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2310 Part XII: Hemostasis and Thrombosis Chapter 135: Fibrinolysis and Thrombolysis 2311

UROKINASE-TYPE PLASMINOGEN ACTIVATOR– may reflect alteration of its tertiary structure upon cleavage of an
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MEDIATED PLASMIN GENERATION aminoterminal glycopeptide. Once activated by plasmin, TGF-β can
stimulate production of PAI–1, thus impairing further activation of Plg.
For the activation of Glu–Plg by u-PA in a fibrin–free system, reported The role of the fibrinolytic system in vascular remodeling during
Michaelis constants (K ) vary from 1.4 to 200 μM, while catalytic rate atherosclerosis appears to be complex. In the evolution of an injury to
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m
–1 1
constants (kcat) range from 0.26 to 1.48 sec . Interestingly, activation the endothelial cell lining of blood vessels, deposition of intravascular
of Glu–Plg by two–chain u-PA is increased in the presence of fibrin by fibrin and organization of a thrombus occurs. As the injury resolves,
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approximately 10–fold even though u-PA does not bind to fibrin. In fibrin participates in plaque growth and luminal narrowing. Evidence
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contrast, single-chain u-PA has considerable fibrin–specificity. This may of the importance of fibrinolytic balance in this process is that, in the
reflect neutralization by fibrin of components in plasma that impair Plg absence of PAI-1, there is less neointima formation and reduced luminal
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also reflect a conformational change in Plg upon binding to fibrin. It is stenosis, possibly because of more rapid resolution of fibrin. In areas
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important to recognize, however, that the intrinsic Plg activating poten- of the vasculature where injury is not associated with fibrin deposition,
tial of single-chain u-PA is less than 1 percent of that of two-chain u-PA. however, absence of PAI-1 may lead to enhanced lesion formation, as
Two–chain u-PA has been used effectively as a thrombolytic agent for cells that invade the developing plaque may require plasmin activity for
many years. 229 their directed migration. 261
THE NONFIBRINOLYTIC ACTIONS OF FIBRINOLYSIS AND ANGIOGENESIS
PLASMIN Although the fibrinolytic system has generally been assumed to be
proangiogenic by virtue of its ability to promote “tunneling” of endo-
PLASMIN AS A TISSUE REMODELER thelial cells through fibrin-containing matrices, its effect, in actuality,
A large number of in vitro studies suggest a role for plasmin in tissue appears to be context specific. 262,263 PAI-1 deficiency in mice, for exam-
remodeling. Basement membrane proteins such as thrombospondin, ple, seems to prevent tumor vascularization in a malignant keratinocyte
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laminin, fibronectin, and fibrinogen, are readily degraded by model. The same mice are also resistant to laser-induced neovascu-
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plasmin in vitro, suggesting possible roles in inflammation, tumor cell larization of the choroid. 265,266 The paradoxical proangiogenic effect of
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invasion, embryogenesis, ovulation, neurodevelopment, 238,239 and PAI-1 in some settings may relate to its ability to protect endothelial
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prohormone activation. 240,241 Plasmin also activates MMPs 3 and 13 in cells from apoptosis mediated by FasL, which is activated by plasmin. 267
the mouse, thereby facilitating the degradation of matrix proteins such In the mouse cornea, absence of t-PA, u-PA, or TAFI, had no effect
as the collagens, laminin, fibronectin, vitronectin, elastin, aggrecan, and on neovascularization, whereas loss of Plg, PAI-1, or annexin A2 sig-
tenascin C. On the other hand, activation of other MMPs apparently nificantly diminished this response. 205,268 Within the atherosclerotic
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proceeds in the absence of Plg, possibly providing the basis for the mild plaque, moreover, expression of a truncated form of PAI-1 (rPAI-1 )
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phenotype observed in Plg-null homozygote animals. 80 was antiangiogenic, inhibiting the proliferation of vasa vasorum, and
Roles for plasmin in tissue remodeling and host defense mech- reducing overall plaque area and plaque cholesterol in the descend-
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anisms are further supported by in vivo observations in Plg-deficient ing aorta. As a gene product that is transcriptionally upregulated
mice (see Table 135–2). Impaired wound healing is observed in the Plg by hypoxia, annexin A2 is required for the normal corneal angiogenic
“knockout,” and is reversed upon simultaneous deletion of fibrin- response to growth factor stimulation, and also for hypoxia-induced
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ogen. Plg-deficient mice also display diminished recruitment of retinal angiogenesis. 198,205,270
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monocytes in response to intraperitoneal thioglycolate, and impaired
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neointima formation following electrical injury to blood vessels. In
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studies involving Borrelia burgdorferi, the agent of Lyme disease, dis- DISORDERS OF PLASMIN GENERATION
semination of the spirochete within its arthropod vector Ixodes dam-
mini is absolutely dependent upon host Plg even though the deer tick FIBRINOLYTIC DEFICIENCY AND THROMBOSIS
contains no fibrin. Furthermore, kainate-induced excitotoxicity and Although partial human Plg deficiency was first described in a young
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attendant neuronal cell dropout in the hippocampus is not observed man with a history of venous thrombosis and pulmonary embolism,
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in Plg knockout mice but does occur in fibrinogen-deficient animals. there is currently little evidence that hypoplasminogenemia alone is a
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The latter two studies may define new roles for plasmin, which appear significant cause of deep venous thrombosis. In a study of 23 consec-
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to be unrelated to degradation of fibrin. utive patients with thrombophilia, the prevalence of Plg deficiency was
In the lung, the fibrinolytic system mediates lung matrix remod- only 1.9 percent. Approximately half of these individuals had other
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eling, through mechanisms that appear to be independent of fibrin risk factors such as deficiency of antithrombin, protein C, or protein S,
degradation. In mice, deficiency of fibrinogen has no effect on the or resistance to activated protein C. Among 93 patients with type I Plg
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development of bleomycin-induced pulmonary fibrosis. Mice lack- deficiency, the prevalence of thrombosis was 24 percent, or 9 percent
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ing either PAI-1 or TAFI are protected from lung fibrosis in the same when the propositi were excluded. Two additional epidemiologic
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model, 251–253 whereas inducible expression of u-PA within alveoli abro- studies concluded, moreover, that isolated hypoplasminogenemia is not
gates the fibrotic response. 254 a risk factor for thrombosis. 275,276
Plasmin may play a role in the activation of growth factors. TGF-β Although there are no reported cases of complete absence of Plg
is a Mr 25,000 homodimeric polypeptide that regulates vascular cell in humans, a large number of Plg polymorphisms and dysplasmino-
responses and epithelial-mesenchymal transformation in development genemias have been reported. Congenital Plg deficiency has been
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and in tissue fibrosis. 255,256 In culture, cell–associated plasmin appears to classified into two types: in type I the concentration of immunoreactive
convert latent TGF-β to its physiologically relevant active state. Inhibi- Plg is reduced in parallel with functional activity, whereas in type II
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tion of wound healing in this system was dependent upon active TGF-β, (dysplasminogenemia), immunoreactive protein is normal while func-
and activation of this agent could be blocked in the presence of plasmin tional activity is reduced. Patients with type I Plg deficiency are most
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inhibitors such as aprotinin or α -PI. Activation of TGF-β by plasmin likely to present with ligneous conjunctivitis, which resolves completely
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Kaushansky_chapter 135_p2303-2326.indd 2311 9/18/15 5:13 PM