Summary: Fibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen’s structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen’s and factor XIII’s function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control.

Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis (RA) in the Japanese population. Such an association could not previously be confirmed in different European populations. In the present study, we analysed exons 2–4 of PADI4 in 102 German RA patients and 102 healthy individuals to study the influence of PADI4 variability on RA susceptibility by means of haplotype-specific DNA sequencing. Analyses of the influence of PADI4 and HLA-DRB1 genotypes on disease activity and on levels of anti-cyclic citrullinated peptide antibodies were performed.Comparing the frequencies of PADI4 haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) (patients, 14.7%; controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1–3.8) and carriers of this haplotype (patients, 27.5%; controls, 13.7%; odds ratio = 2.4, 95% confidence interval = 1.2–4.8), a significant positive association of PADI4 haplotype 4 with RA could be demonstrated. Other PADI4 haplotypes did not differ significantly between patients and controls. Regarding the individual PADI4 variants, padi4_89 (A→G), padi4_90 (C→T), and padi4_94 (C→T) were significantly associated with RA (patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95% confidence interval = 1.1–2.3). Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated. While the PADI4 genotype did not influence disease activity and the anti-cyclic citrullinated peptide antibody level, the presence of the HLA-DRB1 shared epitope was significantly associated with higher anti-cyclic citrullinated peptide antibody levels (P = 0.033).The results of this small case–control study support the hypothesis that variability of the PADI4 gene may influence susceptibility to RA in the German population. Quantitative or qualitative differences in previously undefined PADI4 variants between patients and controls could not be demonstrated.

The factor VII–activating protease (FSAP) variant Marburg I is known to attenuate the profibrinolytic system in vitro and was recently shown to be a significant predictor for the evolution and progression of carotid stenosis. The objective of this case-control study was to assess FSAP Marburg I9s role in the occurrence of venous thromboembolism (VTE). The frequency of FSAP Marburg I was significantly increased in patients with a history of VTE (17 of 213 patients, 8.0%, P = .014) or idiopathic VTE (12 of 103 patients, 11.7%, P = .002) compared to healthy controls (5 of 213 controls, 2.3%). Logistic regression analysis confirmed FSAP Marburg I to be an independent risk factor for VTE (odds ratio, 3.5; 95% confidence interval [CI], 1.2-10.0) and idiopathic VTE (odds ratio, 6.2; 95% CI, 2.0-18.9).

Presence of antiphospholipid antibodies (aPL) is associated with unsuccessful pregnancy outcome. Based on an early concept of aPL-induced thrombophilia and placental thrombosis, antithrombotic interventions have been used to reduce incidence of miscarriage in antiphospholipid antibody syndrome (APS). The aim of this review is to summarize current knowledge on pathogenesis of miscarriage in APS and the impact of different antithrombotic therapy strategies. Pathogenetic concepts on miscarriage in APS comprise aPL-mediated cell activation, disturbance of coagulation along with increased complement activation. There is increasing evidence that heparin exerts its effect by inhibiting complement activation rather than by its anticoagulation capacity. In this regard, the outcome of pregnancies in APS has considerably improved by the invention of therapies using combinations of aspirin, unfractionated heparin (UFH) and/or low molecular weight heparin (LMWH). However, there is no clear evidence as to which treatment regimen should be preferred. Some studies indicate superiority of aspirin plus heparin over aspirin-only. Whether heparin-only treatment would confer equal effects and whether UFH and LMWH were of comparable efficacy currently is unknown. Treatment with aspirin and heparin decreases the risk of miscarriages in APS. Well designed trials as well as better patients-at-risk profiling are warranted that identify which treatment strategy should be favored and whether detailed characterization of aPL specificities could help in individualizing therapy.

Background: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anti-cyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. Objectives: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. Methods: 373 patients with RA were studied. SE, padi4_94C>T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. Results: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C>T genotype (C/C: OR_adj = 0.93, p_adj = 0.92; C/T: OR_adj = 2.92, p_adj = 0.093; T/T: OR_adj = 15.3, p_adj = 0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C>T with ANAs was observed, with noteworthy differences depending on SE status (SE−: OR_adj = 6.20, p_adj<0.04; SE+: OR_adj = 0.36, p_adj = 0.02) and significant heterogeneity between the two SE strata (p = 0.006). Conclusions: PADI4 genotype in combination with anti-CCPs and SE modulates clinical and serological characteristics of RA.

Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced bya multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to givea detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, β-fibrinogen –455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1–675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy- Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.