Effective prophylaxis of thrombosis by antithrombin III concentrate in a pregnant woman with congenital antithrombin III deficiency: relations between plasma antithrombin III activity and the plasma levels of hemostatic molecular markers.

The value of antithrombin III (AT III) concentrate and a standard criterion for its use were examined in a pregnant woman with congenital AT III deficiency by continuous monitoring of plasma AT III activity and the plasma levels of hemostatic molecular markers. The rates of improvement of various markers after AT III administration (frequency of improvement/frequency of administration) were as follows: fibrinopeptide A (FPA) 82%, D-dimer 70%, fibrinopeptide B beta 15-42 73%, beta-thromboglobulin 60%, and platelet factor 4 50%. There was no significant correlation between the plasma AT III activity and all plasma FPA values, but FPA values of over 3.9 ng/ml showed a significant negative correlation with AT III activity: AT III activity (%) = -6.59 x FPA (ng/ml) + 125, r = -0.851, p less than 0.02. We therefore recommend continuous monitoring of the plasma FPA level and administration of AT III concentrate when the FPA level is elevated. According to the regression line shown above, plasma AT III activity should be raised to 100% to keep the FPA level below 6.0 ng/ml with 95% confidence limit.     

Management with antithrombin III concentrate in a pregnant woman with hereditary antithrombin III deficiency

Pregnant women with hereditary antithrombin III (AT-III) deficiency are frequently associated with thromboembolic disorders. We have treated a pregnant woman with hereditary AT-III deficiency, who had suffered from thromboembolic disorders at her past three gestations, with AT-III concentrate. Dosage of AT-III concentrate to maintain plasma AT-III activity over 80% was 3,500 units per week during second and third trimesters, but more frequent administration was necessary around delivery. In recent reports, pregnant women with hereditary AT-III deficiency had been treated with heparin or warfarin except for during abortion and delivery, in which time AT-III concentrate was widely utilized. But the use of heparin or warfarin during gestation is occasionally harmful, AT-III concentrate should be chosen for management in pregnancy in women with hereditary AT-III deficiency.     

Cerebral thrombosis in a newborn with a congenital deficiency of antithrombin III

An Israeli Arab family with type I antithrombin III (AT-III) deficiency with several affected symptomatic members in three generations is reported. The propositus presented with deep vein thrombosis and pulmonary emboli associated with gestation. The propositus infant presented at the age of 2 weeks with superior sagittal and rectus sinus thrombosis. Hereditary AT-III deficiency should be considered in infants with cerebral thrombosis, especially if they have a family history of thromboembolism. The role of prophylactic therapy by AT-III concentrates in these infants should be further assessed.     

Treatment of deep venous thrombosis in congenital antithrombin III deficiency with low molecular weight heparin

A 19-year old male patient with hereditary antithrombin III type I deficiency was admitted for thrombosis of the right iliac, femoral and popliteal veins. Treatment with a low molecular weight heparin resulted in recanalization of the veins confirmed by phlebography. After two weeks of treatment, the drug was replaced by another low molecular weight heparin and this was followed, 3 weeks later, by a documented relapse of thrombosis.     

Treatment of congenital antithrombin III deficiency with concentrates

Antithrombin III concentrates were administered to a patient with hereditary AT III deficiency undergoing orthopaedic surgery. The plasma AT III level (heparin cofactor activity) was maintained at values in excess of 100% postoperatively. A mean dose of 0.74 u/kg (range 0.64—0.83) of AT III resulted in a 1% increase in AT III level after concentrate infusion. The half-life of AT III (mean 66 h; range 58-76) was shorter during surgery and in the early postoperative period suggesting an increased consumption of the inhibitor. At III antigen was consistently higher than heparin cofactor activity during the first 24 h after concentrate infusions. This discrepancy was associated with the presence in the patient's plasma of an AT III fraction showing a slower mobility than the main AT III peak on two-dimensional immunoelectrophoresis in the presence of heparin. A biological assay is preferred to an immunological assay in monitoring replacement therapy with AT III concentrates.     

Prophylactic use of antithrombin III concentrate following surgery in congenital antithrombin III deficiency

Antithrombin III is the major physiological inhibitor of thrombin, and congenital deficiency of antithrombin III is associated with increased risk of venous thrombosis either spontaneously or following trauma, surgery or pregnancy. The successful use of antithrombin III concentrate during and following surgery to prevent venous thrombosis is described in a previously asymptomatic man with familial antithrombin III deficiency.     

Management of planned pregnancy in a patient with congenital antithrombin III deficiency

Long-term warfarin therapy was changed to subcutaneous heparin to cover a planned pregnancy in a patient with congenital antithrombin III (AT III) deficiency. Satisfactory anticoagulation was easily maintained in spite of low levels of biologically active AT III. Delivery and the puerperium were covered by a reduced dose of heparin and alternate day infusions of AT III concentrate. A mean dose of 0.77 U/kg of AT III concentrate produced a rise of 1% in AT III and the half-life was of the order of 24 h, with no evidence of increased consumption during labour and delivery. Pregnancy and labour were uncomplicated and resulted in delivery of a healthy female infant. The importance of early and adequate anticoagulation during pregnancy is emphasized.     

Familial thrombosis due to antithrombin III deficiency in a Greek family.

A Greek family with hereditary antithrombin III (AT III) deficiency associated with venous thrombosis is reported. 5 members of the family were affected. In these patients, AT III and heparin cofactor activities were decreased. Immunoreactive AT III showed a positive correlation to both AT III and heparin cofactor activities. alpha2-Macroglobulin and alpha1-antitrypsin were normal. The pattern of inheritance of the defect is autosomal dominant.     

Acute aortic thrombosis and antithrombin III deficiency in the nephrotic syndrome: a case report

A 25-year-old Oriental woman with nephrotic syndrome was admitted to the United States Naval Hospital in Okinawa. She had acute aortic thrombosis, which was managed initially with bilateral femoral thrombectomy and calf fasciotomies. In the early postoperative period, increasing doses of heparin were required to maintain adequate anticoagulation. Hematologic evaluation revealed a deficiency of antithrombin III (AT-III). Such a deficiency has been recognized as occurring in nephrotic syndrome, most probably due to urinary loss of this serum protein. Five prior cases of acute aortic thrombosis have been described in the nephrotic syndrome, but only three reports of acute aortic thrombosis have been attributed to documented AT-III deficiency. Acute thrombosis due to AT-III deficiency may be confirmed by measuring decreased serum levels of this protein. Treatment is initiated with fresh frozen plasma and heparin, with subsequent utilization of oral warfarin.     

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.     

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.     

Serial changes in hemostatic molecular markers after urokinase therapy of acute myocardial infarction]

We have examined the changes in fibrinolysis after urokinase administration for 6 patients with acute myocardial infarction. Patients were treated with urokinase with doses between 960,000 and 1,440,000 units, and fibrinolytic activities were determined by using newly developed molecular markers: alpha 2-plasmin inhibitor (alpha 2-PI), plasminogen, alpha 2-PI plasmin complex (PIC) and FDP D dimer. We also used classical hemostatic tests such as prothrombin time (PT) and plasma fibrinogen level. These tests were measured with 1 to 2 hour intervals, during the first 6 hours of therapy, daily during the next 3 days, and subsequently on day 7 and 14. The initial intravenous administration of urokinase with a dose of 460,000 units produced a significant decrease in alpha 2-PI level, but induced only minimal changes in the level of fibrinogen, FDP-E, and FDP D-dimer, suggesting that enhancement of fibrinolytic activity was less pronounced under such therapy. This might be due to the ability of residual amounts of alpha 2-PI to sufficiently inhibit plasmin generation in the circulating blood. However, a subsequent injection of 960,000 units of urokinase into the coronary artery induced a profound reduction in the alpha 2-PI to an unmeasurable level, and resulted in a marked enhancement of fibrinolytic activity. The elevation of FDP-E and FDP D-dimer was accompanied with this decrease in alpha 2-PI and persisted for more than 6 hours after urokinase injection. Prolongation of PT due to decrease in fibrinogen level was also observed over 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.     

Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin III

Summary Two patients with familial antithrombin III deficiency developed deep venous thrombosis of the lower limb. The diagnosis of venous thrombosis was made by the indium labelled platelet technique which also allowed for the daily assessment of thrombus size. Each patient received treatment with Warfarin, subcutaneous heparin, and infusions of antithrombin III concentrates. The authors conclude that infusions of antithrombin III concentrates may be of value in limiting the extent of acute thrombosis in patients with a severe deficiency of this protein and may help prevent pulmonary embolism. The haemorrhagic risk of continuing modest doses of heparin with high dose ATIII therapy appears small. In addition to its value in the diagnosis of venous thrombosis the indium platelet technique may give an early indication of thrombus extension and may thus indicate the effectiveness of treatment.