Exogenous supplementation of antithrombin III in adult and pediatric patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Antithrombin III deficiency can occur with heparin anticoagulation during extracorporeal membrane oxygenation leading to heparin resistance. Antithrombin III supplementation has been shown to improve anticoagulation; however, there is no consensus on appropriate administration. We described the effect of antithrombin III supplementation on coagulation parameters in adult and pediatric extracorporeal membrane oxygenation patients. METHODS: We conducted a retrospective cohort study using electronic medical records of patients who received ⩾1 dose of antithrombin III during extracorporeal membrane oxygenation while on continuous heparin. Endpoints included the change in anti-Xa levels and antithrombin III activity at -6 versus 6 h relative to antithrombin III supplementation, and heparin infusion rates at 6 versus 12 h after antithrombin III supplementation. RESULTS: Eighteen patients receiving 36 antithrombin III administrations were analyzed. Mean (standard deviation) anti-Xa values at -6 versus 6 h were 0.15 (0.07) versus 0.24 (0.15) IU/mL (p-value: 0.250) for pediatrics and 0.19 (0.22) versus 0.31 (0.27) IU/mL (p-value: 0.052) for adults. Mean (standard deviation) plasma antithrombin III activity at the same intervals were 32% (14.2%) versus 66.8% (25.1%; p-value: 0.062) for pediatrics and 30.3% (14%) versus 52.8% (8.1%; p-value: 0.094) for adults. Mean (standard deviation) heparin rates at 6 versus 12 h after antithrombin III for pediatrics were 23.6 (6) versus 23.5 (6.5) units/kg/h (p-value: 0.728), and 15.3 (6.6) versus 13.5 (8) units/kg/h (p-value: 0.188) for adults. CONCLUSION: Administration of antithrombin III improved anti-Xa levels in both populations, however, did not significantly reduce heparin rates. Our findings suggest that the use of antithrombin III restores heparin responsiveness in patients with low antithrombin III activity and low anti-Xa activity.

Thrombectomy and Catheter-Directed Thrombolysis Combined With Antithrombin Concentrate for Treatment of Antithrombin Deficiency Complicated by Acute Deep Vein Thrombosis That Is Refractory to Anticoagulation.

A 22-year-old male was admitted to our hospital with deep vein thrombosis that was complicated by antithrombin deficiency. This deficiency was refractory to anticoagulation therapy. Although catheter-directed thrombolysis could not reperfuse the total occlusion in the left deep vein, a combination of thrombectomy, catheter-directed thrombolysis, and antithrombin concentrate treatment was able to dissolve the clots and ameliorate the blood flow into the left deep vein. Antithrombin concentrate administration would be effective in the treatment of antithrombin deficiency with medical refractory deep vein thrombosis.

Overcoming Challenges in the Management of Critical Events During Cardiopulmonary Bypass.

Critical events during cardiopulmonary bypass (CPB) can challenge the most experienced perfusionists, anesthesiologists, and surgeons and can potentially lead to devastating outcomes. Much of the challenge of troubleshooting these events requires a key understanding of these situations and a well-defined strategy for early recognition and treatment. Adverse situations may be anticipated prior to going on CPB. Atherosclerosis is pervasive, and a high plaque burden may have implications in surgical technique modification and planning of CPB. Hematologic abnormalities such as cold agglutinins, antithrombin III deficiency, and hemoglobin S have been discussed with emphasis on managing complications arising from their altered pathophysiology. Jehovah's witness patients require appropriate techniques for cell salvage to minimize blood loss. During initiation of CPB, devastating situations leading to acute hypoperfusion and multiorgan failure may be encountered in patients undergoing surgery for aortic dissection. Massive air emboli during CPB, though rare, necessitate an urgent diagnosis to detect the source and prompt management to contain catastrophic outcomes. Gaseous microemboli remain ubiquitous and continue to be a major concern for neurocognitive impairment despite our best efforts to improve techniques and refine the CPB circuit. During maintenance of CPB, adverse events reflect inability to provide optimal perfusion and can be ascribed to CPB machine malfunction or physiological aberrations. We also discuss critical events that can occur during perfusion and the need to monitor for organ perfusion in altered physiologic states emanating from hemodilution, hypothermia, and acid-base alterations.

Homozygous antithrombin deficiency in adolescents presenting with lower extremity thrombosis and renal complications: two case reports from Turkey.

We present 2 cases of lower extremity deep venous thrombosis in 2 gypsy adolescents from related families. The patients had low antithrombin activity levels and inherited homozygous antithrombin deficiency was confirmed by molecular analysis (Leu131Phe mutation). One patient had a history of nephrectomy at the age of 9 due to nonfunctioning kidney and 2 siblings died at 4 months of age. His mother had 3 fetal losses in the third trimester. The other propositus had an elder sister who suffered from postpartum deep vein thrombosis and pulmonary embolism. Heterozygous mutation was demonstrated in both parents.

How I treat heterozygous hereditary antithrombin deficiency in pregnancy.

Untreated hereditary antithrombin deficiency in pregnancy is associated with maternal venous thromboembolism (VTE) and possibly with fetal loss. Thromboprophylaxis during pregnancy is recommended, but dosages remain controversial.Our objective was to perform a retrospective assessment of thrombotic events and pregnancy outcomes in women with hereditary antithrombin deficiency managed according to a standard protocol. Pregnancies in individuals with hereditary antithrombin deficiency were identified from a hospital database. Women with no prior VTE received enoxaparin 40 mg daily until 16 weeks gestation and thereafter 40 mg twice daily. Women with prior VTE received intermediate dose enoxaparin (1 mg/kg) once daily, increased to twice daily at 16 weeks and anti-Xa monitored dosing. Thromboprophylaxis was stopped at initiation of labour or 12 hours prior to caesarean and 50 IU/kg antithrombin concentrate given. Thromboprophylaxis was restarted after delivery. Eighteen pregnancies in 11 women with antithrombin deficiency were identified. Seventeen pregnancies (94%) were successful. Median gestation was 39 weeks (range 30-41) and median birth-weight was 2,995 g (910-4,120 g), but 6/17 infants (35%) were small for gestational age (p=0.01). Estimated blood loss at delivery was median 375 ml (200-600 ml). Four pregnancies were complicated by VTE; one newly presented with a thrombotic event, two patients were not taking thromboprophylaxis and one occurred despite thromboprophylaxis. Two novel mutations (p.Leu317Ser and p.His33GInfsX32) are described. In conclusion, in antithrombin deficiency the use of low-molecular-weight heparin in pregnancy and puerperium with antithrombin concentrate pre-delivery was associated with successful pregnancy outcome; rates of VTE appear to be lower than previously reported, but remain elevated.

A successful outcome of pregnancy in a patient with congenital antithrombin deficiency.

BACKGROUND: Presence of inherited thrombophilia is an additional risk factor for maternal thromboembolism and certain adverse pregnancy outcomes, including recurrent fetal loss, placental abruption, intrauterine growth restriction and early-onset severe preeclampsia. Pregnant women with thrombophilia, especially those with antithrombin (AT) deficiency, are at high risk of both kinds of complications. CASE REPORT: We presented a pregnant women with congenital antithrombin deficiency in the first pregnancy, whose mother had had four times pregnancy-related deep vein thrombosis, and antithrombin deficiency. With the regular laboratory monitoring of hemostatic parameters and gynaecology surveillance including the follow-up of placental vascular flow, the whole pregnancy proceeded without complications. The prophylactic therapy with low molecular weight heparin was introduced from the 20th week of gestation and one dose of substitution therapy with antithrombin concentrate was administrated before delivery. Pregnancy and labour were terminated without complications at the 37th week of gestation, resulting in the delivery of a healthy male newborn of 3.6 kg body weight, 52 cm long, and with the Apgar scores of 9/10. CONCLUSION: A timely made diagnosis of thrombophilia, accompanied with regular obstetrics check-ups and follow-ups of hemostatic parameters during pregnancy, as well as the use of adequate prophylactic and substitution therapy, are the successful tools for the prevention of possible maternal complications and pregnancy itself in our patient with congenital AT deficiency.

Simultaneous thromboses of double coronary arteries in a young male with antithrombin III deficiency.

In most acute ST-segment elevation myocardial infarction, a single culprit vessel is often found; however, multivessel occlusion, although uncommon, can occur and usually with a poor prognosis, including mortality. We reported a 22-year-old young male who presented to our emergency department because of chest pain after exercise. On physical examination, the cardiac auscultation revealed gallop rhythm without murmur, and the pulmonary auscultation revealed minimal basal moist rales. Other physical examinations were unremarkable. Twelve-lead electrocardiography showed normal sinus rhythm with rate of 96 beats per minute, hyperacute T wave in V1 to V6 and II, III, aVF with reciprocal change in lead I, aVL. He underwent immediate coronary angiography that revealed simultaneous total occlusion of proximal portion of right coronary artery and left anterior descending coronary artery. Successful percutaneous coronary intervention with angioplasty was performed with optimal angiographic result. Although simultaneous total occlusion of double coronary arteries is a rare condition, especially in young group with antithrombin III deficiency, percutaneous coronary intervention and long-term anticoagulant agent are still one of the standard treatments, but the operator should be aware of the hemodynamic change and the importance of mechanical support.

Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options.

Antithrombin is a glycoprotein critical to the regulation of coagulation. Its primary action is the inhibition of the activated coagulation factors IIa (thrombin) and Xa. In addition there is growing evidence to suggest that antithrombin also plays a role in the inhibition of inflammation within the environment of the vascular endothelium. Reduced plasma antithrombin may result from congenital deficiency or arise secondarily from a range of disorders such as liver dysfunction, premature infancy and sepsis, or as a result of interventions such as major surgery or cardiopulmonary bypass. Congenital antithrombin deficiency is the most clinically important of the inherited thrombophilias resulting in thrombosis in the majority of those affected. The challenge in managing these patients is preventing potentially life-threatening thrombosis, while minimising the equally significant risk of haemorrhage associated with long-term anticoagulation. This is achieved in the first instance by identifying high-risk episodes such as surgery, immobility and pregnancy for which prophylactic anticoagulation can be used in the short term. Prophylaxis for such periods is best provided by the use of low molecular weight heparin (LMWH) with substitution by or addition of antithrombin concentrate in particularly high-risk circumstances. In the case of pregnancy, antithrombin concentrate is often used around the time of birth when LMWH may increase the risk of post-partum haemorrhage. As patients with congenital antithrombin deficiency get older so their thrombotic risk gradually increases and for many patients long-term anticoagulation becomes unavoidable because of recurrent episodes of venous thromboembolism. There has been much interest in the role of antithrombin deficiency in the setting of sepsis and the critically ill patient where there is a clear correlation between severity of illness and degree of antithrombin reduction. It is not clear yet, however, to what extent the depletion of antithrombin affects the clinical condition of such patients. A number of trials have investigated the use of antithrombin as a treatment in the intensive care setting with the overall conclusion being that there is some benefit to its use but only if large supra-physiological doses are used. It has also become clear that the concurrent use of any form of heparin removes whatever benefit may be derived from antithrombin treatment in this setting. Until recently, antithrombin replacement was only available as a pooled plasma-derived product, which despite effective viral inactivation still carries an uncertain risk of transfusion transmitted infection. A recombinant antithrombin product now under investigation, and recently licensed in Europe, may provide a useful alternative treatment option.

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study.

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.

Pulmonary arterial thrombosis in a neonate with homozygous deficiency of antithrombin III: successful outcome following pulmonary thrombectomy and infusions of antithrombin III concentrate.

We report a newborn male who presented with severe central cyanosis on the third day of life. Partial thrombotic obstruction of the pulmonary trunk secondary to Antithrombin III (homozygous defect of heparin binding site) deficiency was subsequently diagnosed. Surgical thrombectomy, and infusions of Antithrombin III concentrate, led to a successful outcome. We postulate that intrauterine thrombosis occurred to give this unusual presentation.

Uso del filtro de Greenfield durante la gestación en pacientes con deficit de antitrombina III / Use of Greenfield filter during pregnacy in patients with antithrombin III deficiency

El tromboembolismo pulmonar se asocia a una elevada morbimortalidad materna y neonatal. En pacientes con riesgo de tromboembolismo pulmonar, el empleo de filtros de vena cava inferior es una alternativa eficiente y segura para prevenir espisodios recurrentes. El presente trabajo resume nuestra experiencia con dos pacientes embarazadas portadoras de déficit de antitrombina III. Una paciente era portadora de un filtro de vena cava inferior de Greenfield y se embarazó. La segunda presentó un episodio de tromboembolismo pulmonar masivo por lo que se instaló el filtro a las 16 semanas de gestación. Se discute su manejo, características técnicas de instalación, complicaciones durante el embarazo y el resultado perinatal