High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin

Brouwer, Jasperina; Lijfering, Willem M.; Kate, Min Ki ten; Kluin‐Nelemans, Hanneke C.; Veeger, Nic J. G. M.; Meer, Jan van der

doi:10.1160/th08-06-0364

Cited by 124 publications

(117 citation statements)

References 25 publications

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“…The relative risk of VTE in patients with AT deficiency was estimated to be approximately 25-50-fold [29][30][31][32]. AT deficiency also represents an increased risk of pulmonary embolism and recurrence of VTE [16,33,34]. The clinical phenotype of type II-HBS AT deficiency is different from that of type I, and other type II AT deficiencies [19,35,36].…”

Section: Discussionmentioning

confidence: 99%

“…Anti-FXa determinations were also performed on the plasma samples from 24 first-degree relatives of the patients, in which causative AT mutation was excluded by DNA sequencing. The reference sample group consisted of 188 apparently healthy individuals, 104 females and 84 males, median age: 34 [interquartile range (IQR): [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Exclusion criteria for the healthy group were the history of arterial and venous thrombosis and, in the case of women, being on oral contraceptive or pregnancy.…”

Section: Subjectsmentioning

confidence: 99%

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Progressive chromogenic anti-factor Xa assay and its use in the classification of antithrombin deficiencies

Kovács¹,

Bereczky

Selmeczi

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: Antithrombin (AT) is a slow-acting progressive inhibitor of activated clotting factors, particularly thrombin and activated factor X (FXa). However, the presence of heparin or heparan sulfate accelerates its effect by several magnitudes. AT deficiency, a severe thrombophilia, is classified as type I (quantitative) and type II (qualitative) deficiency. In the latter case mutations may influence the reactive site, the heparin binding-site (HBS) and exert pleiotropic effect. Heterozygous type II-HBS deficiency is a less severe thrombophilia than other heterozygous subtypes. However, as opposed to other subtypes, it also exists in homozygous form which represents a very high risk of venous thromboembolism. Methods: A modified anti-FXa chromogenic AT assay was developed which determines both the progressive (p) and the heparin cofactor (hc) activities, in parallel. The method was evaluated and reference intervals were established. The usefulness of the assay in detecting type II-HBS AT deficiency was tested on 78 AT deficient patients including 51 type II-HBS heterozygotes and 18 homozygotes. Results: Both p-anti-FXa and hc-anti-FXa assays showed excellent reproducibility and were not influenced by high concentrations of triglyceride, bilirubin and hemoglobin. Reference intervals for p-anti-FXa and hc-anti-FXa AT activities were 84%-117% and 81%-117%, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Progressive chromogenic anti-factor Xa assay and its use in the classification of antithrombin deficiencies

Kovács¹,

Bereczky

Selmeczi

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…In an Italian study of patients with proximal DVT, the risk of pulmonary embolism (PE) was 2.4-fold (95% CI: 1.61-3.63) in AT deficient patients compared to individuals who developed DVT without inherited thrombophilia (50). In AT deficiency, the annual incidence of recurrent VTE was found to be 10% (95% CI: 6.1%-15.4%) in a recently released Dutch study (51). In an Italian cohort, the adjusted hazard ratio for the recurrence of VTE was 1.9 (95% CI: 1.0-3.9) (52).…”

Section: Epidemiology Of Antithrombin Deficiencymentioning

confidence: 99%

Antithrombin deficiency and its laboratory diagnosis

Muszbek¹,

Bereczky²,

Kovács³

et al. 2010

Clinical Chemistry and Laboratory Medicine

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Antithrombin (AT) belongs to the serpin family and is a key regulator of the coagulation system. AT inhibits active clotting factors, particularly thrombin and factor Xa; its absence is incompatible with life. This review gives an overview of the protein and gene structure of AT, and attempts to explain how glucosaminoglycans, such as heparin and heparan sulfate accelerate the inhibitory reaction that is accompanied by drastic conformational change. Hypotheses on the regulation of blood coagulation by AT in physiological conditions are discussed. Epidemiology of inherited thrombophilia caused by AT deficiency and its molecular genetic background with genotype-phenotype correlations are summarized. The importance of the classification of AT deficiencies and the phenotypic differences of various subtypes are emphasized. The causes of acquired AT deficiency are also included in the review. Particular attention is devoted to the laboratory diagnosis of AT deficiency. The assay principles of functional first line laboratory tests and tests required for classification are discussed critically, and test results expected in various AT deficiency subtypes are summarized. The reader is provided with a clinically oriented algorithm for the correct diagnosis and classification of AT deficiency, which could be useful in the practice of routine diagnosis of thrombophilia.

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“…Data on natural anticoagulant deficiencies are less extensive, because only a few studies with a limited number of patients have assessed the risk of VTE recurrence associated with these thrombophilic abnormalities, suggesting limited effects on the risk of recurrent VTE [16]. However, a recent study reported a higher risk of VTE recurrence during follow-up in patients with deficiencies of natural anticoagulants compared with the risk of recurrence in the general VTE population [21]. Inherited thrombophilia has also been implicated in pregnancy complications, such as recurrent miscarriage, foetal death, preeclampsia and intra-uterine growth retardation, although a causal association is still controversial [22].…”

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confidence: 99%

The utility of thrombophilia testing

Franchini

2014

Clinical Chemistry and Laboratory Medicine

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Abstract:In the past decades, the recognition of several inherited thrombophilic traits has greatly improved our knowledge of the pathogenesis of venous thromboembolism, explaining about half of all idiopathic cases. As a consequence, thrombophilia testing has enormously increased in the past years for various clinical conditions. In this paper, the current indications of the most commonly tested thrombophilic abnormalities (i.e., Factor V Leiden, prothrombin G20210A mutation, protein C, S and antithrombin deficiencies) are analysed. When used appropriately thrombophilia testing has a positive impact on the health care of the people tested and their relatives.Keywords: Factor V Leiden; inherited thrombophilia; prothrombin mutation; testing. In the past five decades our knowledge on the aetiology of venous thromboembolism (VTE) has dramatically improved [1][2][3]. Indeed, the recognition of a number of inherited coagulation abnormalities, first the deficiencies of natural anticoagulant proteins C and S and then the gain-of-function mutations Factor V Leiden and prothrombin G20210A [4][5][6][7][8], has allowed the identification of a thrombophilic defect in at least 50% of cases with idiopathic VTE. Accordingly, the number of patients tested for thrombophilia has exponentially increased in the last years, despite the usefulness and cost-effectiveness of testing still remains a matter of debate [9,10]. Table 1 shows epidemiological data and association with risk of VTE of the most commonly tested thrombophilic defects. Overall, literature data shows that deficiencies of natural anticoagulant proteins are relatively rare ( < 0.5% in the general population), but are associated with a more severe thrombophilic tendency, with an increased risk of 5-10-fold and annual incidence of VTE > 1% [11]. Conversely, Factor V Leiden and prothrombin G20210A polymorphisms are more common abnormalities, with a prevalence of about 5% in the general population and up to 50% of patients with VTE, especially in studies on familial thrombophilia [12]. However, these mutations are associated with a lower increase of risk (2-5-fold) and incidence of VTE ( < 0.5% per year). Notably, patients carrying homozygous Factor V Leiden or combined defects show a more severe phenotype, with a 20-50-fold increased risk and an earlier onset of first VTE or recurrence. Interestingly, the different thrombotic risks associated with thrombophilic traits interplay in different manners with concomitant acquired conditions (see below) for development of VTE. Thus, a higher prevalence of unprovoked VTE (55%-60%) is observed in patients with natural anticoagulant deficiencies, who frequently show the first thrombotic event before 45 years of age. Globally, approximately 50% of subjects with antithrombin deficiency will have developed a VTE episode by 50 years of age. Conversely, patients with Factor V Leiden often develop the first VTE episode after 45 years of age, most frequently in association with acquired (triggering) risk factors such trauma, surgery, pre...

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High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin

Cited by 124 publications

References 25 publications

Progressive chromogenic anti-factor Xa assay and its use in the classification of antithrombin deficiencies

Progressive chromogenic anti-factor Xa assay and its use in the classification of antithrombin deficiencies

Antithrombin deficiency and its laboratory diagnosis

The utility of thrombophilia testing

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