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.     

Familial deficiency of antithrombin III

The systematic search for a deficiency in antithrombin III must be considered in case of: venous thrombosis in a young patient, recurrent venous thrombosis especially if these occurred under Heparin, venous mesenteric infarction since this type of thrombosis is rare and seems relatively frequent in case of congenital deficiency in antithrombin III, familial past history of venous thrombosis in a woman desiring to undergo estrogen-progesterone therapy. The most often used techniques are: study of antithrombin III activity by amidolytic method and titration by immunodiffusion. Anti-vitamin K treatment is the only effective therapy proposed to patients suffering from a hereditary deficiency in antithrombin III.     

Early graft thrombosis due to antithrombin III deficiency following CABG

The serine protease inhibitor antithrombin III (AT-III), an ??2-globulin synthesized in the liver and endothelial cells, is the principal in vivo inhibitor of blood coagulation inactivating mainly thrombin. AT-III deficiency presents a rare hereditary or acquired disorder that most often comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. Triggers for the onset of the thrombosis include various mechanisms such as pregnancy, delivery, surgery, trauma, and contraceptive pill use. Decreased response to heparin may be the first sign of AT-III deficiency. Since heparin is a conditio sine qua non for cardiopulmonary bypass, rapid consumption of AT-III promoted by heparin may lead to systemic thrombosis. The effect of heparin on graft patency after CABG in patients with AT-III deficiency, particularly with respect to early graft thrombosis, has not been fully investigated. The early detection and timely treatment of this disorder may impact perioperative morbidity. We present a case of simultaneous thrombosis of three venous grafts after elective coronary artery bypass surgery in a patient with AT-III deficiency.     

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.     

An abnormal antithrombin III (AT III) with low heparin affinity: AT III Clichy

We have identified an inherited qualitative deficiency of antithrombin III (AT III) in a family with apparently no increased incidence of venous thrombosis. Plasma antithrombin and anti-Xa activities were normal, but the interaction with heparin, heparan sulphate and low molecular weight heparin was uniformly decreased. An immunoblotting technique performed in plasma showed normal complex formation with thrombin. By using heparin-Sepharose affinity chromatography and crossed immunoelectrophoresis, the variant could be separated: at least two fractions of low affinity AT III were obtained. A minor one had no antiprotease activity; the other one was further purified to homogeneity and found to have normal specific activity in absence of heparin and a 50% decreased activity in presence of heparin. We propose to call this new variant AT III Clichy.     

Congenital antithrombin III deficiency causing mesenteric venous infarction: a lesson to remember--a case history.

Congenital antithrombin III deficiency is an uncommon but important cause of venous thrombosis, usually presenting with recurrent or atypical venous thromboembolism. Its importance lies in the fact that early recognition can lead to treatment in the acute stage, which can prevent propagation of the disease, and further prophylactic treatment may reduce the incidence of further episodes. The authors present a case of mesenteric venous infarction associated with congenital antithrombin III deficiency and briefly discuss the diagnosis, surgical implications, and treatment of this disorder.     

Choice of anticoagulant in a congenital antithrombin III (AT III)-deficient patient with chronic renal failure undergoing regular haemodialysis

Summary We describe a 43-year-old male patient with congenital antithrombin III deficiency requiring haemodialysis due to extension of venous thrombus from recurrent deep vein thrombosis. During dialysis with adequate heparinization, the patient often revealed clot formation in the extracorporeal circuit resulting in unexpected discontinuation of dialysis. When either a combination of antithrombin III concentrate plus heparin or the newly developed synthetic antithrombin preparation, MD805, was infused during dialysis, he could be uneventfully dialysed with either of the two regimens. The functional antithrombin III activity with MD805 increased to the same level as that obtained with antithrombin III concentrate, and it was possible to achieve an antithrombotic effect, as measured from the APTT and thrombin-antithrombin III complex with MD805 during and after dialysis. We thus found that MD805 could be used as an anticoagulant drug when an AT III-deficient patient required anticoagulation in the extracorporeal circulation.     

Hereditary antithrombin III deficiency: case report and review of recent therapeutic advances

We report on a newly diagnosed family with hereditary antithrombin III deficiency, with thromboembolic complications in the propositus. Both the propositus and his asymptomatic sister had decreased plasma levels of antithrombin III antigen and activity (28-52% of normal with good agreement between functional and immunologic assays). The propositus developed deep venous thrombosis, followed by massive pulmonary emboli despite heparin therapy and was treated with streptokinase and heparin with excellent results. Shortly thereafter, small bowel obstruction required surgical intervention, and antithrombin III concentrate, recently available in the United States as an investigational new drug (I.N.D.), was administered with no postoperative thrombotic complications. He was subsequently asymptomatic while on warfarin prophylaxis but twice developed venous thrombosis when he failed to take warfarin. The addition of danazol therapy led to a sustained rise in the antithrombin III level. Each of these therapeutic approaches is discussed and the literature reviewed with emphasis on the newer agents--streptokinase, antithrombin III concentrate, and danazol.     

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.     

Antithrombin III metabolism in two colitis patients with acquired antithrombin III deficiency

125I-Antithrombin III metabolism studies were performed in 2 patients with ischemic and ulcerative colitis, respectively. Both patients had acquired antithrombin III deficiency and objectively diagnosed deep venous thrombosis. A decreased 125I-antithrombin III plasma disappearance halflife and an increased fractional catabolic rate was found in both patients. The transcapillary flux ratio was elevated in the patient with ischemic colitis. A follow-up study of the first patient during a period when no signs of an ischemic colitis were present and no medication was taken showed completely normal tracer data. The data are consistent with both gastrointestinal loss and intravascular consumption of antithrombin III. The antithrombin III deficiency could not be explained by other causes such as proteinuria, liver dysfunction, or obvious disseminated intravascular coagulation. Reduced antithrombin III plasma levels were considered to have contributed to the development of deep venous thrombosis in both patients.     

A Swedish family with abnormal antithrombin III

An abnormal variant of antithrombin III is reported in a young male with deep vein thrombosis. The heparin cofactor, progressive thrombin inhibition, and factor Xa inactivation are decreased. The abnormality seems to be a mutation which is transmitted in an autosomaldominant way. The half-life and fractional catabolic rate of 125I antithrombin III concentrate is the same in this patient as in patients with the classic type of antithrombin III deficiency and in a control.     

Familial Thrombosis Due to Antithrombin III Deficiency

A large kindred from eastern Kentucky, withextensive history of recurrent venous thrombosis and pulmonary embolism, was studied.Low antithrombin III titers, ranging from 26%to 49% of normal values, were found in plasmaof nine members in three consecutive generations; another five members, four of whomwere not available for study, are suspected ofhaving the biochemical defect. There was agood correlation between clinical symptomsand antithrombin III deficiency, although threeof the younger members with the defect stillremained free of thrombosis. In serum of theaffected subjects antithrombin III was almostcompletely utilized, which indicates that stoichiometric binding to coagulation enzymes dominates under biological conditions. Antithrombinand antifactor Xa activities residing in themacroglobulin region of plasma and serum remained unchanged. The responsiveness to heparin in vitro and in vivo confirmed the evidencethat antithrombin III is the sole blood component through which heparin exerts its anticoagulant effect. In five affected memberstherapy with oral anticoagulants increased verysignificantly the level of antithrombin III inplasma and contributed to a remarkable increase of residual antithrombin III in serum.This objective improvement after warfarin therapy may create significant difficulties in thelaboratory diagnosis of antithrombin III deficiency.

Submitted on May 7, 1973 Revised on July 5, 1973 Accepted on July 16, 1973     

Prophylactic antithrombotic therapy with stanozolol in patients with familial antithrombin III deficiency

Three patients with familial antithrombin III deficiency underwent a trial of prophylactic antithrombotic therapy with stanozolol. An increase in plasma fibrinolytic activity and antithrombin III was seen. Acute venous thrombosis occurred in two patients; in the first patient thrombosis was precipitated by venography but in the second no precipitating factor was found. Our experience suggests that stanozolol is not a suitable prophylactic agent in patients with familial antithrombin III deficiency.     

Studies of the heterogeneity of antithrombin III concentrates

The biological activities of antithrombin III (At III) concentrates, prepared by several manufacturers for clinical use, have been compared by three assay methods, and their heparin-binding properties studied by crossed immunoelectrophoresis and heparin affinity chromatography. Concentrates from two of the four manufacturers showed discrepancies between assay methods, with concentrations by heparin co-factor assays significantly lower than those by immunological and progressive antithrombin methods. Heterogeneity was also found by heparin binding studies, with about half the total At III antigen in these concentrates being unable to bind to heparin. These results confirm previous findings of heterogeneity in At III concentrates and show that some concentrates contain substantial amounts of altered At III molecules in which the heparin-binding site has been denatured but the thrombin-neutralizing site left largely intact.     

Extensive thrombus formation with heparin resistance during extracorporeal circulation. A new presentation of familial antithrombin III deficiency

Extensive thrombus formation during extracorporeal circulation despite the administration of heparin sodium prompted investigation of a 15-year-old boy with a calcified right ventricular thrombus and a history of subacute bacterial endocarditis. In vitro studies confirmed the failure of heparin in standard doses to have an anticoagulant effect. Antithrombin III concentrations were low. The patient's mother, who had no history of thromboembolic disease, was also antithrombin III deficient. Resistance to heparin is a theoretical, but inconsistently documented, feature of antithrombin III deficiency. This deficiency state should be considered whenever heparin resistance is encountered, even in the absence of a personal and family history of thromboses.     

Antithrombin III Deficiency Appearing as Mesenteric Vein Thrombosis

Mesenteric vein thrombosis is a relatively uncommon but devastating problem. Absence of any of the generally accepted etiologic factors of mesenteric vein thrombosis has lead to the diagnosis of "primary" mesenteric vein thrombosis in 25-55% of all cases.
In this report we identify a young man with antithrombin III deficiency presenting as "primary" mesenteric vein thrombosis with massive bowel infarction. It again raises the possibility that other cases of "primary" mesenteric vein thrombosis may have been associated with this coagulopathy. Factors influencing antithrombin III levels are discussed in relation to diagnosis of the familial deficiency state in a patient with mesenteric vein thrombosis. The association of intraabdominal venous occlusion and antithrombin III deficiency is emphasized.     

Cerebral sinus thrombosis in a patient with hereditary protein S deficiency: Case report and review of the literature

Summary Hereditary protein S deficiency is an established risk factor for venous thrombosis. The common sites of thrombosis are the deep leg and pelvic veins. We report on a 38-year-old female patient with hereditary protein S deficiency and a previous history of deep leg vein thrombosis, who developed thrombosis of the cerebral straight and superior sagittal sinus while taking oral contraceptives. The diagnosis was established by computerized tomography and carotid angiography. Lysis of the thrombus occurred during heparin treatment. The hereditary nature of protein S deficiency was documented by family studies, since nine additional family members deficient in protein S were identified. Nineteen published cases of cerebral vein thrombosis and a deficiency of either antithrombin III, protein C, or protein S were reviewed. Compared with patients without a deficiency state, the clinical features of cerebral vein thrombosis were similar except for an earlier onset and a positive medical history of venous thromboembolic events in a considerable number of patients.     

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.     

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.