Antithrombin concentrate during pregnancy in congenital antithrombin deficiency: a single-center experience.

: Pregnancy carries a high risk of thromboembolic complications, especially in the postpartum period. This risk is particularly high in women with inherited thrombophilias, among these antithrombin deficiency seems to carry the highest risk. In this case, the use of low molecular weight heparin (LMWH) is recommended, while the use of antithrombin concentrate is controversial. We report our experience of seven pregnancies occurred in five women: two, with a personal and familiar history negative for venous thromboembolism, were treated with LMWH during pregnancy and antithrombin concentrate immediately before and after the delivery. The other three women had a personal and familiar history positive for venous thromboembolism and were treated with LMWH and antithrombin concentrate during all the pregnancy and the postpartum period. No thromboembolic or hemorrhagic complications were observed in both groups, demonstrating that our strategy could be safe and effective.

Revisiting antithrombin in health and disease, congenital deficiencies and genetic variants, and laboratory studies on α and ß forms.

Antithrombin [AT] is the main inhibitor for activated plasma coagulation serine esterases, inhibiting thrombin, Factors Xa and IXa, but also Factors XIIa, XIa, VIIa, kallicrein, and plasmin. Its activity is highly enhanced by heparin, through binding to the pentasaccharide sequences, for inhibition of all coagulation proteases, except thrombin, which inhibition requires its additional binding to the heparin polysaccharide chain. However, AT is the major inhibitor of thrombin in the blood circulation. Congenital or acquired deficiencies of AT expose affected patients to an increased risk of developing unprovoked and recurrent thrombo-embolic diseases. Antithrombin can be measured with various laboratory techniques, by either immunological or functional methods. Earlier, a radial immunodiffusion immunoassay allowed measurement of the protein antigenic content. Functional assays are mainly designed with Anti-Thrombin or Anti-Factor Xa chromogenic methods and are useful for detecting genetic molecular mutations with decreased inhibitory activity and contributed to study the conformational changes of antithrombin and its variants, which potentially regulate the activity of this serine protease inhibitor. These assays are not equivalent in terms of diagnosing protein abnormalities, associated with increased thrombotic incidence, and they have variable performance for reflecting impaired antithrombin binding capacity for heparin, reduced progressive inhibition of serine proteases, or accelerated switch rates to the latent and less active forms. A small proportion of AT (<10%) is present in blood in the ß-form, with a lower oligosaccharide content, a lower Molecular Weight, a higher binding rate to endothelial glycosaminoglycans, and a higher anticoagulant activity, hence requiring specific laboratory methods for its measurement. The ß-AT form is then of critical importance for controlling blood activation by tissue injury and preventing development of thrombo-embolic diseases. This article reviews the performance characteristics of the currently available assays, and their usefulness for monitoring the use of AT concentrates in intensive care units, disseminated intravascular coagulation or severe infections, to restore the anticoagulant protective effect of heparin by supplementing the requested AT concentration. The issues of automation, harmonization and standardization are also revisited and discussed.

[Atrial Septal Defect with Hereditary Deficiency of Antithrombin III].

A 41-year-old female with hereditary deficiency of antithrombin III (ATIII) was diagnosed with atrial septal defect( ASD) and scheduled for the closure of ASD. She had been taking warfarin since she suffered from deep vein thrombosis 10 years ago. Preoperative management of anticoagulation included discontinuation of warfarin, and supplementation of antithrombin with heparin infusion. On the day of operation, antithrombin activity was maintained above 80% by administering antithrombin, and closure of ASD was carried out under standard cardiopulmonary bypass support using heparin. Heparin infusion was continued with antithrombin supplementation until prothrombin time-international normalized ratio(PT-INR) recovered to around 2.5 with warfarin. Her intra-and postoperative courses did not show any thromboembolic events, and she was discharged 20 days after the surgery.

Arterial thrombosis in homozygous antithrombin deficiency.

UNLABELLED: Antithrombin (AT), a serin protease inhibitor (serpin) produced in the liver, inhibits mainly thrombin and factor Xa. Antithrombin deficiency (AD) is associated with a higher incidence of thrombosis. CASE REPORT: We report a newborn with uncomplicated birth in the 40+5 week of gestation and postnatal appearance of a reticular, livide haematoma on the right upper arm and a tonic clonic epileptic seizure. Clinical examination revealed weak pulses in the A. radialis and ulnaris. MRI scan showed a large thrombus in the A. carotis interna and externa with large cerebral infarction and a thrombus in the A. subclavia. Laboratory work up showed elevated D-dimers and antithrombin levels <20% (lowest 15%), age-related values for protein C, protein S, plasminogen, and no other inherited thrombophilia. THERAPY: We started anticoagulation with unfractionated heparin intravenously (aPTT: 50-60 s) and under suspicion of an AD the substitution of AT (70 U/kg body weight). In course of time we changed anticoagulation to low molecular weight heparin (Anti Xa 0.6-0.8 U/ml) and substitution of 250 E/kg AT every second day. In the molecular work up we found a homozygous missense mutation in exon 2 of SERPINC1 gene (type "Budapest 3"). Molecular analysis showed also heterozygous mutations in both parents and a homozygous mutation in the asymptomatic brother aged three years. At age of six months we changed the anticoagulation to coumadin (INR 2.5-3.5). Anticoagulation with coumadin was also started in the brother. DISCUSSION: Hereditary AD is associated with an increased risk of thrombosis. The homozygous status mainly leads to intrauterine fetal loss or the occurrence of peri- and postnatal thrombosis. Therapy consists in the substitution of AT and a lifelong anticoagulation with vitamin K antagonists also in asymptomatic patients.

A novel splice-site mutation c.42-2A>T (IVS1-2A>T) of SERPINC1 in a Korean family with inherited antithrombin deficiency.

Inherited antithrombin (AT) deficiency (OMIM 107300) is an autosomal dominant disorder and causes a 20-fold increase in the risk of venous thromboembolism. Herein, we describe a case of a novel splice-site mutation in the SERPINC1 gene in a Korean patient with inherited AT deficiency. The patient was a 35-year-old woman who presented with deep vein thrombosis (DVT) and pulmonary embolism and was without a recent history of any precipitating factors. The obtaining of her family history revealed that her mother had an ischemic stroke and a pulmonary embolism and her two sisters both had an episode of DVT during pregnancy. DNA sequencing of SERPINC1 revealed the novel variant IVS1-2A>T (c.42-2A>T), a substitution in intron 1, in the proband and her daughter. The mutation IVS1-2A>T eliminates the acceptor splice-site of intron 1. The present case is the first novel splice-site mutation of SERPINC1 in a Korean family with inherited AT deficiency.

Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes.

OBJECTIVE: To describe the outcome of pregnancy in women with inherited antithrombin (AT) deficiency. STUDY DESIGN: A descriptive retrospective study was performed. Medical records were reviewed in order to collect data about maternal thrombotic complications and pregnancy outcomes. All women with known inherited AT deficiency and at least one pregnancy looked after at the Vall d'Hebron University Hospital were included. Relatives with known AT deficiency but no pregnancies looked after in our institution were excluded. Eighteen pregnancies were registered among nine AT-deficient women during 1991-2005. This cohort included women without antithrombotic treatment because AT deficiency was not known at the time of their pregnancies. RESULTS: In 12 pregnancies (66.7%) anticoagulant therapy with low-molecular weight heparin was given, while not in the other six (33.3%) because AT deficiency was not known at this time. Three episodes of venous thromboembolism were recorded (16.7%). Among all pregnancies 10 suffered an adverse outcome (55.6%), including miscarriage (11.1%), stillbirth (11.1%), intrauterine growth restriction (33.3%), placental abruption (6.7%), preeclampsia (6.7%) and intrapartum fetal distress (23.1%). No relation between AT activity and pregnancy complications was found. A lower incidence of pregnancy complications was observed among women with antithrombotic treatment. CONCLUSIONS: Inherited antithrombin deficiency is associated with a high risk of venous thromboembolism during pregnancy and the puerperium. We also observed a high incidence of poor pregnancy outcome among AT-deficient women.

[Perioperative management for transurethral resection of bladder tumor (TUR-Bt) associated with congenital antithrombin III deficiency].

Congenital antithrombin III (ATIII) deficiency is a hereditary disease that predisposes to thromboembolic complications. We report perioperative management for twice in a patient with congenital ATIII deficiency. A 69-year-old man with congenital ATIII deficiency, with history of deep vein thrombosis (DVT) in his left popliteal vein, was scheduled for transurethral resection of bladder tumor (TUR-Bt). The plasma ATIII activity was 57% of normal vale. As ATIII concentrates 3,000U per day had been administered intravenously since the second day before the operation, the plasma ATIII activity was 147% on the operation day. TUR-Bt was performed in the lithotomy position under general anesthesia. ATIII concentrates 3,000 U per day were administered intravenously for two days after the operation and low molecular weight heparin (LMWH) 2,500 U per day was administered subcutaneously for five days after the operation. One year later he had a recurrence of bladder tumor. The plasma ATIII activity was 54%. ATIII concentrates 3,000 U per day had been administered intravenously since the three days before the operation. The second TUR-Bt was also performed in the lithotomy position under general anesthesia. ATIII concentrates 1,500 U per day were administered intravenously for three days after the operation. LMWH was not administered due to postoperative bleeding from the bladder. He had no thromboembolism during each perioperative period. The lithotomy position with fixation of both hips and both knees may decrease venous blood flow, increase muscle compartment pressure of the lower extremities, predispose to DVT in the lower extremity, and lead to pulmonary thromboembolism (PE). Control of blood coagulation and maintenance of sufficient venous blood flow in the lower extremities with ATIII adjuvant therapy and LMWH administration during the perioperative period are important for TUR-Bt in a patient with congenital ATIII deficiency to prevent DVT and PE.

Congenital hypoplasia of the inferior vena cava and inherited thrombophilia: rare associated risk factors for idiopathic deep vein thrombosis. A case report.

In young patients, acquired and genetic causes of deep vein thrombosis frequently interact. The association of congenital hypoplasia of the inferior vena cava with antithrombin III deficiency has never been described in the literature as a causal factor of proximal deep vein thrombosis in young patients. We report the case of an 18-year-old patient affected by deep vein thrombosis due to this rare association without other common risk factors.

Harriton, Waller And Australian negligence law: is there a place for wrongful life?

Following the decision by the Supreme Court of New South Wales in Harriton and Waller, the controversial action for wrongful life has been thrown back into the public spotlight. This article examines the legal and public policy dilemmas arising from a wrongful life claim in light of the Court of Appeal's reasons for its decision in the jointly heard cases of Harriton (by her tutor) v Stephens; Waller (by his tutor) v James; Waller (by his tutor) v Hoolahan (2004) 59 NSWLR 694 and analyses whether there is a sound doctrinal basis for recognising the claim within the Australian tort system. It will be argued that each of the legal elements comprising the claim fall squarely within the traditional tort framework and that public policy considerations favouring recognition of the claim outweigh those raised against it.

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.

Management of pregnancy with congenital antithrombin III deficiency: two case reports and a review of the literature.

Women with antithrombin (AT) III deficiency are prone to pregnancy-associated venous thromboembolism. We report 2 cases with genetically confirmed ATIII deficiency, one with a mutation in exon 3A and the other with an exon 4 deletion, in whom the pregnancies were successfully managed with prophylactic therapies for thrombosis. A 35-year-old pregnant woman was treated with intravenous infusions of ATIII concentrate alone, and the other 22-year-old pregnant woman was mainly treated with subcutaneous injections of heparin and oral low-dose aspirin therapy. Both pregnancies resulted in vaginal deliveries of healthy neonates. The literature concerning prophylactic therapies for thrombosis in ATIII deficiency-complicated pregnancy is reviewed, and the clinical problems, including the adverse effects of the therapies, are discussed.

[Anesthetic management of a patient with congenital antithrombin III Deficiency using temporal inferior vena cava filter].

We described the perioperative management of a patient with congenital antithrombin III deficiency using temporal inferior vena cava filter. A 30-year-old man with congenital antithrombin III deficiency was scheduled for artificial head replacement of the hip joint under general anesthesia. He was diagnosed as having congenital antithrombin III deficiency when he had had an episode of venous thrombosis after artificial head replacement of the right hip joint. He had been taking warfarin as an anticoagulant, and it was discontinued three days before surgery. To prevent perioperative thrombus formation, the plasma AT III activity was maintained above 80% before, during and after surgery using AT III concentrates. We also placed the temporal inferior vena cava filter. There was no serious thrombosis or embolism perioperatively. The use of the filter during the perioperative period helped to avoid development of serious thrombosis and embolism.

[Anesthetic management for cesarean delivery in a pregnant patient with congenital antithrombin III deficiency and pulmonary thromboembolism]. / Manejo anestésico de cesárea en gestante con déficit congénito de antitrombina III y tromboemboliso pulmonar.

Antithrombin III (AT III) deficiency is a rare hereditary disease that predisposes a patient to thromboembolic complications. Anticoagulation is essential for preventing recurrence of thrombi. Concentrated AT III replacement is reserved for acute periods of thromboembolism or moments of increased risk. Hemostatic anomalies are generally considered a contraindication for regional anesthesia, due to the potential risk of spinal hematoma. This paper describes a woman with congenital AT III deficiency and heparin-treated pulmonary embolism whose pregnancy of 29 weeks had to be terminated by cesarean section upon signs of fetal distress. We discuss the pathophysiology and treatment in such cases.

Budd-Chiari syndrome and extrahepatic portal obstruction associated with congenital antithrombin III deficiency.

We report a patient with Budd-Chiari syndrome (BCS) and extrahepatic portal obstruction (EHO) associated with congenital antithrombin (AT) III deficiency. A 35-year-old man was admitted to Nishi Kobe Medical Center for evaluation of abnormal intrahepatic veins. By various imaging modalities, BCS and EHO were diagnosed. Laboratory data revealed parallel decreases in activity and antigen concentration of AT III despite normal liver function. Taken together, the etiology of both BCS and EHO was considered to be thrombosis, associated with congenital AT III deficiency. Two years after beginning warfarin therapy, the patient has no symptoms and his liver function remains normal. Anticoagulant therapy is considered useful for preventing progression of the disease.

[Hereditary antithrombin deficiency resulting in severe neonatal thrombosis]. / Alvorlig neonatal trombose grundet hereditaer antitrombinmangel.

We report a severe vena cava inferior thrombosis in a mature two day-old boy. Pregnancy and birth were event free. The mother had antithrombin deficiency. During pregnancy she was treated with enoxaparin and just before delivery with 2000 IE antithrombin concentrate. At admission the child had unmeasurable antithrombin and low protein C concentrations. He was treated with antithrombin concentrate and heparin. The thrombus disappeared, and now he is on maintenance treatment with warfarin. Risk factors and treatment of inherited antithrombin deficiency are discussed.