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PubMed1988

Hemostatic abnormalities in nephrotic syndrome.

Nephrotic syndrome is often associated with a hypercoagulable state and thrombotic complications. Thrombosis may be due to a number of abnormalities in blood, including AT III deficiency, increased concentrations of fibrinogen, factors V and VIII, and platelet hyperaggregability. The therapeutic approach to thrombosis in nephrotic syndrome is the use of anticoagulants as a preventive measure or an attempt at thrombolysis with streptokinase, urokinase, or stanozolol.

Animals↗
PubMed1988

Antithrombin III molecular variants with defective binding to heparin or to serine proteases: evidence of two different abnormal patterns identified by crossed immunoelectrofocusing.

Molecular 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III↗
PubMed1996

Molecular genetics of antithrombin deficiency.

Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism. Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence. The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identified that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or 'pleiotropic effects' (Type II deficiency, altering both functional domains and the level of protein).

Antithrombin III↗
PubMed1989

Antithrombotic therapy in patients with known risk factors for thromboembolism.

In about 50% of the cases of spontaneous deep vein thrombosis a congenital deficiency of an inhibitor of coagulation or an insufficient fibrinolytic mechanism can be detected. In arterial thromboembolism a connection with hyperactive platelets or with a diminished availability of tissue plasminogen activator can be found in about 70%. However, in these cases the defect which provokes thrombosis is mostly acquired and is connected with hyperlipidemia and/or with atherosclerotic alterations of the vessel wall. A study on patients with thromboembolic tendency and detectable risk factors was carried out. A total of 470 patients could be observed for 2 years under an adequate antithrombotic prophylaxis. The occurrence of thromboembolic episodes 2 years prior to prophylaxis and 2 years under prophylaxis was compared. In venous cases thrombosis could be controlled almost completely by coumarins when the underlying cause was a deficient plasmatic inhibitor. In patients with diminished fibrinolysis there was only a partial effect of oral anticoagulants. A better result could be obtained when pentosan polysulfate was administered. In arterial thromboembolism the results of prophylaxis were less convincing. The efficacy of ASA in patients with an increased platelet function was only moderate. In addition, ASA hat to be discontinued in about 20% of the patients because of gastrointestinal problems. Pentosan polysulfate in patients with a diminished fibrinolytic capacity had a fairly good effect and resulted in a 60% reduction of thromboembolic manifestations. It is shown that an exact diagnosis of the underlying deficiency which is likely to cause thrombosis can also improve the efficacy and the specificity of prophylaxis.

Age Factors↗
PubMed1981

Deficiency of protein C in congenital thrombotic disease.

A family with a history of recurring thrombosis was studied to determine if a plasma protein deficiency could account for the observed disease. Protein C levels in plasma were determined immunologically using the Laurell rocket technique. The propositus, his father, and his paternal uncle, who are severely affected, had 38-49% of normal levels of protein C antigen, whereas unaffected family members had normal levels. There was no familial deficiency of antithrombin III and plasminogen. Because activated protein C is a potent in vitro anticoagulant enzyme and an in vivo profibrinolytic agent, it is suggested that the recurrent thrombotic disease in this family is due to an inherited deficiency in protein C.

Adult↗
PubMed1993

[The clinical characteristics, complications and therapeutic problems of protein C deficiency].

Examination was performed of 20 patients from 15 families with heterozygous deficiency of protein C (27-62% against the mean standard). Recurrent thromboses were seen in 17 of them. Thromboses of the lower veins, pulmonary artery thromboembolism, thromboses of the surface veins, those of cerebral vessels, myocardial infarction, of renal and mesenterial vessels were registered in 15, 5, 4, 3, 3, 1 and 1 patients, respectively. There was a tendency to recurrent thrombosis during pregnancy with high risk of spontaneous or induced abortions. The highest effect was produced with low-molecular heparin combined with transfusions of recently frozen plasma and introduction of disaggregating agents. Anabolic hormones were used to prevent thrombosis. The data are provided on a 4-fold increase in the prevalence of protein C deficiency in polythrombotic patients living in the West Siberia vs. deficiency of antithrombin III.

Adolescent↗
PubMed1997

Recurrence of venous thromboembolism in patients with familial thrombophilia.

BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

Anticoagulants↗
PubMed1997

Thrombosis in congenital deficiencies of AT III, protein C or protein S: a study of 44 children.

Congenital deficiency in coagulation inhibitors is a cause of hereditary thrombotic disease. The severity of symptoms is variable and depends on the type of deficit. In this paper, 44 children suffering from deep venous thrombosis, with a mean age of 5 years, were studied. A search for Lupus anticoagulant (LA) and coagulation inhibitor deficiency showed: 3/44 cases (6.8%) had protein S deficiency, 2/44 cases (4.5%) had protein C deficiency, 1/44 cases (2.3%) had deficiencies in both protein C and S; no cases of AT III deficiency and LA was positive in 2/44 cases (4.5%). Only 1 case of APC resistance out of 13 studied was found. Four family studies were performed and confirmed the congenital origin of the disorder.

Adolescent↗
PubMed1997

Acquired deficiency of antithrombin in association with a hypercoagulable state and impaired function of liver and/or kidney in preeclampsia.

To determine whether decreases in plasma antithrombin (AT) level, as seen in non-gestational acquired AT deficiency, result from a hypercoagulable state and/or liver/kidney damage, AT activity was measured in 24 uncomplicated and 30 preeclamptic women. The fifth percentile of AT levels in the normal pregnancies was used as a cut-off value to subdivide the preeclamptic patients into two groups. Markers of activated coagulation, i.e, levels of thrombin-antithrombin complex (TAT), fibrin D-dimer, soluble fibrin, von Willebrand factor (vWF) and platelet counts, were determined. Indicators of hepatic or renal function, i.e. concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urinary albumin (U-albumin) and serum albumin (S-albumin), were assayed. AT levels were lower in those with preeclampsia than in the normal pregnancy group (P < 0.01). In the group with AT levels less than the cut-off point, levels of fibrin D-dimer (P < 0.05), soluble fibrin (P < 0.05), vWF (P < 0.05), ALT (P < 0.05), AST (P < 0.05), creatinine (P < 0.01) and U-albumin (P < 0.01) were increased, whereas platelet counts (P < 0.05) and S-albumin (P < 0.05) were decreased. All patients with ALT levels > 0.46 mu kat/1, AST > 0.58 mu kat/1, S-albumin < 23 g/1 and/or U-albumin > 4.9 g/24 h had AT levels < or = cut off. AT levels correlated with vWF (rs = - 0.73, P < 0.01) and creatinine (Rs = -0.70, P < 0.01). It is suggested that in preeclampsia, acquired AT deficiency is secondary to a hypercoagulable state, and/or associated with impaired hepatic and/or renal function.

Alanine Transaminase↗
PubMed2004

Effects of anticoagulation protein defect in maternal plasma on spontaneous abortion.

OBJECTIVE: To investigate the mechanism of anticoagulation protein defect in the pathogenesis of unexplained recurrent miscarriage. METHODS: Fifty-seven patients with a history of unexplained abortion were enrolled as the investigation group for tests of protein C, protein S, antithrombin III (AT-III), as well as activated protein C resistance (APC-R). The control group consisted of fifty healthy women with a history of normal pregnancy and delivery. Blood samples were obtained for, measuring serum activity of protein C, protein S, AT-III, and APC-R. Patients with positive APC-R were tested for factor V (FV) Leiden gene mutation by PCR-RFLP method. RESULTS: Of the 57 patients, 12 (21.1%), 1 (1.8%), and 5 (8.8%) cases were found with protein S, protein C, and AT-III deficiency respectively, and 13 (22.8%) cases with positive results of APC-R. Of the control group, no protein C or AT-III deficiency was ever found, whereas 2 (4.0%) volunteers were presented with protein S deficiency and 3 (6.0%) with positive results of APC-R. No FV Leiden gene mutation was identified in all the patients with positive APC-R results. Late spontaneous abortion cases had higher incidence of anticoagulation protein defect than the early cases. CONCLUSION: Anticoagulation protein defect may play a role in the pathogenesis of fetal loss, especially for those occurring in late stage of pregnancy.

Abortion, Habitual↗
PubMed1996

Young women with advanced aortoiliac occlusive disease: new insights.

We identified a group of 24 young (less than 50 years of age) women with isolated, premature atherosclerotic aortoiliac occlusive disease and attempted to identify distinguishing hemostatic characteristics. Most of these patients (62%) presented with acute thromboembolic events (blue toe syndrome, n = 6; macroemboli, n = 6; or aortoiliac thrombosis, n = 3). Aortoiliac reconstruction (aortoiliac endarterectomy, n = 10, aortobifurcation bypass grafts, n = 6; and percutaneous angioplasty, n = 4) was complicated by early thrombosis in 6 of 20 cases (30%), (1 of 10 endarterectomies, 4 of 6 bypass grafts, and 1 of 4 angioplasties). Fresh thrombus overlying an atherosclerotic plaque was a common finding at surgery. This observation and the relatively high incidence of thromboembolic events led us to hypothesize that a characteristic hemostatic profile might underlie the remarkably similar clinical presentations of these women. Levels of antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant), plasminogen activator inhibitor-1, fibrinogen, antithrombin III, protein C, protein S, plasminogen, prothrombin fragment F1 + 2, and D-dimer were determined for these young women and for 21 age-matched white female control subjects without vascular disease and nine white male patients with aortoiliac occlusive disease (mean 61 years, range 43 to 74 years). The incidence of anticardiolipin antibodies was 42% (8 of 19) in the female patients, which was significantly elevated (p = 0.028). The female (62.5%) and male (100%) patients had significantly elevated D-dimer levels (p < 0.001). Deficiencies of antithrombin III, protein C, and protein S were rare. A unique pattern of premature aortoiliac atherosclerosis exists in some young women. Intra-arterial thromboembolic events are common at presentation and complicate surgical management. The role of antiphospholipid antibodies remains uncertain.

Adult↗
PubMed2005

Identification of a novel amino acid deletion mutation and a very rare single nucleotide variant in a Japanese family with type I antithrombin deficiency.

We studied a Japanese family with type I antithrombin (AT) deficiency and identified a novel in-frame deletion mutation (-ATG at nucleotide position of 2771-2773) in the AT gene, which predicted loss of a methionine (Met) at amino acid number of 103. In addition, we found a single base replacement of G to A at nucleotide position of 67 (4 base upstream to the initial codon) in the mutant allele. Since the G67A substitution in the AT gene was very rare, this family was the second case, in which the nucleotide change was transmitted. To elucidate the mechanism of AT deficiency, we transiently expressed wild type and the mutant AT (DeltaM103) in HuH-7 human hepatoma cells and performed pulse-chase studies. The experiments revealed that the mutant AT (DeltaM103) hardly secreted into the medium and underwent partial intracellular degradation. In addition, we performed luciferase reporter assay to examine the effect of G67A substitution on the AT gene expression, and found that the substitution did not reduce the luciferase activity. These results suggested that secretion defect and intracellular degradation of the variant molecule with the deletion of Met 103 were responsible for AT deficiency in this family.

Adult↗
PubMed1985

Antithrombin III "Northwick Park": a variant antithrombin with normal affinity for heparin but reduced heparin cofactor activity.

Further studies have been carried out in a previously reported family with congenital antithrombin III (AT III) deficiency due to an abnormal variant of AT III (AT III Northwick Park). The variant has been identified in five members of the family, three of whom had a history of venous thrombosis. Inheritance followed an autosomal dominant pattern. The affected family members have reduced levels of antithrombin heparin cofactor (41-67%) and progressive antithrombin activity (44-62%) but normal levels of immunoreactive AT III (91-162%). Two dimensional immunoelectrophoresis (2 DIE) of AT III in the absence of heparin revealed an abnormal fast-moving peak in addition to the normal peak but 2 DIE in the presence of heparin appeared normal. Further studies confirmed that the abnormal AT III binds completely to heparin but has no heparin cofactor or progressive antithrombin activity. These results would be consistent with a mutation affecting the binding site for thrombin.

Adolescent↗
PubMed2005

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency.

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.

Adult↗
PubMed2004

Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis.

BACKGROUND: Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear. METHODS AND RESULTS: We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene. CONCLUSIONS: Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, human alpha1-antitrypsin, and human HCII, which explains their plasma deficiency. In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype.

Adult↗
PubMed1996

The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.

Hereditary deficiencies of the naturally occurring anticoagulants are well recognized conditions predisposing to recurrent venous thromboembolism. Since thrombotic phenomena have been implied as a cause of abortion and stillbirth, we hypothesized that these deficiencies increase the risk of fetal demise. A group of 129 female subjects who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of AT, PC or PS were studied. We first assessed the obstetric history and subsequently determined the deficiency status. In the 60 deficient subjects 42 (22.3%) of the 188 pregnancies resulted in miscarriage or stillbirth as compared to 23 (11.4%) of the 202 pregnancies in the 69 non-deficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to non-deficient women was 2.0 (95% C.I. 1.2-3.3).

Abortion, Spontaneous↗