scholarly journals Familial Thrombosis Due to Antithrombin III Deficiency

Blood ◽  
1974 ◽  
Vol 43 (2) ◽  
pp. 219-231 ◽  
Author(s):  
Ewa Marciniak ◽  
Claude H. Farley ◽  
Philip A. DeSimone
Keyword(s):  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Oral Anticoagulants ◽  
Laboratory Diagnosis ◽  
Blood Component ◽  
History Of ◽  
Antithrombin Iii Deficiency ◽  
Recurrent Venous Thrombosis

Abstract A large kindred from eastern Kentucky, with extensive history of recurrent venous thrombosis and pulmonary embolism, was studied. Low antithrombin III titers, ranging from 26% to 49% of normal values, were found in plasma of nine members in three consecutive generations; another five members, four of whom were not available for study, are suspected of having the biochemical defect. There was a good correlation between clinical symptoms and antithrombin III deficiency, although three of the younger members with the defect still remained free of thrombosis. In serum of the affected subjects antithrombin III was almost completely utilized, which indicates that stoichiometric binding to coagulation enzymes dominates under biological conditions. Antithrombin and antifactor Xa activities residing in the macroglobulin region of plasma and serum remained unchanged. The responsiveness to heparin in vitro and in vivo confirmed the evidence that antithrombin III is the sole blood component through which heparin exerts its anticoagulant effect. In five affected members therapy with oral anticoagulants increased very significantly the level of antithrombin III in plasma and contributed to a remarkable increase of residual antithrombin III in serum. This objective improvement after warfarin therapy may create significant difficulties in the laboratory diagnosis of antithrombin III deficiency.

The Prevalence of Hereditary Antithrombin-III Deficiency in Patients with a History of Venous Thromboembolism

1985 ◽  
Vol 54 (04) ◽  
pp. 744-745 ◽  
Author(s):  
R Vikydal ◽  
C Korninger ◽  
P A Kyrle ◽  
H Niessner ◽  
I Pabinger ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii ◽  
Positive Family History ◽  
Normal Range ◽  
The Family ◽  
History Of ◽  
Antithrombin Iii Deficiency ◽  
Recurrent Venous Thrombosis ◽  
Antithrombin Iii Activity ◽  
Slight Deficiency

SummaryAntithrombin-III activity was determined in 752 patients with a history of venous thrombosis and/or pulmonary embolism. 54 patients (7.18%) had an antithrombin-III activity below the normal range. Among these were 13 patients (1.73%) with proven hereditary deficiency. 14 patients were judged to have probable hereditary antithrombin-III deficiency, because they had a positive family history, but antithrombin-III deficiency could not be verified in other members of the family. In the 27 remaining patients (most of them with only slight deficiency) hereditary antithrombin-III deficiency was unlikely. The prevalence of hereditary antithrombin-III deficiency was higher in patients with recurrent venous thrombosis.

scholarly journals Hereditary Antithrombin III Deficiency. Evidence of Increased Thrombin Formation in the Early Stage of Hemostasis

1977 ◽  
Author(s):  
F. Josso ◽  
M. H. Aurousseau ◽  
A. M. Fischer ◽  
M. D. Dautzenberg ◽  
S. Beguin
Keyword(s):  
Antithrombin Iii ◽  
Early Stage ◽  
Young Male ◽  
Massive Pulmonary Embolism ◽  
New Family ◽  
Mild Deficiency ◽  
Antithrombin Iii Deficiency ◽  
Thrombin Formation

High incidence of thromboembolism in observed in families with antithrombin III deficiency, despite the rather moderate defect (25 to 50 per cent) observed in the affected subjects, considered as heterozygous for the disease. The mechanism by which such a mild deficiency may promote thrombosis still remains unknown.A new family with antirhrombin III deficiency is reported, including three affected generations. Three young male adults of a same sibship died from massive pulmonary embolism aged from 22 to 28 years. In four living members of the family, three of which had antecedents of thrombophlebitis, antithrombin III level was close to 50 per cent by all assay methods used. Electro-phoretic and immunochemical studies failed to demonstrate any qualitative defect of the antithrombin III molecule.In these patients the only abnormalities of hemostasis lied in the early stage of the hemostatic pathway. In vitro, thrombin formation occured very rapidly after initiation of coagulation, as demonstrated by the kinetics of thrombin generation and factors V and VIII activation. In vivo, factors V and VIII were activated during bleeding much more rapidly than in controls and this activation was not suppressed by low doses of heparin (10 u./kg) as in the controls.These findings indicate that antithrombin III acts chiefly in the regulation balance of the early stages of hemostasis and thrombosis.

Adverse Effect of Heparin on Thrombin Inactivation

1975 ◽  
Author(s):  
E. Marciniak
Keyword(s):  
Adverse Effect ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Binding Properties ◽  
Inhibitory Capacity ◽  
Antithrombin Iii Deficiency ◽  
Final Amount ◽  
Native Plasma

In the presence of heparin thrombin, although fast inactivated, impairs the inhibitory capacity of antithrombin III, in result of which the final amount of neutralized enzyme markedly decreases. This adverse effect of heparin was found during the reaction of purified thrombin with both purified human antithrombin III and native plasma hepariniz purified thrombin with both purified human antithrombin III and native plasma heparinized in vitro or in vivo. In the absence of heparin, at concentration equal to that in normal plasma antithrombin III binds 450 Iowa units of thrombin; in the presence of heparin (at 1 unit concentration) this binding is reduced to 145 thrombin units. A fast depletion of inhibitory capacity is also evident after a stepwise addition of thrombin in small installments into a medium containing antithrombin III and heparin. Portions of enzyme initially added disappear with great velocity; subsequent additions, however, accumulate building up a high thrombin level not seen in the absence of heparin. The escalation of thrombin is reversely proportional to the reacting antithrombin III level, thus especially noticeable in antithrombin III deficient plasma. Residual thrombin left in the presence of heparin disappears at a fast rate upon a new addition of antithrombin III. No decrease in anticoagulant properties of heparin is observed during these interactions. Binding of factor Xa to antithrombin III which reacted with thrombin and heparin is also decreased or abolished.These results indicate that in the presence of heparin thrombin not only exposes rapidly a binding site on the inhibitor, but also causes a further change leading to the deletion of antithrombin III binding properties. This may explain adverse, thrombotic effect of heparin sporadically seen in vivo, and suggests that heparin should be applied with caution in patients with antithrombin III deficiency.

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group [see comments]

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 33-39 ◽  
Author(s):  
D Menache ◽  
JP O'Malley ◽  
JB Schorr ◽  
B Wagner ◽  
C Williams ◽  
...  
Keyword(s):  
Half Life ◽  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Cooperative Study Group ◽  
Significant Difference ◽  
At Iii ◽  
Thrombotic Complications ◽  
Antithrombin Iii Deficiency

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

scholarly journals Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group [see comments]

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 33-39 ◽  
Author(s):  
D Menache ◽  
JP O'Malley ◽  
JB Schorr ◽  
B Wagner ◽  
C Williams ◽  
...  
Keyword(s):  
Half Life ◽  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Cooperative Study Group ◽  
Significant Difference ◽  
At Iii ◽  
Thrombotic Complications ◽  
Antithrombin Iii Deficiency

Abstract Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Potentially Thrombogenic Materials in Factor IX Concentrates

1975 ◽  
Vol 33 (03) ◽  
pp. 617-631 ◽  
Author(s):  
H. S Kingdon ◽  
R. L Lundblad ◽  
J. J Veltkamp ◽  
D. L Aronson
Keyword(s):  
Human Plasma ◽  
Antithrombin Iii ◽  
Factor Ix ◽  
In Vitro Assays ◽  
Substantial Agreement ◽  
Coefficient Of Correlation

SummaryFactor IX concentrates manufactured from human plasma and intended for therapeutic infusion in man have been suspected for some time of being potentially thrombogenic. In the current studies, assays were carried out in vitro and in vivo for potentially thrombogenic materials. It was possible to rank the various materials tested according to the amount of thrombogenic material detected. For concentrates not containing heparin, there was substantial agreement between the in vivo and in vitro assays, with a coefficient of correlation of 0.77. There was no correlation between the assays for thrombogenicity and the antithrombin III content. We conclude that many presently available concentrates of Factor IX contain substantial amounts of potentially thrombogenic enzymes, and that this fact must be considered in arriving at the decision whether or not to use them therapeutically.

Effects of Heparin Oligosaccharides with High Affinity for Antithrombin III in Experimental Venous Thrombosis

1982 ◽  
Vol 47 (03) ◽  
pp. 244-248 ◽  
Author(s):  
D P Thomas ◽  
Rosemary E Merton ◽  
T W Barrowcliffe ◽  
L Thunberg ◽  
U Lindahl
Keyword(s):  
Antithrombin Iii ◽  
Specific Activity ◽  
High Specific Activity ◽  
Factor Xa ◽  
Blood Levels ◽  
Thrombin Time ◽  
High Affinity ◽  
Very High

SummaryThe in vitro and in vivo characteristics of two oligosaccharide heparin fragments have been compared to those of unfractionated mucosal heparin. A decasaccharide fragment had essentially no activity by APTT or calcium thrombin time assays in vitro, but possessed very high specific activity by anti-Factor Xa assays. When injected into rabbits at doses of up to 80 ¼g/kg, this fragment was relatively ineffective in impairing stasis thrombosis despite producing high blood levels by anti-Xa assays. A 16-18 monosaccharide fragment had even higher specific activity (almost 2000 iu/mg) by chromogenic substrate anti-Xa assay, with minimal activity by APTT. When injected in vivo, this fragment gave low blood levels by APTT, very high anti-Xa levels, and was more effective in preventing thrombosis than the decasaccharide fragment. However, in comparison with unfractionated heparin, the 16-18 monosaccharide fragment was only partially effective in preventing thrombosis, despite producing much higher blood levels by anti-Xa assays.It is concluded that the high-affinity binding of a heparin fragment to antithrombin III does not by itself impair venous thrombogenesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential.

Heparin

1985 ◽  
Vol 05 (03) ◽  
pp. 121-126
Author(s):  
L. B. Jaques
Keyword(s):  
Lipoprotein Lipase ◽  
Antithrombin Iii

ZusammenfassungIn vivo bewirkt Heparin das Auftreten einer Lipoprotein-Lipase, einer Diaminoxydase (Histaminase) und anderer Enzyme. In Tierversuchen konnten viele günstige Wirkungen von Heparin und Heparinoiden aufgezeigt werden, wie z.B. Schutzeffekte gegen toxische Medikamente und Prozeduren, gegen Überempfindlichkeitsreaktionen, Änderungen von Hormoneffekten und die Erhöhung der negativen elektrischen Ladung von Körperzellen. Die Einzelwirkungen sind für bestimmte Kettenstrukturen spezifisch. Während Heparin in vitro gerinnungshemmend wirksam ist, zeigt der Vergleich der gerinnungshemmenden Wirkung in der Blutzirkulation mit der chemischen Konzentration im Blut, daß in vivo eine Aktivierung von nicht gerinnungshemmend aktiven Fraktionen bzw. Heparinketten erfolgt. Heparin wird rasch von den Zellen des RES-Systems gegen einen Konzentrationsgradienten aufgenommen, so daß in vivo die Heparinkonzentration im Gefäßendothel lOOOfach höher ist als im Blut.Die Fixierung des Heparins im Endothel vermehrt das elektronegative Potential des Endothels. Diese Wirkung und andere Wirkungen (die Aktivierung von Antithrombin III etc.) sind lokal die Basis der thromboseverhütenden Heparinwirkung. Demnach ist das Endothel das Zielorgan für Heparin.

Congenital Antithrombin III Deficiency in 3 Families (7 Affected Members)

1979 ◽  
Author(s):  
J. Conard ◽  
M. Samama ◽  
M. H. Horellou ◽  
B. Cazenave ◽  
P. Griguer ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Antithrombin Iii ◽  
Oral Anticoagulants ◽  
Vena Cava ◽  
Oral Contraception ◽  
Vein Thrombosis ◽  
Heparin Treatment ◽  
At Iii ◽  
Antithrombin Iii Deficiency ◽  
Deep Vein

A congenital Antithrombin III (AT III) deficiency affecting 7 members of 3 families is reported.The first throrabo-embolic accidents were observed between the age of 22 and 35 : they were spontaneous or occured after delivery or oral contraception. in one patient, a deep vein thrombosis was observed during heparin treatment. in 2 cases, recurrent pulmonary embolic episodes required vena cava ligation. No thromboembolic accident was observed during oral anticoagulation.AT III was measured by an amidolytic method and by the Mancini method on plasma and serum ; the antithrombin activity was determined on serum by the von Kaulla method. in 7 patients, a decreased AT III was found by all the methods performed. The AT III level was around 50 % in patients treated or not by oral anticoagulants One patient was studied during heparin treatment and then under oral anticoagulants : AT III levels were lower under heparin.

Thrombogenicity of the Injured Vessel Wall – Role of Antithrombin and Heparin

1994 ◽  
Vol 71 (01) ◽  
pp. 147-153 ◽  
Author(s):  
Siw Frebelius ◽  
Ulf Hedin ◽  
Jesper Swedenborg
Keyword(s):  
Vessel Wall ◽  
Antithrombin Iii ◽  
Rabbit Aorta ◽  
Continuous Treatment ◽  
Balloon Injury ◽  
Coagulant Activity ◽  
Risk For Thrombosis ◽  
Inhibition Of Thrombin

SummaryThe thrombogenicity of the vessel wall after endothelial denudation is partly explained by an impaired inhibition of thrombin on the subendothelium. We have previously reported that thrombin coagulant activity can be detected on the vessel wall after balloon injury in vivo. The glycosaminoglycans of the subendothelium differ from those of the endothelium and have a lower catalyzing effect on antithrombin III, but inhibition of thrombin can still be augmented by addition of antithrombin III to the injured vessel surface.In this study the effect of antithrombin III and heparin on thrombin coagulant activity on the vessel wall was studied after in vivo balloon injury of the rabbit aorta using biochemical and immunohistochemical methods and thrombin was analysed after excision of the vessel. Continuous treatment with heparin, lasting until sacrifice of the animal, or treatment with antithrombin III resulted in significant reduction of thrombin coagulant activity on the injured aorta. Heparin given only in conjunction with the injury did not prevent thrombin coagulant activity or deposition of fibrin on the surface.The capacity of the injured vessel wall to inhibit thrombin in vitro was improved on aortic segments obtained from animals receiving antithrombin III but not from those given heparin. It is concluded that treatment with antithrombin III interferes with thrombin appearance on the vessel wall after injury and thereby reduces the risk for thrombosis.

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