On the Role of C1-Inhibitor as Inhibitor of Tissue-type Plasminogen Activator in Human Plasma

Abstract

SummaryAn enzyme immuno assay was developed to measure complexes of tissue-type plasminogen activator (t-PA) with C1-inhibitor in order to study the role of C1-inhibitor as an inhibitor of t-PA in plasma. In vitro experiments with melanoma and recombinant t-PA learned that purified C1-inhibitor reacts with both single chain t-PA and two chain t-PA. The rate constants ranged from 3.0 to 5.2 M-1s-1 In plasma, melanoma and recombinant two chain t-PA were hardly inhibited by C1-inhibitor, in contrast to melanoma and recombinant single chain t-PA which were inhibited to the same extent by endogenous C1-inhibitor as they were by purified C1-inhibitor. In vivo, t-PA/C1-inhibitor complex could be measured in plasma in a few cases in healthy volunteers (0.62 ± 0.43 ng/ml t-PA equivalents), after exercise (0.84 ± 0.25 ng/ml t-PA equivalents) and after a desmopressin infusion (0.26 ± 0.04 ng/ml t-PA equivalents). However, t-PA/C1-inhibitor complex was found in plasma in all cases after venous occlusion (1.7 ± 0.5 ng/ml t-PA equivalents), in peritoneal fluid from patients suffering from peritoneal inflammatory disease (2.2 ± 1.3 ng/ml t-PA equivalents) and in plasma from healthy volunteers during a t-PA infusion (27.7 ± 18.5 ng/ml t-PA equivalents at peak level). In the last case, about 8 % of the infused dose of recombinant t-PA (alteplase) was inhibited by C1-inhibitor at peak level. The half-life (t1/2α) of t-PA antigen in plasma was found not to be altered when t-PA was inhibited by C1-inhibitor (4.0 min and 4.2 min, respectively). Thus, in vivo, t-PA/C1-inhibitor complex is mostly present when t-PA escapes rapid liver clearance and accumulates in one place (e.g. during venous occlusion or in peritoneal fluid) or when it circulates in high concentrations (e.g. during t-PA infusion).

Tissue plasminogen activator (tPA) antigen in plasma: correlation with different tPA/inhibitor complexes

“…The tPA/C1 inhibitor concentrations measured in this investigation are slightly higher than those in an earlier study on a small number of individuals [12]. This might, at least partially, be due to a standardization problem.…”

“…These compounds, in addition to free tPA and tPA in complex with a 2 -macroglobulin [9,12] constitute tPA antigen in plasma. The latter two compounds have functional tPA activity, while tPA in complex with PAI-1, antiplasmin and C1 inhibitor are inactive.…”

“…If the PAI-1 concentration is increased, as is frequently the case in individuals with thrombotic disease, the tPA inhibition and formation of the tPA/PAI-1 complex is so rapid that the ¢brinolytic process is a¡ected. However, the tPA/antiplasmin and tPA/C1 inhibitor [10,12] is present in plasma in quite high concentrations, which is surprising, since the reaction rate between tPA and these inhibitors is very low. The molar concentrations of antiplasmin and C1 inhibitor in plasma are, however, more than 1000-fold higher compared with PAI-1.…”

Formation, Inhibition and Clearance of Plasmin in vivo

“…Separate extraction fractions were used for each factor measured. Huisman et al [41] reported a half-life of 4.2 min for the clearance of t-PA/C1-I complex [41]. The hepatic extraction fraction for t-PA/C1-I was adjusted to produce a halflife of 4.2 min in the simulation.…”

Diagnosis and Management of Hereditary Angioedema: An Emergency Medicine Perspective

“…C1 inhibitor has also been implicated in regulating the formation of the C4C2 complex via the lectin pathway by inactivating mannan-binding, lectin-associated proteases 1 and 2 (12,13). Similarly, inhibitory effects on tissue plasminogen activator and plasmin (with a consequent increased breakdown of the fibrin clot) have been described, although these are thought to play only a minor role (14). Despite the regulatory role C1-INH plays in the previous pathways, most authorities believe that C1-INH's function of inhibiting the conversion of prekallikrein to kallikrein is the major pathophysiologic event resulting in angioedema in HAE patients.…”