scholarly journals Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism

2021 ◽  
Vol 22 (4) ◽  
pp. 1607
Author(s):  
Michał Ząbczyk ◽  
Joanna Natorska ◽  
Anetta Undas
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xiii ◽  
Active Form ◽  
Coagulation Factor ◽  
Proteome Analysis ◽  
Fibrin Clot ◽  
Subsequent Increase ◽  
Vein Thrombosis ◽  
Acute Pe ◽  
Fxiii Activity

Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. Better understanding of FXIII’s involvement in the pathophysiology of acute VTE might help to improve current therapeutic strategies in patients with acute VTE.

FACTOR XIII CONCENTRATE FOR PROPHYLAXIS OF REBLEEDING IN SUBARACHNOID HEMORRHAGE (SAH) - RESULTS OF A PROSPER TIVE MULTICENTER PILOT STUDY

1987 ◽  
Author(s):  
A Thie ◽  
T h Henze ◽  
D Deggar ◽  
M Obering ◽  
R Clemers ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Pilot Study ◽  
Mortality Rate ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Stage I ◽  
Stage Iii ◽  
Double Blind Study ◽  
Overall Mortality

Rebleeding occurs in subarachnoid hemorrhage (SAH) in 20 - 25 % of patients, with a mortality rate being above 50 %. The cause of rebleeding is considered to be premature fibrinolysis of the fibrin clot surrounding the site of rupture. Since the stability of the fibrin clot is influenced by the activity of coagulation factor XIII, and moreover, a factor XIII deficiency has been reported in SAH patients, the question arises as to whether the incidence of rebleeding can be influenced by the administration of F XIII concentrate.During a period of 6 months, 69 patients with acute SAH were enlisted in an open, prospective, multicenter study. On admission, 5 patients were classified as stage I (7.2%) according to the Hunt and Hess scale, 22 as stage III (31.9%), 11 as stage IV (16%) and 9 as stage V (13%). Aneurysm was confirmed by angiography in 52 patients (75%). All the patients received 10 x 1250 U F XIII concentrate during the first 15 days after the initial hemorrhage. Surgery on the aneurysm was performed between day 3 and 32 (median: day 13) in 35 patients.A total of 7 rebleedings occurred in 6 patients (8.7%), of whom 2 were stage I - II and 4 were stage III - V cases. Cerebral infarction was observed in 10 patients (14.5%), and hydrocephalus requiring shunting occurred in 1 patient. There were no cases of peripheral thromboses or embolisms. After 4 weeks, the overall mortality rate was 26%. (stage I - II: 11.1%, stage III - V: 37.5%).The conventional approach in the prophylaxis of rebleeding in SAH is an early operation or intravenous administration of antifibrinolytics. However, as none of these measures significantly reduce overall mortality, the present pilot study investigated a new, therapeutic approach in which F XIII concentrates were administered in order to stabilize the fibrin clots and prevent premature fibrinolysis. The data so far show that Fibrogammin P is an effective and well tolerated agent for the prophylaxis of post-SAH rebleeding. In order to statistically confirm the results of the pilot study, we have, in the meantime, started a prospective, randomized, placebo-controlled, multicenter double-blind study, which will involve 750 patients over a period of 2 years.

A Novel Nonsense Mutation of F13A1 Gene Causing Inherited Factor XIII Deficiency in a Chinese Han Family

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4661-4661
Author(s):  
Dawei Wang ◽  
Liang Tang ◽  
Wei Shi ◽  
Heng Mei ◽  
Rui Yang ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Factor Xiii ◽  
Family Members ◽  
Coagulation Factor ◽  
Maternal Grandmother ◽  
Chinese Han ◽  
Factor Xiii Deficiency ◽  
Fxiii Activity ◽  
Fxiii Deficiency

Abstract Abstract 4661 Introduction: Coagulation factor XIII (FXIII) is a protransglutaminase that has a major role in the final stage of blood coagulation process by forming cross-links between γ-glutamyl and ε-lysine residues of fibrin chains. The plasma FXIII (pFXIII) circulates in plasma as a heterotetramer (FXIII-A2B2) consisting of two catalytic A subunits (FXIII-A2) and two carrier B subunits (FXIII-B2). Inherited FXIII deficiency is a rare autosomal recessive disease with lifelong bleeding. Most cases of FXIII deficiency are heterogeneous due to mutations in the F13A gene. Currently, more than 100 mutations have been reported. Aim: To identify the genetic defect of inherited coagulation factor XIII (FXIII) deficiency in a Chinese Han family. Methods and Results: A 13 year-old patient complained of poor wound healing after operation and had a history of an excessive bleeding from the umbilical cord stump after her birth. The routine laboratory tests are normal. Her bleeding time is more than 15 minutes and fibrin clot was solubilized very quickly in 5mol/L urea, and became insoluble when normal plasma was mixed with her plasma in vitro. Her plasma FXIII activity was zero with the amine incorporation assay and plasma FXIII antigen was also near zero by one-step sandwich ELISA method, the plasma FXIIIA antigen was zero using an indirect competitive ELISA assay. The plasma FXIIIA antigen, FXIII activity and antigen were assayed in all available family members. The testing results of patient’s grandfather and maternal grandmother were within normal range. But the other pedigree members’ results were lower in different level compare with normal ranges. All members of her family had normal coagulation test. All the exons of F13A gene as well as F13B gene and their flanking regions were amplified by PCR for direct sequencing to identify the mutations in the proband. Direct DNA sequencing of all purified amplification products from the patient’s F13A gene demonstrated a homozygous nonsense mutation in exon8 (C to A transversion at nucleotide 98531 which caused Cys327X). And the patient didn’t have the Val34Leu polymorphism. In the pedigree except of the proband, the Cys327X mutation was found in the heterozygous state in all investigated members except for her grandfather and maternal grandmother. A family study revealed that the mutation was inherited from both parents. The identified mutation was validated by PCR-RFLP technique in the family members and healthy people. Restriction enzyme analysis of amplified exon 8 DNA fragment confirmed that the patient was homozygous for this mutation. Then the quantitative RT-PCR method was used for studying the mRNA expression level of mutant FXIIIA. And the results indicated that F13A mRNA transcripts in heterozygous mutant were reduced by 25% when compared to transcripts in wild-type one, while the homozygous mutant level of F13A mRNA transcript was nearly zero relative to the normal transcript. Conclusion: We have identified a novel Cys327X nonsense mutation in human FXIIIA gene which we have not found in the FXIII database (www.f13-database.de) or in previous publications.And the identified nonsense mutation is causative for severe factor XIII deficiency with a bleeding disorder. Further, in vitro expression studies of the factor XIII mutation is required to confirm their pathological mechanism. Disclosures: No relevant conflicts of interest to declare.

Genotype/Phenotype Correlations for Coagulation Factor XIII: Specific Normal Polymorphisms Are Associated With High or Low Factor XIII Specific Activity

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 897-905 ◽  
Author(s):  
Rashida Anwar ◽  
Louise Gallivan ◽  
Stuart D. Edmonds ◽  
Alexander F. Markham
Keyword(s):  
Factor Xiii ◽  
Specific Activity ◽  
Recurrent Miscarriage ◽  
Coagulation Factor ◽  
Preliminary Evidence ◽  
Activity Levels ◽  
Normal Hemostasis ◽  
Fxiii Activity ◽  
Normally Distributed

Abstract Factor XIII is a transglutaminase essential for normal hemostasis. We have studied the plasma FXIII levels and FXIII activity in 71 individuals and found these to be normally distributed. FXIII specific activity is also normally distributed. However, we show that FXIII activity is not directly dependent on FXIII levels, and individuals with low FXIII levels may have high FXIII activity and vice versa. We have determined the FXIIIA genotype in these individuals to assess whether the variation observed in FXIII specific activity is dependent on specific polymorphisms in the FXIIIA gene. Our data show that the Leu34 and Leu564 variants give rise to increased FXIII specific activity, while the Phe204 variant results in lower FXIII specific activity. We also report preliminary evidence that the Phe204 polymorphism may be associated with recurrent miscarriage. Overall, we have identified 23 unique FXIIIA genotypes. Certain specific FXIIIA genotypes consistently give rise to high, low, or median FXIII specific activity levels, while others appear to have little or no consistent influence on the FXIII phenotype. These genotype to phenotype relationships are discussed in light of the growing interest in the role of FXIII in clinical problems involving an increased thrombotic tendency.

scholarly journals Association of Fibrinogen and Plasmin Inhibitor, but not Coagulation Factor XIII Gene Polymorphisms with Coronary Artery Disease

2020 ◽  
Author(s):  
Ana Bronic ◽  
Goran Ferencak ◽  
Robert Bernat ◽  
Jasna Lenicek Krleza ◽  
Jerka Dumic ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Factor Xiii ◽  
Active Form ◽  
Coagulation Factor ◽  
Rflp Analysis ◽  
Chain Gene ◽  
Nucleotide Polymorphisms ◽  
Artery Disease ◽  
Plasmin Inhibitor

Background: In the final phase of cloth formation, fibri(noge)n constitutes frame whereas factor XIII (FXIII) active form is responsible for the covalent cross-linking of fibrin fibers and plasmin inhibitor (PI), thus contributing to clot stability. It could be expected that any change of coagulation factors’ structure affects the clot formation and modulate the atherothrombotic risk. The aim was to determine the frequency of four single nucleotide polymorphisms: (i) A>G in codon 312 of the fibrinogen α-chain gene (rs6050, Thr312Ala FGA), (ii) C>T at position 10034 of the 3´untranslated region in the fibrinogen γ-chain gene (rs2066865, 10034C>T FGG), (iii) C>T in codon 564 of the FXIII-A subunit gene (rs5982, Pro564Leu FXIII-A), and (iv) C>T in codon 6 of the plasmin inhibitor gene (rs2070863, Arg6Trp PI) in Croatian patients and their association with coronary artery disease (CAD). Methods: We performed the unrelated case-control association study on the consecutive sample of patients ≥18 years old, who had undergone coronary angiography for investigation of chest pain and suspected CAD. Cases were patients with confirmed CAD (N=201) and controls were the subjects with no CAD (N=119). Samples were genotyped using PCR-RFLP analysis. Results: Observed frequencies of the rare alleles of Thr312Ala FGA, 10034C>T FGG, Leu564Pro FXIII-A and Arg6Trp PI polymorphisms were 21%, 17%, 14%, 20%, respectively. Patients with 10034C> T FGG CC genotype had 3.5 times (95% CI 1.02-12.03) higher adjusted odds for CAD than patients with 10034C> T FGG TT genotype. Patients with Arg6Trp PI CC genotype had 3.86 times (95% CI 1.23-12.12) higher odds for CAD than patients with Arg6Trp PI TT genotype. No difference was observed regarding any other investigated polymorphism, Conclusion: Our finding suggests that 10034C>T FGG and Arg6Trp PI are associated with CAD.

scholarly journals Normalization of Blood Clotting Characteristics Using Prothrombin Complex Concentrate, Fibrinogen and Fxiii In an Albumin Based Fluid: Experimental Studies In Thromboelastometry.

2020 ◽  
Author(s):  
Tobias Koller ◽  
Nadia Kinast ◽  
Andres Guilarte Castellanos ◽  
Sergio Perez Garcia ◽  
Pilar Paniagua Iglesias ◽  
...  
Keyword(s):  
Whole Blood ◽  
Factor Xiii ◽  
Prothrombin Complex Concentrate ◽  
Massive Transfusion ◽  
Experimental Studies ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Fibrinogen Concentrate ◽  
Coagulation Factor Concentrates

Abstract Background: Colloid fluids supplemented with adequate combinations of coagulation factor concentrates with capability to restore coagulation could be a desirable future treatment component in massive transfusion.Methods: Starting from a coagulation factor and blood cell free albumin solution we added Prothrombin Complex Concentrate, Fibrinogen Concentrate and Factor XIII in different combinations and concentrations to analyze their properties to restore thromboelastometry parameters without the use of plasma. Further analysis under presence of platelets was performed for comparability to whole blood conditions.Results: Albumin solutions enriched with Fibrinogen Concentrate, Factor XIII and Prothrombin Complex Concentrate at optimized concentrations show restoring coagulation potential. Prothrombin Complex Concentrate showed sufficient thrombin formation for inducing fibrinogen polymerization. The combination of Prothrombin Complex Concentrate and Fibrinogen Concentrate led to the formation of a stable in vitro fibrin clot. Fibrinogen and Factor XIII showed excellent capacity to improve fibrin clot firmness expressed as Amplitude at 10 minutes and Maximal Clot Firmness. Fibrinogen alone, or in combination with Factor XIII, was able to restore normal Amplitude at 10 minutes and Maximal Clot Firmness values. In the presence of platelets, the thromboelastometry surrogate parameter for thrombin generation (Clotting Time) improves and normalizes when compared to whole blood.Conclusions: Combinations of coagulation factor concentrates suspended in albumin solutions have the capacity to restore thromboelastometry parameters in the absence of plasma. This kind of artificial colloid fluids with coagulation-restoring characteristics might offer new treatment alternatives for massive transfusion.Trial registration: Study registered at the institutional ethic committee “Institut de Recerca, Hospital Santa Creu i Sant Pau, with protocol number IIBSP-CFC-2013-165.

scholarly journals Normalization Of Blood Clotting Characteristics Using Prothrombin Complex Concentrate, Fibrinogen And FXIII In An Albumin Based Fluid: Experimental Studies In Thromboelastometry.

2021 ◽  
Author(s):  
Tobias Koller ◽  
Nadia Kinast ◽  
Andres Guilarte Castellanos ◽  
Sergio Perez Garcia ◽  
Pilar Paniagua Iglesias ◽  
...  
Keyword(s):  
Whole Blood ◽  
Factor Xiii ◽  
Prothrombin Complex Concentrate ◽  
Massive Transfusion ◽  
Experimental Studies ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Fibrinogen Concentrate ◽  
Coagulation Factor Concentrates

Abstract Background: Colloid fluids supplemented with adequate combinations of coagulation factor concentrates with the capability to restore coagulation could be a desirable future treatment component in massive transfusion.Methods: Starting from a coagulation factor and blood cell-free albumin solution we added Prothrombin Complex Concentrate, Fibrinogen Concentrate and Factor XIII in different combinations and concentrations to analyze their properties to restore thromboelastometry parameters without the use of plasma. Further analysis under the presence of platelets was performed for comparability to whole blood conditions.Results: Albumin solutions enriched with Fibrinogen Concentrate, Factor XIII and Prothrombin Complex Concentrate at optimized concentrations show restoring coagulation potential. Prothrombin Complex Concentrate showed sufficient thrombin formation for inducing fibrinogen polymerization. The combination of Prothrombin Complex Concentrate and Fibrinogen Concentrate led to the formation of a stable in vitro fibrin clot. Fibrinogen and Factor XIII showed excellent capacity to improve fibrin clot firmness expressed as Amplitude at 10 minutes and Maximal Clot Firmness. Fibrinogen alone, or in combination with Factor XIII, was able to restore normal Amplitude at 10 minutes and Maximal Clot Firmness values. In the presence of platelets, the thromboelastometry surrogate parameter for thrombin generation (Clotting Time) improves and normalizes when compared to whole blood.Conclusions: Combinations of coagulation factor concentrates suspended in albumin solutions can restore thromboelastometry parameters in the absence of plasma. This kind of artificial colloid fluids with coagulation-restoring characteristics might offer new treatment alternatives for massive transfusion.Trial registration: Study registered at the institutional ethic committee “Institut de Recerca, Hospital Santa Creu i Sant Pau, with protocol number IIBSP-CFC-2013-165.

α-Fibrinogen Thr312Ala polymorphism and venous thromboembolism

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1177-1179 ◽  
Author(s):  
Angela M. Carter ◽  
Andrew J. Catto ◽  
Hans P. Kohler ◽  
Robert A. S. Ariëns ◽  
Max H. Stickland ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Significant Interaction ◽  
Fibrin Clot ◽  
Cross Linking ◽  
Genotype Distribution ◽  
Inverse Association ◽  
Vein Thrombosis ◽  
Control Subjects ◽  
Healthy Control ◽  
Deep Vein

The A-fibrinogen Thr312Ala polymorphism, which occurs in a region involved in factor XIII (FXIII)-dependent cross-linking processes, is associated with poststroke mortality in subjects with atrial fibrillation, suggesting an influence either on intraatrial clot formation or embolization. We have determined the association of Thr312Ala with deep vein thrombosis (DVT) and pulmonary embolism (PE) and have assessed the interaction of Thr312Ala with the FXIII Val34Leu polymorphism in 122 patients with DVT, 99 patients with PE, and 254 healthy control subjects. The genotype distribution of patients with PE (TT = 49%, TA = 36%, AA = 15%), but not DVT (TT = 50%, TA = 42%, AA = 8%), differed significantly from healthy control subjects (TT = 60%, TA = 34%, AA = 6%, P = .02). A significant interaction of Thr312Ala and Val34Leu was also identified (P = .01), indicating an inverse association between Leu34 and Ala312. These results support the hypothesis that Thr312Ala alters FXIII-dependent cross-linking, making formed fibrin clot more susceptible to embolization.

Effect of Val34Leu Polymorphism on the Activation of the Coagulation Factor XIII-A

2000 ◽  
Vol 84 (10) ◽  
pp. 595-600 ◽  
Author(s):  
H. Mikkola ◽  
G. Szôke ◽  
G. Haramura ◽  
L. Kárpáti ◽  
I. Balogh ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Specific Activity ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Coagulation Cascade ◽  
Wild Type ◽  
Subunit A ◽  
Coagulation Factor Xiii

SummaryCoagulation factor XIII (FXIII) is a protransglutaminase involved in the last step of the coagulation cascade by stabilising the fibrin clot. Recently, a common variation (FXIII Val34Leu) has been associated with a decreased risk of myocardial infarction and deep venous thrombosis. Val34Leu is critically located near the thrombin activation site of FXIII-A. In this study we investigated its effects on the activation of FXIII. Both recombinant and platelet-derived FXIII Val34Leu variants were shown to be more susceptible to thrombin cleavage than the wild type FXIII. The rate of enzymatic activation of FXIII Val34Leu was found increased, however, the specific activity of fully activated wild type FXIII and the Val34Leu mutant did not differ. During the course of thrombin-induced activation of FXIII fibrin γ-chain dimerisation and α-chain polymerisation developed more rapidly with the Val34Leu mutant. The increased rate of fibrin stabilisation brought about by the Val34Leu FXIII seems to be paradoxically associated with a protective effect against pathological thrombosis. Abbreviations: AP, activation peptide of factor XIII; FXIII, blood coagulation factor XIII; FXIII-A, factor XIII subunit A; FXIII-A’, proteolytically activated subunit A; FXIII-B, factor XIII subunit B; SDS PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis

scholarly journals The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis

2014 ◽  
Vol 12 (2) ◽  
pp. 197-205 ◽  
Author(s):  
E. L. Hethershaw ◽  
A. L. Cilia La Corte ◽  
C. Duval ◽  
M. Ali ◽  
P. J. Grant ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Coagulation Factor Xiii ◽  
Clot Structure

Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4272-4278 ◽  
Author(s):  
Anetta Undas ◽  
Krystyna Zawilska ◽  
Mariola Ciesla-Dul ◽  
Agata Lehmann-Kopydłowska ◽  
Agnieszka Skubiszak ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Structure Function ◽  
Ex Vivo ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Vein Thrombosis ◽  
Reactive Protein ◽  
History Of ◽  
Deep Vein ◽  
Clot Structure

Abstract We tested the hypothesis that fibrin structure/function is unfavorably altered in patients after idiopathic venous thromboembolism (VTE) and their relatives. Ex vivo plasma fibrin clot permeability, turbidimetry, and efficiency of fibrinolysis were investigated in 100 patients with first-ever VTE, including 34 with pulmonary embolism (PE), 100 first-degree relatives, and 100 asymptomatic controls with no history of thrombotic events. Known thrombophilia, cancer, trauma, and surgery were exclusion criteria. VTE patients and their relatives were characterized by lower clot permeability (P < .001), lower compaction (P < .001), higher maximum clot absorbancy (P < .001), and prolonged clot lysis time (P < .001) than controls, with more pronounced abnormalities, except maximum clot absorbance, in the patients versus relatives (all P < .01). Fibrin clots obtained for PE patients were more permeable, less compact, and were lysed more efficiently compared with deep-vein thrombosis patients (all P < .05) with no differences in their relatives. Being VTE relative, fibrinogen, and C-reactive protein were independent predictors of clot permeability and fibrinolysis time in combined analysis of controls and relatives. We conclude that altered fibrin clot features are associated with idiopathic VTE with a different profile of fibrin variables in PE. Similar features can be detected in VTE relatives. Fibrin properties might represent novel risk factors for thrombosis.

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