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1974 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1975

PAI-1 mRNA production by cultured endothelial cells, but has no effect TABLE 115–3. The Fibrinolytic System in Cardiovascular
138
on t-PA. Thus, synthesis and secretion of PAI-1 by the endothelial cell
in vitro appears to be regulated independently of t-PA. Disease—Transgenic Mouse Models
In vivo, elevated levels of circulating PAI-1 have been linked epi- Genotype Result Reference(s)
124
demiologically to risk for myocardial infarction. Although the liver Atherogenesis:
is the major source of plasma PAI-1, endothelial expression of PAI-1 is –/– –/–
detected near neovascular sprouts during decidual neovascularization PLG ApoE Increased atherogenesis 178
128
in the ovary. In addition, inflammatory cytokines are powerful stimuli t-PA ApoE –/– Unchanged atherogenesis 179
–/–
for induction of PAI-1 in a variety of tissues including liver, as injection u-PA ApoE –/– Unchanged atherogenesis 179
–/–
of TNF in both rats and humans with active malignancy results in a –/– –/–
striking increase plasma concentrations of PAI-1. 105,123 PAI-1 ApoE Decrease in early plaque size; 180–182
increase in advanced plaque size
The endothelial cell coreceptor for t-PA and plasminogen, the
annexin A2/S100A10 complex (see Fig. 115–6), appears to be expressed Transplant arteriosclerosis:
constitutively in vivo by endothelial cells in a wide variety of tissues in PLG –/– Reduced leukocyte invasion in 185
141
142
140
the chicken, mouse, rat, and human. Annexin A2 is upregu- transplantation model; reduced
139
lated transcriptionally by hypoxia both in vivo and in endothelial cells extent of disease
in vitro, and by nerve growth factor in neuronal-like PC12 cells. In Coronary ligation:
143
144
addition, the in vitro transition of human monocyte to macrophage is
associated with a severalfold increase in both annexin A2 protein and u-PA –/– Protection from ventricular rup- 186
steady state mRNA expression. 145 ture; but poor revascularization
and late death from heart failure
The evidence that the annexin A2 system plays a role in main-
taining vascular patency includes the findings that (1) overexpression t-PA –/– No protection 186
of annexin A2 in blast cells in acute promyelocytic leukemia blast cells uPAR –/– No protection 186
increases plasmin production and contributes to hyperfibrinolytic
bleeding, 146–149 (2) systemic injection of annexin A2 diminishes throm- Aortic aneurysm:
–/–
botic vascular occlusion resulting from vascular injury in experimen- u-PA ApoE –/– Protected 179
150
tal animals, (3) annexin A2–deficient mice display fibrin deposition t-PA ApoE –/– Not protected 179
–/–
on microvessels and impaired clearance of arterial thrombi following
151
vascular injury, (4) high titer antibodies directed against annexin A2 Early oxidative injury:
are associated with thrombosis in antiphospholipid syndrome and in PAI-1 –/– Attenuated thrombotic occlu- 194
individuals with cerebral venous thrombosis, 152,153 and (5) that polymor- sion (Rose Bengal)
phisms in the ANXA2 gene are associated with cerebral vascular occlu- PAI-1 –/– Attenuated thrombotic occlu- 195
sion and osteonecrosis of bone in patients with sickle cell disease. 154–156 sion (FeCl )
3
Whether defects in S100A10, which could serve either as a chaperone u-PA –/– Increased thrombosis (FeCl ) 196
157
for annexin A2 or as a direct binding site for plasminogen, might also 3
be associated with these clinical entities remains to be determined. t-PA –/– Increased thrombosis (FeCl ) 196
3
A2 –/– Increased thrombosis (FeCl ) 155
3
NONFIBRINOLYTIC VASCULAR FUNCTIONS Restenosis with prominent thrombosis:
OF PLASMIN PAI-1 –/– No neointima (Cu cuff) 199
Although not yet demonstrated in vivo, plasmin may inactivate factor PAI-1 –/– Reduced neointima (ligation) 317
Va in vitro by cleaving both the heavy and light chains of this 168-kDa PAI-1 –/– Reduced neointima (FeCl ) 317
protein, in a manner that is distinct from the action of activated protein 3
–/–
C. 158,159 Plasmin can also inactivate factor VIIIa, a procoagulant cofactor PAI-1 ApoE –/– Reduced neointima (FeCl ) 198
3
that is structurally related to factor Va. In addition, platelet GPIIb/IIIa Restenosis without prominent thrombosis:
160
and GPIb, the cell surface receptors for fibrinogen and VWF, respec- PLG –/– Reduced neointima (electrical) 187, 188
tively, are both plasmin substrates. 161,162 Thus, plasmin formation in the
vicinity of a hemostatic plug could lead to impaired adhesion and poor t-PA –/– No change (electrical or 187, 189
aggregation in response to agonists. In vivo, prolonged bleeding times mechanical)
were found in patients 90 minutes after t-PA infusion for thrombolysis, u-PA –/– Reduced neointima (electrical or 187, 189
suggesting early impairment of platelet function upon plasmin gen- mechanical)
eration. However, there is also evidence that platelets may promote u-PA t-PA –/– Reduced neointima (electrical or 187, 189
163
–/–
thrombotic reocclusion following successful thrombolytic therapy. 164 mechanical)
uPAR –/– No change (electrical) 190
FIBRINOLYTIC FUNCTION IN PAI-1 –/– Increased neointima (ligation) 318
VASCULAR INJURY PAI-1 –/– Increased neointima (electrical 191
Transgenic mouse models of vascular disease have helped to eluci- or mechanical)
date the complex role of the fibrinolytic system in atherosclerosis
(Table 115–3). 165,166 In mice, the general effects of plasminogen defi- A2, annexin A2; ApoE, apolipoprotein E; PAI-1, plasminogen-activator
ciency include runting, fibrin deposition in intra- and extravascu- inhibitor-1; PLG, plasminogen; t-PA, tissue-type plasminogen activa-
lar locations, and premature death. 167,168 In addition, the mice display tor; u-PA, urokinase plasminogen activator; uPAR, u-PA receptor.

Kaushansky_chapter 115_p1967-1984.indd 1974 9/18/15 10:08 AM