Double-Blind, Randomized, Placebo-Controlled Trial Comparing the Effects of Antithrombin Versus Placebo on the Coagulation System in Infants with Low Antithrombin Undergoing Congenital Cardiac Surgery.

OBJECTIVES: To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN: Randomized, double-blinded, placebo-controlled prospective study. SETTING: Multicenter study performed in 2 academic hospitals. PARTICIPANTS: The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS: Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS: Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION: Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.

Characterization of thrombosis in patients with Proteus syndrome.

Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic, progressive overgrowth disorder involving vasculature, skin, and skeleton, and caused by a somatic activating mutation in AKT1. We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. We found that six of ten patients, who were deceased, died secondary to deep venous thrombosis and/or pulmonary embolism. Of the remaining 47 living patients, six had thromboembolic events that all occurred postoperatively and in an affected limb. Eleven of 21 patients had an abnormal hypercoagulable panel including Factor V Leiden heterozygotes, antithrombin III deficiency, positive lupus anticoagulant, or Protein C or S deficiencies. We observed that eight of 17 patients had an abnormal D-dimer level >0.5 mcg/dl, but deep venous thromboses occurred in only four of those with D-dimer >1.0 mcg/dl. We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation on platelet function or the vascular endothelium. The D-dimer test is useful as a screen for thromboembolism, although the screening threshold may need to be adjusted for patients with this disorder. We propose developing a registry to collect D-dimer and outcome data to facilitate adjustment of the D-dimer threshold for Proteus syndrome and related disorders, including PIK3CA-Related Overgrowth Spectrum.

Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism.

BACKGROUND: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation. METHODS: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis. RESULTS: Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0-2 y, 45%), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75%), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism. CONCLUSION: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

Issues in the Diagnosis and Management of Hereditary Antithrombin Deficiency.

OBJECTIVE: To review insights gained in the past several years about hereditary antithrombin (AT) deficiency and to outline approaches to the management of patients with AT deficiency in the acute and chronic settings. DATA SOURCES: An extensive literature search of Scopus (January 2008-April 2016) was performed for the terms congenital antithrombin deficiency, inherited antithrombin deficiency, or hereditary antithrombin deficiency Additional references were identified by reviewing literature citations. STUDY SELECTION: All relevant English-language case reports, reviews, clinical studies, meeting abstracts, and book chapters assessing hereditary AT deficiency were included. DATA SYNTHESIS: AT deficiency significantly increases the risk of venous thromboembolism (VTE). The risk of VTE is particularly high during pregnancy, the postpartum period, and following major surgery. Effective clinical management includes determination of the appropriate type and duration of antithrombotic therapy (ie, AT replacement for acute situations) while minimizing the risk of bleeding. For persons newly diagnosed with AT deficiency, age, lifestyle, concurrent medical conditions, family history, and personal treatment preferences can be used to individualize patient management. Patients should be informed of the risks associated with hormonal therapy, pregnancy, surgical procedures, and immobility, which further increase the risk of VTE in patients with AT deficiency. CONCLUSION: AT deficiency poses the highest risk for VTE among the hereditary thrombophilias, often requiring long-term anticoagulation. Undertaking an evaluation for hereditary thrombophilia is controversial; however, a diagnosis of VTE in association with AT deficiency can have management implications. An important treatment option for patients with this disorder in high-risk situations is AT concentrate.

Mild antithrombin deficiency and risk of recurrent venous thromboembolism: a prospective cohort study.

BACKGROUND: Antithrombin deficiency, defined by antithrombin levels of <70%, is a major thrombophilic condition associated with an increased risk of venous thromboembolism (VTE). No prospective data are available about the risk of recurrent VTE associated with mildly decreased antithrombin levels (70-80%). METHODS AND RESULTS: Consecutive patients with a first VTE were stratified according to functional antithrombin levels (<70%, 70-80%, >80%) and were followed up for a mean of 8.70 years to assess the incidence of VTE recurrence. A total of 823 patients (mean age, 48.3 years; 41.9% male) were enrolled. Recurrent VTE occurred in 253 patients (3.53% per patient-year). With stratification for antithrombin levels, VTE recurrence occurred in 19 patients with antithrombin levels <70% (5.90% per patient-year), in 20 patients with antithrombin levels 70% to 80% (5.35% per patient-year), and in 214 patients with antithrombin levels >80% (3.31% per patient-year). After adjustment for major VTE risk factors and for anticoagulation duration, the risk of VTE recurrence was significantly higher in patients with antithrombin levels <70% (hazard ratio, 3.48; 95% confidence interval, 2.16-5.61) and antithrombin levels 70% to 80% (hazard ratio, 2.40; 95% confidence interval, 1.51-3.80) compared with patients with antithrombin levels >80%. When the population was stratified according to the presence or absence of major risk factors for the index event, the association remained significant only in patients with unprovoked VTE. CONCLUSIONS: The presence of mild antithrombin deficiency (70-80% antithrombin) in patients with unprovoked VTE is associated with a significantly increased risk of recurrence and should be taken into account when the duration of secondary prevention is determined. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382550.

Anticoagulant proteins in a population of Mexican mestizo donors.

BACKGROUND: To determine the activity of antithrombin (AT), protein C (PC), and protein S (PS), as well as the frequency of deficiencies of these proteins in a population of healthy Mexican mestizo blood donors. METHODS: AT, PC, and PS were determined from 1,502 plasma samples of healthy blood donors by using commercial kits in a coagulometer 4 STA (Diagnostica Stago, Asnières, France). RESULTS: A total of 741 women and 761 men were under study. They were divided into age range groups (18-24, 25-34, 35-44, 45-54, and 55-64 years). Activity of AT, PC, and PS was determined. For AT, activity values were specific for each age group according to gender when it had to do with PS, as well as when PC was determined. Frequencies of AT, PC, PS, and activated PC resistance activity deficiencies were obtained from reference levels (RLs) and average levels of this study. Differences were found between both frequencies for AT, PC, and PS, and the average levels obtained were used in this study. The frequencies of the activity deficiencies obtained through the values gotten in this population were: AT, 0.6%; PC, 1.06% (which is higher than the one obtained using the RLs described by commercial kits 0.33% and 0.66%, respectively); and PS, 1% (which is less than 4.5%). CONCLUSIONS: It is necessary to know the characteristics and biological behavior of the coagulation proteins in the Mexican population because the RLs used have been established for populations that are genetically different.

Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

Initial experience with recombinant antithrombin to treat antithrombin deficiency in patients on extracorporeal membrane oxygenation.

Acquired antithrombin (AT) deficiency has been associated with patients on extracorporeal membrane oxygenation (ECMO) as a result of hemodilution, blood coagulation activation, and the use of heparin. Replacement of AT has been typically utilized through the use of fresh-frozen plasma or AT concentrate. Antithrombin alfa (ATryn) is a recombinant form of AT (rAT) with an identical amino acid sequence as that of plasma-derived antithrombin. The primary objective of this study is to examine the relationship of rAT dose to measured plasma antithrombin activity in a small series of patients who received rAT while on ECMO. A retrospective chart review was performed of all patients at Medical City Children's Hospital who received ATryn while supported on ECMO between December 2011 and April 2012. Five patients were identified and the patients' weight, bolus dose of ATryn, drip rate of ATryn, and AT blood levels were collected for analysis. The median age of these patients was 1 month (range, 1 day to 3.75 years). Because no dosing guidelines exist for pediatric ECMO, a starting dose of ATryn was chosen based on the manufacturer's labeled indication (prevention of thromboembolic events in patients with AT hereditary deficiency). The median dose of rAT was 368 IU/kg/day (range, 104-520 IU/kg/day) to obtain AT activity level of 80-120%. The average time to reach the targeted AT activity level (80-120%) was 12.7 hours (range, 11-17 hours). Our findings suggest that the published ATryn dose may be inadequate to reach desired AT activity concentrations for pediatric patients on ECMO. Difference in patient population, use of extracorporeal circuits, and the use of heparin are likely explanations for this finding. We would also recommend frequent checking of AT levels while delivering this drug because making timely adjustments is necessary for achieving and maintaining the target AT activity level.

[A patient with congenital antithrombin III deficiency who underwent laparoscopic renal resection].

A 66-year-old man with congenital antithrombin III (ATIII) deficiency was scheduled to undergo laparoscopic renal resection. On admission the plasma ATIII activity was as low as 56%. After giving ATIII intravenously, the plasma ATIII activity increased to 103% on the day of surgery. It is usually difficult to monitor ATIII during surgery. Instead, we measured activated clotting times (ACTs). The ACT before operation was 178 seconds. During the operation, the ACT dropped to 81 seconds. We administered 3,000 units of heparin, and the ACT increased to 182 seconds. After surgery, the plasma ATIII activity was 68%. We managed the ACT activity to a target value of 100% postoperatively, until the patient was switched from heparin to oral warfarin. He was discharged without complications 10 days after surgery. In this patient, the ACT decreased during the operation, as did the ATIII activity. Although the half-life of the ATIII preparation was 3 days, it appeared that the ATIII activity, which was high preoperatively, decreased during the operation. Coagulation abnormalities could be managed quickly by measuring ACT. Our results suggest that the measurement of ACT is an effective technique for the intraoperative monitoring of patients with congenital ATIII deficiency.

Thr90Ser Mutation in Antithrombin is Associated with Recurrent Thrombosis in a Heterozygous Carrier.

Antithrombin (AT) is a serine protease inhibitor that regulates the activity of coagulation proteases of both intrinsic and extrinsic pathways. We identified an AT-deficient patient with a heterozygous Thr90Ser (T90S) mutation who experiences recurrent venous thrombosis. To understand the molecular basis of the clotting defect, we expressed AT-T90S in mammalian cells, purified it to homogeneity, and characterized its properties in established kinetics, binding, and coagulation assays. The possible effect of mutation on the AT structure was also evaluated by molecular modeling. Results demonstrate the inhibitory activity of AT-T90S toward thrombin and factor Xa has been impaired three- to fivefold in both the absence and presence of heparin. The affinity of heparin for AT-T90S has been decreased by four- to fivefold. Kinetic analysis revealed the stoichiometry of AT-T90S inhibition of both thrombin and factor Xa has been elevated by three- to fourfold in both the absence and presence of heparin, suggesting that the reactivity of coagulation proteases with AT-T90S has been elevated in the substrate pathway. The anticoagulant activity of AT-T90S has been significantly impaired as analyzed in the AT-deficient plasma supplemented with AT-T90S. The anti-inflammatory effect of AT-T90S was also decreased. Structural analysis predicts the shorter side-chain of Ser in AT-T90S has a destabilizing effect on the structure of AT and/or the AT-protease complex, possibly increasing the size of an internal cavity and altering a hydrogen-bonding network that modulates conformations of the allosterically linked heparin-binding site and reactive center loop of the serpin. This mutational effect increases the reactivity of AT-T90S with coagulation proteases in the substrate pathway.

Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update.

Antithrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses antiinflammatory properties, many of which are mediated by its actions as an anticoagulant. Hereditary AT deficiency is a rare, underrecognised medical condition that is associated with inadequate endogenous anticoagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40-60% of normal. As a result, individuals with hereditary AT deficiency have a > or = 50% lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a three- to seven-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anticoagulant thromboprophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of haemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labour, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to > or = 120% of normal levels followed by maintenance of AT activity at > or = 80% of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency. The objective of this review is to discuss hereditary AT deficiency and the role of AT replacement therapy in the treatment of patients with this congenital disorder.

Impact of reduced endogenous anti-coagulation protein activity on vascular events of peripheral arterial disease.

AIM: Aim of the study is to elucidate the prevalence and the prognosis of patients with peripheral arterial disease (PAD) who have reduced endogenous anti-coagulation protein activity. METHODS: Ninety six patients with PAD were studied, including 45 patients with intermittent claudication and 51 with critical limb ischemia. Among them 65 patients underwent peripheral artery bypass grafting. Venous blood samples were obtained and plasma activity level of Protein C (PC), Protein S (PS), Plasminogen (PLG), Antithrombin (AT) were measured. Based on the patients' clinical database the prevalence and clinical relevance was studied. RESULTS: In our PAD patients PC activity is reduced in 18.8%, PS activity is reduced in 16.7%, PLG activity was reduced in 15.6% and AT activity was reduced in 24.0%. The incidence of AT activity deficiency was significantly higher in patients with critical limb ischemia than patients with claudication (P<0.01). After revascularization, arterial event free rate of patients with PC or PS activity deficiency and those with PLG deficiency were significantly lower than those without during the mean follow-up period of 26+/-31 months. The incidence of thromboembolic episodes and leg amputation rate were significantly worse in patients with PC deficiency. CONCLUSIONS: PAD patients with reduced endogenous anti-coagulation proteins show worse prognosis than those without. Surgeons must be aware of it to improve the outcome of arterial revascularization.

[Klippel-Trenaunay syndrome associated with antithrombin III deficiency]. / Syndrome de Klippel-Trenaunay et déficit en antithrombine III A propos d'une observation.

Klippel-Trenaunay syndrome (KTS) is a rare phakomatosis characterized by cutaneous hemangiomata, venous varicosities and bone and soft tissue hypertrophy also of the affected limb. Central nervous system involvement is rare, arising from a malformation or from coagulation disorders. We report the case of a patient presenting a KTS with stroke. The biological assessment revealed antithrombin III deficiency. Although rare, antithrombin III deficiency should be kept in mind in KTS patients with neurological involvement.

[Pregnancy and delivery in type II hereditary antithrombin deficient patients]. / Prubeh tehotenství a porodu pri vrozeném deficitu antitrombinu typu II.

Antithrombin is a plasma protein that regulates haemostasis by inhibiting procoagulant serine proteases. Hereditary antithrombin deficiency is associated with an increased risk of venous thromboembolism. The risk of vessel occlusion escalates especially during the pregnancy due to hyperestrogen condition both in the maternal and in foetal circulation. Our case report describes a 24-years old gipsy-woman with severe congenital AT deficiency and recurrent foetal loss in her history. She informed us about her 4th pregnancy in the 12th gestation week therefore warfarin treatment and regular checking up INR was recommended. We didn't have any information about the pregnancy course till the 41st gestation week. When the patient came to give birth, the entry INR value was 1.0. She has delivered a healthy male newborn by caesarean section. Two weeks after delivery when effective INR value due to peroral anticoagulant therapy was achieved, she was released from the hospital and since that we have not seen her.

ß-Antithrombin, subtype of antithrombin deficiency and the risk of venous thromboembolism in hereditary antithrombin deficiency: A family cohort study.

Hereditary antithrombin deficiency is associated with a high incidence of venous thromboembolism (VTE), but VTE risk differs between families. Beta-antithrombin is reported to be the most active isoform of antithrombin in vivo. Whether ß-antithrombin activity and subtypes in antithrombin deficiency have impact on VTE risk has not been investigated outside the proband setting. We performed a retrospective family cohort study to investigate whether subtypes of antithrombin deficiency or ß-antithrombin levels are associated with the risk of first or recurrent VTE. Eighty-one subjects from 21 families were included, of which 52 were antithrombin deficient. Βeta-antithrombin levels were decreased in most type I and type IIPE subjects, but normal levels were found in all subtypes of antithrombin deficiency. The annual incidence of VTE in antithrombin-deficient family members was 1.24%, 95%CI: 0.72-1.99%, in low ß-antithrombin 1.36% (95%CI: 0.76-2.25%) and in normal ß-antithrombin 0.79% (95%CI: 0.10-2.77). The annual incidence of recurrence in family members was 3.1% (95%CI: 0.9-7.1%). Duration of anticoagulation had an impact on recurrence risk: In family members annual recurrence with fixed duration was 10% (95%CI: 2.1-29.2%), with indefinite duration 1.5% (95%CI: 0.2-5.4%), p < 0.05. Beta-antithrombin levels were not associated with the risk for first or recurrent VTE in antithrombin deficient subjects. CONCLUSIONS: In this high-risk antithrombin-deficient population, both subjects with low and normal plasma ß-antithrombin activity had high risks of first and recurrent VTE. This puts the importance of ß-antithrombin into question. Long-term anticoagulation is warranted in antithrombin-deficient VTE patients.