Protein C Inhibitor

Meijers, Joost C. M.; Herwald, Heiko

doi:10.1055/s-0031-1276583

Cited by 31 publications

(20 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 Moreover, we show strongly decreased protein C inhibitor levels in TB-patients. Since this protein can be used as a marker for APC-activation, 17 these data suggest that the availability of APC is altered during pulmonary TB. Altogether we provide clear evidence that lung TB is associated with an impairment of anticoagulant mechanisms at the systemic level.…”

Section: Discussionmentioning

confidence: 91%

“…The calculated TATc/protein C ratio was increased in primary TB patients (P < 0.001, data not shown), which illustrates a misbalance in pro-and anticoagulant factors, representing a net procoagulant state. Levels of protein C inhibitor, a sensitive marker for activated protein C (APC) generation, 17 were significantly decreased in both primary and recurrent TB patients (Fig. 3C).…”

Section: Systemic Coagulation Is Activated In Patients With Pulmonary Tbmentioning

confidence: 99%

See 1 more Smart Citation

Pulmonary tuberculosis induces a systemic hypercoagulable state

Kager

Blok

Lede

et al. 2015

Journal of Infection

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 91%

Section: Systemic Coagulation Is Activated In Patients With Pulmonary Tbmentioning

confidence: 99%

Pulmonary tuberculosis induces a systemic hypercoagulable state

Kager

Blok

Lede

et al. 2015

Journal of Infection

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…This gene is located on human chromosome 14 at position 14q32.1 and codes the protein C inhibitor (PCI), a member of the plasma serine protease inhibitor family [30]. While originally it was discovered as an inhibitor of activated protein C, today PCI is known to play a role in many biological processes beyond hemostasis and thrombosis including inflammation, innate immunity, carcinogenesis, and fertilization [30]–[33]. Recent proteomic analysis of human multiple sclerosis lesions by sensitive mass spectrometry implicated PCI in the development of chronic active plaques and suggested an unexpected intersection between coagulation and inflammation [34].…”

Section: Discussionmentioning

confidence: 99%

Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer

et al. 2013

View full text Add to dashboard Cite

Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (PRegion and PPathway) were assessed by combining individual PSNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (PSNP-FDR/PSNP-trend = 0.02/6×10−6 and PSNP-FDR/PSNP-trend = 0.04/2×10−5, respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (PRegion-FDR/PRegion = 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (PPathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.

show abstract

“…APC, a serine protease derived from its plasma precursor protein C (PC) in a thrombin dependent process [12], plays a critical role in inactivating the non-enzymatic cofactor components of both the prothrombinase and the intrinsic tenase complexes, factors Va and VIIIa, respectively [13-15]. Additional key components of the PC pathway include: thrombomodulin and endothelial protein C receptor (EPCR) which contribute to APC formation [16]; protein S which functions as a cofactor enhancing APC efficacy [17]; and protein C inhibitor, a suppressor of APC formation [18,19]. …”

Section: Introductionmentioning

confidence: 99%

Modeling of human factor Va inactivation by activated protein C

et al. 2012

View full text Add to dashboard Cite

BackgroundBecause understanding of the inventory, connectivity and dynamics of the components characterizing the process of coagulation is relatively mature, it has become an attractive target for physiochemical modeling. Such models can potentially improve the design of therapeutics. The prothrombinase complex (composed of the protease factor (F)Xa and its cofactor FVa) plays a central role in this network as the main producer of thrombin, which catalyses both the activation of platelets and the conversion of fibrinogen to fibrin, the main substances of a clot. A key negative feedback loop that prevents clot propagation beyond the site of injury is the thrombin-dependent generation of activated protein C (APC), an enzyme that inactivates FVa, thus neutralizing the prothrombinase complex. APC inactivation of FVa is complex, involving the production of partially active intermediates and “protection” of FVa from APC by both FXa and prothrombin. An empirically validated mathematical model of this process would be useful in advancing the predictive capacity of comprehensive models of coagulation.ResultsA model of human APC inactivation of prothrombinase was constructed in a stepwise fashion by analyzing time courses of FVa inactivation in empirical reaction systems with increasing number of interacting components and generating corresponding model constructs of each reaction system. Reaction mechanisms, rate constants and equilibrium constants informing these model constructs were initially derived from various research groups reporting on APC inactivation of FVa in isolation, or in the presence of FXa or prothrombin. Model predictions were assessed against empirical data measuring the appearance and disappearance of multiple FVa degradation intermediates as well as prothrombinase activity changes, with plasma proteins derived from multiple preparations. Our work integrates previously published findings and through the cooperative analysis of in vitro experiments and mathematical constructs we are able to produce a final validated model that includes 24 chemical reactions and interactions with 14 unique rate constants which describe the flux in concentrations of 24 species.ConclusionThis study highlights the complexity of the inactivation process and provides a module of equations describing the Protein C pathway that can be integrated into existing comprehensive mathematical models describing tissue factor initiated coagulation.

show abstract

Protein C Inhibitor

Cited by 31 publications

References 58 publications

Pulmonary tuberculosis induces a systemic hypercoagulable state

Pulmonary tuberculosis induces a systemic hypercoagulable state

Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer

Modeling of human factor Va inactivation by activated protein C

Contact Info

Product

Resources

About