Acquired Antithrombin III Deficiency: Replacement with Antithrombin III Concentrates in a Patient with Protein S Deficiency Accelerates Response to Therapy
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A 33-year-old man with inherited protein S deficiency and a 20-year history of deep and superficial venous thrombosis was admitted for treatment of extensive, acute, superficial venous thrombosis of the left lower extremity. Clinical response to intravenous heparin was very slow. After discovery of acquired antithrombin III deficiency superimposed on the protein S deficiency, he was given antithrombin III concentrates with the intravenous heparin. His response to therapy was accelerated. The development of acquired antithrombin III deficiency in patients with venous thrombosis may slow the response to standard anticoagulant therapy. Therapy of the thrombosis may be improved with administration of antithrombin III concentrates.Keywords:
Antithrombin III deficiency
Anticoagulant Therapy
Protein S deficiency
Protein C deficiency
Antithrombin III deficiency
Protein S deficiency
Intracranial Thrombosis
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Protein C, protein S, and antithrombin III are naturally occurring anticoagulant proteins. Activated protein C and protein S act by inhibiting the action of the cofactors factor Va and factor VIIIa. Antithrombin III inhibits the serine proteases (factors II, IX, X, XI, and XII); its anticoagulant action is dramatically enhanced by heparin. Deficiencies of these proteins are associated with thromboembolic disease. Antigen and activity assays practical for the clinical laboratory are available for protein C and antithrombin III. Protein S antigen assays are also available. Diagnosis of an anticoagulant protein deficiency has serious implications for a patient and his kindred, and should therefore only be made on the basis of repeated abnormal determinations of a single protein in an individual patient, or documentation of the same protein deficiency in other family members.
Heparin cofactor II
Antithrombin III deficiency
Factor IX
Protein C deficiency
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Clinical laboratories are at present confronted with increasing demands for thrombophilia work-up, which may seriously overwhelm their capacity. Recently, methods able to investigate the protein C anticoagulant pathway globally have been proposed. In this study we investigated the reliability of one such method for its ability to detect patients with known defects of the pathway by testing plasmas from patients with the FVQ506 mutation, with congenital protein C, protein S or antithrombin deficiencies, and patients with previous history of thrombosis, but no identifiable defects. The results show that the new global test fulfils the requirements for congenital protein C deficiency and activated protein C resistance associated with the FVQ506 mutation, which account for more than half of the congenital defects found in thrombophilia. However, congenital protein S deficiency very often remains undetected by this test. Improvement of sensitivity toward this component of the protein C anticoagulant pathway would enroll the global test as a suitable candidate to explore the pathway. Since antithrombin, which also remains undetected by this test, is an additional important risk factor for venous thrombosis, devoting time and effort to developing global tests able to detect defects in both the antithrombin and protein C pathways is warranted.
Protein S deficiency
Antithrombin III deficiency
Protein C deficiency
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Summary The frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
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Background Inherited deficiency of antithrombin, protein C and protein S, three important, naturally occurring coagulation inhibitors, might play a major role in the occurrence of venous thromboembolism in Chinese. The establishment of age- and gender-related normal ranges of these inhibitors is crucial for an accurate diagnosis of these deficiencies.Design and Methods We designed a prospective cross-sectional study recruiting healthy adults from four university–affiliated hospitals in China. Antithrombin, protein C and protein S were studied by measuring their activity. Gene analysis was performed when natural anticoagulant deficiency was suspected. Polymorphisms of the factor V gene were searched for among subjects who were positive for activated protein C resistance.Results In 3493 healthy Chinese adults (1734 men, 1759 women; age 17–83 years), we found higher age-adjusted activities for protein C and protein S in men than in women but no sex difference for antithrombin. In women, mean protein C and protein S activities increased with age. In men, mean protein C levels increased with age up to the age of 49 but decreased after 50 years old; mean protein S levels decreased after 50 years of age. Antithrombin levels remained stable over time in women but decreased significantly after 50 years of age in men. Reference values according to age and sex allowed the identification of 15 genetic variants (protein C: 10, antithrombin: 3, protein S: 2) in subjects with protein activity below the 1st percentile.Conclusions This is the largest survey ever conducted in the healthy general Chinese population. These normal ranges provide the essential basis for the diagnosis and treatment of thrombosis in Chinese.
Protein S deficiency
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Inherited thrombophilia can be defined as a genetically determined tendency to venous thromboembolism. Genetic risk factors for venous thrombosis include antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance due to the factor V gene Leiden mutation, inherited hyperhomocysteinaemia, elevated factor VIII levels and the prothrombin gene G20210 A variant. A genetic risk factor is now identifiable in up to 50% of unselected patients with venous thrombosis. Individuals with inherited thrombophilia may develop venous thrombosis at a young age, or they may present with thrombosis at an unusual site or in the apparent absence of any precipitating event. A family history of thrombosis is suggestive of inherited thrombophilia. Laboratory investigations for inherited thrombophilia should include testing for activated protein C resistance and the factor V gene Leiden mutation, and screening for deficiencies of antithrombin, protein C or protein S. Screening for the prothrombin gene G20210 A variant, and measurement of plasma factor VIII and homocysteine levels should be considered in individual cases. In recent years the multifactorial nature of thrombophilia, both circumstantially and on a genetic level, has become increasingly apparent. Individuals with more than one inherited thrombophilia risk factor are particularly prone to thrombosis and their identification is a priority.
Protein S deficiency
Factor V
Antithrombin III deficiency
Hyperhomocysteinemia
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SUMMARY Plasma concentrations of protein C, protein S and antithrombin III were measured in 33 unselected children with a history of cryptogenic stroke (group 1), four children with previously ascertained low plasma concentrations of protein C following stroke (group 2) and 42 healthy children underging minor surgery (group 3). Protein S and antithrombin III were normal in all patients. Low concentrations of protein C were found in two patients in group 1 and in six healthy children in group 3. Low protein C concentrations returned to normal over many months in three of the four patients in group 2. Prophylactic antithrombotic therapy and/or termination of pregnancy had been carried out unneccessarily in two families in whom inherited protein C deficiency was not confirmed. The suggestion that heterozygous protein C deficiency contributes to the risk of arterial stroke was not supported by this study. RÉSUMÉ Déficience en protéinc C ct accident vasculo‐cérébral précoce Les concentrations plasmatiques de la protéine C, la proteinc S et L'antithrombine III ont été mesurées chez 33 enfants non sélectionnés présentant une histoire d'accident vasculo‐cérébral cryptogénétique (groupe 1), quatre enfants chez qui une concentration plasmatique basse de protéine C avait été trouvée aprés un accident vasculo‐cérébral (groupe 2) et 42 enfants en bonne santé hospitalisés pour un acte chirurgical mineur (groupe 3). La protéine S et L'antithrombine III étaient à des taux normaux chez tous les enfants. Des faibles concentrations de protéine C ont été trouvées chez deux patients du groupe 1 et six sujets du groupe 3. Les concentrations basses de protéines C ne redevinrent normales qu'aprés de nombreux mois chez trois des enfants du groupe 2. Un traitement prophylactique antithrombique et/ou une interruption de grossesse ont été pratiqués inutilemenl dans deux families chez qui une déficience héréditaire de protéine C ne fut pas confirmée. L'étude ne confirme done pas l'hypothése scion laquclle une déficience hétérozygote en protéine C contribue au risque d'accidents artérials cérébraux. ZUSAMMENFASSUNG Protein C Mangel undfrüher Schlaganfall Bei 33 nicht ausgewählten Kindern mit der Anamnese eines kryptogenen Schlaganfalls (Gruppe I), vier Kindern mit einer zuvor bestätigten niedrigen Plasniakonzentration von Protein C nach einem Schlaganfall (Gruppe 2) und 42 gesunden Kindern, die kleine chirurgische Fingriffe hatten (Gruppe 3), wurden die Plasmakonzentrationen von Protein C, Protein S und Antithrombin III gemessen. Protein S und Antithrombim III waren bei alien Patienten normal. Niedrige Konzentrationen von Protein C wurden bei zwei Patienten der Gruppe 1 und bei sechs gesunden Kindern der Gruppe 3 gefunden. Die niedrigen Protein C Konzentrationen bei drei der vier Patienten aus Gruppe 2 haben sich im Verlauf mehrerer Monate normalisiert. Bei zwei Familien. bei denen ein vererbter Protein C Mangel nicht bestätigt wurde, sind die prophylaktische antithrombotische Therapie und/oder die Beendigung der Schwangerschaft unnötigerweise durchgefürt worden. Die Vermutung, daß der heterozygote Protein C Mangel zum Risiko des arteriellen Schlaganfalls beiträgt, wurde in dieser Studie nich bestätigt. RUSUMEN Deficiencia de proteina C e ictus precoz Se midio las concentraciones plasmáticas de la proteína C, la proteína S y la antitrombina III en 33 niños no seleccionados con una historia de ictus criptogénico (grupo 1), cuatro niños con concentraciones plasmáticas bajas de proteína C post‐ictus previamente determinadas (grupo 2) y 42 niños sanos sujetos a una cirugl'a menor (grupo 3). La proteína S y la antitrombina III eran normales en todos los pacientes: Concentraciones bajas de proteîna C se hallaron en dos pacientes del grupo 1 y en seis niños sanos del grupo 3. Las concentraciones bajas de proteína C se normalizaron después de muchos meses en tres de los cuatro pacientes del grupo 2. La terapeutica antitrombótica profiláctica y/o la termination de embarazo se realizaron de forma innecesaria en dos familias, en las que la deficiencia hereditaria de proteina C no fue confirmada. La sugerencia de que la deficiencia en proteína C heterizigótica contribuye al riesgo de un ictus arterial no fue corroborada por este estudio.
Protein S deficiency
Protein C deficiency
Stroke
Antithrombin III deficiency
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Hereditary thrombophilia is caused by various inherited disorders. Most lead to a familial tendency to recurrent venous, not arterial, thrombosis, usually at a young age, and with spontaneous onset. Most of the genetic defects known today affect the function of natural anticoagulant pathways, in particular, the protein C system. In this study, 602 (265 female, 337 male) patients with suspected thrombosis, arterial or venous, were referred to King Hussein Medical Center in Amman, Jordan. The prevalence of hereditary deficiencies of antithrombin (AT), protein S (PS), and protein C (PC) were studied over a seven-year period (1993-2000). Activated protein C (APC-R) resistance subjects were studied over four years (1996-2000). The mean age was 30 years in females and 42 years in males. A diagnosis was established in 22.4% (n = 135) of the subjects (20.3% venous, 2.1% arterial). Protein C deficiency was found in 3.8%, protein S deficiency in 2.3% and antithrombin deficiency in 1.4% of our sample group. An APC-R problem was seen in 23.0% (n = 89) of the surveyed population. Out of the APC-R patients, 75.0% had the DNA analysis of a factor V Leiden mutation present. Of the subjects found to have the mutation 87.0% were heterozygous and 13.0% were homozygous. These results confirm that APC-R, as a result of factor V Leiden mutation, is the most prevalent cause of thrombosis, and thrombophilia is related to venous, not arterial, thrombosis.
Protein S deficiency
Protein C deficiency
Antithrombin III deficiency
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Protein S deficiency
Factor V
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Antithrombin III deficiency
Protein S deficiency
Superficial thrombophlebitis
Protein C deficiency
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