Biomedical subjects

William P Fay

Publications and source records attributed to William P Fay.

At least 19 recordsLinked to original sources

PubMed2007

The duration of anticoagulation bridging therapy in clinical practice may significantly exceed that observed in clinical trials.

BACKGROUND: Clinical trials involving frequent, standardized monitoring of the international normalized ratio (INR) demonstrated that a short course of low-molecular-weight-heparin (LMWH) can successfully bridge patients to oral anticoagulation. However, rigidly performed INR testing is often not feasible in the outpatient setting in actual clinical practice. The purpose of this study was to determine if the anticoagulation results of clinical trials of LMWH bridging therapy are also achieved in a single-center clinical practice setting. METHODS: We conducted a retrospective analysis of 100 patients initiating warfarin while receiving LMWH under the care of a university-based anticoagulation management service. RESULTS: Mean patient age was 56.1 +/- 16.3 years. The commonest indications for anticoagulation were venous thrombosis (57%) and atrial fibrillation (25%). Mean initial warfarin dose was 5.1 +/- 1.8 mg/day; 30% of patients received antiplatelet therapy. The mean total duration of LMWH therapy was 12.0 +/- 8.2 days, of which 9.8 +/- 8.0 days (median 7.5 days; interquartile range 4.3-13.0 days) occurred in the outpatient setting. Forty-one percent of patients received outpatient LMWH for < 7 days, 40% for 7-14 days, and 19% for > 14 days. A mean of 3.9 +/- 2.0 INRs were performed during LMWH therapy. Complications included 11 minor and 1 major bleeding episodes and 1 thrombotic event. CONCLUSIONS: The duration of LMWH bridging therapy in practice may be significantly greater than previously reported in clinical trials, and the incidence of patients requiring prolonged (>14 days) LMWH therapy is relatively high. Outpatient LMWH as employed in clinical practice safely bridges patients to oral anticoagulation. Strategies to shorten the duration of LMWH therapy are needed and are likely to improve clinical outcomes and reduce health care expenses. In prospective clinical trials low-molecular-weight-heparin (LMWH) has proven effective in transitioning patients with venous thromboembolic disease to therapeutic warfarin anticoagulation. However, it is unknown if the anticoagulation results obtained in these trials, which involved rigidly performed anticoagulation monitoring, are achieved in standard clinical practice involving patients with a variety of indications for anticoagulation. We conducted a retrospective analysis of 100 patients initiating warfarin while receiving LMWH under the management of a university-based anticoagulation management service. The mean total duration of LMWH therapy was 12.0 +/- 8.2 days, of which 9.8 +/- 8.0 days (median 7.5 days; interquartile range 4.3-13.0 days) occurred in the outpatient setting. Forty-one percent of patients received outpatient LMWH for <7 days, 40% for 7-14 days, and 19% for >14 days. We conclude that the duration of LMWH bridging therapy in practice may be significantly greater than previously reported in clinical trials, and the incidence of patients requiring prolonged (>14 days) LMWH therapy is relatively high.

Adult↗

PubMed2005

Atherosclerosis in mice is not affected by a reduction in tissue factor expression.

OBJECTIVE: To determine whether tissue factor (TF) contributes to the progression of atherosclerotic lesions in mice. METHODS AND RESULTS: We determined the effect of a 50% reduction of TF levels in all cells on atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. No differences were observed in the extent of atherosclerosis in apoE(-/-)/TF(+/+) and apoE(-/-)/TF(+/-) mice fed regular chow for 34 weeks. Atherosclerosis could not be analyzed in apoE(-/-) mice expressing low levels of TF because of premature death of these mice. Macrophages are a major source of TF in atherosclerotic plaques. Therefore, in a second series of experiments, we investigated the effect on atherosclerosis of selectively reducing hematopoietic cell-derived TF by transplanting bone marrow from mice expressing low levels of TF into low-density lipoprotein receptor deficient (LDLR(-/-)) mice. Atherosclerosis within the arterial tree and aortic root were similar in LDLR(-/-) mice with low-TF bone marrow compared with control bone marrow (TF(+/+) or TF(+/-)) after 4 and 16 weeks on an atherogenic diet. Furthermore, the cellular composition of the aortic root lesions was similar between the 2 groups. CONCLUSIONS: Our data indicate that either a 50% reduction of TF in all cells or a selective reduction in hematopoietic cell-derived TF does not affect the development of atherosclerotic lesions in mice.

Animals↗

PubMed2005

MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.

Animals↗

PubMed2004

Factor VLeiden inhibits fibrinolysis in vivo.

BACKGROUND: Factor V(Leiden) (fV(Leiden)) predisposes to thrombosis by enhancing thrombin formation. This study tested the hypothesis that fV(Leiden) inhibits fibrinolysis in vivo. METHODS AND RESULTS: Radiolabeled clots were injected into the jugular veins of wild-type mice and mice heterozygous (fV(+/Q)) or homozygous (fV(Q/Q)) for fV(Leiden). Mean percent clot lysis 5 hours later was significantly reduced in fV(Q/Q) mice (14.3+/-3.6%, n=13) compared with wild-type mice (40.2+/-7.0%, n=17; P<0.01) and intermediate in fV(+/Q) mice (29.4+/-8.7%, n=9; P<0.03 versus fV(Q/Q), P=0.36 versus wild type). The rate of in vitro lysis of plasma clots prepared from fV(+/Q) or fV(Q/Q) mice was significantly slower than that of wild-type plasma clots, whereas in vitro clot lysis did not differ significantly between groups after inhibiting thrombin-activatable fibrinolysis inhibitor. CONCLUSIONS: fV(Leiden) inhibits fibrinolysis in vivo, suggesting an additional pathway by which this mutation promotes thrombosis.

Animals↗

PubMed2004

Antidote-mediated control of an anticoagulant aptamer in vivo.

Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.

Animals↗

PubMed2004

Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall.

Leukocytes and leukocyte-derived microparticles contain low levels of tissue factor (TF) and incorporate into forming thrombi. Although this circulating pool of TF has been proposed to play a key role in thrombosis, its functional significance relative to that of vascular wall TF is poorly defined. We tested the hypothesis that leukocyte-derived TF contributes to thrombus formation in vivo. Compared to wild-type mice, mice with severe TF deficiency (ie, TF(-/-), hTF-Tg+, or "low-TF") demonstrated markedly impaired thrombus formation after carotid artery injury or inferior vena cava ligation. A bone marrow transplantation strategy was used to modulate levels of leukocyte-derived TF. Transplantation of low-TF marrow into wild-type mice did not suppress arterial or venous thrombus formation. Similarly, transplantation of wild-type marrow into low-TF mice did not accelerate thrombosis. In vitro analyses revealed that TF activity in the blood was very low and was markedly exceeded by that present in the vessel wall. Therefore, our results suggest that thrombus formation in the arterial and venous macrovasculature is driven primarily by TF derived from the blood vessel wall as opposed to leukocytes.

Animals↗

PubMed2004

Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.

Group A streptococci, a common human pathogen, secrete streptokinase, which activates the host's blood clot-dissolving protein, plasminogen. Streptokinase is highly specific for human plasminogen, exhibiting little or no activity against other mammalian species, including mouse. Here, a transgene expressing human plasminogen markedly increased mortality in mice infected with streptococci, and this susceptibility was dependent on bacterial streptokinase expression. Thus, streptokinase is a key pathogenicity factor and the primary determinant of host species specificity for group A streptococcal infection. In addition, local fibrin clot formation may be implicated in host defense against microbial pathogens.

Ancrod↗

PubMed2004

Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury.

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.

Animals↗

PubMed2004

Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis.

Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions.

Animals↗

PubMed2004

Murine thrombosis models.

Due to exciting advances in molecular biology, the laboratory mouse has become an important and frequently used model for studying thrombosis. This article reviews several experimental approaches that have been used to study arterial, venous, and microvascular thrombosis in mice. The advantages and limitations of different models are examined. Related topics of mouse anesthesia, phlebotomy, and in vitro hemostasis testing are also reviewed.

Anesthesia↗

PubMed2003

Plasminogen enhances virulence of group A streptococci by streptokinase-dependent and streptokinase-independent mechanisms.

Interactions between host plasminogen (Plg) and streptokinase (SK) secreted by group A streptococci (GAS) have been hypothesized to promote bacterial invasion of tissues. The virulence of GAS strain UMAA2616, after being subcutaneously inoculated into mice, was studied. Skin lesions and mortality were observed after inoculation of 7x106 cfu. Coadministration of human Plg with UMAA2616 markedly increased virulence. SK-deficient UMAA2616 (UMAA2616-SK(-)) was generated. Mean skin-lesion area and mortality, after bacterial inoculation (3x105 cfu), were significantly greater with UMAA2616 in the presence of human Plg than with UMAA2616-SK(-) in the presence of human Plg (P=.0001). Human Plg also enhanced UMAA2616-SK(-) virulence. Exogenous human Plg enhanced the virulence of MGAS166, a human clinical isolate. These findings suggest that SK-Plg interactions are an important determinant of GAS invasiveness in vivo and that both SK and host Plg activators appear to promote virulence of GAS by catalyzing plasmin formation.

Animals↗

PubMed2003

Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.

BACKGROUND: C-reactive protein (CRP), an acute-phase reactant long considered merely an innocent bystander in the inflammatory process, is now recognized as a powerful predictor of cardiovascular events. Emerging in vitro evidence suggests that CRP may have direct proinflammatory and prothrombotic effects on monocytes and endothelial cells. To determine whether CRP directly modulates vascular cell function in vivo, we subjected wild-type mice, which do not express CRP, and human CRP-transgenic (CRPtg) mice to 2 models of arterial injury. METHODS AND RESULTS: Baseline serum CRP levels in CRPtg mice were 18+/-6 mg/L. CRP levels were undetectable in wild-type mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 75% of CRPtg arteries (6 of 8) compared with 17% (2 of 12) in wild-type mice (P<0.05). In a model of arterial photochemical injury, clot formation time was shortened in CRPtg mice; mean time to occlusion was 33+/-19 minutes compared with 59+/-19 minutes in wild-type mice (n=10; P<0.05). CONCLUSIONS: Arterial injury in CRPtg mice results in an expedited and higher rate of thrombotic occlusion. This is the first report of a prothrombotic phenotype directly attributable to the presence of human CRP in vivo. Investigation of the inflammatory-thrombotic axis in CRPtg mice may elucidate the prothrombotic actions of CRP in unstable arterial diseases and may pave the way for novel therapeutic interventions for preventing cardiovascular events.

Animals↗

PubMed2003

Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis.

BACKGROUND: Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. METHODS AND RESULTS: We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4+/-8.5 minutes; n=10) compared with control mice (54.5+/-35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of dl-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. CONCLUSIONS: Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.

Adenosine Diphosphate↗

PubMed2003

Structure-function analysis of the streptokinase amino terminus (residues 1-59).

Streptokinase (SK) binds to plasminogen (Pg) to form a complex that converts substrate Pg to plasmin. Residues 1-59 of SK regulate its capacity to induce an active site in bound Pg by a nonproteolytic mechanism and to activate substrate Pg in a fibrin-independent manner. We analyzed 24 SK mutants to better define the functional properties of SK-(1-59). Mutations within the alphabeta1 strand (residues 17-26) of SK completely prevented nonproteolytic active site induction in bound Pg and rendered SK incapable of protecting plasmin from inhibition by alpha2-antiplasmin. However, when fibrin-bound, the activities of alphabeta1 strand mutants were similar to that of wild-type (WT) SK and resistant to alpha2-antiplasmin. Mutation of Ile1 of SK also prevented nonproteolytic active site induction in bound Pg. However, unlike alphabeta1 strand mutants, the functional defect of Ile1 mutants was not relieved by fibrin, and complexes of Ile1 mutants and plasmin were resistant to alpha2-antiplasmin. Plasmin enhanced the activities of alphabeta1 strand and Ile1 mutants, suggesting that SK-plasmin complexes activated mutant SK.Pg complexes by hydrolyzing the Pg Arg561-Val562 bond. Mutational analysis of Glu39 of SK suggested that a salt bridge between Glu39 and Arg719 of Pg is important, but not essential, for nonproteolytic active site induction in Pg. Deleting residues 1-59 rendered SK dependent on plasmin and fibrin to generate plasminogen activator (PA) activity. However, the PA activity of SK-(60-414) in the presence of fibrin was markedly reduced compared with WT SK. Despite its reduced PA activity, the fibrinolytic potency of SK-(60-414) was greater than that of WT SK at higher (but not lower) SK concentrations due to its capacity to deplete plasma Pg. These studies define mechanisms by which the SK alpha domain regulates rapid active site induction in bound Pg, contributes to the resistance of the SK-plasmin complex to alpha2-antiplasmin, and controls fibrin-independent Pg activation.

Catalytic Domain↗

PubMed2003

Myocardial proinflammatory cytokine expression and left ventricular remodeling in patients with chronic mitral regurgitation.

BACKGROUND: In an animal model, stretch was shown to induce myocardial tumor necrosis factor-alpha (TNF-alpha) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF-alpha expression and whether there is a relationship between TNF-alpha expression and LV remodeling. METHODS AND RESULTS: Plasma TNF-alpha and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23+/-12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF-alpha were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF-alpha (3.59+/-1.81 versus 2.03+/-1.02 pg/mL, P<0.005) and its receptor levels were elevated in MR patients. Myocardial TNF-alpha mRNA copies (corrected for beta-actin mRNA expression) in MR patients and donor hearts were 38.96+/-42.74x10(6) and 0.88+/-0.75x10(6), respectively (P=0.01). After MV surgery, there was a decrease in the plasma levels of TNF-alpha (2.79+/-1.14 versus 3.51+/-1.34 pg/mL, P=0.02) and its receptors. There was a correlation between myocardial TNF-alpha expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF-alpha expression and regression in LV end-diastolic (r=-0.76, P=0.007) and end-systolic (r=-0.73, P=0.01) volumes after MV surgery. CONCLUSIONS: TNF-alpha is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF-alpha expression. There is a relationship between TNF-alpha expression and parameters of LV remodeling, suggesting that TNF-alpha may play a role in the pathogenesis of the LV remodeling that occurs in MR.

Adult↗

PubMed2002

Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries.

We examined the roles of vitronectin and plasminogen activator inhibitor-1 (PAI-1) in neointima development. Neointima formation after carotid artery ligation or chemical injury was significantly greater in wild-type mice than in vitronectin-deficient (Vn(-/-)) mice. Vascular smooth muscle cell (VSMC) proliferation did not differ between groups, suggesting that vitronectin promoted neointima development by enhancing VSMC migration. Neointima formation was significantly attenuated in PAI-1-deficient (PAI-1(-/-)) mice compared with control mice. Because intravascular fibrin may function as a provisional matrix for invading VSMCs, we examined potential mechanisms by which vitronectin and PAI-1 regulate fibrin stability and fibrin-VSMC interactions. Inhibition of activated protein C by PAI-1 was markedly attenuated in vitronectin-deficient plasma. The capacity of PAI-1 to inhibit clot lysis was significantly attenuated in vitronectin-deficient plasma, and this effect was not explained simply by the PAI-1-stabilizing properties of vitronectin. The adhesion and spreading of VSMCs were significantly greater on wild-type plasma clots and PAI-1-deficient plasma clots than on vitronectin-deficient plasma clots. We conclude that endogenous levels of vitronectin and PAI-1 enhance neointima formation in response to vascular occlusion or injury. Their effects may be mediated to a significant extent by their capacity to promote intravascular fibrin deposition and by the capacity of vitronectin to enhance VSMC-fibrin interactions.

Animals↗

PubMed2002

Do clinically relevant circulating concentrations of radiographic contrast agents inhibit platelet-dependent arterial thrombosis?

OBJECTIVES: The purpose of this study was to determine if radiographic contrast agents (RCAs) inhibit thrombosis in a rat carotid artery injury model. BACKGROUND: Whether ionic and nonionic RCAs differentially affect thrombus formation during coronary artery angioplasty is controversial. Although there are numerous in vitro studies and clinical trials addressing this issue, it is unknown whether clinically relevant plasma concentrations of RCA inhibit platelet-dependent thrombosis after injury of medium-sized arteries. METHODS: Rats received RCA or control solution by bolus (0.7 ml/kg) and constant (0.04 ml/kg/min) intravenous infusion. Carotid arteries were injured with ferric chloride. Blood flow was monitored for 1 h. In vitro platelet aggregation and plasma clotting were studied. RESULTS: After injury, mean times free from formation of an occlusive, platelet-rich thrombus were 16.2+/-2.3, 49.6+/-18.9, 47.9+/-21.0, and 37.1+/-22.8 min for rats (n=5/group) that received saline, diatrizoate (P<.002 vs. saline), ioxaglate (P<.002 vs. saline), and iohexol (P=.06 vs. saline), respectively. Reperfusion after initial occlusion did not occur in saline-treated animals, but was common in rats that received RCA. The antithrombotic properties of RCA were not explained by their high osmolarities or by detectable effects on in vitro platelet aggregation and plasma clotting. Plasma concentrations of RCA were <1%. CONCLUSIONS: Systemic administration of RCA at doses that achieve low, clinically relevant plasma concentrations can inhibit platelet-rich thrombus formation after arterial injury. Antithrombotic properties of ionic RCA appear to be greater than those of nonionic RCA.

Animals↗

PubMed2002

Prolonged low-dose thrombolytic therapy: a novel adjunctive strategy in the management of an infected right atrial thrombus.

An 81-year-old man presented with a large, infected right atrial thrombus that was refractory to anticoagulants and several courses of antibiotics. The risk of surgical removal of the thrombus, which was associated with a pacemaker electrode, was considered prohibitive. The patient was treated for 7 days with low-dose (40 mg/day) tissue-type plasminogen activator (t-PA). Hemostatic monitoring during infusion revealed (1) a plasma t-PA antigen that was approximately 5% of that achieved during short-course t-PA for acute myocardial infarction, (2) biochemical evidence of prolonged clot lysis, and (3) no significant depletion of fibrinogen or plasminogen. Nearly complete dissolution of the thrombus was observed. His bacteremia was eradicated by intravenous penicillin despite the presence of the pacemaker lead. This case highlights the benefits of combined antibiotic and thrombolytic therapy and documents for the first time the response of the human hemostatic system to prolonged t-PA infusion and the plasma t-PA levels attained when thrombolytic therapy is administered in this manner. Prolonged courses of fibrinolytic agents may be a good alternative to surgical intervention in selected patients with infected, right-sided intracardiac thrombi.

Aged↗