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PubMed1991

Molecular basis for antithrombin III type I deficiency: three novel mutations located in exon IV.

Antithrombin III (AT III) type I deficiencies are characterized by a 50% decrease of both immunoreactive and functional protein and carry a high risk of thrombotic complication. We have studied the molecular basis for such deficiencies by asymmetric polymerase chain reaction amplification and direct sequencing of the seven exons and of the intron-exon junction of the AT III gene. Three different mutations were observed in the exon IV: a 4-bp deletion, a 2-bp deletion, and a nucleotide insertion. Each of these mutations results in a frameshift introducing premature stop codons at positions 313, 309, and 232, respectively. These results were confirmed by dot-blot analysis with allele-specific oligonucleotide probes. Furthermore, no mutation was observed in the other six exons. The comparison of the type of mutations observed by our group in six cases of type I deficiencies and in 16 cases of type II heparin binding site variants deficiencies suggests that the former are caused by heterogeneous molecular abnormalities while the latter are caused by recurrent missense mutations.

Adult↗
PubMed1975

Adverse effect of heparin in thrombin-antithrombin III interaction.

Thrombin, while reacting in the presence of hepatin, impairs the inhibitory capacity of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased or abolished. This adverse effect of hepatin has been observed directly with at least 1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating in the reaction. The inhibitory capacity was then totally destroyed and some residual thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation of thrombin in the presence of hepatin was fast and complete, however, a significant decrease of inhibitory capacity below that found in reaction without heparin, has been established by measuring the residual antithrombin III activity. In defibrinated human plasma at least 2 units of thrombin per each antithrombin III unit were required to demonstrate directly the adverse effect of heparin but a fast depletion of inhibitory capacity has been also observed after repeated additions of small thrombin portions into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared with great velocity; subsequent portions, however, accumulated building up a high thrombin level not seen in the absence of heparin. The accumulation of residual enzyme was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant at lower concentrations and was particularly noticeable in antithrombin III deficient plasma. These results may have some bearings on the approach to heparin therapy in the event when thrombin continuously generates or when a marked deficiency of antithrombin III exists.

Antithrombins↗
PubMedDate not supplied

[Hereditary deficiency of antithrombin III, protein C, protein S and factor XII in 121 patients with venous or arterial thrombosis].

INTRODUCTION: Hereditary thrombophilia is caused by various inherited disorders which lead to familial tendency to recurrent venous thrombosis usually at an early age and with spontaneous onset. In the studies reported so far, the different prevalence of hereditary thrombophilia among patients with venous thrombosis was found, greatly depending on criteria for selection of patients. Arterial thrombosis is most often the consequence of arteriosclerosis but the prevalence of hereditary thrombophilia among young patients with arterial thrombosis and without recognized risk factors for arteriosclerosis is not known . In this study, the frequency of hereditary deficiencies of antithrombin III (AT III), protein C (PC), protein S (PS), plasminogen (PLMG), factor XII (F XII) and dysfibrinogenaemia was investigated over a 2-year period in 121 patients with venous or arterial thrombosis selected according to the recommendations of the British Committee for Standards in Haematology. PATIENTS AND METHODS: The study included total a of 121 patients (58 males and 63 females) with documented venous or arterial thrombosis. Table 1 shows patient's characteristics regarding gender, age and clinical manifestation of thrombosis. Each patient fulfilled at least one of the following criteria: a) venous thrombosis prior to the age of 45; b) arterial thrombosis prior to the age of 30, without risk factors for arteriosclerosis; c) recurrent thrombosis; d) familial tendency to thrombosis; e) thrombosis of unusual localization. A detailed history was taken from each patient on earlier personal or familial occurrence of thrombosis. For the purpose of this study, thrombophilia was characterized as congenital when the deficient protein was constantly below normal value and when the same deficiency was confirmed in a close family member; acquired when the acquired disorder predisposing to thrombosis was present in absence of constant protein deficiency; and idiopathic when the cause of thrombosis was unknown. All tests were performed in plasma obtained after centrifugation of venous blood anticoagulated with 0.129 mol/1 sodium citrate. Concentrations of fibrinogen, PT, PTT and F XII were measured by standard clotting methods. At III, PC and plasminogen activity were determined by chromogenic methods using commercial reagents (Boehring, Marburg, Germany). AT III, PC and total PS antigen were assayed by Laurell immunoelectrophoresis. The presence of lupus anticoagulant was investigated by recommended tests. RESULTS: A total of 15 patients (12.4%) fulfilled criteria for hereditary thrombophilia. Seven of them (5.8%) had AT III deficiency, five (4.1%) PC deficiency, two (1.6%) PS deficiency, and one patient had F XII deficiency. Secondary thrombophilia was found in 21.5% of patients and the cause of thrombosis in 66.1% of patients was not elucidated. A high frequency of hereditary thrombophilia has been found in patients with arterial thrombosis (40%). Among patients with hereditary thrombophilia thrombosis occurred at significantly younger age (29.9 vs. 42.2 and 40.9 yr.) compared to the patients with secondary and idiopathic thrombophilia, respectively. Patients with hereditary thrombophilia had also a higher occurrence of positive family history related to thrombosis (66.7% vs. 7.7% and 27.5%). DISCUSSION: The prevalence of hereditary thrombophilia in nonselected patients with venous thrombosis is relatively low, and for that reason the selection of patients, according recommended criteria, in whom the screening tests for congenital thrombophilia should be performed, is strongly suggested by many authors. In our study we used the generally accepted recommendations for investigation of patients with venous and arterial thrombosis. The presence of congenital thrombophilia was found in 15 (12.4%) of 121 studied patients, what is in accordance with results of other similarly designed studies. (ABSTRACT TRUNCATED)

Adolescent↗
PubMed1979

[Thrombosis of the portal and superior mesenteric veins in a patient with a congenital and familial deficiency in antithrombin III (author's transl)].

Thrombosis of the visceral veins is an extremely rare condition in cases of congenital and hereditary deficiency of antithrombin III, associated with recurring venous thorbosis of the limbs. The authors report such a case in a man of 40 years of age, who had this deficiency, associated with thrombosis of the portal and superior mesenteric veins and a portal cavernoma. They stress the frequent association of recurring peripheral vein thrombosis, portal vein thrombosis in adults, and thrombosis of the mesenteric vein, and the importance of systematic measurements of antithrombin III levels in these pathological conditions.

Adult↗
PubMed1986

Laboratory determination of heparin cofactor II.

Heparin cofactor II (HC II) is a recently characterized protein that is capable of neutralizing thrombin but not activated factor X. Recent evidence suggests that it may be a physiologically important regulator of thrombin activity. We evaluated and modified a method for clinical laboratory determination of this protein and then utilized the method to analyze HC II activity in various clinical samples. Low levels were associated with liver disease, consumptive coagulopathy, and preeclampsia; normal levels were seen with uncomplicated pregnancy, oral anticoagulant therapy, hereditary antithrombin III (AT III) deficiency, and in 31 patients evaluated for a thrombotic tendency. Except in hereditary AT III deficiency, decreased HC II activity was associated with decreased AT III activity. The potential clinical role of this assay is discussed.

Antithrombin III↗
PubMed1991

[Hemostasis anomalies and prognosis during severe infectious purpura in children. Retrospective study in 69 cases].

In 69 children with severe infectious purpura (SIP), anomalies of hemostasis on admission were studied retrospectively. Forty-four children presented with disseminated intravascular coagulation (DIC) and 18 with factor VII deficiency +/- thrombocytopenia +/- antithrombin III deficiency. Seven patients were free of hemostasis anomalies. In 5 children, purpura was necrotic on admission, whereas in 9 additional patients skin necrosis occurred subsequently (5 patients with and 4 without DIC). Among the 18 children (26%) who died, 16 were in the DIC group. Factors II and V, fibrinogen and platelet counts were lower in children who died and were correlated with the prognostic score. In the DIC group, however, factor VII + X level was not correlated with the prognostic score and was equally low in fatal and non-fatal cases. Antithrombin III level was markedly decreased in patients who subsequently developed necrosis. These results indicate that factor VII level decreases early in the course of SIP and that consumption of physiologic coagulation inhibitors probably plays a central part in the development of necrotic purpura.

Adolescent↗
PubMed1989

Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. The Antithrombin III Study Group.

Phase I clinical studies of antithrombin III (ATIII) concentrate demonstrated a mean in vivo incremental recovery of functional activity of 1.4 percent per unit/kg administered, an initial 50 percent disappearance time of 22 hours, and a biologic half-life of 3.8 days. Based on these observations, a treatment regimen designed to maintain plasma ATIII levels between 75 and 120 percent of normal has been developed. None of 10 subjects with congenital ATIII deficiency treated prophylactically had evidence of thromboembolism, including four pregnant women at the time of delivery. Five subjects treated for acute thrombosis and/or thromboembolism, four of whom were pregnant, recovered without further thrombotic extension or recurrence. Heparin resistance was reversed in two subjects, both pregnant. Nine subjects with acquired ATIII deficiency also received ATIII treatment for venous or arterial thrombosis or disseminated intravascular coagulation, all with low plasma ATIII levels. Two subjects with disseminated intravascular coagulation demonstrated improvement, one clinically, the other biochemically. All patients with congenital ATIII deficiency survived, but only five of nine with acquired deficiency survived, highlighting the importance in acquired ATIII deficiency of the underlying disease in prognosis. Survival rate was especially poor in subjects with arterial thrombosis in the setting of low plasma ATIII. Administration of ATIII concentrate was well tolerated. None of the subjects who received ATIII concentrate demonstrated evidence of an infectious transmissible agent. These studies demonstrate that it is now feasible to safely replace the deficient protein in congenital ATIII deficiency, either prophylactically or therapeutically.

Antithrombin III↗
PubMed1991

[Thrombolytic therapy of antithrombin III-deficiency-induced mesenteric vein thrombosis in a newly operated patient].

A 21-year-old patient presented with extensive thrombosis of the mesenteric veins. He was in a serious condition after laparatomy in another hospital. The cause of the thrombotic event was found to be an inherited antithrombin III-deficiency. As a sole therapeutic possibility a systemic lysis with streptokinase was performed and was followed by a favourable immediate result. Unfortunately the subsequent course was complicated by a histologically confirmed necrotizing arteritis which was responsible for the lethal outcome 57 days after admission.

Adult↗
PubMed1984

[Biology of recurrent venous thrombosis].

Important recent advances in the field of the biology of recurrent venous thrombosis include greater understanding of congenital deficiency states involving antithrombin III (AT III) and protein C. Other disturbances demonstrated were related to fibrinolysis frequently, and rarely platelet function and coagulation factors. Possible existence of these anomalies requires investigation during biologic tests in cases of recurrent venous thrombosis, particularly in the presence of a family history or onset of the initial affection before 40 years of age. Confirmation of the importance of screening for such anomalies is supplied by results of a study of 11 families with antithrombin III deficiency and 9 families deficients in protein C, and a literature review of cases. However, currently available biologic tests provide data enabling only partial explanation of the mechanism underlying recurrent venous thrombosis accidents.

Antithrombin III Deficiency↗
PubMed1993

Hereditary thrombophilia among 217 consecutive patients with thromboembolic disease in Jordan.

This is a four-year prospective study on patients admitted or referred with thromboembolic disease to Jordan University Hospital or to the Thrombosis/Haemostasis Laboratory at the University of Jordan. The aim of the study was to find the relative prevalence of hereditary thrombophilia. For the purpose of this work, hereditary thrombophilia was diagnosed in the absence of an acquired cause of thrombophilia in addition to two of the following: 1) positive family history of thrombophilia, 2) confirmed same deficiency in a closely related family member, 3) the deficient protein is constantly below 2 SD of the normal mean on repeated testing. All ages were admitted to the study. Acquired systemic factors or local factors known to cause thrombosis or affect the levels of proteins opposing thrombosis were excluded. There were a total of 217 patients (102 males and 115 females) with confirmed thromboembolic disease. Their mean age was 34 years. A total of 49 patients (26 males and 23 females) fulfilled the criteria of hereditary thrombophilia. There were 17 cases of protein C deficiency (PC), 15 protein S deficiency (PS), 10 antithrombin III deficiency (ATIII), 3 dyfibrinogenemia, 2 heparin cofactor II deficiency, and 2 plasminogen defects. In this group most of the thrombosis was venous. A positive family history was obtained in 65.3% of patients with hereditary thrombophilia. Twenty-seven additional relatives with deficiency were identified upon family studies. The calculated prevalence of hereditary thrombophilia in Jordan is put at 1/25,000. Screening for PC, PS, and ATIII is advocated in young patients who have thromboembolic disease, especially when there is a positive family history of thrombosis.

Adolescent↗
PubMed2004

[Primary thrombophilia. Report of 93 cases and 12 asymptomatic relatives].

BACKGROUND: Thrombophilia is defined as an altered hemostasis that predisposes to thrombosis. It can be primary when there is a family clustering of the disease or secondary, when it is associated to an acquired risk factor. AIM: To report clinical features in a series of patients with primary thrombophilia. MATERIAL AND METHODS: Review of clinical records of patients with thrombotic episodes that lead to the suspicions of primary thrombophilia. Analysis of asymptomatic adult close relatives of these patients. RESULTS: We report 93 subjects (56 females, age range 14-77 years) with repeated episodes of thrombosis and a family history of thrombosis and 12 asymptomatic close relatives. Seventy one percent had the first thrombotic episode before the age of 40 years, 62% had more than one thrombotic episode and 37% had a family history of thrombosis. Twenty four percent had protein C deficiency, 24% had antithrombin III deficiency, 18% had resistance to activated C protein by factor V Leiden, 10% had protein S deficiency, and 10% had the G20210 mutation of prothrombin gene. Among acquired defects studied simultaneously, 30% had lupus anticoagulant and 11% had hyperhomocysteinemia. Twenty four percent of cases had more than one thrombophilic risk factor. Among asymptomatic relatives, five had factor V Leiden, four had protein C deficiency and three had the G20210 mutation of prothrombin gene. CONCLUSIONS: Thrombophilia must be suspected in young subjects with thrombotic episodes and a family history. The type of coagulation defect will determine prognosis, and the type of treatment.

Adolescent↗
PubMed1973

Antithrombin-3 deficiency in a Dutch family.

A Dutch family (family A) with inherited antithrombin-III deficiency and an increased incidence of venous thrombosis was investigated. Antithrombin-III levels were measured by means of a coagulation assay in plasma and by single radial immunodiffusion in plasma and serum.THREE GROUPS COULD BE DISTINGUISHED: group I comprised the relations-in-law of family A, group II the members of family A with a plasma antithrombin-III level higher than 90% of normal, when determined by the immunoassay, and group III the members of family A with an antithrombin-III level of less than 60%. To group III belonged all eight adults with an abnormal tendency to thrombosis, and furthermore nine children, all having a parent with abnormally low antithrombin-III levels. Mean plasma and serum antithrombin-III levels were significantly decreased in group III. However, the results of the coagulation assay showed some overlap between groups II and III. In addition, the immunoassay appeared to be much less laborious than the coagulation assay. Therefore, the former assay is recommended in any search for similar families. The results of our family investigation confirm the findings of Egeberg (1965) that inherited antithrombin-III deficiency, giving rise to plasma levels between 50 and 60% of normal, causes thrombophilia and that the pattern of inheritance is autosomal dominant.

Adult↗
PubMed1988

Assessment of interference by heparin cofactor II in the DuPont aca antithrombin-III assay.

Hereditary deficiency of antithrombin-III (AT-III), the major heparin cofactor in human plasma, is a well-established cause of recurrent venous thrombosis. Cross-reactivity of heparin cofactor II (HC II) in assays of AT-III may, in some cases, interfere with the ability to diagnose hereditary deficiency of AT-III. For that reason, we have evaluated the interference by HC II in the new DuPont aca antithrombin assay. Response of the assay to purified AT-III and HC II was compared. Inhibition of the bovine thrombin in the assay was sixfold less per molecule of HC II than of AT-III. This level of selectivity should be adequate to prevent misdiagnosis of patients. Analysis of patient samples showed close correlation (r = 0.91) of values from the automated aca assay with those of a manual assay (Coatest antithrombin, Helena Laboratories).

Antithrombin III↗
PubMed1983

[Experiences with the substitution of antithrombin III concentrates in congenital and acquired deficiency disorders].

Antithrombin III (AT III) is the most important inhibitor for factor X and thrombin. Hence, it essentielly influences the regulation of haemostasis. In the aetiology of AT III decreases, hereditary as well as acquired deficiencies can be differentiated. With the exception of patients with hereditary AT III deficiency it is not possible to define the heavy tendency of thrombosis clearly on a biochemical basis. Acquired AT III decreases lead much often to clinical relevant problems than the congenital ones. Since 1974 we substitute AT III using AT III concentrates. The evaluation of the clinical success was often impeded due to the polypragmatic additional therapy. Well-founded and strict indications for the substitution of AT III with a therapeutical concentrate are acute macro- and microthrombosis with decreased AT III levels, e.g. in severe thromboembolic diseases and in hereditary AT III deficiencies. Concerning other clinical pictures with acquired AT III deficiency, a substitution may be indicated very reasonably, however, further studies are necessary to prove this.

Aged↗