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PubMed1984

Distribution of antithrombin III and glucosylceramide in human plasma lipoproteins and lipoprotein deficient plasma.

We have investigated the distribution of antithrombin-III and glucosylceramide (Glc-Cer) in human plasma, plasma lipoproteins and lipoprotein-deficient plasma. Antithrombin III activity was measured employing immunochemical and biological assays. Glc-Cer was quantified by gas liquid chromatography (GLC). Whole plasma contained 145 micrograms antithrombin III/ml plasma, all of which was associated with the lipoprotein-deficient plasma (d greater than 1.25 g/ml). Whereas, most if not all the plasma GlcCer was associated with plasma low density lipoproteins (LDL) (d-1.022-1.055 g/ml) and high density lipoproteins (HDL) (d-1.063-1.25). GlcCer was not found in the lipoprotein-deficient plasma. We conclude that GlcCer on lipoproteins does not contribute to antithrombin III activity. Moreover, the absence of GlcCer in lipoprotein-deficient plasma does not impair antithrombin-III activity.

Antithrombin III↗
PubMed1978

Antithrombin III. Theory and clinical applications. H. P. Smith Memorial Lecture.

Antithrombin III is one of the main inhibitors in the blood coagulation mechanisms. Thrombin and factor Xa are slowly inactivated by it, as well as other serine proteinases of the coagulation mechanisms. Heparin tremendously accelerates the inhibitory function of antithrombin III. In the process antithrombin III activity is also reduced. Heparin retards the thrombin-fibrinogen reaction, but otherwise the effectiveness of heparin as an anticoagulant depends on antithrombin III in laboratory experiments, as well as in therapeutics. The activation of prothrombin is inhibited, and any thrombin or other vulnerable protease that might generate becomes inactivated. The measurement of antithrombin III concentration in blood is now achieved by research methods, as well as by methods that are practical for routine use. The tests require either thrombin or factor Xa as substrate, and could be specific for antithrombin III. There are congenital as well as acquired deficiencies of antithrombin III. The inhibitor is also found in tissues.

Antithrombins↗
PubMed1994

Antithrombin III: summary of first database update.

Antithrombin III is the most important inhibitor of coagulation proteinases such as thrombin and factor Xa. Inherited deficiency of antithrombin III is a well recognised risk factor for the early development of venous thromboembolism. The gene for antithrombin III is located at chromosome 1q 23-25 and its structural organisation has been described. A database of mutations of the antithrombin III gene has been compiled and a recent update lists 184 entries. These entries are listed according to subtype of deficiency and to nucleotide sequence number. There are 68 reports of type I 'classical' and 116 reports of type II 'variant' deficiencies. This summary considers the entries in terms of the number of unique molecular events, the nature of the genetic defects and the role of CpG dinucleotides in deficiency. Sample listings of type I and II deficiency entries are provided.

Antithrombin III↗
PubMed2002

[Role of newly developed technology in blood coagulation disorders].

Clarification of blood coagulation disorders has been made progress based on newly developed technologies. ANTITHROMBIN III: In 1979, studies were carried out on antithrombin III(AT III) as a blood coagulation inhibitor from the first Japanese case of congenital AT III deficiency found in the laboratory sample. An alternative anticoagulant to maintain fluidity in extracorporeal circuit in an AT III deficient patient requiring hemodialysis was needed. In 1989, it was firstly introduced argatroban, a synthetic thrombin inhibitor as an alternative anticoagulant instead of human antithrombin III concentrate plus heparin regimen during hemodialysis. In 1992, success of good delivery in pregnant woman with an AT III deficiency was obtained to maintain normal level of AT III by the concentrates. DYSFIBRINOGENEMIA: Two families of congenital dysfibrinogenemia in clue to abnormally high levels of serum fibrinogen degradation products(FDP) were found. Polymerization detect due to dysfibrinogenemia induced high level of serum FDP and normal level of fibrin d-dimer products. HEPARIN COFACTOR II DEFICIENCY: A patient with congenital heparin cofactor II(HCII) deficiency was found in clue to four episodes of repeated restenosis under heparin-anticoagulated coronary angioplasty. For preventing the restenosis, argatroban as an alternative of heparin was used during coronary angioplasty. No restenosis after the angioplasty was appeared in anticoagulation with argatroban. Genetic analysis of the HCII was described that gene protein is secreted normally, but rapidly degraded in the circulation. FACTOR VII: In Japanese elderly, increase of Factor VII clotting activity was found to relate to high risk of cardiovascular disease. Elevation of activated FVII(FVIIa) as an activation marker of FVII in cardiovascular disease indicates to be an independent risk factor for cardiovascular disease. HEPARIN INDUCED THROMBOCYTOPENIA: HIT: HIT is believed to be less frequent in Japanese because of lack of recognition due to poor understanding of HIT's paradox. A survey in Japanese indicated to be no less frequent compared with that of the West. A causativity for HIT has been identified as antibodies against PF4/heparin complexes. As detection of the antibodies can easily be done by ELISA test, the test is desirable to become popular. Treatment for HIT is recommended to stop heparin and start a thrombin inhibitor. In Japan, argatroban and nafamostat mesilate are selected as an alternative agent for HIT, but both drugs have no approval for Japanese HIT patients.

Adult↗
PubMed2003

Different circumstances of the first venous thromboembolism among younger or older heterozygous carriers of the G20210A polymorphism in the prothrombin gene.

BACKGROUND AND OBJECTIVES: The G20210A polymorphism in the prothrombin gene is a common cause of inherited thrombophilia. Scarce information is available about the circumstances of the heralding thrombotic manifestation at different ages. The aim of this study was to determine the risk of spontaneous or secondary venous thromboembolism (VTE) among younger and older carriers of the G20210A prothrombin polymorphism. DESIGN AND METHODS: We performed a case-control study, investigating 650 patients with a first objectively documented deep venous thrombosis of the legs or pulmonary embolism and 703 individuals with no history of vascular disease. In all of them we carried out laboratory screening for antithrombin III, protein C and protein S deficiencies, and for the presence of the factor V Leiden and the G20210A prothrombin polymorphisms. RESULTS: After adjustment for other inherited causes of thrombophilia (deficiency of antithrombin III, protein C or S, factor V Leiden) the overall risk for VTE associated with the prothrombin polymorphism was 3.4 times higher than in the controls (95% CI, 2.0 to 5.8). Stratification according to the age and to the circumstances of the first event revealed an increased risk of spontaneous VTE only among the patients older than 45 years in comparison with age-matched controls (odds ratio 4.4, 95% CI 1.8 to 10.6); among the younger individuals the risk was increased for secondary VTE (odds ratio 4.8, 95% CI, 2.3 to 9.8) but not for spontaneous VTE. INTERPRETATION AND CONCLUSIONS: The clinical penetrance of the thrombotic tendency associated with the G20210A prothrombin polymorphism is more expressed in the presence of a circumstantial risk factor (oral contraceptives, pregnancy, surgery, trauma) and in the presence of older age, which acts as an additional circumstantial risk factor. Accordingly, such situations should not discourage from carrying out laboratory screening.

Adult↗
PubMed1997

[Recurrent thrombophlebitis and ulcera crurum as manifestations of hereditary blood coagulation disorders and Klinefelter syndrome. Discussion based on 4 case examples].

Recurrent phlebothromboses in young patients with subsequent severe postthrombotic syndrome and chronic venous leg ulcers may be caused by underlying hereditary disorders of hemostasis or may occur as part of other congenital syndromes. The most common hereditary disorders of hemostasis in this respect appear to be deficiencies of antithrombin III, protein C, and protein S, and activated protein C resistance (mutations of factor V). Less frequently, dysfibrinogenemia, increased plasminogen activator inhibitor levels, or deficiencies of tissue plasminogen activator or heparin cofactor II may be found. Klinefelter's syndrome and homocystinuria are prime examples of those rare congenital disorders indirectly associated with an elevated risk of thrombosis in young individuals. Early diagnosis of these disorders will allow timely treatment, preventive care and counselling of patients as well as family members.

Adult↗
PubMed1990

Heparin cofactor II levels are increased by the use of combined oral contraceptives.

Heparin cofactor II (HCII) was assayed by a microtitre amidolytic substrate technique. A linear response was obtained up to 1.5 U/ml and HCII levels were not affected by freezing and thawing the plasma. The assay was validated by comparing HCII and antithrombin III (AT III) levels in AT-III-deficient plasmas and samples from critically ill patients. Higher HCII levels were found in healthy normal women than in healthy normal men (means 1.16 and 0.97 U/ml, respectively, P less than 0.01). A significant increase in HCII levels from 0.86 to 1.10 U/ml (mean values) was seen in healthy normal women starting on combined oral contraceptive (COC) preparations (P less than 0.001). Increased HCII levels were maintained over a 6-month period, but fell towards normal 14 days after stopping COC, although they were still significantly higher than before starting COCs. The discrepancy in HCII level between normal men and women may be due to COC use. In clinical studies, different reference ranges should be used for men and women, and the need for careful questioning about the use of COCs is emphasized.

Adolescent↗
PubMed2006

Genetics of cerebral venous thrombosis.

Cerebral venous thrombosis (CVT) is rare compared to arterial causes of stroke. It is often encountered in young patients and may occur in children and neonates. Predisposition to CVT also has a genetic basis and inherited thrombophilias are known to cause 22.4% of the CVT cases. Inherited thrombophilias should be suspected if a patient has recurrent CVT, is less than 45 years age, has a family history of venous thrombosis or has no apparent acquired risk factor. Factor V Leiden (FVL) is the most common genetic risk factor, followed by the prothrombin gene mutation G20210A. Other less common inherited venous thrombophilias include deficiencies of Protein S, Protein C and antithrombin III. FVL, the G20210A prothrombin gene mutation and a deficiency of protein S and C, cause a reduction in the control of thrombin generation. Deficiency of antithrombin causes a decreased neutralization of thrombin. Both these mechanisms are responsible for venous thrombosis. Inherited thrombophilias with concomitant acquired risk factors like surgery, trauma, prolonged immobilization, pregnancy and puerperium, oral contraceptives, antiphospholipid antibodies and hyperhomocysteinemia may increase the risk of CVT manifold. Similarly the co-inheritance of two or more known mutations also increases the risk markedly. FVL, prothrombin G20210A mutation, increased factor VIIIc, protein C & S deficiency and antithrombin III deficiency have all been reported to cause neonatal stroke due to CVT. Maternal and foetal testing is suggested when CVT occurs in neonates.

Cerebral Veins↗
PubMedDate not supplied

Screening for inherited thrombotic disorders.

In order to determine a scheme for the screening of inherited thrombotic disorders, abnormalities considered as predisposing to thrombosis have been reviewed. Owing to the low prevalence of biological alterations, a selection of patients is required: documented venous thromboses, possibly at unusual sites (mesenteric vein, portal, cerebral veins), occurring before the age of 40 in patients with a positive family history of thromboses are relatively frequently associated with coagulation abnormalities. In addition, patients with skin necrosis at the initiation of oral anticoagulants, or with repeated superficial vein thrombosis or unexplained arterial occlusions at a young age might be included for screening. Tests have also to be selected. Some abnormalities, such as congenital deficiencies in antithrombin III, protein C and protein S, are recognized risk factors and have to be searched. Some others cannot be at present considered as definite risk factors (e.g., dysfibrinogenemias or deficiencies in factor XII), but their detection is easy by routine tests: prothrombin time, fibrinogen assay. Other abnormalities are recognized risk factors (or not) and need specific uncommon tests (e.g., study of fibrinolysis). Each time a biological abnormality is found, it is important to verify it is isolated since combined deficiencies have been observed and we should be able to answer the question whether the abnormality is the cause or the consequence of thrombosis, or a coincidence. Finally, in our experience, even in well selected patients, a coagulation disorder is detected in less than 30% of patients, so that new tests are needed to improve our knowledge in this field.

Antithrombin III Deficiency↗
PubMed2000

Successful anticoagulation with hirudin in a patient with mesenteric venous thrombosis and multiple coagulation abnormalities.

A case of multiple thrombotic diatheses discovered in the setting of mesenteric venous infarction is discussed. The patient had deficiencies of protein C, protein S, antithrombin III; was heterozygous for factor V Leiden; and had polycythemia vera. Adequate anticoagulation could not be established with heparin administration and hirudin was used. The diagnosis of mesenteric venous infarction, thrombotic tendency of multiple coagulation diatheses, and use of hirudin are discussed.

Activated Protein C Resistance↗
PubMed1996

[Role of coagulation disorders in mesenteric ischemia].

Mesenteric ischemic process can lead to bowel infarction or indolent low-grade ischemia. Inherited thrombophilia represents about 30 to 40% of mesenteric vein thrombosis. Analysis of thromboembolism sites occurring during genetic defect of coagulant factors showed that mesenteric thrombosis is the third localization after lung and legs, in equal incidence with cerebral thrombosis. The genetic defects known to be associated with thrombophilia, as deficiencies of protein C, protein S, antithrombin III, and dysfibrinogenemia, are discussed. A special interest is devoted to resistance to activated protein C. Acquired diseases, as myeloproliferative disease or paroxysmal nocturnal hemoglobinemia, inducing thrombosis are also discussed. Recent advances in both basic and clinical research have provided new insights that may be integrated into diagnostic and therapeutic practices.

Adult↗
PubMed1990

Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis.

BACKGROUND: Isolated deficiencies of antithrombin III, protein C, protein S, and plasminogen have been implicated as a cause of deep-vein thrombosis. It is assumed that patients with recurrent, familial, or juvenile thrombosis are very likely to have such a deficiency. METHODS: We studied the prevalence of isolated deficiencies of these proteins in 277 consecutive outpatients with venographically proved acute deep-vein thrombosis, as compared with 138 age-matched and sex-matched controls without deep-vein thrombosis, and calculated the positive predictive value of a history of recurrent, familial, or juvenile venous thromboembolism for the presence of such a deficiency. RESULTS: The overall prevalence of deficiencies of any of these proteins in the patients with venous thrombosis was 8.3 percent (23 of 277 patients) (95 percent confidence interval, 5.4 to 12.4), as compared with 2.2 percent in the controls (3 of 138 subjects) (95 percent confidence interval, 0.5 to 6.1; P less than 0.05 for the comparison between groups). The positive predictive values for the presence of an isolated protein deficiency in patients with recurrent, familial, or juvenile deep-vein thrombosis, defined as the proportion of patients with the clinical finding who had a deficiency of one or more of the proteins, were 9, 16, and 12 percent, respectively. CONCLUSIONS: The cause of acute venous thrombosis in most outpatients (91.7 percent) cannot be explained by abnormalities of coagulation-inhibiting and fibrinolytic proteins. The information obtained from the medical history concerning recurrent or familial venous thrombosis or the onset of the disease at a young age is not useful for the identification of patients with protein deficiencies.

Acute Disease↗
PubMed1992

Partial deletion of an antithrombin III allele in a kindred with a type 1 deficiency.

This report details the precise mapping of a partially deleted human antithrombin III (AT-III) allele, found in a kindred with an inherited type 1 AT-III deficiency. Using truncated AT-III probes generated by polymerase chain reaction (PCR) amplification from a full-length AT-III cDNA, as well as other genomic probes specific for the 5' upstream region of the AT-III gene, we were able to characterize a partial deletion on an AT-III allele encompassing exons 1 and 2 of the AT-III gene, and a region 5' to the coding sequences. The absence of the 5' upstream region in the affected AT-III allele was confirmed directly by the PCR amplification of a 1.5-kb polymorphic fragment of genomic DNA samples from family members. The precise determination of the 5' breakpoint of the affected allele was made possible by two different approaches: (1) subcloning plus biotin capture PCR, or (2) inverse PCR. This allowed us to confirm the mapping of the deletion obtained by Southern analysis; to show that the 3' region of the mutant AT-III allele, including exons 3 to 7, was intact; and to sequence approximately 0.7 kb upstream to the breakpoint in the mutant allele. Furthermore, PCR amplification of the region of the breakpoint provided unique products detectable only in affected members of this kindred. The breakpoint in the partially deleted allele is 480 bp upstream from the 5' boundary of exon 3. No significant homology was found between the 0.7-kb sequence upstream to the breakpoint of the mutant allele and known human sequences.

Alleles↗
PubMedDate not supplied

[Antithrombin III concentrate use in patients with cirrhosis with coagulation disorders].

BACKGROUND: Patients with severe hepatic failure present acquired deficiency of antithrombin III (ATIII) owing to reduced synthesis associated with intravascular activation of blood coagulation, which may be corrected by ATIII infusion. OBJECTIVE: The aim of this uncontrolled trial was to verify the effect of a standard dose of ATIII concentrate (Kybernin), that is, 50 U/kg of body weight per day, every 2 days, on ATIII levels in patients with severe hepatic failure and hemostatic imbalance. PATIENTS AND METHODS: Six cirrhotic patients were studied: mean age of 44 years (14 to 63 years), who presented at least 2 abnormal coagulation tests (PT > 1.40, APTT > 1.25, Fibrinogen < 1.5 g/dL, Platelet count < 80,000/mm3). Mean serum albumin was 2.6 g/dL (1.9 to 3.8 g/dL). Blood was drawn before infusion, 4 h after the first infusion, and just before the next infusion. ATIII levels were measured by amidolytic method. RESULTS: Mean ATIII levels were: initial = 35.8%, 4th h = 56.2%*, 2nd d = 48.7%*, 4th d = 45.7%*, and 8th d = 42.3%. ATIII levels increased significantly after infusion of this standard dose in all patients, although they have not been fully corrected (Friedman test, * p < 0.02), which has been sustained till the 4th day. There was no improvement on the clinical outcome. CONCLUSIONS: These findings suggest that doses of ATIII concentrate higher than 50 U/kg/infusion must be administered to patients with severe hepatic failure, to guarantee normal levels of the inhibitor, in order to verify its influence on the hemostatic mechanism.

Adolescent↗
PubMed1994

Fresh frozen plasma has no beneficial effect on the hemostatic system in children receiving L-asparaginase.

L-Asparaginase (ASP), a chemotherapeutic agent used in the treatment of children with acute lymphoblastic leukaemia (ALL), is linked to thromboembolic complications secondary to an acquired deficiency of antithrombin III (ATIII). Fresh frozen plasma (FFP) is used to prevent and/or treat thrombotic complications in these children. However, the effect of FFP on plasma concentrations of ATIII and biochemical markers of activation of coagulation has never been tested. In this study, FFP (20 ml/kg) was administered to eight children with ALL receiving ASP in the consolidation phase of their treatment. Plasma samples were drawn pre-infusion, and following infusion at 1, 24, and 48 hr. Prior to the FFP infusions, plasma concentrations of prothrombin, fibrinogen, alpha 2-macroglobulin, heparin cofactor II, protein C, and protein S were similar to levels in healthy children. Only plasma concentrations of ATIII were significantly decreased (0.55 U/ml). Following FFP infusions, there was no statistical or clinically important increase in plasma concentrations of any coagulation protein at any time point. Pre-infusion plasma concentrations of markers of endogenous thrombin generation (thrombin-antithrombin III complexes (TAT)) and activation of the fibrinolytic system in response to activation of the coagulation system (D-dimer levels) were significantly increased. However, FFP had no statistical or clinically important effect on concentrations of these markers. We conclude that FFP administration for the prevention and treatment of acquired ATIII deficiency secondary to ASP has no demonstrable benefit on plasma levels of coagulation proteins and is unlikely to be of clinical benefit.

Adolescent↗