Antithrombin-III-Konzentrate: Klinische Anwendung*

ZusammenfassungSeit kurzer Zeit stehen hochgereinigte, kommerziell hergestellte AT-III-Konzentrate für die klinische Erprobung und teilweise auch zur therapeutischen Anwendung zur Verfügung. Bezüglich ihres In-vivo-Verhal-tens scheinen sie gleichwertig zu sein. Über ihre klinische Wirksamkeit existieren allerdings noch keine größeren kontrollierten Studien. Aus bisherigen Untersuchungsergebnissen kann bereits eine vorläufige Wertung über weitgehend gesicherte und wahrscheinliche Indikationen zur Verabreichung von AT-III-Konzentraten aufgestellt werden.Klare Indikationen zur AT-III-Substitution sind der angeborene und erworbene AT-III-Mangel, wenn eine akute tiefe Venenthrombose oder eine Pulmonalembolie eine gerinnungshemmende Therapie erforderlich macht oder in Situationen erhöhter Thrombosegefährdung eine prophylaktische, niedrig dosierte Heparintherapie angezeigt ist.Eine mögliche Indikation zur AT-III-Substitution ist die klinisch relevante disseminierte intravaskuläre Gerinnung mit nachgewiesenem AT-III-Mangel, bei welcher bisher mit einer alleinigen Heparintherapie kein klinischer Erfolg erzielt werden konnte, jedoch von einer wirksamen Anti-koagulation zu erwarten wäre. Wahrscheinlich erfolgversprechend ist die AT-III-Substitution beim akuten Leberversagen, wenn Hoffnung auf eine Regeneration des Leberparenchyms besteht. Unter AT-III-Substitution und niedrigdosierter Heparintherapie konnten ohne intravasale Gerinnungskomplikationen Prothrombinkom-plexkonzentrate substituiert, sowie auch extrakorporale Blutreinigungsverfahren effektiver und komplikationsärmer durchgeführt werden. Eine weitere, erfolgversprechende Indikation ist die prophylaktische Substitution bei Patienten mit Leberzirrhose, wenn ein peritoneo-jugularer Shunt angelegt werden soll oder das Hämo-stasesystem mit Faktorenkonzentraten vor und nach großen operativen Eingriffen normalisiert werden muß. Über weitere mögliche Indikationen existieren bisher nur kasuistisch positive Berichte. Empfehlungen zur AT-III-Substitution können in diesen Fällen nur für gut geplante klinische Studien abgegeben werden.Ungeachtet dessen kann in Einzelfällen in Situationen mit AT-III-Mangel, D.I.G. und lebensbedrohlicher Erkrankung der Therapieversuch mit AT-III-Konzentrat auch absolut indiziert sein. Um aus solchen Situationen lernen zu können ist aber eine ausreichende Dokumentation wünschenswert.

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In Vitro Characterization of Rabbit Thrombin, Antithrombin III, and Thrombin-Antithrombin III Complex, and Determination of Their Survival Times in Vivo

10.1055/s-0039-1682652 ◽

1977 ◽

Author(s):

Christine N. Vogel ◽

Kingdon S. Henry ◽

Roger L. Lundblad

Keyword(s):

Gel Electrophoresis ◽

Half Life ◽

Antithrombin Iii ◽

Specific Activity ◽

Sodium Dodecyl ◽

In Vivo Studies ◽

Survival Times ◽

At Iii

Our intention is to study the interaction of rabbit thrombin with antithrombin III (AT-III) in vitro and in vivo. After activation of crude prothrombin with tissue thromboplastin and CaCl2, thrombin was purified and showed two species of thrombin with molecular weights of 36,000 and 39,000 daltons as determined by sodium dodecyl sulfate discontinuous gel electrophoresis. Rabbit AT-III was purified using a heparin agarose column and had a molecular weight of 55,000 daltons. The inhibition of thrombin by AT-III was followed by fibrinogen clotting assays and an AT-III-thrombin complex was observed on gel electrophoresis. For the in vivo studies both thrombin and AT-III were radiolabelled with Na125i using the solid state lactoperoxidase method and retained 99% of the pre-iodinated specific activity. Radiolabelled thrombin and a radiolabelled AT-III-thrombin complex were injected into different rabbits. The rate of removal of both was very similar with a half-life of approximately 9 hours. When radiolabelled AT-III was injected, the half-life was approximately 60 hours. Since the disappearance rate of thrombin more closely approximates that of the preformed AT-III-thrombin complex and is clearly shorter than the turnover rate of AT-III, the possibility is raised that thrombin combines in vivo with a native inhibitor such as AT-III and may in fact be removed from the circulation as a complex rather than as a native molecule.

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Isolation and Partial Characterization of Equine Antithrombin III.

10.1055/s-0039-1684573 ◽

1979 ◽

Cited By ~ 1

Author(s):

D.W. Estry ◽

T.G. Bell ◽

G.H. Tishkoff ◽

J.C. Mattson ◽

S.C. Estry

Keyword(s):

Molecular Weight ◽

Antithrombin Iii ◽

Stable Complex ◽

Sds Page ◽

At Iii ◽

Human Thrombin ◽

Horse Plasma ◽

Stoichiometric Complex

A protein analogous to human antithrombin III was isolated from fresh horse plasma. The procedure for purification was a modification of Thaler and Schmer’s two-step isolation procedure. The horse protein was homogeneous on 7.5% SDS-PAGE gels and had a molecular weight of 62,000 to 64,000 daltons in both reducing and non-reducing systems (human; 62,300). Rabbit anti-human antithrombin III was used to demonstrate a line of partial identity by Immunoelectrophoresis between the horse and human protein. The horse protein rapidly neutralizes human thrombin (34,000 daltons) and the reaction appears to be greatly potentiated by heparin. In order to establish the formation of 1:1 covalent stoichiometric complex between horse AT III and thrombin (IIa), time studies were run in the presence and absence of heparin. AT III (62,000) at 15 seconds, 2, 5, 10 and 60 minutes formed a stable complex with thrombin (32,000) having a molecular weight of 86,000 daltons. Additional bands developing with time are due to the autolytic capabilities of the uncomplexed IIa. The major autolytic band had a molecular weight of 70,000 daltons. Addition of heparin potentiated the interaction although it did not change the stoichio-metry of the complexes formed. The data accumulated to date demonstrates the similarities between the human and horse protein and the possibilities of using the horse as a model system for the evaluation of AT III replacement therapy in vivo.

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Effect of Heparin on Antithrombin III Activity During Delivery and Early Puerperium

10.1055/s-0039-1689222 ◽

1975 ◽

Author(s):

I. Rákóczi ◽

B. Garadnay ◽

L. Arnold ◽

I. Gáti

Keyword(s):

Pregnant Women ◽

Blood Coagulation ◽

Antithrombin Iii ◽

Modified Method ◽

Heparin Treatment ◽

At Iii ◽

Antithrombin Iii Activity

It is known that antithrombin III (AT III) is the main inhibitor of blood coagulation. It inactivates thrombin and activated × factor. Heparin increases the AT III activity in vitro as well as in vivo. The authors have studied the AT III activity in sera of 30 pregnant women, at term, before labour started (2–24 hrs) and 30 as well as 60 min after the birth of placenta and daily for five days after delivery. The AT III activity was determined using the modified method of Gerendas. Out of the 30 women 15 were given 5000 IU heparin subcutaneously 1½—2 hours before delivery. In the 15 women with no heparin treatment AT III activity of serum significantly decreased after birth of placenta compared with the predelivery value and became normal on the fifth postpartum day. Heparin given subcutaneously prevented development of this decrease.

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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 ◽

10.1182/blood.v75.1.33.bloodjournal75133 ◽

1990 ◽

Vol 75 (1) ◽

pp. 33-39 ◽

Cited By ~ 1

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.

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Attenuation of endotoxin-induced pulmonary vascular injury by antithrombin III

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.270.6.l921 ◽

1996 ◽

Vol 270 (6) ◽

pp. L921-L930 ◽

Cited By ~ 5

Author(s):

M. Uchiba ◽

K. Okajima ◽

K. Murakami ◽

H. Okabe ◽

K. Takatsuki

Keyword(s):

Endothelial Cells ◽

Vascular Permeability ◽

Vascular Injury ◽

Antithrombin Iii ◽

Myeloperoxidase Activity ◽

Granulocyte Elastase ◽

Pulmonary Vascular Permeability ◽

Elastase Inhibitor ◽

At Iii

We evaluated the effects of antithrombin III (AT III) on the pulmonary vascular injury induced by injecting rats with lipopolysaccharide (LPS) to investigate the possible usefulness of AT III as a treatment for acute respiratory distress syndrome. The intravenous administration of AT III prevented the pulmonary accumulation of leukocytes (as evaluated by myeloperoxidase activity) and the increase in pulmonary vascular permeability to 125I-bovine serum albumin induced by LPS. The increase in pulmonary vascular permeability induced by LPS administration was unaffected by various anticoagulants but was inhibited by the leukocytopenia induced by nitrogen mustard or by the administration of a granulocyte elastase inhibitor, ONO-5046. AT III given alone, but not heparin plus AT III or Trp49-modified AT III, which lacks affinity for heparin, significantly increased the plasma concentration of 6-keto-prostaglandin F1alpha, suggesting that the interaction of AT III with heparin-like substances at the endothelial cell surface promotes the release of prostacyclin from endothelial cells in vivo. Trp49-modified AT III failed to prevent the LPS-induced accumulation of leukocytes and vascular injury. The pulmonary accumulation of leukocytes and vascular injury induced by LPS were not prevented by administering AT III to rats that were pretreated with indomethacin. The continuous intravenous infusion of prostacyclin prevented the LPS-induced pulmonary accumulation of leukocytes and vascular injury. Findings suggest that AT III depends on its ability to promote the release of prostacyclin, a potent inhibitor of leukocyte activation, from endothelial cells to prevent pulmonary vascular injury induced by LPS.

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Three Types of Hereditary Antiterombin III Deficiency

10.1055/s-0039-1684714 ◽

1979 ◽

Author(s):

I. Nagy ◽

H. Losonczy

Keyword(s):

Antithrombin Iii ◽

Clinical Signs ◽

Type I ◽

Type Ii ◽

Type Iii ◽

Basic Activity ◽

At Iii ◽

And Function

The authors detected in the last seven years 15 patients with hereditary antithrombin III/AT III/ abnormality. All of them had typical clinical signs of recurrent arterious and venous thromboembolie. The abnormality inherited as an autosomal trait. Three types of the abnormality could be observed. In Type I both quantity and function of AT III were extremely decreased. In type II AT III is normal in quantity but abnormal in function. In Type III AT III is quantitatively normal and also its function seems normal as far as its basic activity is concerned /activity measured in absence of heparin/, but its abnormality becomes manifest in the presence of heparin in vitro/and also in vivo/. 5 of the patients belonged to Type I, 4 to Type II and 6 to Type III. In 60 examined family members of the 15 patients an abnormal AT III could be observed in 44, clinical signs in 23.The examination of AT III activity in the presence of a given amount of heparin ia of great importance in recognition of the different types of antithrombin III abnormalities.

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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 ◽

10.1182/blood.v75.1.33.33 ◽

1990 ◽

Vol 75 (1) ◽

pp. 33-39 ◽

Cited By ~ 63

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.

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Blood Coagulation after Long Distance Running: Antithrombin III Prevents Fibrin Formation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1645060 ◽

1990 ◽

Vol 63 (03) ◽

pp. 430-434 ◽

Cited By ~ 35

Author(s):

Peter Bärtsch ◽

André Haeberli ◽

P Werner Straub

Keyword(s):

Physical Exercise ◽

Blood Coagulation ◽

Antithrombin Iii ◽

Degradation Products ◽

Distance Running ◽

Long Distance ◽

Fibrin Formation ◽

Long Distance Running ◽

At Iii

SummaryPhysical exercise causes shortening of activated partial thromboplastin time (aPTT) and euglobulin clot lysis time. To investigate whether this activation of coagulation and fibrinolysis leads to in vivo thrombin or plasmin action after long distance running, 19 well trained male runners (36-65 years) were examined 5 to 53 min after termination of a 100 km race and 5 days later after at least 1 day without physical exercise. Compared to the control examination aPTT was decreased (30.2 ± 2.8 vs 35.3 ± 3.0 sec) and the following parameters were increased after the race: betathromboglobulin (40 ± 16 vs 23 ± 7 ng/ml), thrombin-antithrombin III (TAT) complexes (5.5 ± 3.4 vs 2.3 ± 0.7 pg/1), the fibrin(ogen) degradation products fragment E (57 ± 15 vs 35 ± 7 ng/ml) and B(3 15-42 (8.5 ± 2.5 vs 6.5 ± 2.5 ng/ml) (all p values <0.001). Platelet count, platelet factor 4, fibrinoepetide A (FPA) and haematocrit did not change significantly. Increased TAT complexes and unchanged FPA suggest that the generated thrombin was fully inactivated by antithrombin III (AT III) and did therefore not give rise to fibrin formation. The small increase of fibrin(ogen) degradation products indicates a minor in vivo activity of the fibrinolytic system. This investigation demonstrates the importance of AT III in the regulation of haemostasis in activated blood coagulation.

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Detection of Antithrombin III /AT-III/ Complexes in “Hypercoagulable” and Hyper-Fibrinolytic States

10.1055/s-0039-1682765 ◽

1977 ◽

Author(s):

G. Sas ◽

Á Köves ◽

I. Pető

Keyword(s):

Antithrombin Iii ◽

Factor X ◽

Similar Increase ◽

At Iii ◽

Streptokinase Therapy ◽

Cirrhotic Patients ◽

Slow Moving ◽

Venous Thromboses ◽

Clearing Mechanism

As it was previously described, the complex of thrombin-AT-III end “free” /uncomplexed/AT-III can be discerned by a modified crossedimmunoelectro -phoresis method /heparin in agarose/. Further investigations with the same technique showed that activated factor X/Xa/ and plasmin also form complexes with purified AT-III which, Just as thrombin-AT-III complex, migrate slower, than “free” AT-III. On the basis of these observations we assumed a significant increase of the quantity of these AT-III fractions in various “hypercoagulable” and hyperfibrinolytic states, mainly in DIC.Only about one third of patients with chronic DIC displayed significant increase of AT-III complexes in their plasmas. In a few patients with deep venous thromboses a similar increase of complexed AT-III was observed. In cirrhotic patients with low prothrombin level the administered PPSB concentrate brought about a mild DIC with a striking decrease of “free” AT-III concentra -tion but there was no increase of the complexes. Streptokinase therapy did not increase the quantity of the slow moving fractions of AT-III at all, but the concentration of “free” AT-III decreased significantly.A fast in vivo clearing mechanism of the AT-III complexes can be postulated which could account for the absence of a significant increase of AT-III complexes while the “free” AT-III concentration decreases.

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Hereditary Deficiency of Antithrombin III.

10.1055/s-0039-1682653 ◽

1977 ◽

Author(s):

E. Marciniak

Keyword(s):

Antithrombin Iii ◽

Binding Capacity ◽

Antigenic Determinants ◽

Moderate Increase ◽

Congenital Deficiency ◽

At Iii ◽

Inhibitor Level ◽

New Perspective ◽

Thrombotic Tendency

The recognition of biological importance of antithrombin III (AT III) stems from the description of a familial thrombotic tendency associated with reduced levels of this protein in blood. A limited number of such families has been reported in the literature. All of the affected members are heterozygous for the abnormal gene. In many, the quantity of AT III as evaluated by antigenic determinants correlates with the capacity of plasma to inactivate coagulation enzymes. Both the existence of genetic polymorphism and the prevalence of the trait are still open to speculation. Although low level of AT III is an important risk factor for the development of venous thromboembolism, it does not preclude longevity. Liver is the major source of AT III synthesis but little is otherwise known of its metabolism. Subjects with hereditary deficiency treated withCoumadin often respond with a moderate increase in both AT III antigen and binding capacity. One can assume that this reflects a diminished rate of AT III utilization in vivo since the requirement for inhibitor apparently decreases with the reduction in procoagulants. More puzzling, however, is the fact that continuous intravenous treatment with heparin markedly diminishes the quantity of circulating AT III in man. This decrease is without proportion to the starting AT III level and a patient with congenital deficiency is at risk of attaining alarmingly low inhibitor level during therapy with heparin. Although the mechamism remains conjectural, the fact that heparin markedly lowers AT III in blood gives some new perspective to AT III metabolism.

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