump ◽

A Subunit ◽

Pump Coronary Artery Bypass

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Factor XIII-A subunit Val34Leu polymorphism is associated with the risk of thrombosis in patients with antiphospholipid antibodies and high fibrinogen levels

Thrombosis and Haemostasis ◽

10.1160/th08-06-0347 ◽

2009 ◽

Vol 101 (02) ◽

pp. 312-316 ◽

Cited By ~ 13

Author(s):

Gloria de la Red ◽

Dolores Tàssies ◽

Gerard Espinosa ◽

Joan Monteagudo ◽

Albert Bové ◽

...

Keyword(s):

Protective Effect ◽

Allele Frequency ◽

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Factor Xiii ◽

Protective Factor ◽

Allele Frequencies ◽

Fibrinogen Concentration ◽

Primary Antiphospholipid Syndrome ◽

A Subunit

SummaryRecent reports have described the factor XIII A subunit (FXIII-A) Val34Leu polymorphism as a protective factor against venous and arterial thrombosis. The aim of this study was to investigate the association between the FXIII-A Val34Leu polymorphism, its interaction with fibrinogen concentration, and thrombosis in patients with antiphospholipid antibodies (aPL). We included 172 consecutive patients with aPL: 88 with primary antiphospholipid syndrome (APS), 38 with APS associated with systemic lupus erythematosus (APS-SLE), 32 with SLE and aPL but without APS (SLE-aPL), and 14 asymptomatic individuals with aPL (A-aPL). The FXIII-A Val34Leu polymorphism was assessed by polymerase chain reaction techniques. We found no significant differences in FXIII-A Leu34 allele frequencies between primary APS (allele frequency 0.22), APS-SLE (0.23), SLE-aPL (0.22) and A-aPL (0.32) patients, or between patients with (0.21) and without thrombosis (0.26). FXIII-A Leu34 allele frequencies were significantly lower in patients with thrombosis and those in the upper fibrinogen tertile (>3.40 g/l) (allele frequency 0.07) compared with patients without thrombosis in the upper fibrinogen tertile (0.29) and patients with (0.29) and without (0.25) thrombosis in the mid- and lower fibrinogen tertiles. The FXIII-A Leu34 allele had a protective effect against thrombosis in patients in the upper fibrinogen tertile (odds ratio [OR]=0.20, 95% confidence interval [CI] 0.07–0.60) but not in those in the other tertiles (OR=1.20, 95% CI 0.67–2.16). The FXIII-A Leu34 allele seems to have a protective effect on the development of thrombosis in patients with aPL, but only in those with high plasma fibrinogen values.

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The Hormone - Dependent Concentration Changes Of Factor XIII (Fibrinoligase) During Pregnancy

10.1055/s-0038-1653026 ◽

1981 ◽

Author(s):

Ch Ebert ◽

H Berg ◽

R E Zimmermann

Keyword(s):

Physiological Response ◽

Factor Xiii ◽

Gradual Increase ◽

Normal Population ◽

Coagulation Factors ◽

Normal Pregnancy ◽

Fibrinogen Concentration ◽

Thromboembolic Complications ◽

Menstrual Cycles ◽

Concentration Changes

The effects of hormones on blood coagulation and fibrinolysis have been studied extensively since oestrogen / progesterone preparations were used for contraceptive purposes. There is a general agreement that such preparations cause a rise in plasma levels of fibrinogen, prothrombin and factors VII, IX, and X. In Comparison, most of the coagulation factors synthesized by the liver show a gradual increase during normal pregnancy. Only factor XIII and calcium reveal a tendency to decrease. In 90 patients out of a normal population the plasmatic factor XIII concentration declined from 0.39 units in the first trimenon to 0.29 and 0.23 units in the second and third trimenon. Since the fibrinogen concentration is higher than during normal menstrual cycles the reduction of factor XIII may be caused by a decreased synthesis or an increased clearance rate from circulation. The abnormal haemostatic conditions during gestation could be interpreted as a physiological response to the increase of oestrogen and progesterone leading to a hypercoagulative state. Reduced levels of factor XIII may counterbalance the increased rate of fibrin formation and serve as protection against thromboembolic complications.

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Thrombin generation as an intermediate phenotype for venous thrombosis

Thrombosis and Haemostasis ◽

10.1160/th09-06-0356 ◽

2010 ◽

Vol 103 (01) ◽

pp. 114-122 ◽

Cited By ~ 31

Author(s):

Olivier Segers ◽

René van Oerle ◽

Hugo ten Cate ◽

Jan Rosing ◽

Elisabetta Castoldi

Keyword(s):

Genetic Variation ◽

Plasma Levels ◽

Thrombin Generation ◽

Activated Protein C ◽

Coagulation Factors ◽

Peak Height ◽

Intermediate Phenotype ◽

Nucleotide Polymorphisms ◽

Thrombin Generation Assay

Summary In vitro thrombin generation, which reflects an individual’s plasma coagulation potential and has been shown to correlate with the risk of venous thromboembolism (VTE), might represent a useful intermediate phenotype for the genetic dissection of VTE. As a proof of principle, we have investigated whether the thrombin generation assay can detect changes in the haemostatic balance associated with common genetic variation affecting the level or function of coagulation factors and inhibitors. The study population consisted of 140 healthy individuals. Plasma levels of coagulation factors and inhibitors and thrombin generation parameters determined at low tissue factor (TF) ± thrombomodulin (TM) and at high TF ± activated protein C (APC) were available from a previous study. All individuals were genotyped for F5 Leiden, F2 G20210A and 19 additional single nucleotide polymorphisms (SNPs) in haemostasis-related genes. The association of each SNP with plasma levels of the corresponding proteins and with thrombin generation parameters (lag time, peak height and endogenous thrombin potential [ETP]) was evaluated by statistical analysis. Not only F5 Leiden and F2 G20210A, but also several other common SNPs, significantly affected thrombin generation parameters. In particular, FGA A1069G (Thr312Ala) decreased the ETP-APC, F2 A19911G increased the ETP-APC, F10 IVS2 C+517G decreased the ETP+APC, F12 C-46T decreased peak height at low TF, and TFPI T-287C and TFPI IVS7 T-33C decreased the ETP+APC. These results indicate that the thrombin generation assay is sensitive to genetic variation in haemostasis-related genes, which makes it a promising tool to identify novel genetic risk factors of VTE.

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