Abnormal antithrombin III with defective serine protease binding (antithrombin III "Denver").

Sambrano, JamesE .; Jacobson, L J; Reeve, E. B.; Manco‐Johnson, M. J.; Hathaway, W. E.

doi:10.1172/jci112386

Cited by 30 publications

(7 citation statements)

References 18 publications

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“…Of the remaining 37 studies, 24 reported on type 1 antithrombin III deficiency (1,40-62), 13 on type 2a or b antithrombin III deficiency (63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75), and none on type 2c antithrombin III deficiency. The prevalence of a history of venous thrombotic disease was statistically significantly higher (p < 0.001) in type 1-deficient family members (44%; 85/192) than in nondeficient family members (2%; 6/248) (estimated common odds ratio, 13.7; 95% confidence interval, 8.4-22.5).…”

Section: Resultsmentioning

confidence: 99%

Familial Thrombophilia: A Review Analysis

Belt¹,

Prins²,

Huisman

et al. 1996

Clin Appl Thromb Hemost

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The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable in formation of the risk of spontaneous (unprovoked) throm bosis in these disorders is not available. To determine the best available estimate of the annual incidence of spon taneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we per formed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we re trieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasmino gen, histidine-rich glycoprotein, heparin cofactor II, and fibrinolysis in relation to thrombosis. Publications were included in the analysis if they (1) reported one or more probands with thrombotic disease and a heterozygous biochemical abnormality of the hemostatic system, (2) assessed the presence of this abnormality in family mem bers independent of the presence or absence of a history of thrombotic disease, and (3) assessed the presence of a history of thrombotic disease in all available family mem bers. The biochemical status and clinical details of all family members reported were extracted from each eligi ble article. For each abnormality the odds ratio for throm bosis was compared in family members with and without the biochemical abnormality. If applicable, thrombosis- free survival and age-specific incidences of thrombosis were calculated. The thrombotic episodes were classified as spontaneous or secondary to a recognized risk factor, and the proportion of spontaneous episodes was calcu lated. The influence of diagnostic suspicion bias in symp tomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of throm bosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically signifi cant associations between the presence of a biochemical abnormality and a history of venous thrombosis were found for antithrombin III deficiency types 1 and 2a and 2b, protein C deficiency type 1, and protein S deficiency type I. Dysfibronogenemia was statistically significantly associated with venous as well as arterial thrombosis. Thirty-five to 67% of the events were classified as being provoked, as they occurred following exposure to a rec ognized risk factor for thrombosis. The recalculated an nual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low inci dence does not warrant life-long continuous use of anti coagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral antico agulants is 2-3 and 0.4%/year, respectively.

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Section: Resultsmentioning

confidence: 99%

Familial Thrombophilia: A Review Analysis

Belt¹,

Prins²,

Huisman

et al. 1996

Clin Appl Thromb Hemost

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“…27 All of them have slightly different molecular structures, which give a diminished activity but have a normal concentration. The type 2b deficiencies have an isolated diminution of the serpin activity and were described as AT Aalborg, 28 Vicenza, 29 Hvidove, 30 Denver, 31 Charleville, 32 Milano 2, 33 Pescara, 34 Hamilton, 35 and Avranches. 36 AT 2c abnormalities are characterized by isolated alterations at the heparin binding site.…”

Section: Deficiency Of Atmentioning

confidence: 99%

Hereditary and Acquired Antithrombin Deficiency

Vinazzer¹

1999

Semin Thromb Hemost

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Antithrombin (AT) is the most important inhibitor of activated coagulation enzymes. Deficiency of this protein can be a congenital defect. Different types have been described with a diminution of the entire molecule as well as diminution of activity only with normal concentration and normal activity and concentration but with a decreased sensitivity to heparin. There exist also different types of acquired deficiency due to a diminished production, an increased loss or an increased consumption of the inhibitor. Because AT deficiency is the cause of an increased thrombotic tendency in many cases the therapeutic and prophylactic possibilities are described. Since highly purified concentrates became available, substitution was attempted in cases of AT deficiency. It was found to be of greatest importance in cases of disseminated intravascular coagulation (DIC) which is a frequent consequence of septic or traumatic shock. In such cases an adequate AT-substitution can even be lifesaving as could be shown in different trials.

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“…The presence of two distinct binding sites for thrombin and for heparin was previously reported in normal AT III (2); accordingly, AT III pathological molecular variants frequently show a defective binding to serine proteases (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) or to heparin (I5-ZI), whereas an impairment of both functional activities was found rarely (22)(23)(24).…”

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confidence: 81%

Antithrombin III Molecular Variants with Defective Binding to Heparin or to Serine Proteases: Evidence of Two Different Abnormal Patterns Identified by Crossed Immunoelectrofocusing

et al. 1988

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SummaryMolecular heterogeneity of antithrombin III (AT III) was investigated by a technique of crossed immunoelectrofocusing (CIEF) in plasma samples of patients from 16 families with AT III congenital defect, including 8 AT III molecular variants. The AT III CIEF pattern was normal in all the patients with AT III quantitative deficiency, showing a balanced decrease of all the peaks. Out of the 8 AT III variants investigated, 6 had an abnormal pattern: the three variants with defective binding to heparin (AT III Roma, AT III Barcelona, AT III Malmö) shared a similar abnormal pattern; three variants with defective binding to serine proteases (AT III Pescara, AT III Milano, AT III Tampere) had a common abnormal pattern clearly different from the first one, whereas the other two variants deficient in the inactivation of the serine proteases (AT III Chicago, AT III Milano 2) showed a normal pattern. The first type of pathological pattern (type Roma) was characterized by the presence of an abnormal peak overlapping the normal isoforms present at pH 4.8-4.6 and by an additional peak at pH 4.5. The second type of pattern (type Pescara) showed an additional peak at pH 4.5 and an abnormal quantitative distribution of the isoantithrombins all throughout the pH range (5.2-4.6). In order to separate the abnormal AT III fraction from the normal one, plasma of a patient with Roma defect and serum of a patient with Pescara defect were passed throughout an heparin-ultrogel column. The CIEF of the different AT III Roma and AT III Pescara fractions obtained by affinity chromatography confirmed that the abnormalities found in the corresponding patterns of the native samples were related to the pathological isoantithrombins only. It was concluded that the CIEF can be an useful tool to characterize abnormal antithrombins and can reveal close affinities among AT III molecular variants belonging to different subgroups according to the conventional tests.

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Abnormal antithrombin III with defective serine protease binding (antithrombin III "Denver").

Cited by 30 publications

References 18 publications

Familial Thrombophilia: A Review Analysis

Familial Thrombophilia: A Review Analysis

Hereditary and Acquired Antithrombin Deficiency

Antithrombin III Molecular Variants with Defective Binding to Heparin or to Serine Proteases: Evidence of Two Different Abnormal Patterns Identified by Crossed Immunoelectrofocusing

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