Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent antithrombin deficiency

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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

Hematology ◽

10.1182/asheducation.v2005.1.1.1 ◽

2005 ◽

Vol 2005 (1) ◽

pp. 1-12 ◽

Cited By ~ 5

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.

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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 ◽

10.1182/blood.v85.10.2756.bloodjournal85102756 ◽

1995 ◽

Vol 85 (10) ◽

pp. 2756-2761 ◽

Cited By ~ 226

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.

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

Thrombosis and Haemostasis ◽

10.1160/th15-11-0871 ◽

2016 ◽

Vol 116 (07) ◽

pp. 146-154 ◽

Cited By ~ 14

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.

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Antithrombin-α for the prophylaxis of venous thrombosis in congenital antithrombin deficiency

Expert Review of Hematology ◽

10.1586/ehm.09.43 ◽

2009 ◽

Vol 2 (5) ◽

pp. 499-507 ◽

Cited By ~ 2

Author(s):

Andrew Fyfe ◽

R Campbell Tait

Keyword(s):

Venous Thrombosis ◽

Antithrombin Deficiency

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First trimester superior sagittal sinus venous thrombosis and antithrombin deficiency

Journal of Obstetrics and Gynaecology ◽

10.1080/01443610500335530 ◽

2005 ◽

Vol 25 (8) ◽

pp. 808-810 ◽

Cited By ~ 2

Author(s):

W. J. MCAuley ◽

B. J. Hunt ◽

H. N. Ahmad ◽

K. Harding ◽

C. Nelson-Piercy

Keyword(s):

Venous Thrombosis ◽

Superior Sagittal Sinus ◽

First Trimester ◽

Antithrombin Deficiency ◽

Sagittal Sinus ◽

Sinus Venous Thrombosis

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Early onset of abdominal venous thrombosis in a newborn with homozygous type II heparin-binding site antithrombin deficiency

Blood Coagulation & Fibrinolysis ◽

10.1097/mbc.0000000000000570 ◽

2017 ◽

Vol 28 (3) ◽

pp. 264-266 ◽

Cited By ~ 2

Author(s):

Mirjana Kovac ◽

Gorana Mitic ◽

Milos Jesic ◽

Valentina Djordjevic ◽

Laszlo Muszbek ◽

...

Keyword(s):

Venous Thrombosis ◽

Binding Site ◽

Early Onset ◽

Type Ii ◽

Heparin Binding ◽

Antithrombin Deficiency ◽

Heparin Binding Site

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Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 antithrombin deficiency (antithrombin Krakow)

Thrombosis and Haemostasis ◽

10.1160/th11-02-0066 ◽

2011 ◽

Vol 106 (08) ◽

pp. 379-381 ◽

Cited By ~ 9

Author(s):

Magdalena Celinska-Lowenhoff ◽

Teresa Iwaniec ◽

Martine Alhenc-Gelas ◽

Jacek Musial ◽

Anetta Undas

Keyword(s):

Venous Thrombosis ◽

Fibrin Clot ◽

Antithrombin Deficiency

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Factor V Gene Mutation Is a Risk Factor for Cerebral Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650284 ◽

1996 ◽

Vol 75 (03) ◽

pp. 393-394 ◽

Cited By ~ 95

Author(s):

I Martinelli ◽

G Landi ◽

G Merati ◽

R Cella ◽

A Tosetto ◽

...

Keyword(s):

Venous Thrombosis ◽

Cerebral Venous Thrombosis ◽

Protein C ◽

Dna Analysis ◽

Protein S ◽

Factor V ◽

Antithrombin Deficiency ◽

Apc Resistance ◽

Factor V Gene ◽

V Gene

SummaryTo evaluate the association between coagulation defects and cerebral venous thrombosis, a case-control study was conducted in 25 patients who had no autoimmune, neoplastic or infectious disease and 75 healthy individuals. There were no patients with deficiency of protein C or protein S. Four had resistance to activated protein C (APC) and one had APC resistance associated with antithrombin deficiency. APC resistance was investigated by DNA analysis, and diagnosed by the presence of a point mutation in the factor V gene, which predicts replacement of Arg506 with Gin at one of the two APC cleavage sites in activated factor V. The prevalence of APC resistance was 20% in patients and 2.7% in controls. This difference was statistically significant (p = 0.01) and the odds ratio was 9.1. A circumstantial factor predisposing to cerebral venous thrombosis (such as oral contraceptive intake, pregnancy, puerperium, trauma or prolonged immobilization) was reported in 72% of cases. In conclusion, APC resistance is the most frequent coagulation abnormality associated with cerebral venous thrombosis.

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