Activity and transport of antithrombin during acute limb ischemia

Antithrombin (AT III), a major circulating anticoagulant, may be influenced by ischemia-induced changes in microvascular integrity and contribute to localized hypercoagulability. In a nonheparinized intact canine hindlimb model we determined AT III activity by chromogenic substrate assay (S-2238); coagulation changes with fibrinogen, activated partial thromboplastin time (aPTT), and prothrombin time (PT); and transvascular exchange by lymph-to-plasma total protein concentration ratio. Femoral venous plasma and lymph samples were assayed during 1 hour of steady state (C), 6 or 8 hours of aortoiliac occlusion (I), and 1 or 3 hours of reperfusion (R). Four groups were studied: GI, sham operated (n = 5); GII, moderate ischemia (n = 7), arterial pressure 30% to 45% C, GIII, 6 hours of severe ischemia (n = 7), arterial pressure 5% to 20% C; and GIV, 8 hours of severe ischemia (n = 5), arterial pressure 5% to 20% C. All parameters varied near baseline in the control group and the group with moderate ischemia. Fibrinogen decreased after 3 hours of ischemia in GIII from 218 ± 38 to 175 ± 46 mg/dl (mean ± SEM) and in GIV from 254 ± 39 to 201 ± 44 mg/dl (p < 0.005) as aPTT and PT increased. All parameters returned to baseline on R in GIII only. Plasma AT III decreased in GIV from 89% ± 4.6% to 53.6% ± 16.2% (p < 0.005) after 3 hours and remained low during late I and R. The decrease was less severe in GIII. Lymph AT III decreased after 3 hours from 33.5% ± 6.6% to 6.4% ± 4.2% (p < 0.01) in GIII and from 40% ± 3.9% to 15.5% ± 6.6% (p < 0.01) in GIV, remained low during late I in both groups, and returned to baseline on R only in GIII. The changes in AT III occurred as lymph-to-plasma total protein ratio increased progressively throughout I (from 0.42 ± 0.02 to 0.64 ± 0.07 [p < 0.001] at 6 hours in GIII and from 0.46 ± 0.03 to 0.85 ± 0.20 [p < 0.01] at 8 hours in GIV). A sustained reduction in plasma and lymph AT III levels is observed during 8 hours of ischemia in contrast to the transient reduction during 6 hours of ischemia. These changes appear to be associated with coagulation changes within the limb but independent of the microvascular permeability changes. (J Vasc Surg 1989;9:740–6.)