Vascular lesions of the placenta are commonly associated with preterm birth and preterm premature rupture of membranes (PPROM) (PROM refers to premature rupture of membranes, meaning before the onset of labor at any gestational age; hence, although “preterm PROM” is apparently redundant, it is not, given the definition of PROM, and is abbreviated here PPROM). Vascular lesions of the placenta have been reported in 34 percent of women with preterm delivery, 35 percent of women with PPROM, and 12 percent of uncomplicated deliveries at term (Arias et al., 1993). These lesions may be characterized as failure of the physiological transformation of the spiral arteries, atherosis, and maternal or fetal arterial thrombosis. The proposed mechanism linking vascular lesions to preterm birth is related to uteroplacental ischemia. Although the pathophysiology remains unclear, thrombin is thought to play a central role.
Independent of its critical role in coagulation, thrombin is a multifunctional protease that elicits the contractile activity of vascular, intestinal, and myometrial smooth muscle. Thrombin activates a unique set of receptors, including protease-activated receptor 1, protease-activated receptor 3, and protease-activated receptor 4 (Bohm et al., 1998; Grand et al., 1996). These transmembrane receptors are members of the heptahelical G-proteincoupled superfamily. Interaction with thrombin results in conformational changes that produce G-protein coupling and phospholipase C activation (Bohm et al., 1998; Grand et al., 1996). Phospholipase C activation initiates the biochemical reactions that lead to the release of intracellular calcium from the endoplasmic reticulum. The combination of intracellular calcium release and the influx of extracellular calcium cause cytosolic calcium oscillations that activate calmodulin, MLCK, actin, and myosin, resulting in phasic uterine contraction (Phillippe and Chien, 1998). Through these intracellular signaling events, thrombin acts as a classic uterotonic agonist.
Thrombin stimulates increases in basal tone and phasic contractions in longitudinal myometrial smooth muscle in vitro in a dose-dependent manner (Elovitz et al., 2000). Recently, these in vitro observations have been confirmed with in vivo models by using thrombin, whole blood, and thrombin inhibitors (Elovitz et al., 2000). Both thrombin and whole blood increased myometrial contractions in a dose-dependent fashion. However, myometrial contractility was significantly reduced by the addition of heparin, a known thrombin inhibitor. These in vitro and in vivo experiments provide a possible mechanistic explanation for the increased uterine activity clinically observed in abruptio placentae and preterm birth following first-or second-trimester bleeding.
A relationship between thrombin and PPROM may also exist. MMPs