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PubMed2001

Antithrombin deficiency in Brazilian patients with venous thrombosis: molecular characterization of a single splice site mutation, an insertion and a de novo point mutation.

The prevalence of antithrombin (AT) deficiency in 342 unselected Brazilian patients with venous thrombosis was 1.16%, which increased to 3% when only patients under the age of 50 or with a familial history of thrombosis were considered. In two patients, a clinical (contraceptive use) or genetic risk factor (factor V Leiden and C677T in the methylene tetrahydrofolate reductase gene [MTHFR]) was identified and corroborated the hypothesis that an interaction of factors accounted for the appearance of thrombosis. However, no risk factor other than AT deficiency was identified in one patient with an important clinical and family history of spontaneous thrombosis. Three mutations were identified in these patients: a G-->A transition in intron 5 at position +1 (5'-->3'), three base insertions corresponding to arginine at position 5383 in exon 3A, and a G-->A transition at 13328, corresponding to an Ala404Thr de novo mutation. The polymorphisms in the genes coding for coagulation factors XII and XIII and fibrinogen normally associated with an increased risk for venous thrombosis were not related to thrombosis in these patients. This is the first study in South America to assess the prevalence of AT deficiency and to report the molecular characterization of the mutations involved.

Adult↗
PubMed1997

Genetic analysis in Japanese kindreds of congenital type I antithrombin deficiency causing thrombosis.

We have identified two novel minor deletions (case 1; -TA or -AT at nucleotide 9831-3 in exon 5 and case 2; -A at nucleotide 7640-1 in exon 4), one novel nonsense mutation (case 3; TAT to TAA at nucleotide 7491 in exon 4), and one recurrent nonsense mutation (case 4; CGA to TGA at nucleotide 5381 in exon 3A) in Japanese kindreds with congenital type I antithrombin deficiency. The deletion detected in case 1 represented a symmetric element (CTCTGTCTC) and possessed a direct repeat (CTCTATGTCTC). The deletion in case 2 was recognized in a consensus sequence (TGAAT) and possessed a direct repeat (GATGAA). The nonsense mutation in case 3 formed a palindrome (CCGTTAACGG) and that in case 4 was caused by a CpG dinucleotide mutation. These results confirm that the mutations of congenital type I antithrombin deficiency are not random events but are influenced strongly by DNA sequences.

Adult↗
PubMed2001

Creation of an additional glycosylation site as a mechanism for type I antithrombin deficiency.

We report the identification of a new mutation resulting in type I antithrombin (AT) deficiency and the mechanism by which the deficiency arose. The single base substitution of G to A at nucleotide 2709 was identified in a proband with a family history of venous thrombosis. The mutation results in a substitution of 82 Ser by Asn, creating a new glycosylation site. Expression studies were then carried out, to confirm Asn-linked glycosylation occurred at this consensus site and that this resulted in the AT deficient phenotype. Cell-free translations using rabbit reticulocyte lysate in the presence of microsomes demonstrated that the 82 Asn variant was post-translationally processed efficiently. The 82 Asn variant protein was of a higher molecular weight than normal AT. consistent with the addition of a fifth glycan chain. Incubation of translation product with endoglycosidase H, confirmed that the higher molecular weight product had resulted from additional carbohydrate. Expression of the 82 Asn variant in COS-7 cells resulted in intracellular accumulation, with a low level of secretion of the protein into culture supernatant, consistent with type I AT deficiency. The addition of an extra carbohydrate side chain to residue 82 of antithrombin may block post-translational folding. trapping the variant intracellulary.

Adolescent↗
PubMedDate not supplied

[Antithrombin III in hip surgery].

Antithrombin III is an important element of the endogenous thrombosis protection system. Congenital Anti-thrombin III deficiencies are associated with increased incidence of thrombo-embolisms. If Antithrombin III is determined at the time of operation, postoperative deficiencies resulting from an increased turnover rate can be identified. Determination of Antithrombin III is not suitable for prognosticating the occurrence of thrombo-embolic complications in isolated cases. Antithrombin III can be administered in the form of fresh frozen plasma (FFP), though it is also available as Antithrombin III concentrate. So far no investigations have been carried out to establish whether it is possible to improve thrombosis protection with or without heparin prophylaxis by concentrated Antithrombin III substitution.

Antithrombin III↗
PubMed2002

Protein C, S and antithrombin III levels in patients with acute mechanical valve thrombosis.

BACKGROUND: Mechanical prosthetic heart valve thrombosis is a serious complication with an incidence of 1-6%. The reduction in active vitamin-K dependent protein C and S levels caused by warfarin treatment also results in a prothrombotic state. This study was conducted to investigate the connection between protein C (PC), protein S (PS), antithrombin III (ATIII) deficiency and prosthetic mechanical valve thrombosis. METHODS: Twenty-nine of the 283 patients who underwent valve replacement with St. Jude medical prosthesis had mechanical valve thrombosis (group 2). The rest were considered as group 1. Twelve of the 29 patients (41.4%) had isolated aortic valve replacement, 12 had isolated mitral valve replacement (41.4%) and 5 patients had double valve replacement (17.2%). Most of the patients had rheumatic valve disease at their 1st operation. The mean time of occurrence for mechanical valve occlusion was 4.1+/-1.0 years following surgery. RESULTS: The values of PC, PS and ATIII were obtained when the mechanical valves stuck or at routine follow-up. PC, PS and ATIII levels were significantly lower in the mechanical valve thrombosis group. PC levels were 75.4+/-37.6% and 49.9+/-32.2% in group 1 and 2, respectively (p=0.001). PC, PS and ATIII values were mostly lower in the 2nd group but this difference only became significant after at least 2 years of warfarin usage. CONCLUSIONS: Natural anticoagulant levels can be low during the use of warfarin. In which case the dose can be increased in order to hold the international normalized ratio (INR) at 3-3.5. However, more frequent follow-up is required and patients should be investigated for hypercoagulation states or deficiency in anticoagulant proteins. Patients referred to hospital with any mechanical valve thrombosis or recurrent thromboembolism should be evaluated for hypercoagulant proteins.

Adult↗
PubMedDate not supplied

[Thrombosis and cardiovascular diseases].

Thrombosis represents the propensity toward arterial and/or venous thrombotic events. Many causes of thrombosis are now known: clinical predisposing factors (recent major surgery, varices of lower limbs, prolonged bedrittening); immunological, hematological and liver diseases; inborn or acquired coagulation factors' or plasmatic proteins' deficiency; platelets disfunction. Thrombotic screening of affected individuals is fundamental to adjust dosage and length of therapy, for secondary prevention and for relatives evaluation.

Activated Protein C Resistance↗
PubMed1994

Use of low molecular weight heparin in the treatment of venous thrombosis in a patient with anti-thrombin III deficiency: a case report.

This paper describes the use of a low molecular weight heparin (LMWH) in the treatment of a thrombotic episode in a patient with anti-thrombin III deficiency. Subcutaneous Fraxiparine, a low molecular weight heparin, was successfully used in the initial treatment of a second thrombotic episode in this patient with good results--no clot extension and an almost complete resolution of pulmonary emboli. This case demonstrates the advantages of using LMWH over conventional unfractionated heparin (UFH) which include ease of administration and the rapid achievement of optimal anticoagulation in conjunction with a diminished need for laboratory monitoring.

Adult↗
PubMed1993

The hypercoagulable states.

In most cases, acute venous thrombosis has a straightforward etiology--for example, the patient who has had prolonged bed rest with a broken leg and received no heparin. A significant minority of patients, however, have an inherited biochemical deficiency or an acquired disorder that increases the risk of thrombosis. Some general guidelines suggest when to suspect such defects and what tests to apply.

Adolescent↗
PubMed1998

Cerebral venous thrombosis and procoagulant factors--a case study.

Cerebral venous thrombosis is a polymorphic clinical entity for which diagnosis has become more frequent with the advent of neuroradiology. The superior sagittal and transverse sinuses are frequently involved, whereas cavernous sinus thrombosis is much less frequent. Inherited resistance to the anticoagulant action of activated protein C (APC resistance), antithrombin deficiency, protein C and S deficiencies, and hyperhomocysteinemia seem to represent major causes of thrombophilia when unusual thromboembolic events (ie, before the age of 45 years) are observed. The authors present the combined occurrence of protein C and protein S deficiencies in a 32-year-old woman, manifested by extensive cerebral venous thrombosis.

Adult↗
PubMed2006

Haematologic disorders and cerebral venous thrombosis.

This review focuses on the several coagulation disorders (the so called hypercoagulable states) that are associated with cerebral venous thrombosis. Hypercoagulable states likely explain the high percentage of cases of cryptogenic cerebral infarction in young people. The most common of the hereditary defects appear to be deficiency of antithrombin III, protein C or protein S, activated protein C resistance and prothrombin 20211A mutation. In a large majority of cases activated protein C resistance is due to the presence of factor V Leiden. Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) represent an acquired disorder of coagulation. Rare defects include heparin cofactor II (HC II), plasminogen or tissue plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor-1 (PAI-1) and dysfibrinogenemia. Hyperhomocystinemia is responsible for both arterial and venous thrombosis. A work-up to identify one of the recognizable hypercoagulable states is indicated, especially in younger patients with stroke. Laboratory evaluation for hypercoagulable states may also often be indicated in those patients who do not have other obvious risk factors for their stroke. If from clinical history, family history and/or laboratory studies, a patient is felt to have a hypercoagulable state, the decision for long term chronic anticoagulation needs to be individualized. If a hereditary hypercoagulable state is found, it also may be appropriate to recommend screening of other family members.

Antiphospholipid Syndrome↗
PubMedDate not supplied

[Protein S deficiency and thrombophilia: presentation of a clinical case and review of the literature].

We report the case of a 22-year-old obese woman with severe protein S deficiency, probably genetic in nature, associated with recurrent venous thrombosis. Protein S deficiency is a rather rare disease: it may be an inherited, either homozygous (purpura fulminans at neonatal age), heterozygous, or acquired disorder. The thrombophilic state may be manifested as deep vein thrombosis or thrombophlebitis of the superficial veins with a high risk of pulmonary embolism in the young, and it is often exacerbated by pregnancy. In our case, the presenting event, bilateral deep venous (iliac-femoral) thrombosis complicated by disseminated intravascular coagulation, had occurred when the patient was 13 years old. We started long-term therapy with oral coagulants, i.e. warfarin even if the latter may cause skin necrosis ("warfarin dermatitis") in some patients with protein S deficiency. The clinician must consider protein S deficiency in cases of recurrent thrombosis, particularly in young patients: the importance of early implementation of long-term preventive therapy should not be underestimated.

Adult↗
PubMed1984

[Significance of disordered antithrombin III function in disseminated intravascular coagulation and deep venous thrombosis for anticoagulant therapy].

In patients with acute deep vein thrombosis of the pelvis and limbs and in patients with decompensating course of DICFS considerable defects in AT III function are regularly demonstrated by laboratory tests, while in groups including patients with old or less pronounced venous thrombosis or in patients with compensated or overcompensated consumption coagulopathy normal AT III values might frequently be expected. This seems to be of interest for the interpretation of laboratory data on AT III. However, from these findings AT III replacement cannot be deduced and they cannot be used as a criterion to assess the prognostic value of AT III deficiency for the course of the underlying disease. In acquired AT III defects the anticoagulant activity of heparin is not necessarily decreased. After continuous infusion of doses below 500 USP in patients with DICFS and after administration of heparin doses of 750 USP/h/70 kg in patients undergoing fibrinolytic therapy the AT III content rather increases continuously. After extremely high heparin doses during extracorporeal circulation in the heart-lung machine transitorily decreased AT III values return to normal. In certain risk situations, however, such as after bolus injection of comparatively high heparin doses in patients with greatly reduced AT III values, a lowered anticoagulant effect of high heparin doses must be expected. In these cases AT III replacement is indicated. However, when enhanced heparin resistance is suspected or diagnosed, treatment with AT III concentrates is justified only when the diagnosis is based on laboratory findings. Cortisone and protamine chloride were found to exert direct effects on AT III function and concentration independent of the AT III defects mentioned.

Antithrombin III↗
PubMed2006

Antithrombin deficiency and its relationship to severe burns.

Antithrombin (AT) is an important endogenous anticoagulant and exhibits marked anti-inflammatory properties. To evaluate the incidence of AT deficiency in severe burn and its correlation to the variables of the abbreviated burn severity index (ABSI), length of hospital stay (LOS) and mortality we collected data on the substitution of human plasma-derived AT concentrate in 201 consecutive patients suffering from severe burn. One hundred and eight patients (54%) developed AT deficiency during their hospitalisation and, according to our institutional practice, received substitution therapy by continuous infusion to maintain physiological plasma activity (70-120%). The mean administered dose served as a measure of AT deficiency. The percentage of patients in an AT deficient state was highest within the first 5 days after injury. It was 26% on day 1 and between 38% and 41% on days 2-5 and thereafter decreased constantly over time. A multiple regression analysis between the dependent variable mean administered dose of AT concentrate and the independent variables age, total body surface area burned (TBSA), gender, inhalation injury (INHAL), full thickness burn (FTB), LOS and mortality was performed. Age, gender and FTB showed no significant influence on the development of AT deficiency. Increasing TBSA and INHAL clearly increase the risk of developing AT deficiency (p-values 0.0001 and 0.037). The analysis also identified AT deficiency as an independent predictor of LOS and mortality (p-values 0.036 and 0.003). Development of AT deficiency is a frequent event after burn with significant correlation to TBSA and INHAL, increased mortality rates and longer hospital stays.

Anticoagulants↗
PubMed1991

The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease.

210 patients, with a history of venous thrombosis, have undergone prothrombotic investigations. In nine cases a consistent deficiency of antithrombin was identified. In five there was a reduction in the plasma antigenic concentration of antithrombin and in a further four cases deficiency was due to the presence of a dysfunctional antithrombin variant. The variants have all been characterized by DNA analysis and in three the mutations have been confirmed by peptide sequencing (antithrombin Basel (41 Pro to Leu). Hamilton (382 Ala to Thr). Cambridge I (384 Ala to Pro) and Cambridge II (384 Ala to Ser). The incidence of antithrombin deficiency in patients with a history of venous thrombosis has previously been quoted at between 2% and 3%: there is no published data available on the incidence of antithrombin variants. In our series 5% of patients who presented before the age of 40 years had antithrombin deficiency, and 2% of the total number of patients investigated had a dysfunctional variant. Our figures indicate that a significant number of cases of antithrombin deficiency are due to dysfunctional variants and that the true incidence of antithrombin deficiency in patients with a history of venous thrombosis is in the order of 5%.

Adult↗
PubMed2006

Antithrombin supplementation for anticoagulation during continuous hemofiltration in critically ill patients with septic shock: a case-control study.

INTRODUCTION: Acquired antithrombin III (AT) deficiency may induce heparin resistance and premature membrane clotting during continuous renal replacement therapy (CRRT). The purpose of this study was to evaluate the effect of AT supplementation on filter lifespan in critically ill patients with septic shock requiring CRRT. METHODS: We conducted a retrospective case-control analysis based on a 4-year observational study with prospectively collected data in two medical intensive care units in a university hospital. In all, 106 patients with septic shock underwent CRRT during the study period (55 during 2001 to 2002 and 51 during 2003 to 2004). Of these, 78 had acquired AT deficiency (plasma level below 70%) at onset of renal supportive therapy, 40 in the first 2-year period and 38 in the last 2-year period. In the latter intervention period, patients received AT supplementation (50 IU/kg) during CRRT each time that plasma AT activity, measured once daily, fell below 70%. RESULTS: In a case-control analysis of the 78 patients with acquired AT deficiency, groups were similar for baseline characteristics, except in severity of illness as assessed by a higher Simplified Acute Physiology Score (SAPS) II after 2002. In comparison with controls, cases had a significantly greater AT level after AT supplementation, but not at baseline, and a smaller number of episodes of clots, without excess bleeding risk. The median hemofilter survival time was longer in the AT group than in the heparin group (44.5 versus 33.4 hours; p = 0.0045). The hemofiltration dose, assessed by the ratio of delivered to prescribed ultrafiltration, increased during intervention. AT supplementation was independently associated with a decrease in clotting rate, whereas femoral angioaccess and higher SAPS II were independent predictors of filter failure. However, mortality did not differ between periods, in the control period the observed mortality was significantly higher than predicted by the SAPS II score, unlike in the treatment period. CONCLUSION: In sepsis patients requiring CRRT and with acquired AT deficiency, anticoagulation with unfractionated heparin plus AT supplementation prevent premature filter clotting and may contribute to improving outcome, but the cost-effectiveness of AT remains to be determined.

Adult↗
PubMed2000

Causes of venous thrombosis in fifty Chinese patients.

In a whole year from July 1997 to June 1998, a total of 50 patients with sonogram-proved venous thrombosis who called on our hematology clinic consecutively entered into the study. Their mean age was 59.1 +/- 17.5 years, range 18-83 years, and 29 were male. A series of examinations were performed in order to find out the cause of venous thrombosis. These examinations included antithrombin, protein C, protein S, plasminogen, heparin cofactor II, activated protein C ratio, factor V Leiden mutation, fibrinogen, factors VIII and XII, euglobulin lysis time, 677 C-->T mutation of methylenetetrahydrofolate reductase (MTHFR), prothrombin 20210 (PT 20210) A allele mutation, lupus anticoagulant, anticardiolipin antibody, and complete blood count. Five patients (10%) were found to have malignancy; an inferior vena cava thrombosis in one patient was due to venous compression by hydronephrosis; two patients had lupus anticoagulant; two had varicose veins of legs; two had protein C deficiency; four had protein S deficiency; two had plasminogen deficiency; two had antithrombin deficiency. No activated protein C resistance, elevated factor VIII level, factor V Leiden, PT 20210 A allele or heparin cofactor II deficiency was found in the present study. Homozygous MTHFR 677 C-->T gene mutation was found in 7 patients (14%); one of them also had a plasminogen deficiency. No possible risk factor of venous thrombosis could be found in 24 patients (48%). In conclusion, malignancy and protein S deficiency were the most frequent acquired and congenital causes of venous thrombosis in the Chinese, respectively.

Adenocarcinoma↗
PubMed1996

[Coagulation-inhibiting proteins; implications for cerebrovascular disorders].

BACKGROUND: Deficiencies in ATIII, PC, and PS are associated with a higher incidence of thromboembolic events. An analysis was made of these three proteins in 239 cases of non-embolic stroke; the incidence of their deficiency and the presence of intersexual variations were evaluated. Two different methods were used to measure PS, functional PS and free PS, comparing the values and the incidence of the deficiency. RESULTS: ATIII, PC, free PS, and functional PS deficiencies were found in 2.93%, 7.5%, 9.52% and 13.72%, respectively. The observed PS values showed statistically significant differences between sexes. CONCLUSION: There was a higher incidence of PS and PC deficiencies in patients with stroke, which were associated with a poorer prognosis. PS differed between sexes and both methods were valid for its quantitation.

Aged↗
PubMed1994

Coagulation factors and markers of activation of coagulation in homocystinuria (HOCY): a study in two siblings.

Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often present with thromboembolic events. In most cases in which coagulation factors have been analysed, a deficiency of AT-IIIc and factor VIIc has been reported, the cause of which has not been elucidated. Activation of coagulation with consumption of coagulation factors has been postulated as the mechanism. This paper reports a longitudinal study of two patients: patient 1 with thromboembolic disease and his asymptomatic sister, patient 2. Before start of therapy in patient 1, a reduction of FVIIc, other coagulation factors, and AT-IIIc was found. Markers of activation of coagulation (F1 + 2, TAT, FM, D-dimers) were elevated only in patient 1, and only at the time of thrombotic complications. In patient 2 reduced levels of FVIIc and other coagulation proteins, and a low borderline AT-IIIc level was found. Thus, in the two patients, sustained activation of coagulation can be reasonably excluded to be the cause of low levels of coagulation proteins. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma. Thrombosis has not recurred to date. FVIIc and the other coagulation proteins and AT-IIIc increased in parallel with the biochemical remission. Direct inhibition of the activity of AT-III and coagulation factor VIII and other factors by homocysteine was attempted in vitro but could not be shown at HC concentrations known to occur in the plasma of HOCY patients. Therefore, in these patients, deficient synthesis of coagulation factors and AT-III due to a disturbance of amino acid metabolism is still the most probable explanation for the observed low levels.

Adult↗