Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency

2016 ◽  
Vol 116 (07) ◽  
pp. 146-154 ◽  
Author(s):  
José Navarro-Fernández ◽  
María Morena-Barrio ◽  
José Padilla ◽  
Antonia Miñano ◽  
Nataliya Bohdan ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Thrombotic Event ◽  
Type I ◽  
Antithrombin Deficiency ◽  
Amino Terminal ◽  
Thrombosis Risk ◽  
Functional Consequences ◽  
Low Incidence ◽  
Two Populations

SummaryThe key haemostatic role of antithrombin and the risk of thrombosis associated with its deficiency support that the low incidence of antithrombin deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient antithrombin deficiency. SERPINC1 was sequenced in 214 cases with a positive test for antithrombin deficiency, including 67 with no deficiency in the sample delivered to our laboratory. The p.Val30Glu mutation (Antithrombin Dublin) was identified in five out of these 67 cases, as well as in three out of 127 cases with other SERPINC1 mutations. Genotyping in 1593 patients with venous thrombosis and 2592 controls from two populations, revealed a low prevalent polymorphism (0.3 %) that moderately increased the risk of venous thrombosis (OR: 2.9; 95 % CI: 1.07–8.09; p= 0.03) and identified one homozygous patient with an early thrombotic event. Carriers had normal anti-FXa activity, and plasma antithrombin was not sensitive to heat stress or proteolytic cleavage. Analysis of one sample with transient deficit revealed a type I deficiency, without aberrant or increased latent forms. The recombinant variant, which lacked the two amino-terminal residues, had reduced secretion from HEK-EBNA cells, formed hyperstable disulphidelinked polymers, and had negligible activity. In conclusion, p.Val30Glu by affecting the cleavage of antithrombin’s signal peptide, results in a mature protein lacking the N-terminal dipeptide with no functional consequences in normal conditions, but that increases the sensitivity to be folded intracellularly into polymers, facilitating transient antithrombin deficiency and the subsequent risk of thrombosis.

Role of the amino-terminal extrahelical region of type I collagen in directing the 4D overlap in fibrillogenesis

Biopolymers ◽  
1979 ◽  
Vol 18 (12) ◽  
pp. 3005-3014 ◽  
Author(s):  
Donald L. Helseth ◽  
Joseph H. Lechner ◽  
Arthur Veis
Keyword(s):  
Type I Collagen ◽  
Type I ◽  
Amino Terminal

scholarly journals Venous Thrombosis: The Role of Genes, Environment, and Behavior

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Frits R. Rosendaal
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein S ◽  
Behavioral Risk ◽  
Antithrombin Deficiency ◽  
Increased Risk ◽  
Environment And Behavior ◽  
And Behavior ◽  
Subsequent Identification

Abstract Over the last decade we have witnessed an avalanche of newly identified risk factors for venous thrombosis. This has advanced our knowledge of its etiology, because more determinants have been described and because the underlying concepts have received a new and broader understanding. Venous thrombosis is a common multicausal disease occurring as the result of interacting genetic, environmental and behavioral risk factors. Some of these have been known since medieval times, such as the increased risk of thrombosis during immobilization in pregnancy and after childbirth (although retained milk of the breast-feeding mother was seen as the primary cause for the latter). Pregnancy and puerperium still cause thrombosis, as do exogenous hormones in oral contraceptives and hormonal replacement therapy. Furthermore, the immobilization in the puerperium of the old days translates directly to situations of immobilization in current times, such as prolonged travel in airplanes or excessive electronic gaming. While pedigrees with abundant thrombosis were observed in the early 1900s, the first cause of heritable thrombophilia (antithrombin deficiency) was discovered in 1965, with the subsequent identification of deficiencies of protein C and protein S in the early 1980s. These were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors.

scholarly journals Kisspeptin Neurons from Mice to Men: Similarities and Differences

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5105-5118 ◽  
Author(s):  
Robert L. Goodman ◽  
Michael N. Lehman
Keyword(s):  
Strong Evidence ◽  
Species Differences ◽  
Mammalian Species ◽  
Limited Area ◽  
Sexually Dimorphic ◽  
Functional Consequences ◽  
Similarities And Differences ◽  
Reproductive Neuroendocrinology ◽  
Two Populations

Abstract The discovery that kisspeptin was critical for normal fertility in humans ushered in a new chapter in our understanding of the control of GnRH secretion. In this paper, we will review recent data on the similarities and differences across several mammalian species in the role of kisspeptin in reproductive neuroendocrinology. In all mammals examined to date, there is strong evidence that kisspeptin plays a key role in the onset of puberty and is necessary for both tonic and surge secretion of GnRH in adults, although kisspeptin-independent systems are also apparent in these studies. Similarly, two groups of kisspeptin neurons, one in the arcuate nucleus (ARC) and the other more rostrally, have been identified in all mammals, although the latter is concentrated in a limited area in rodents and more scattered in other species. Estrogen has divergent actions on kisspeptin expression in these two regions across these species, stimulating it the latter and inhibiting expression in the former. There is also strong evidence that the rostral population participates in the GnRH surge, whereas the ARC population contributes to steroid-negative feedback. There may be species differences in the role of these two populations in puberty, with the ARC cells important in rats, sheep, and monkeys, whereas both have been implicated in mice. ARC kisspeptin neurons also appear to participate in the GnRH surge in sheep and guinea pigs, whereas the data on this possibility in rodents are contradictory. Similarly, both populations are sexually dimorphic in sheep and humans, whereas most data in rodents indicate that this occurs only in the rostral population. The functional consequences of these species differences remain to be fully elucidated but are likely to have significance for understanding normal neuroendocrine control of reproduction as well as for use of kisspeptin agonists/antagonists as a therapeutic tool.

scholarly journals Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2756-2761 ◽  
Author(s):  
T Koster ◽  
FR Rosendaal ◽  
E Briet ◽  
FJ van der Meer ◽  
LP Colly ◽  
...  
Keyword(s):  
Relative Risk ◽  
Venous Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Population Based ◽  
Repeated Measurements ◽  
Protein C Deficiency ◽  
Antithrombin Deficiency ◽  
Vein Thrombosis ◽  
Thrombosis Risk

A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.

Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency

2017 ◽  
Vol 117 (06) ◽  
pp. 1040-1051 ◽  
Author(s):  
Martine Alhenc-Gelas ◽  
Genevieve Plu-Bureau ◽  
Justine Hugon-Rodin ◽  
Veronique Picard ◽  
Marie-Helene Horellou ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Lower Risk ◽  
Thrombotic Event ◽  
Type I ◽  
Adjusted Relative Risk ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Thrombotic Risk ◽  
Mutation Carriers ◽  
Increase Risk

SummaryInherited quantitative (type I) or qualitative (type II) antithrombin deficiency (ATD) due to mutations in the SERPINC1 gene is a well-known risk factor for venous thromboembolism. ATD may also increase risk for arterial thrombosis. Few studies have investigated risk for thrombosis according to mutations. We addressed this topic in a large retrospective cohort study of 540 heterozygous carriers of SERPINC1 mutations and compared risk for first venous or arterial thrombosis associated with carrying of different type II or type I mutations. No clear difference in risk for first venous thrombotic event was observed among type I (missense or null), type IIRS or type IIPE mutation carriers except for a few variants that displayed lower risk [all events, adjusted relative risk: Cambridge II: 0.42 (95%CI 0.25–0.70), Dublin: 0.35 (95%CI 0.13–0.99)]. IIHBS mutation carrying was associated with a clearly lower risk than type I mutation carrying [0.28 (95%CI 0.20–0.40)]. These differences in risk were observed for both all venous thrombotic events and pulmonary embolism associated with deep venous thrombosis. The HBS group was also heterogeneous, with AT Budapest 3 carriers displaying a non-significantly different risk [0.61 (95%CI 0.31–1.20)] compared to type I mutation carriers. We also studied risk for arterial thrombosis and found no significant influence of mutation type. Altogether, our findings suggest a place for SERPINC1 genotyping in the diagnosis of ATD.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Serum Sclerostin Levels Are Decreased in Adult Patients With Different Types of Osteogenesis Imperfecta

2014 ◽  
Vol 99 (2) ◽  
pp. E311-E319 ◽  
Author(s):  
Roland Kocijan ◽  
Christian Muschitz ◽  
Astrid Fahrleitner-Pammer ◽  
Karin Amrein ◽  
Peter Pietschmann ◽  
...  
Keyword(s):  
Body Composition ◽  
Mineral Content ◽  
Adult Patients ◽  
Type I ◽  
Healthy Controls ◽  
Amino Terminal ◽  
Type I Procollagen ◽  
Different Types ◽  
Turnover Markers

Context: There are no specific biochemical bone markers available for osteogenesis imperfecta (OI), and the role of sclerostin as a key regulator of bone formation in OI is unknown. Objectives: We aimed to evaluate the role of sclerostin and its association with bone turnover markers as well as body composition parameters in adult patients with different types of OI. Design, Setting, and Participants: This was a case-control study in 27 adult patients and 50 healthy age- and gender-matched controls. Main Outcome Measures: Serum sclerostin levels and bone turnover markers including serum osteocalcin, amino terminal propeptide of type I procollagen, and CrossLaps as well as body composition parameters were determined in mild OI stage I (OI-I) and moderate-severe OI stages III-IV (OI-III-IV), according to Sillence classification. Data were compared with healthy controls. Results: Sclerostin levels were significantly lower in OI-I (19.9 ± 10.9 pmol/L; P < .001) and OI-III-IV (13.3 ± 10.0 pmol/L; P < .001) compared with healthy adults (45.3 ± 14.9 pmol/L), even after adjustment for age, sex, bone mineral content, and body mass index. CrossLaps and PTH were significantly lower in OI-I (0.197 ± 0.15 ng/L; P = .007 and 33.7 ± 19.1 pg/L; P = .033, respectively) and OI-III-IV (0.221 ± 0.18 ng/L; P = .039, and 27.9 ± 14.7 pg/L; P = .001, respectively) than in healthy controls (0.322 ± 0.15 ng/L and 45.0 ± 16.6 pg/L). Amino-terminal propeptide of type I procollagen was below the reference range for OI-I and OI-III-IV. Patients with OI were shorter and lighter and had a decreased bone mineral content (P < .001) but similar fat distribution and lean body mass, compared with controls. Serum sclerostin levels were not related to any bone marker except osteocalcin, the number of prevalent fractures, or body composition readings. Conclusion: Decreased sclerostin levels in OI might reflect a down-regulation or negative feedback mechanism to prevent further bone loss.

Venous Thrombosis: The Role of Genes, Environment, and Behavior

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Frits R. Rosendaal
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein S ◽  
Behavioral Risk ◽  
Antithrombin Deficiency ◽  
Increased Risk ◽  
Environment And Behavior ◽  
And Behavior ◽  
Subsequent Identification

Over the last decade we have witnessed an avalanche of newly identified risk factors for venous thrombosis. This has advanced our knowledge of its etiology, because more determinants have been described and because the underlying concepts have received a new and broader understanding. Venous thrombosis is a common multicausal disease occurring as the result of interacting genetic, environmental and behavioral risk factors. Some of these have been known since medieval times, such as the increased risk of thrombosis during immobilization in pregnancy and after childbirth (although retained milk of the breast-feeding mother was seen as the primary cause for the latter). Pregnancy and puerperium still cause thrombosis, as do exogenous hormones in oral contraceptives and hormonal replacement therapy. Furthermore, the immobilization in the puerperium of the old days translates directly to situations of immobilization in current times, such as prolonged travel in airplanes or excessive electronic gaming. While pedigrees with abundant thrombosis were observed in the early 1900s, the first cause of heritable thrombophilia (antithrombin deficiency) was discovered in 1965, with the subsequent identification of deficiencies of protein C and protein S in the early 1980s. These were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors.

Past provoking venous thrombosis risk situations on the risk of a recurrent thrombotic event: A cohort study

2011 ◽  
Vol 128 (3) ◽  
pp. 227-232 ◽  
Author(s):  
Daniel D. Ribeiro ◽  
Willem M. Lijfering ◽  
Sandhi M. Barreto ◽  
Izabella B.R. Silva ◽  
Mariana M.B.S. Chalup ◽  
...  
Keyword(s):  
Cohort Study ◽  
Venous Thrombosis ◽  
Thrombotic Event ◽  
Thrombosis Risk

Cerebral Venous Thrombosis During Pregnancy in the Setting of Type I Antithrombin Deficiency: Case Report and Literature Review.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4447-4447
Author(s):  
Christopher J. Sharpe ◽  
Mark A. Crowther ◽  
Kathryn E Webert
Keyword(s):  
Venous Thrombosis ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Molecular Weight Heparin ◽  
Low Molecular Weight ◽  
Type I ◽  
Successful Pregnancy ◽  
Advisory Committees ◽  
Antithrombin Deficiency ◽  
History Of

Abstract Abstract 4447 Antithrombin is a serine protease inhibitor that primarily inactivates thrombin and factor Xa as well as multiple other coagulation factors. Hereditary deficiency of antithrombin is associated with a 50%-lifetime risk of venous thrombosis. For women who are antithrombin deficient, each single pregnancy and puerperium also carries a 50% risk of a venous thrombotic complication, with the majority of episodes occurring post-partum. Lower extremity thrombosis is most common but unusual sites such as the central nervous system may also be involved. Although there have been previous reports of successful pregnancy outcomes in antithrombin-deficient women without the use of prophylactic anticoagulation in the form of unfractionated heparin or low molecular weight heparin, current treatment guidelines state that asymptomatic women with hereditary antithrombin deficiency should receive thromboprophylaxis during pregnancy. However, the indications for the use of antithrombin concentrate are less defined and current guidelines do not mandate their use during pregnancy in the absence of an episode of venous thromboembolism. Some authors have advocated that antithrombin should be maintained at adequate levels in women with documented antithrombin deficiency throughout the course of pregnancy and the puerperium, while others have recommended normalization of antithrombin levels during the time of delivery only. The use of plasma-derived antithrombin concentrate is controversial considering its expense as well as issues with the frequency and route of administration (daily intravenous injection) and serial monitoring of antithrombin levels. We present a case of a female with a family history of antithrombin deficiency in multiple first-degree relatives and a documented personal history of Type I antithrombin deficiency who presented with a central nervous system transverse sinus thrombosis in the third trimester of pregnancy despite the use of prophylactic therapeutic doses of low molecular weight heparin since conception. Once the cerebral venous thrombosis was diagnosed, a successful pregnancy outcome was achieved with the combined use of therapeutic anticoagulation and antithrombin concentrate to normalize antithrombin levels. This case further illustrates the highly thrombophilic state that exists in the setting of pregnancy and concomitant antithrombin deficiency and lends further debate to the issue of whether antithrombin concentrate, in addition to anticoagulation, should be routinely administered for venous thromboembolic prophylaxis during pregnancy and puerperium to women with documented antithrombin deficiency. This point may become more relevant as further experience is gained with the use of recombinant human antithrombin. Disclosures: Crowther: BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Artisan Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Webert:Baxter: Research Funding.

Increased Levels of Factor VIII and Fibrinogen in Patients with Venous Thrombosis Are not Caused by Acute Phase Reactions

1999 ◽  
Vol 81 (05) ◽  
pp. 680-683 ◽  
Author(s):  
Pieter Kamphuisen ◽  
Jeroen Eikenboom ◽  
Hans Vos ◽  
Renee Pablo ◽  
Auguste Sturk ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Viii ◽  
Acute Phase ◽  
Inflammatory Responses ◽  
Thrombotic Event ◽  
First Episode ◽  
Phase Reaction ◽  
Thrombosis Risk ◽  
Increased Risk ◽  
Acute Phase Reactions

SummaryFactor VIII activity (factor VIII:C) levels ≥150 IU/dl are associated with a 5- to 6-fold increased risk of venous thrombosis compared to levels <100 IU/dl, and fibrinogen levels ≥5.0 g/l increase the thrombosis risk 4-fold. These high levels are present in 25% resp. 3% of the patients with a first episode of venous thrombosis. These findings were based on measurements after the thrombotic event, so the factor VIII and fibrinogen levels in thrombosis patients may have been influenced by acute phase reactions or ongoing inflammatory responses. In the present study we measured plasma C-reactive protein (CRP) as a sensitive marker of an acute phase reaction in 474 thrombosis patients and 474 age- and sex-matched healthy controls, that were part of the Leiden Thrombophilia Study (LETS). Mean and median CRP levels were higher in thrombosis patients than in the controls, suggesting inflammation in some patients. CRP affected both factor VIII and fibrinogen levels, in patients and controls alike. After adjustment for the effect of CRP, high factor VIII:C levels still increased the thrombosis risk 6-fold and high fibrinogen levels 4-fold, which is for both very similar to the risk before correction for CRP levels. These results show that although systemic inflammation may be present in some of the patients, elevated levels of factor VIII:C and fibrinogen were in general not caused by acute phase reactions. This further supports a causal relationship between both high factor VIII:C and fibrinogen levels and venous thrombosis.

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