Endogenous Tissue-type Plasminogen Activator Research Articles

Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke.

Intravenous injection of alteplase, a recombinant tPA (tissue-type plasminogen activator) as a thrombolytic agent has revolutionized ischemic stroke management. However, tPA is a more complex enzyme than expected, being for instance able to promote thrombolysis, but at the same time, also able to influence neuronal survival and to affect the integrity of the blood-brain barrier. Accordingly, the respective impact of endogenous tPA expressed/present in the brain parenchyma versus in the circulation during stroke remains debated. To address this issue, we used mice with constitutive deletion of tPA (tPANull [tPA-deficient mice]) or conditional deletion of endothelial tPA (VECad [vascular endothelial-Cadherin-Cre-recombinase]-Cre∆tPA). We also developed parabioses between tPANull and wild-type mice (tPAWT), anticipating that a tPAWT donor would restore levels of tPA to normal ones, in the circulation but not in the brain parenchyma of a tPANull recipient. Stroke outcomes were investigated by magnetic resonance imaging in a thrombo-embolic or a thrombotic stroke model, induced by local thrombin injection or FeCl3 application on the endothelium, respectively. First, our data show that endothelial tPA, released into the circulation after stroke onset, plays an overall beneficial role following thrombo-embolic stroke. Accordingly, after 24 hours, tPANull/tPANull parabionts displayed less spontaneous recanalization and reperfusion and larger infarcts compared with tPAWT/tPAWT littermates. However, when associated to tPAWT littermates, tPANull mice had similar perfusion deficits, but less severe brain infarcts. In the thrombotic stroke model, homo- and hetero-typic parabionts did not differ in the extent of brain damages and did not differentially recanalize and reperfuse. Together, our data reveal that during thromboembolic stroke, endogenous circulating tPA from endothelial cells sustains a spontaneous recanalization and reperfusion of the tissue, thus, limiting the extension of ischemic lesions. In this context, the impact of endogenous parenchymal tPA is limited.

The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?

Endogenous protease tissue-type plasminogen activator (tPA) has highly efficient fibrinolytic activity and its recombinant variants alteplase and tenecteplase are established as highly effective thrombolytic drugs for ischemic stroke. Endogenous tPA is constituted of five functional domains through which it interacts with a variety of substrates, binding proteins and receptors, thus having enzymatic and cytokine-like effects to act on all cell types of the brain. In the past 2decades, numerous studies have explored the clinical relevance of endogenous tPA in neurological diseases, especially in ischemic stroke. tPA is released from many cells within the brain parenchyma exposed to ischemia conditions in vitro and in vivo, which is believed to control neuronal fate. Some studies proved that tPA could induce blood-brain barrier disruption, neural excitotoxicity and inflammation, while others indicated that tPA also has anti-excitotoxic, neurotrophic and anti-apoptotic effects on neurons. Therefore, more work is needed to elucidate how tPA mediates such opposing functions that may amplify tPA from a therapeutic means into a key therapeutic target in endogenous neuroprotection after stroke. In this review, we summarize the biological characteristics and pleiotropic functions of tPA in the brain. Then we focus on possible hypotheses about why and how endogenous tPA mediates ischemic neuronal death and survival. Finally, we analyze how endogenous tPA affects neuron fate in ischemic stroke in a comprehensive view.

Abstract T P75: Temporal Profiles of Plasminogen Activator Inhibitor-1 Concentration and Activity Changes in Circulation after Focal Stroke and Tissue Type Plasminogen Activator Administration in Rats

Aims: Plasminogen activator inhibitor-1 (PAI-1) is the main and potent endogenous tissue-type plasminogen activator (tPA) inhibitor, but an important question on whether PAI-1 in blood stream responds and interferes with the exogenously administered tPA remains unexplored. We for the first time investigated temporal profiles of PAI-1 concentration and activity in circulation after stroke and tPA administration in rats. Methods: Permanent MCAO focal stroke of rats were treated with saline or 10mg/kg tPA at 3 hours after stroke (n=10 per group). Plasma (platelet free) PAI-1 antigen and activity levels were measured by ELISA at before stroke, 3, 4.5 (1.5 hours after saline or tPA treatments) and 24 hours after stroke. Since vascular endothelial cells and platelets are two major cellular sources for PAI-1 in circulation, we measured releases of PAI-1 from cultured endothelial cells and isolated platelets after direct tPA (4 μg/ml) exposures for 60 min in vitro by ELISA (n=4 per group). Results: At 3 hours after stroke, both plasma PAI-1 antigen and activity were significantly increased (3.09±0.67, and 3.42±0.57 fold of before stroke baseline, respectively, all data are expressed as mean±SE). At 4.5 hours after stroke, intravenous tPA administration significantly further elevated PAI-1 antigen levels (5.26±1.24), while as expected that tPA neutralized most elevated PAI-1 activity (0.33±0.05). At 24 hours after stroke, PAI-1 antigen levels returned to the before baseline level, however, there was a significantly higher PAI-1 activity (2.51±0.53) in tPA treated rats. In vitro tPA exposures significantly increased PAI-1 releases into culture medium in cultured endothelial cells (1.65±0.08) and platelets (2.02±0.17). Conclution: Our experimental results suggest that tPA administration may further elevate stroke-increased blood PAI-1 concentration, but also increase PAI-1 activity at late 24 hours after stroke. The increased PAI-1 releases after tPA exposures in vitro suggest tPA may directly stimulate PAI-1 secretions from vascular walls and circulation platelets, which partially contributes to the PAI-1 elevation observed in focal stroke rats. The underlying regulation mechanisms and pathological consequence need further investigation.

Response to Letter Regarding Article, “Smoking-Thrombolysis Paradox: Recanalization and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischemic Stroke”

HomeStrokeVol. 44, No. 5Response to Letter Regarding Article, “Smoking-Thrombolysis Paradox: Recanalization and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischemic Stroke” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Smoking-Thrombolysis Paradox: Recanalization and Reperfusion Rates After Intravenous Tissue Plasminogen Activator in Smokers With Ischemic Stroke” Anna Kufner, MSc, Christian H. Nolte, MD and Martin Ebinger, MD Anna KufnerAnna Kufner Klinik und Hochschulambulanz für NeurologieCharité—Universitätsmedizin BerlinBerlin, Germany Search for more papers by this author , Christian H. NolteChristian H. Nolte Klinik und Hochschulambulanz für NeurologieCharité—Universitätsmedizin BerlinBerlin, Germany Search for more papers by this author and Martin EbingerMartin Ebinger Klinik und Hochschulambulanz für NeurologieCharité—Universitätsmedizin BerlinBerlin, Germany Search for more papers by this author Originally published4 Apr 2013https://doi.org/10.1161/STROKEAHA.113.001287Stroke. 2013;44:e59Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 Response:We thank Plas et al1 for their interest in our article and for sharing their results about the smoking–thrombolysis paradox in ischemic stroke. A meta-analysis is an important further step to clarify the much debated and often conflicting results on this topic. Plas et al1 performed an analysis of 7 studies including 7494 patients receiving thrombolysis, which revealed an odds ratio of 1.38 (95% confidence interval, 1.24–1.53; P=0.02) for smoking in favor of a good functional outcome (modified Rankin Scale score ≤2) 3 months after stroke. The authors pointed out that the lack of adjustment for age and sex is a limitation of their analysis. This is an essential point, because smokers tend to be significantly younger and more often are men. Age is a strong predictor for outcome and studies have shown gender-specific differences in vascular risk factors and functional recovery.2 Nonetheless, the meta-analysis is reassuring that our observation is not a mere result of chance. An appropriately adjusted meta-analysis is without a doubt still necessary to determine the concrete effects of smoking on ischemic stroke.Two recent studies have shed light on possible pathophysiological mechanisms underlying this peculiar phenomenon. One suggests smoking to have early protective effects and the other suggests an enhanced treatment efficacy in patients with this risk factor. Lisi et al3 provide evidence suggesting that short-term exposure to reactive oxygen species caused by smoking triggers ischemic preconditioning, reducing endothelial susceptibility to ischemia and reperfusion damage. Nielsen et al4 propose that smoking alters the nature of plasmin–antiplasmin–carbon monoxide interactions in blood plasma, consequently modifying fibrin clot kinetics. Earlier studies have demonstrated that smoking decreases endogenous tissue-type plasminogen activator release, causing an increase in fibrinogen levels and more fibrin-rich thrombi, thereby increasing susceptibility to exogenous tissue-type plasminogen activator treatment.5Smoking remains a proven risk factor for stroke and has detrimental effects on the cardiovascular system. Whether smoking leads to increased tissue-type plasminogen activator efficacy deserves further studies. Either way, we continue to believe that no stroke is always better than a recanalized stroke.Anna Kufner, MScChristian H. Nolte, MDMartin Ebinger, MDKlinik und Hochschulambulanz für NeurologieCharité—Universitätsmedizin BerlinBerlin, GermanyDisclosuresNone.FootnotesStroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited. Include a completed copyright transfer agreement form (available online at http://stroke.ahajournals.org and http://submit-stroke.ahajournals.org).

Endogenous tissue-type plasminogen activator impairs host defense during severe experimental gram-negative sepsis (melioidosis)*

Melioidosis is a frequent cause of severe sepsis in Southeast Asia caused by the gram-negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of tissue-type plasminogen activator, an important regulator of fibrinolysis. In this study, we aimed to investigate the role of tissue-type plasminogen activator during melioidosis. Animal study. University research laboratory. Wild-type and tissue-type plasminogen activator-deficient C57BL/6 mice. Mice were intranasally infected with viable Burkholderia pseudomallei and killed after 24, 48, or 72 hrs for harvesting of lungs, liver, and blood. Additionally, survival studies were performed. Experimentally induced melioidosis was associated with elevated levels of tissue-type plasminogen activator in lungs of infected wild-type mice. During infection with Burkholderia pseudomallei, tissue-type plasminogen activator-deficient mice were protected when compared to wild-type mice as demonstrated by a strongly decreased mortality (62% vs. 100% amongst wild-type mice, p < .0001), together with decreased pulmonary bacterial loads, less severe histopathological scores, and decreased fibrinolysis. These results were accompanied with an early increase in cytokine levels in tissue-type plasminogen activator-deficient mice. During severe gram-negative sepsis caused by Burkholderia pseudomallei, endogenous tissue-type plasminogen activator has harmful effects with respect to survival and pulmonary bacterial growth. These effects are related to tissue-type plasminogen activator-associated plasmin-induced fibrinolysis and/or a tissue-type plasminogen activator-associated decrease in proinflammatory cytokine production.

Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection

Acute pyelonephritis is one of the most common bacterial infections. Tissue-type plasminogen activator (tPA) is a potent fibrinolytic agent, but can play a role in inflammatory processes as well. We induced pyelonephritis in tPA(-/-) and C57BL/6 wild-type (WT) mice by intravesical inoculation with 10(10) CFU uropathogenic Escherichia coli 1677. The mice were killed after 24 and 48 h, after which bacterial outgrowth and cytokine levels in kidney homogenates were determined. Influx of neutrophils was quantified by myeloperoxidase-ELISA. Neutrophil phagocytosis and oxidative burst were measured. The tPA(-/-) kidneys contained significantly higher numbers of E. coli CFU, accompanied by higher levels of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha). The number of infiltrating neutrophils was similar in tPA(-/-) and WT mice at both time points, suggesting that tPA(-/-) neutrophils have a lower ability to eliminate E. coli. Phagocytosis of E. coli organisms was not diminished in tPA(-/-) neutrophils. Interestingly, tPA(-/-) neutrophils showed a significantly lower ability to generate an oxidative burst reaction upon stimulation with E. coli than WT neutrophils. Incubation with recombinant tPA reversed this effect completely. These results show that deletion of the tPA-gene in mice leads to lower bactericidal potential of tPA(-/-) neutrophils, which results in significantly more bacterial outgrowth during experimental pyelonephritis.

脳虚血とｔＰＡ

Role of endogenous tissue-type plasminogen activator (tPA) on focal cerebral ischemic injury (FII) after middle cerebral artery occlusion (MCAo) was studied by using tPA deficient mice (KO) and wild type mice (WT). FII size in KO was smaller than that in WT in permanent MCAo whereas larger in transient MCAo. These findings suggest that endogenous tPA protected FII through its thrombolytic action on transient MCAo, but deteriorated by neurotoxicity of tPA on persistent occlusion. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We demonstrated that heparin administration after the MCAo caused cerebral hemorrhage in WT, but not in KO. We observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. We also investigated about hemorrhage induced by tPA administration using MMP3 deficient mouse. The hemorrhage is induced by tPA in wild type mice, but not in MMP3 deficient mice. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation and that hemorrhage induced by tPA administration is related with MMP3.

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Sepsis is associated with enhanced production of tissue-type plasminogen activator (tPA). We investigated the function of endogenous tPA in the immune responses to Escherichia coli-induced abdominal sepsis using tPA gene-deficient (tPA(-/-)) and normal wild-type (WT) mice. tPA(-/-) mice demonstrated an impaired defense against E. coli peritonitis as indicated by higher bacterial loads at the primary site of the infection, enhanced dissemination, and reduced survival. The protective function of tPA was independent of plasmin since plasminogen gene-deficient (Plg(-/-)) mice were indistinguishable from WT mice. Relative to WT mice, tPA(-/-) mice demonstrated similar neutrophil counts in the peritoneal cavity despite much higher bacterial loads and higher local concentrations of neutrophil attracting chemokines, suggesting a reduced migratory response. In line, tPA(-/-) mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis. These findings identify a novel protective function of tPA in abdominal sepsis caused by E. coli that seems independent of its role in the generation of plasmin.

Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage

To investigate the role of tissue plasminogen activator (tPA) in retinal damage, tPA-deficient and wild-type mice were employed. Two different retinal neuron insult models were used in the present study. One is an excitotoxin-treated retinal model, created by direct intravitreal injection of glutamate analogs, NMDA or kainic acid (KA), and the other is an ischemia–reperfusion model induced by transient elevation of intraocular pressure. TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine the retinal cell nuclear damage. The number of TUNEL-positive cells in ganglion cell layer (GCL) and inner nuclear layer (INL) in tPA-deficient mice after low-, but not high-dose NMDA was significantly less compared to wild type. In contrast, neither intravitreal KA or transient ischemia produced significant difference in retinal damage in tPA vs. wild-type mice. These data show that tPA-deficient mice are resistant to retinal damage by intravitreal injection of NMDA, and indicate that tPA plays a role in the retinal cell damage induced by excitotoxins, especially NMDA.

Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage

To investigate the role of tissue plasminogen activator (tPA) in retinal damage, tPA-deficient and wild-type mice were employed. Two different retinal neuron insult models were used in the present study. One is an excitotoxin-treated retinal model, created by direct intravitreal injection of glutamate analogs, NMDA or kainic acid (KA), and the other is an ischemia–reperfusion model induced by transient elevation of intraocular pressure. TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine the retinal cell nuclear damage. The number of TUNEL-positive cells in ganglion cell layer (GCL) and inner nuclear layer (INL) in tPA-deficient mice after low-, but not high-dose NMDA was significantly less compared to wild type. In contrast, neither intravitreal KA or transient ischemia produced significant difference in retinal damage in tPA vs. wild-type mice. These data show that tPA-deficient mice are resistant to retinal damage by intravitreal injection of NMDA, and indicate that tPA plays a role in the retinal cell damage induced by excitotoxins, especially NMDA.

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the “breakdown” of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg–/– mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor–related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.

Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein.

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.

Tissue-type plasminogen activator has paradoxical roles in focal cerebral ischemic injury by thrombotic middle cerebral artery occlusion with mild or severe photochemical damage in mice.

The role of endogenous tissue-type plasminogen activator (tPA) in focal cerebral ischemic injury (FCII) after middle cerebral artery occlusion was studied using tPA gene-deficient (KO) mice and their wild-type (WT) littermates. The middle cerebral artery was occluded by thrombi induced by three different intensities of photochemical damage, a method that was newly introduced in mice. In both WT and KO mice, the intensity-dependent increase of FCII size was observed. The FCII size in tPA WT mice was smaller than in KO mice in cases of mild damage, whereas the FCII size was larger in WT mice than in KO mice in cases of severe damage. There was no difference in FCII size between WT and KO mice in cases of moderate damage. The number of microthrombi also increased with damage intensity in both WT and KO mice, but was less in WT mice at all intensities of damage. The results support the validity of the model of thrombotic occlusion by photochemical damage in mice, and suggest that endogenous tPA protects FCII through thrombolytic action on transient occlusion of middle cerebral artery with mild damage, but deteriorates on persistent occlusion with severe damage.

Targeting of a Heterologous Protein to a Regulated Secretion Pathway in Cultured Endothelial Cells

The stimulation of regulated exocytosis in vascular endothelial cells (EC) by a variety of naturally occurring agonists contributes to the interrelated processes of inflammation, thrombosis, and fibrinolysis. The Weibel-Palade body (WPB) is a well-described secretory granule in EC that contains both von Willebrand factor (vWF) and P-selectin, but the mechanisms responsible for the targeting of these proteins into this organelle remain poorly understood. Through adenoviral transduction, we have expressed human growth hormone (GH) as a model of regulated secretory protein sorting in EC. Immunofluorescence microscopy of EC infected with GH-containing recombinant adenovirus (GHrAd) demonstrated a granular distribution of GH that colocalized with vWF. In contrast, EC infected with an rAd expressing the IgG(1) heavy chain (IG), a constitutively secreted protein, did not demonstrate colocalization of IG and vWF. In response to phorbol ester, GH as well as endogenously synthesized vWF were rapidly released from GHrAd-infected EC. By immunofluorescence microscopy, granular colocalization of GH with endogenous tissue-type plasminogen activator (tPA) was also demonstrated, and most of the tPA colocalized with vWF. These data indicate that EC are capable of selectively targeting heterologous proteins, such as GH, to the regulated secretory pathway, which suggests that EC and neuroendocrine cells share common protein targeting recognition signals or receptors.

Von Willebrand factor: a marker of endothelial damage?

von Willebrand factor: a marker of endothelial damage?

Endogenous fibrinolytic function and risks of future myocardial infarction and stroke: observations from the Physicians' Health Study

Summary Employing plasma and DNA samples collected at baseline among 14,916 participants in the Physicians' Health Study who were free of reported vascular disease at study initiation and were then followed prospectively for the occurrence of myocardial infarction, stroke, and venous thrombosis, we have found that baseline evaluations of endogenous tissue-type plasminogen activator (tPA:ag) as well as cross linked fibrin degradation products (D-dimer) are highly predictive of risk of future coronary and cerebral thrombosis, but not venous thrombosis. We have also found that levels of tPA:ag directly correlate with body mass index and cigarette consumption and inversely correlate with alcohol consumption and HDL cholesterol. In contrast, we have found no association between Lp(a) and risk of future myocardial infarction or stroke. Despite strong associations between plasma levels of tPA:ag and thrombotic risk, we have not found significant relationships between specific genetic polymorphisms associated with PAI-1 or tPA production to be predictive of risk. Thus, environmental and behavioural factors are likely to be critical in determining the net fibrinolytic balance on a systemic and local basis. Data from the Physicians' Health Study, taken in context with other important prospective evaluations of fibrinolytic potential, strongly support the hypothesis that hemostatic and thrombotic risk factors for vascular disease can be detected reliably on a population basis, and raise the possibility that assessment of novel risk factors may prove valuable in the detection and prevention of cardiovascular disease.

Ancrod in the treatment of acute ischaemic stroke.

Ancrod converts fibrinogen into soluble fibrin products, resulting in a decrease in plasma fibrinogen and blood viscosity, and also induces the release of endogenous tissue-type plasminogen activator from the vessel wall. These activities suggest that treating patients with acute ischaemic stroke with ancrod might result in improved cerebral blood flow and patient outcome. Two large randomised placebo-controlled studies have evaluated treatment with ancrod in patients with acute ischaemic stroke. In the first, patients were treated within 6 hours of symptom onset: this was not successful in quickly lowering fibrinogen levels to the target range (0.7 to 1.0 g/L) and the results were inconclusive. However, a post hoc analysis suggested that treatment with ancrod was effective in patients whose fibrinogen level was reduced to less than 1.3 g/L within 6 hours of starting treatment. A second larger study is still in progress, but preliminary results in patients treated within 3 hours of onset of ischaemic stroke are available and indicate that the target fibrinogen level of less than 1 g/L within 6 hours of instituting treatment is being achieved in most patients.

Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.

Plasma levels of D-dimer, the primary degradation product of cross-linked fibrin, are elevated in several acute thrombotic disorders. However, whether elevated D-dimer levels among healthy individuals are associated with future coronary thrombosis is unknown. To evaluate whether levels of D-dimer are associated with the occurrence of future myocardial infarction (MI) among apparently healthy men, levels were measured in plasma samples collected at baseline from 296 participants in the Physicians' Health Study who later developed a first MI and from an equal number of age- and smoking status-matched control subjects who remained free of vascular disease during a mean follow-up period of 60.2 months. In univariate analyses, baseline plasma concentrations of D-dimer in the upper ranges of normal were associated with elevated risks of MI. Specifically, the relative risk of future MI for individuals with baseline D-dimer concentration exceeding the 95th percentile of the control distribution was two times higher than that of individuals with lower levels (relative risk [RR], 2.02; 95% confidence interval [CI], 1.04 to 4.02; P = .04). This association persisted in multivariate analyses controlling for nonlipid cardiovascular risk factors (RR, 2.12; 95% CI, 1.05 to 4.28; P = .04) and for lipoprotein(a) (RR, 2.02; 95% CI, 1.04 to 3.94; P = .03). In contrast, this association was attenuated and no longer statistically significant in analyses that controlled for total and high-density lipoprotein cholesterol (RR, 1.74; 95% CI, 0.78 to 3.91; P = .2) or for endogenous tissue-type plasminogen activator and its primary inhibitor, plasminogen activator inhibitor type 1 (RR, 1.58; 95% CI, 0.67 to 3.77; P = .3). Elevated levels of D-dimer are associated with increased risks of future MI, although they do not appear to be an independent predictor when other risk factors are considered. As the presence of D-dimer in plasma reflects ongoing fibrin degradation, these data support the hypothesis that activation of the endogenous fibrinolytic system occurs many years in advance of coronary arterial occlusion.

Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator

Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator

Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction

Objectives. This study investigated the effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction.Background. Angiotensin-converting enzyme inhibitors reduce the incidence of acute coronary syndromes in patients with mild left ventricular dysfunction after myocardial infarction. Abnormal endogenous fibrinolysis, reflected in increased levels of endogenous tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1 activity, is associated with an increased risk of myocardial infarction in patients with ischemic heart disease.Methods. In a randomized, double-blind crossover study beginning 8 weeks after uncomplicated myocardial infarction, patients received 4 weeks of placebo and 4 weeks of captopril (75 mg daily) therapy. At the end of each treatment period, we measured t-PA antigen and plasminogen activator inhibitor type 1 antigen and activity.Results. Median values in the 15 patients after placebo and in 12 normal men matched for age and body mass index were, respectively, t-PA antigen 16.0 versus 9.5 ng/ml (p = 0.001), plasminogen activator inhibitor type 1 antigen 17.3 versus 8.6 ng/ml (p = 0.29) and plasminogen activator inhibitor type 1 activity 13.2 versus 6.3 AU/ml (p = 0.04). After 4 weeks of treatment with captopril in the 15 patients, the estimated (95% confidence interval) median reduction in t-PA antigen was 7.3 ng/ml (−4.6 to −10.3 ng/ml, p = 0.001), in plasminogen activator inhibitor type 1 antigen 3.1 ng/ml (+1.5 to −8.4 ng/ml, p = 0.17) and in plasminogen activator inhibitor type 1 activity −2.2 AU/ml (−1.0 to −4.3 AU/ml, p = 0.02).Conclusions. Treatment with captopril after uncomplicated myocardial infarction is associated with a significant decrease in elevated levels of t-PA antigen and plasminogen activator inhibitor type 1 activity. This may help to explain the reduction in risk of coronary thrombosis associated with the use of angiotensin-converting enzyme inhibitors.