Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction.

Abstract

Plasminogen (Plg)-deficient mice were generated to define the physiological roles of this key fibrinolytic protein and its proteolytic derivatives, plasmin and angiostatin, in development, hemostasis, and reproduction. Pig -/-mice complete embryonic development, survive to adulthood, and are fertile. There is no evidence of fetal loss of Pig -/-mice based on the Mendelian pattern of transmission of the mutant Pig allele. Furthermore, embryonic development continues to term in the absence of endogenous, sibling-derived, or maternal Pig. However, Pig -/-mice are predisposed to severe thrombosis, and young animals developed multiple spontaneous thrombotic lesions in liver, stomach, colon, rectum, lung, pancreas, and other tissues. Fibrin deposition in the liver was a uniform finding in 5-to 21-week-old mice, and ulcerated lesions in the gastrointestinal tract and rectal tissue were common. A remarkable finding, considering the well-established linkage between plasmin and the proteolytic activation of plasminogen activators, was that the level of active urokinase-type plasminogen activator in urine was unaffected in Pig -/-mice. Therefore, Pig plays a pivotal role in fibrinolysis and hemostasis but is not essential for urokinase proenzyme activation, development, or growth to sexual maturity.

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

“…The recent availability of gene-deficient mice (for example, deficient in plasminogen, uPA, and tPA) has helped to clarify the roles of these components in the steady state and in pathology. For example, Plg Ϫ/Ϫ mice are severely impaired in their ability to clear fibrin deposits (4,5). This phenotype is similar to that noted for the combined uPA Ϫ/Ϫ ;tPA Ϫ/Ϫ phenotype and is more severe than that for either PA-deficient mouse alone, suggesting that there is no significant additional pathway for physiologic plasminogen activation in mice (5) (but see below).…”

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

“…In contrast, uPA binds to a specific cell surface receptor (uPAR) and is generally thought to be involved in cell-mediated proteolysis, and removal of fibrin at extravascular sites. 57 There is now considerable evidence that uPA-mediated plasmin generation and MMP activation occurs at the cell surface. 4 Therefore, absence of this interaction with uPA-deficient fibroblasts within a fibrin matrix may prevent pericellular collagenolysis and thus deposited collagen accumulates around each cell.…”

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

“…31,32 The singly deficient mice, either urokinase PAϪ/Ϫ or tPAϪ/Ϫ, do not develop spontaneous fibrin deposits under basal conditions, but they are significantly more susceptible to development of venous or arterial thrombosis if exposed to provocative stimuli (eg, endotoxin) or subjected to injury of the peripheral arteries. 31,33 Our present data concur with these studies by demonstrating increased brain fibrin deposition, enhanced brain injury, and reduced CBF in tPA-deficient mice versus genetically matched tPAϩ/ϩ mice challenged by an ischemic insult.…”