Hereditary antithrombin deficiency in pregnancy – severe thrombophilic disorder as a danger for mother and foetus

2021 ◽  
Vol 86 (3) ◽  
pp. 175-182
Author(s):  
Irena Čápová ◽  
◽  
Peter Salaj ◽  
Ingrid Hrachovinová
Keyword(s):  
Case Reports ◽  
Concomitant Administration ◽  
Type I ◽  
Antithrombin Deficiency ◽  
Thromboembolic Risk ◽  
Different Types ◽  
Estimated Risk ◽  
At Deficiency ◽  
Regulation Of Synthesis ◽  
In Pregnancy

Summary Setting: In the article, we remember the role of antithrombin (AT) in hemostasis, escalation of AT-potential with heparin and difficulties with monitoring the effectiveness of LMWH therapy (low molecular weight heparin) in patients with AT deficiency. We pay most of our attention to hereditary AT deficiency and its thromboembolic risk in pregnancy. Methods: In the introduction, the principle of AT function, its two main domains and the regulation of synthesis are cleared. We describe the causal mutations of hereditary AT deficiency in SERPINC1 gen and the relation to a thromboembolic risk. The general recommendations for patients with hereditary AT deficiency and pregnant women are mentioned. As the risk of thromboembolic disease is escalated in pregnancy, the LMWH should always be considered. There has been frequently observed that patients with AT deficiency do not elevate anti-Xa-levels when standard prophylactic LMWH doses are used. This fact well illustrates that heparin without AT may not inhibit the active coagulant factors efficiently enough. Therefore, if a high thromboembolic risk in the patient’s anamnesis is present, the LMWH dosing should be escalated. In individual cases, concomitant administration of an antithrombin concentrate to the heparin treatment is recommended at the time of delivery or in the case of deep venous thrombosis. In this article, three cases of unusual pregnancy in patients with different types of AT deficiency are reported. The case reports are summarized from the Department of Hematology at Hospital Kolín, the Centre of Hemostasis and Thrombosis at Institute of Hematology and Blood Transfusion in Prague and from cooperating obstetrical departments in the Czech Republic. Results: We demonstrated the threat of hereditary AT deficiency in three case reports. In one case, the estimated risk of thromboembolism – type I of AT-deficiency (quantitative) – was in a good correlation with real peripartal complications. In the next two cases with different types of AT deficiency, we showed surprising courses of complicated pregnancies. Conclusion: As it has been shown, it is not safe to estimate the risk of thromboembolism on the base of causal mutation for AT deficiency. For present clinical practice, we should still remember AT deficiency as a potentially very dangerous thromboembolic disorder for mother and fetus; thus, excellent cooperation of an obstetrician and a hematologist is necessary.

The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families

1998 ◽  
Vol 80 (09) ◽  
pp. 376-381 ◽  
Author(s):  
W. Lissens ◽  
S. Seneca ◽  
P. Capel ◽  
B. Chatelain ◽  
P. Meeus ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gene Deletion ◽  
Direct Sequencing ◽  
Genetic Defect ◽  
Polymorphism Analysis ◽  
Type I ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Venous Thromboembolic Events ◽  
At Deficiency

SummaryThe molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed.DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intronexon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect.

Molecular analysis and genotype-phenotype correlation in patients with antithrombin deficiency from Southern Italy

2012 ◽  
Vol 107 (04) ◽  
pp. 673-680 ◽  
Author(s):  
Giuseppe Castaldo ◽  
Anna Cerbone ◽  
Anna Guida ◽  
Igor Tandurella ◽  
Rosaria Ingino ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Southern Italy ◽  
Stop Codon ◽  
Type I ◽  
Missense Mutations ◽  
Type Ii ◽  
Clinical Expression ◽  
Antithrombin Deficiency ◽  
At Deficiency ◽  
Molecular Bases

SummaryWe sequenced the SERPINC1 gene in 26 patients (11 males) with antithrombin (AT) deficiency (22 type I, 4 type II), belonging to 18 unrelated families from Southern Italy. Heterozygous mutations were identified in 15/18 (83.3%) families. Of them, eight were novel mutations, each being identified in one family. Seven clearly cause impaired protein synthesis (four frameshift, one non-stop, one splicing and one 21bp deletion). One, present in a single patient, is a missense mutation thought to be causative because: a) it is absent in 100 chromosomes from controls; b) it involves a highly conserved amino acid, whose change is predicted to impair AT activity; c) no other mutation is present in the propositus. Severe mutations (i.e. nonsense, frameshift, deletions) were invariably identified in type I patients. In type II patients, 3/4 were missense mutations; the fourth leads to a 19 nucleotides shift in the stop codon. In addition to the type of mutation, the co-existence of other predisposing factors in most patients helps explain the severity of the present type I cases (age at first event, recurrence during prophylaxis). In the five families in which there was more than one member affected, the same genotype and a concordant clinical expression of the disease were found. We conclude that the molecular bases of AT deficiency in Southern Italy are different as compared to other geographic areas, and that molecular analysis and the study of the effect of the mutation may help predict the clinical expression of the disease.

Creation of an Additional Glycosylation Site as a Mechanism for Type I Antithrombin Deficiency

2001 ◽  
Vol 86 (10) ◽  
pp. 1023-1027 ◽  
Author(s):  
Krzysztof Lewandowski ◽  
Robin Olds ◽  
Alison Fitches
Keyword(s):  
Molecular Weight ◽  
Glycosylation Site ◽  
Base Substitution ◽  
Type I ◽  
Antithrombin Deficiency ◽  
Expression Studies ◽  
Glycan Chain ◽  
Reticulocyte Lysate ◽  
History Of ◽  
At Deficiency

SummaryWe report the identification of a new mutation resulting in type I antithrombin (AT) deficiency and the mechanism by which the deficiency arose. The single base substitution of G to A at nucleotide 2709 was identified in a proband with a family history of venous thrombosis. The mutation results in a substitution of 82 Ser by Asn, creating a new glycosylation site. Expression studies were then carried out, to confirm Asn-linked glycosylation occurred at this consensus site and that this resulted in the AT deficient phenotype. Cell-free translations using rabbit reticulocyte lysate in the presence of microsomes demonstrated that the 82 Asn variant was post-translationally processed efficiently. The 82 Asn variant protein was of a higher molecular weight than normal AT, consistent with the addition of a fifth glycan chain. Incubation of translation product with endoglycosidase H, confirmed that the higher molecular weight product had resulted from additional carbohydrate. Expression of the 82 Asn variant in COS-7 cells resulted in intracellular accumulation, with a low level of secretion of the protein into culture supernatant, consistent with type I AT deficiency. The addition of an extra carbohydrate side chain to residue 82 of antithrombin may block post-translational folding, trapping the variant intracellulary.

Molecular mechanisms of antithrombin deficiency in two Chinese families

2005 ◽  
Vol 94 (12) ◽  
pp. 1172-1176 ◽  
Author(s):  
Rong-Fu Zhou ◽  
Qi-Hua Fu ◽  
Wen-Bin Wang ◽  
Shuang Xie ◽  
Jin Dai ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Sequencing ◽  
Type I ◽  
Wild Type ◽  
Antithrombin Deficiency ◽  
Chinese Families ◽  
Real Time Quantitative Pcr ◽  
Intracellular Degradation ◽  
Phenotype Analysis ◽  
At Deficiency

SummaryWe investigated the molecular mechanisms responsible for type I congenital antithrombin (AT) deficiency in two unrelated Chinese pedigrees manifesting multiple site venous thrombosis. Phenotype analysis showed both probands had almost 50% of normal AT levels. Direct sequencing of amplified DNA revealed 2757C>T in proband 1 and 13328G>A in proband 2, predicting a heterozygous Thr98Ile (T98I) and Ala404Thr (A404T), respectively. No proband had 20210A allele or factorV Leiden mutation. Transient expression of complementary DNA coding for the mutations in COS-7 cells showed impaired secretion of the mutant molecules. Real-time quantitative PCR indicated that the mutant AT mRNA was transcribed at a similar or even higher level as that of wild-type (wt). Pulse-chase labeling studies suggested both AT variants did not accumulate, but degraded intracellularly. Immunohistochemical staining of the transfected cells revealed that CHO cells expressing the AT-I98 mutant were stained diffusely without perinuclear enhancement and cells expressing AT-T404 mutant mainly in the whole cytoplasm with weaker perinuclear enhancement. We conclude that the impaired secretion of the mutant AT molecules, due to intracellular degradation, is the molecular pathogenesis of AT deficiency caused by T98I and A404T mutation for the two families, respectively.

Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency

2014 ◽  
Vol 111 (02) ◽  
pp. 249-257 ◽  
Author(s):  
Anna Pavlova ◽  
Christof Geisen ◽  
Michael Spannagl ◽  
Frauke Bergmann ◽  
Manuela Krause ◽  
...  
Keyword(s):  
Lower Risk ◽  
Type I ◽  
Missense Mutations ◽  
Type Ii ◽  
Antithrombin Deficiency ◽  
Vein Thrombosis ◽  
At Deficiency ◽  
Deficiency Type ◽  
Deep Vein ◽  
The Impact

SummaryMutations in the antithrombin (AT) gene can impair the capacity of AT to bind heparin (AT deficiency type IIHBS), its target proteases such as thrombin (type IIRS), or both (type IIPE). Type II AT deficiencies are almost exclusively caused by missense mutations, whereas type I AT deficiency can originate from missense or null mutations. In a retrospective cohort study, we investigated the impact of the type of mutation and type of AT deficiency on the manifestation of thromboembolic events in 377 patients with hereditary AT deficiencies (133 from our own cohort, 244 reported in the literature). Carriers of missense mutations showed a lower risk of venous thromboembolism (VTE) than those of null mutations (adjusted hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.27–0.58, p<0.001), and the risk of VTE was significantly decreased among patients with type IIHBS AT deficiency compared to patients with other types of AT deficiency (HR 0.23, 95%CI 0.13–0.41, p<0.001). The risk of pulmonary embolism complicating deep-vein thrombosis was lower in all type II AT deficiencies compared to type I AT deficiency (relative risk 0.69, 95%CI 0.56–0.84). By contrast, the risk of arterial thromboembolism tended to be higher in carriers of missense mutations than in those with null mutations (HR 6.08-fold, 95%CI 0.74–49.81, p=0.093) and was 5.9-fold increased (95%CI 1.22–28.62, p=0.028) in type IIHBS versus other types of AT deficiency. Our data indicate that the type of inherited AT defect modulates not only the risk of thromboembolism but also the localisation and encourage further studies to unravel this phenomenon.

Impaired Cotranslational Processing as a Mechanism for Type I Antithrombin Deficiency

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4671-4676
Author(s):  
Alison C. Fitches ◽  
Ruth Appleby ◽  
David A. Lane ◽  
Valerio De Stefano ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
Signal Peptide ◽  
Mammalian Cells ◽  
Novel Mutation ◽  
Secretory Proteins ◽  
Type I ◽  
Wild Type ◽  
Antithrombin Deficiency ◽  
Hydrophobic Domain ◽  
At Deficiency ◽  
Hydrophobic Nature

Most secretory proteins, including antithrombin (AT), are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). We have identified a novel mutation, 2436T→C L(-10)P, which affects the central hydrophobic domain of the AT signal peptide, in a proband presenting with venous thrombotic disease and type I AT deficiency. We investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT cDNAs with mutations affecting the –10 residue. Glycosylated AT was secreted from COS-7 cells transfected with wild-type AT, –10L deletion, -10V or -10M variants, but not variants with P, T, R, or G at -10. Cell-free expression of wild-type and variant AT cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for ER. Variant AT proteins with P, T, R, or G at residue –10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested they had not been translocated into microsomes. Our results suggest that the ability of AT signal peptide to direct the protein to ER for cotranslational processing events appears to be critically dependent on maintaining the hydrophobic nature of the region including residue –10. The investigations have defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT deficiency.

Impaired Cotranslational Processing as a Mechanism for Type I Antithrombin Deficiency

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4671-4676 ◽  
Author(s):  
Alison C. Fitches ◽  
Ruth Appleby ◽  
David A. Lane ◽  
Valerio De Stefano ◽  
Giuseppe Leone ◽  
...  
Keyword(s):  
Signal Peptide ◽  
Mammalian Cells ◽  
Novel Mutation ◽  
Secretory Proteins ◽  
Type I ◽  
Wild Type ◽  
Antithrombin Deficiency ◽  
Hydrophobic Domain ◽  
At Deficiency ◽  
Hydrophobic Nature

Abstract Most secretory proteins, including antithrombin (AT), are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). We have identified a novel mutation, 2436T→C L(-10)P, which affects the central hydrophobic domain of the AT signal peptide, in a proband presenting with venous thrombotic disease and type I AT deficiency. We investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT cDNAs with mutations affecting the –10 residue. Glycosylated AT was secreted from COS-7 cells transfected with wild-type AT, –10L deletion, -10V or -10M variants, but not variants with P, T, R, or G at -10. Cell-free expression of wild-type and variant AT cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for ER. Variant AT proteins with P, T, R, or G at residue –10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested they had not been translocated into microsomes. Our results suggest that the ability of AT signal peptide to direct the protein to ER for cotranslational processing events appears to be critically dependent on maintaining the hydrophobic nature of the region including residue –10. The investigations have defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT deficiency.

Infantile SVT in Consequence of a Congenital Antithrombin Deficiency

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5260-5260
Author(s):  
Susan Halimeh ◽  
Stephan Dreher ◽  
Thorsten Rosenbaum ◽  
Martin Rekus ◽  
Hannelore Rott ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Care Center ◽  
Residual Activity ◽  
Hereditary Disease ◽  
Type I ◽  
Antithrombin Deficiency ◽  
Health Care Center ◽  
Function Loss ◽  
Different Types ◽  
Deficiency Type

Abstract Abstract 5260 The liver-made antithrombin is a natural coagulation inhibitor in human blood. Exceptionally it takes effect in inhibiting the coagulation-supporting factors IIa (thrombin) and Xa. A congenital antithrombin deficiency leads to thrombosis and has to be heterozygous, because homozygous ATIII deficiencies are incompatible with life. Unfortunately it's dominant inherited. In 1965 a congenital ATIII deficiency was first detected as a hereditary disease. There are two different types, type I describes a less produced ATIII deficiency, type II is a function loss of ATIII. Special testing can define more subclasses. In cases of congenital ATIII deficiency, vascular blockage (thrombosis) appears, especially in leg veins. Released clots can cause pulmonal embolism, rarely are other arteries affected. Although this disease is hereditary, it appears mostly between ages of 15 'til 30. Clinical trials showed that 80% of affected patient have a thrombosis or embolism until the age of 40. Has there be no kind of illness appeared until there, it's very improbable to get one becaus eof ATIII deficiency. Every hundredth below the age of 70, who comes to a health care center has a ATIII deficiency. In total population it's a freqzuency of 1:2000 until 1:5000. Mostly there's a deficiency nown in familary history why they are investigated. The residual activity is between 40 – 60%. Conclusion: Most cases of thrombosis are treated with heparine. Heparin binds to ATIII, so ATIII can be much more effective and inhibits thrombin and Xa much more intense. For the future we have to make sure that antithrombin deficiencies especially in childhood have to be treated with phenprocumone. Disclosures: No relevant conflicts of interest to declare.

Methionine-Specific Staining of Collagen

1982 ◽  
Vol 40 ◽  
pp. 294-295
Author(s):  
E.M. Kuhn ◽  
K.D. Marenus ◽  
M. Beer
Keyword(s):  
Amino Acids ◽  
Collagen Fibers ◽  
Type Iii Collagen ◽  
Type I ◽  
Electron Microscopic ◽  
Good Correspondence ◽  
Specific Staining ◽  
Type Iii ◽  
Different Types ◽  
Sulfur Containing

Fibers composed of different types of collagen cannot be differentiated by conventional electron microscopic stains. We are developing staining procedures aimed at identifying collagen fibers of different types.Pt(Gly-L-Met)Cl binds specifically to sulfur-containing amino acids. Different collagens have methionine (met) residues at somewhat different positions. A good correspondence has been reported between known met positions and Pt(GLM) bands in rat Type I SLS (collagen aggregates in which molecules lie adjacent to each other in exact register). We have confirmed this relationship in Type III collagen SLS (Fig. 1).

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