A 29-yr-old white female has suffered from recurrent venous thromboses over the last 12 yr. Plasma antithrombin III (AT-III) levels were 48% of normal by immunoelectrophoresis and 56% by chromogenic assay. Three of four siblings and the father had similar AT-III levels without associated venous thromboses. Heparin-Sepharose chromatography demonstrated normal behavior of the patient's AT-III. Her purified AT- III could not be distinguished from AT-III purified from a normal control either by SDS polyacrylamide gel electrophoresis or by crossed immunoelectrophoresis, and the heparin cofactor activity and the progressive antithrombin activity of both AT-III samples were identical. Turnover studies were made in the patient using her own purified AT-III labeled with 131I, (*I). The results did not differ significantly from studies made with autologous *I-AT-III in two normal control women. Her fractional breakdown rate of 0.54 total plasma AT- III per day compared with 0.45 and 0.52 in the controls. These studies indicate that the patient synthesizes a normal AT-III molecule at half normal rates.
A 29-yr-old white female has suffered from recurrent venous thromboses over the last 12 yr. Plasma antithrombin III (AT-III) levels were 48% of normal by immunoelectrophoresis and 56% by chromogenic assay. Three of four siblings and the father had similar AT-III levels without associated venous thromboses. Heparin-Sepharose chromatography demonstrated normal behavior of the patient's AT-III. Her purified AT- III could not be distinguished from AT-III purified from a normal control either by SDS polyacrylamide gel electrophoresis or by crossed immunoelectrophoresis, and the heparin cofactor activity and the progressive antithrombin activity of both AT-III samples were identical. Turnover studies were made in the patient using her own purified AT-III labeled with 131I, (*I). The results did not differ significantly from studies made with autologous *I-AT-III in two normal control women. Her fractional breakdown rate of 0.54 total plasma AT- III per day compared with 0.45 and 0.52 in the controls. These studies indicate that the patient synthesizes a normal AT-III molecule at half normal rates.
Patients with 50 percent of normal levels of AT are at serious risk of deep venous thrombosis. Possible causes of 50 percent levels are (1) a halving of synthetic rate, or (2) a doubling of fractional catabolic rate. In health fractional catabolic rate is 50 percent of the plasma AT per day. Doubling of fractional catabolic rate-might be due to (a) the presence of a structurally defective AT molecule or (b) might be directly related to a great excess of AT consumption by complex formation with released clotting proteases. These possible causes of low AT levels can be distinguished by turnover studies with 131I-iabelled AT from the patient and from a healthy donor.We have developed simple, rapid methods of preparing highly purified AT from 30 to 60 ml of citrated blood and of labelling it with 131I without denaturation at about 0.5 iodine atom per AT molecule. A turnover study requires intravenous injection of 4-6 µC of 131I.Studies in a female patient with hereditary AT deficiency (40-50 percent AT level) compared to normal subjects indicates our approach. Fractional breakdown rate of her own 131l-AT was 50 percent per day indicating no obvious structural abnormality. Fractional breakdown rate of 131I_labelled donor AT was also 50 percent per day further indicating no difference in the behavior of her own and of normal AT and no excess consumption by clotting proteases. The patient's ability to compensate for increased AT-III consumption during an episode of thrombosis was impaired. Thus the patient suffered from a synthetic defect resulting in the ability to synthesize only 50 percent of her AT requirements per day.AT turnover studies provide an approach to the definition of the etiology of depressed AT levels in various disease states.
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