Spontaneous inhibitors of factor VIII: Kinetics of inactivation of human and porcine factor VIII

Autoantibodies to factor VIII (FVIII)(spontaneous inhibitors) often inactiv ate FVIII in a complex fashion (type II inhibitors) as compared with alloan tibodies (hemophilic inhibitors), which usually demonstrate second-order re action kinetics (type I inhibitors). The infusion of porcine FVIII in patie nts with spontaneous inhibitors may give rise to anti-porcine FVIII antibod ies, The purpose of this study was to determine whether these were type I o r type II inhibitors. Plasma from 8 patients with spontaneous inhibitors an d 6 patients with hemophilia with inhibitors were studied, Equal volumes of patient plasma and either pooled normal human plasma or porcine FVIII (Hya te-C) were incubated at 37 degrees C for 90 minutes. Aliquots were removed immediately after mixing and at 30-minute intervals and assayed for FVIII b y using a two-stage method. The values for residual FVIII were log-transfor med and plotted against the time of incubation, and the resultant curves we re analyzed for goodness of fit (coefficient of determination, r(2)) by usi ng linear and exponential equations, The values were examined by paired t t ests; P values were two-tailed. Values are expressed as mean +/- SD, The ti ters of spontaneous inhibitors against human FVIII ranged from 2.6 to 416 B ethesda Units (BU), and those against porcine FVIII ranged from 0.7 to 47 B U, Samples were diluted so that the FVIII levels in the mixtures before inc ubation were similar: human, 0.44 U/ml; porcine, 0.47 U/ml; P = not signifi cant. Four of the 8 patients with spontaneous inhibitors inactivated human FVIII in a fashion consistent with complex kinetics; their P values with th e linear equation were less than 0.90. All r(2) values improved when the ex ponential equation was used (linear, 0.90 +/- 0.08; exponential, 0.92 +/- 0 .06; P = .007), In contrast, r(2) values with porcine FVIII were the same ( 0.94) with either the linear or the exponential equation (P = not significa nt), r(2) for the 6 hemophilic inhibitors showed no significant difference between the linear and exponential equations; the values were 0.99 with hum an FVIII and 0.95 with porcine FVIII, In non-hemophilic patients, antibodie s developing to porcine FVIII have kinetics of inhibition that are second o rder (type I), even though antibodies to human FVIII in these same patients may have complex (type II) kinetics.