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Biomedical subjects

L A Harker

Publications and source records attributed to L A Harker.

At least 37 records · Page 2Linked to original sources
PubMed1998

Therapeutic cytokine stimulation of thrombocytopoiesis.

Endogenous thrombopoietin (TPO) stimulates platelet production by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human (rHu) TPO or pegylated recombinant human megakaryocyte growth and development factor (PEG-rHu MGDF) produce log-linear responses in experimental animals and humans when administered over the dose range of 0.05-25 micrograms/kg/day with respect to peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number and mass. Other cytokines stimulating megakaryocytopoiesis in various species using different dosing regimens include Interleukin 1 (IL-1), Interleukin 3 (IL-3), Interleukin 6 (IL-6), Interleukin 11 (IL-11), stem cell factor (SCF), granulocytemacrophage colony stimulating factor, (GM-CSF), fusion proteins, such as promegapoietin, and a peptide agonist of TPO receptor. Whereas neither rHuTPO nor PEG-rHuMGDF induce platelet aggregation in vitro, they transiently enhance aggregatory responsiveness of platelets to physiologic agonists from several different experimental animals both in vitro and ex vivo. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration per se. These findings indicate that appropriate dosing of these agents following marrow suppression prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.

Blood Platelets↗
PubMed1998

Therapeutic inhibition of platelet function in stroke.

Platelet-dependent thrombotic- and thromboembolic-occlusive events are the usual cause of ischemic strokes. Antiplatelet strategies target one of the three platelet recruitment pathways (thromboxane A2, adenosine diphosphate, or thrombin) or the common cohesion pathway involving integrin alphaIIbbeta3 fibrinogen receptors. Aspirin selectively and irreversibly interrupts TxA2 and decreases events by 20-25%. Clopidogrel selectively and irreversibly inactivates platelet-ADP receptors and reduces events by 30-35%. Additive effects are produced by combining aspirin and clopidogrel. Integrin alphaIIbbeta3 fibrinogen receptor antagonists, such as abciximab, produce dose-dependent inhibition of platelet recruitment and thrombo-occlusive events, regardless of the agonist(s) initiating platelet activation, but correspondingly impair platelet hemostatic function. Because chronic antiplatelet therapy has the potential for producing abnormal bleeding it is important for current clinical trials to evaluate the benefit risk relationship.

Blood Platelets↗
PubMed1998

Platelets in thrombotic disorders: quantitative and qualitative platelet disorders predisposing to arterial thrombosis.

Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. In nonhuman primates, recombinant human TPO, nonpegylated or pegylated rHu megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number, and mass. Mpl ligands can support normal peripheral platelet concentrations after myelosuppressive chemotherapy in baboons, and correct the thrombocytopenia in human immunodeficiency virus-infected chimpanzees. Whereas mpl ligands do not induce platelet aggregation in vitro, mpl ligands enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo after treatment with mpl ligands in nonhuman primates. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration, per se. These findings indicate that appropriate dosing of mpl ligands prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.

Animals↗
PubMed1998

Tone burst auditory brain stem response latency estimates of cochlear travel time in Meniere's disease, cochlear hearing loss, and normal ears.

OBJECTIVE: The current study sought to determine whether tone burst auditory brain stem response (ABR) latencies could be used to detect an increase in the cochlear traveling wave velocity in patients with Meniere's disease. BACKGROUND: It has been proposed that the derived band ABR technique can be used to show an increase in cochlear traveling wave velocity in patients with Meniere's disease. The current study sought to replicate these findings using tone burst ABR at frequencies of 0.5, 1, 2, 4, and 8 kHz and intensities from 40-100 dB hearing loss (HL) in 10-dB steps. METHODS: Wave V latency differences between adjacent frequencies were taken to represent the time it takes the traveling wave to travel between the "place" on the basilar membrane where these two frequencies are represented. Thirty-two subjects participated in the project consisting of 10 with normal hearing, 10 with cochlear HL (not caused by Meniere's disease), and 12 with Meniere's disease. RESULTS: There were no significant differences in absolute wave V latencies or in wave V latency differences (travel time estimates) between the groups (repeated measures analysis of variance, p > 0.05). CONCLUSION: These results suggest that wave V latencies and estimates of cochlear travel time cannot be used to distinguish Meniere's disease from other forms of cochlear HL or from normal-hearing ears. The results of this study differ from those using the derived band ABR technique. This difference may be because of the disease state of the authors' subjects or differences in stimulus paradigm.

Adult↗
PubMed1997

Reduction in stent and vascular graft thrombosis and enhancement of thrombolysis by recombinant Lys-plasminogen in nonhuman primates.

BACKGROUND: To enhance thrombolytic responses without increasing hemorrhagic risks, the antithrombotic effects of recombinant Lys-plasminogen (r-LysPgn), a prothrombolytic plasminogen intermediate, were examined in baboon models of thrombus formation and dissolution. METHODS AND RESULTS: The dose-response effects of r-LysPgn, alone or in combination with subthreshold dosing of tissue plasminogen activator (TPA), were measured with respect to the accumulation of (111)In-labeled platelets and (125)I-fibrin in thrombus forming on endovascular metallic stents or thrombogenic segments of vascular graft interposed in exteriorized long-term arteriovenous (AV) femoral shunts. Thrombolytic losses have also been determined for preformed, stable, (111)In-platelet- and (125)I-fibrin-labeled graft thrombus and corresponding propagated thrombotic tails, together with changes in blood tests of thrombosis, thrombolysis, and hemostasis. Bolus intravenous r-LysPgn in escalating doses (2, 4, or 8 mg/kg) increased circulating plasminogen levels in a dose-dependent manner, was removed by log-linear clearance with a T50 of 120 minutes, and reciprocally decreased the accumulating thrombus on metallic stents and segments of vascular graft (P<.001 in all cases for 8-mg/kg doses). r-LysPgn also impaired platelet aggregatory responses to physiological agonists in vitro but not ex vivo. Prethrombosis administration of low-dose r-LysPgn (2 mg/kg) greatly enhanced the lysis of radiolabeled nonoccluding thrombus by a subthreshold dose of TPA (0.1 mg/kg) compared with TPA-only controls (P=.03). CONCLUSIONS: Elective bolus injections of r-LysPgn before stent deployment decrease the amount of thrombus formed without compromising hemostasis by facilitating endogenous TPA thrombolysis. r-LysPgn may provide effective and safe antithrombotic therapy for interventional vascular procedures.

Animals↗
PubMed1997

Antithrombotic potency of hirudin is increased in nonhuman primates by fibrin targeting.

BACKGROUND: Inhibition of thrombin by either the indirect thrombin inhibitor heparin or by more potent direct thrombin inhibitors such as hirudin reduces thrombus formation after arterial injury. The present study was designed to determine if a fibrin-specific thrombin inhibitor could, by local thrombin inhibition, prevent thrombosis more effectively. METHODS AND RESULTS: We first studied antithrombotic potency in vitro, comparing fibrin-targeted hirudin (recombinant hirudin covalently linked to the Fab' fragment of the anti-fibrin monoclonal antibody 59D8) to recombinant hirudin in baboon plasma. Fibrin-targeted hirudin was nine times more effective than recombinant hirudin in inhibiting fibrin deposition on experimental clot surfaces in baboon plasma (P < .01). The potency of fibrin-targeted hirudin was then compared with that of recombinant hirudin in a baboon model of thrombus formation. 111In-labeled platelet deposition was measured in a synthetic graft segment of an extracorporeal arteriovenous shunt in control animals and in animals receiving either fibrin-targeted hirudin or hirudin. In these experiments, fibrin-targeted hirudin was 10-fold more potent than hirudin in inhibiting platelet deposition and thrombus formation (P < .05). CONCLUSIONS: These data indicate that targeting a thrombin inhibitors such as hirudin to an epitope present in thrombi results in increased antithrombotic potency.

Animals↗
PubMed1997

Prevention of thrombocytopenia and neutropenia in a nonhuman primate model of marrow suppressive chemotherapy by combining pegylated recombinant human megakaryocyte growth and development factor and recombinant human granulocyte colony-stimulating factor.

This report examines the effects on hematopoietic regeneration of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) (2.5 micrograms/ kg/d) alone and in combination with recombinant human granulocyte colony stimulating factor (rHu-GCSF) (10 micrograms/ kg/d) for 21 days in rhesus macaques receiving intense marrow suppression produced by single bolus injections of hepsulfam (1.5 g/m2). In six hepsulfam-only control animals thrombocytopenia (platelet count < 100 x 10(9)/L) was observed between days 12 and 25 (nadir 39 +/- 20 x 10(9)/L on day 17), and neutropenia (absolute neutrophil count < 1 x 10(9)/L) occurred between days 8 and 30 (nadir 0.167 +/- 0.120 x 10(9)/L on day 15). PEG-rHuMGDF (2.5 micrograms/kg/d) injected subcutaneously into four animals from day 1 to day 22 following hepsulfam administration produced trough serum concentrations of 1.9 +/- 0.2 ng/mL and increased the platelet count twofold over basal prechemotherapy levels (856 +/- 594 x 10(9)/L v baseline of 416 +/- 88 x 10(9)/L; P = .01). PEG-rHuMGDF alone also shortened the period of posthepsulfam neutropenia from 22 days to 12 days (P = .01), although the neutropenic nadir was not significantly altered (neutrophil count 0.224 +/- 0.112 x 10(9)/L v 0.167 +/- 0.120 x 10(9)/L; P > .3). rHu-GCSF (10 micrograms/kg/d) injected subcutaneously into four animals from day 1 to day 22 following hepsulfam administration produced trough serum concentrations of 1.4 +/- 1.1 ng/mL, and reduced the time for the postchemotherapy neutrophil count to attain 1 x 10(9)/L from 22 days to 4 days (P = .005). The postchemotherapy neutropenic nadir was 0.554 +/- 0.490 x 10(9)neutrophils/L (P = .3 v hepsulfam-only control of 0.167 +/- 0.120 x 10(9)/L). However, thrombocytopenia of < 100 x 10(9) platelets/L was not shortened (persisted from day 12 to day 25), or less severe (nadir of 56 +/- 32 x 10(9) platelets/L on day 14; P = .7 compared with untreated hepsulfam animals). The concurrent administration of rHu-GCSF (10 micrograms/kg/d) and PEG-rHuMGDF (2.5 micrograms/kg/d) in four animals resulted in postchemotherapy peripheral platelet counts of 127 +/- 85 x 10(9)/L (P = .03 compared with 39 +/- 20 x 10(9)/L for untreated hepsulfam alone, and P = .02 compared with 856 +/- 594 x 10(9)/L for PEG-rHuMGDF alone), and shortened the period of neutropenia < 1 x 10(9)/L from 22 days to 4 days (P = .8 compared with rHu-GCSF alone). Increasing PEG-rHuMGDF to 10 micrograms/kg/d and maintaining the 21-day schedule of coadministration with rHu-GCSF (10 micrograms/kg/d) in another four animals produced postchemotherapy platelet counts of 509 +/- 459 x 10(9)/L (P < 10(-4) compared with untreated hepsulfam alone, and P = .04 compared with 2.5 micrograms/kg/d PEG-rHuMGDF alone), and 4 days of neutropenia. Coadministration of rHu-GCSF and PEG-rHuMGDF did not significantly alter the pharmacokinetics of either agent. The administration of PEG-rHuMGDF (2.5 micrograms/kg/d) from day 1 through day 22 and rHu-GCSF (10 micrograms/kg/d) from day 8 through day 22 in six animals produced peak postchemotherapy platelet counts of 747 +/- 317 x 10(9)/L(P < 10(-4) compared with untreated hepsulfam alone, and P = .7 compared with PEG-rHuMGDF alone), and maintained the neutrophil count > 3.5 x 10(9)/L (P = .008 v rHu-GCSF therapy alone). Thus, both thrombocytopenia and neutropenia are eliminated by initiating daily PEG-rHuMGDF therapy on day 1 and subsequently adding daily rHu-GCSF after 1 week in the rhesus model of hepsulfam marrow suppression. This improvement in platelet and neutrophil responses by delaying the addition of rHu-GCSF to PEG-rHuMGDF therapy demonstrates the importance of optimizing the dose and schedule of cytokine combinations after severe myelosuppressive chemotherap

Alkylating Agents↗
PubMed1997

Hemodialysis access graft stenosis: percutaneous transluminal angioplasty.

Maintenance of dialysis access continues to plague care of the patient with ESRD. Because of the poor outcomes from surgical revision, there is increasing interest in balloon angioplasty as a technique for dilating stenoses in the functioning, but compromised graft. Forty patients treated with percutaneous transluminal angioplasty (PTA), without subsequent intervention, for graft dysfunction were retrospectively studied. Time to thrombosis of the graft was noted. Patency was determined using the Kaplan-Meier technique. Patency following PTA at 1, 6, and 12 months was 76, 27, and 10%. Patency following PTA of arteriovenous graft stenoses results in disappointing medium and long-term patency. Alternate strategies for improving patency of these conduits should be explored.

Angioplasty, Balloon↗
PubMed1997

Prophylactic balloon angioplasty fails to prolong the patency of expanded polytetrafluoroethylene arteriovenous grafts: results of a prospective randomized study.

PURPOSE: Maintenance of hemodialysis access grafts represents an enormous social and clinical problem. Current grafts and graft salvage techniques are inadequate. Consequently, there has been increasing interest in the use of minimally invasive catheter techniques to prophylactically treat stenoses in functioning arteriovenous grafts. Prophylactic balloon angioplasty has been widely suggested as prolonging assisted primary patency. We have performed a prospective randomized trial to compare patients who underwent percutaneous transluminal angioplasty (PTA) for graft stenoses > 50% with a control group that received no intervention. Our hypothesis was that to be efficacious a minimal benefit of 20% prolongation in patency would be necessary. METHODS: Color flow duplex scanning was used to detect > 50% stenoses in functioning expanded polytetrafluoroethylene grafts. Patients were then subjected to confirmatory angiographic evaluation. Those who had angiographic stenoses > 50% were randomized to balloon angioplasty or observation. Patients were followed-up with duplex scanning every 2 months. Statistical analysis was performed using the Kaplan-Meier technique. Although demographically the patient groups were well matched, there were more prior interventions and concurrent central stenoses in the treatment group. Outcomes were graft thrombosis, graft dysfunction that precluded dialysis, and six or more PTA procedures within 18 months. RESULTS: In the treatment and observation groups, the 6-month patency rates were 69% +/- 7% and 70% +/- 7%, respectively. The 12-month patency rates for the treatment and observation groups were 51% +/- 6% and 47% +/- 4%, respectively. There was no significant difference between these two groups (p = 0.97), with an 80% confidence limit for detection of a difference greater than 20%. CONCLUSIONS: This study demonstrates that a generic approach of PTA to treat all polytetrafluoroethylene grafts with stenoses > 50% does not prolong patency and cannot be supported.

Adult↗
PubMed1997

Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates.

PURPOSE: Recently, very late antigen-4 (VLA-4) has been shown to mediate initial monocyte adhesion and migration to the injured artery. We hypothesized that blocking monocyte adhesion using a specific monoclonal antibody against VLA-4 may reduce intimal hyperplasia. METHODS: Bilateral carotid endarterectomies were performed in eight adult baboons. Among them, five animals received an intravenous bolus injection of anti-VLA-4 antibody (3 mg/kg) during surgery and again after 2 weeks. Three animals underwent bilateral carotid endarterectomies and served as untreated control subjects. Specimens were harvested at 4 weeks and subjected to morphometric analysis, cell proliferation assay, and immunostaining for macrophages. RESULTS: All of the endarterectomized arteries were patent except for one in the treated group. The number of macrophages in the intimal tissues was significantly reduced in the treated arteries compared with that in the control vessels (15.78 +/- 3.05 cells/section versus 33.50 +/- 6.13 cells/section; p < 0.001). The cell proliferation rate was significantly lower (p < 0.001) in the treated vessels (2.88% +/- 1.07%) compared with the control vessels (4.89% +/- 0.77%). The intimal area at the endarterectomized sites of carotid arteries was significantly less (p < 0.05) in the group treated with the anti-VLA-4 antibody (1.10 +/- 0.68 mm2) than in the control group (2.00 +/- 0.52 mm2). CONCLUSION: These data show that blocking monocyte adhesion by use of an anti-VLA-4 antibody significantly reduces the number of intimal macrophages, intimal cell proliferation, and intimal hyperplasia in injured carotid arteries in baboons. This study supports a central role for macrophages in the development of intimal hyperplasia and may suggest a new therapeutic strategy to prevent clinical restenosis.

Animals↗
PubMed1997

Central venous stenosis in the hemodialysis patient: incidence and efficacy of endovascular treatment.

Central venous stenosis occurs as a complication of central venous catheterization and significantly complicates delivery of dialysis through arteriovenous grafts in the ipsilateral upper limb. This report includes two separate studies. Functioning expanded polytetrafluorethylene grafts have been prospectively evaluated using duplex scanning and angiography performed in all patients with stenoses > 50%. From this, it has been prospectively established that the incidence of unsuspected central venous stenoses in patients with functioning grafts is 29%. In the second part of the report, the authors' experience in the treatment of 25 central venous stenoses with percutaneous angioplasty and stent placement has been retrospectively reviewed. Initial technical success rate was 88%. Primary patency was 84% at 1 month, 42% at 6 months, and 17% at 1 year. Mean primary patency was 5.7 months. Stents were placed in five patients. Prevention of central venous stenosis by avoiding subclavian catheterization is optimal. Balloon angioplasty provides short-term patency, but it is the only option in most cases. The role for endovascular stent placement remains to be defined but early results are not optimistic.

Angioplasty, Balloon↗
PubMed1997

Determination of appropriate recording force for non-invasive measurement of arterial pressure pulses.

1. Non-invasive recording techniques of the arterial pressure pulse will distort the arterial wall and may alter pulse wave measurements. We hypothesized that intersubject variability of these measurements would be reduced if recording forces were normalized to reflect individualized arterial occlusion forces. 2. In 10 normal male subjects (age 24 +/- 1 years), brachial, radial and finger arterial pressure pulses were recorded simultaneously using volume displacement pulse transducers (Fukuda TY-303) and a finger pressure monitoring system (Finapres, Ohmeda 2300) and were made at 2, 5 and 10-100% (10% increments) of the brachial arterial force associated with marked distortion of finger pulsations. Forces were applied at the brachial site in a randomized order while a constant 1.8 N force was applied at the radial artery site. Pressure pulses were analysed using the discrete fast Fourier transform. 3. Pulse amplitude, contour, wave velocity and relative transmission ratios remained relatively constant until the branchial artery recording force exceeded 59.9 +/- 0.3% of the largest recording force used in each subject (7.14 +/- 0.75 N). The finger pulse pressures (P < 0.0001), radial pulse amplitudes (P < 0.0001) and contours (harmonics 2-6, P < 0.003), pulse wave velocity (P < 0.021) and relative transmission ratios (harmonics 3-7, P < 0.01) then decreased with higher recording forces. 4. To avoid distortion, non-invasive recordings of arterial pressure pulse amplitude, contour, pressure wave velocity and relative transmission ratios along a peripheral arterial segment should use recording forces of less than 60% of the force associated with marked distortion of finger pulsations.

Adult↗
PubMed1997

Induction of vascular endothelial growth factor in balloon-injured baboon arteries. A novel role for reactive oxygen species in atherosclerosis.

Neovascularization is a hallmark of neointimal formation in atherosclerotic plaques and restenotic lesions. Vascular endothelial growth factor (VEGF) promotes neovascular growth, whereas oxidative stress is a potent factor in vascular cell proliferation. To investigate the mechanisms of neovascular formation, we treated human and rat vascular smooth muscle cells (VSMCs) with H2O2. Northern blot analysis demonstrated a dose- and time-dependent increase in VEGF mRNA, with a maximum of 4-fold at 3 hours (200 mumol/L). As determined by immunoblotting and enzyme-linked immunosorbent assay, VEGF protein expression and secretion were similarly increased. Human umbilical vein endothelial cells were treated with conditioned medium from VSMCs incubated with 200 mumol/L H2O2. DNA synthesis, measured by thymidine incorporation, was increased 4-fold compared with control, an effect that was blocked by a neutralizing anti-VEGF antibody. The lipid peroxidation product 4-hydroxynonenal (1 mumol/L), an endogenous reactive oxygen species present in human atherosclerotic lesions, also increased VEGF secretion in VSMCs in a similar time-dependent fashion. Immunohistochemical staining and in situ hybridization of aortic sections from balloon-injured baboons demonstrated increased VEGF expression in discrete areas of the neointima and media compared with control sections, and expression correlated with the generation of 4-hydroxynonenal. Regulators of VEGF expression, such as reactive oxygen species, may enhance neovascularization of atherosclerotic and restenotic arteries.

Animals↗
PubMed1997

Antithrombotic strategies targeting thrombin activities, thrombin receptors and thrombin generation.

Thrombin mediates acute vascular thrombosis and subsequent vascular lesion formation following mechanical denuding injury or spontaneous atherosclerotic plaque rupture. In the process of generating thrombin Factor VII/VIIa binds avidly with tissue factor (TF) exposed on cellular membranes, and coagulation serine proteases are sequentially cleaved via macromolecular catalytic complexes on phospholipid surfaces. Thrombin activates platelets, blood leukocytes, endothelium and vascular smooth muscle cells (SMCs) by cleaving G protein-coupled thrombin receptors (TRs), leading to SMC intimal proliferation and synthesis of extracellular matrix in the local formation of stenosing neointimal vascular lesions. Therapeutic strategies include inactivation of bound thrombin, inhibition of TR activation by thrombin, and interruption of thrombin generation. In patients having orthopedic surgery, inactivating bound thrombin with direct antithrombins markedly reduces venous thromboembolic events, compared with heparin or its derivatives, without significant impairment of hemostasis. However, acute coronary syndrome patients are not benefitted when given systemic direct antithrombins at safe levels, because interrupting TR-dependent platelet thrombosis demands systemic levels of direct antithrombins that concurrently compromise hemostatic function. Local drug delivery strategies have yet to be explored. In preclinical studies: a) enhancing the formation of endogenous activated Protein C (APC) by Protein C-selective thrombin mutants produces antithrombotic levels of APC; b) inhibiting thrombin activation of TRs abolishes platelet recruitment in arterial thrombogenesis in nonhuman primates, while sparing fibrin formation in hemostatic plugs; and c) preventing thrombin generation by inhibiting precursor serine protease function interrupts the formation of both acute thrombosis and chronic stenotic lesions after denuding vascular damage without significant hemostatic compromise. TF antagonists appear to have a highly favorable efficacy:safety therapeutic relationship for preventing the formation of thrombosis and vascular lesions.

Blood Vessels↗
PubMed1996

Enhanced thrombolytic and antithrombotic potency of a fibrin-targeted plasminogen activator in baboons.

BACKGROUND: Thrombolytic therapy reduces mortality in patients with acute myocardial infarction, but significant limitations exist with the use of currently available agents. In the present report, we describe the thrombolytic and antithrombotic potencies of a hybrid recombinant plasminogen activator consisting of an antifibrin antibody 59D8 (AFA) and low-molecular-weight single-chain urokinase-type plasminogen activator (scuPA). METHODS AND RESULTS: A thrombolysis model in which thrombi are preformed in vivo in juvenile baboons was developed to compare the potencies of AFA-scuPA, recombinant tissue plasminogen activator (rTPA), and recombinant scuPA (rscuPA) in lysing nonocclusive 111In-labeled platelet-rich arterial-type thrombi and 125I-labeled fibrin-rich venous-type thrombi. Systemic infusion of 1.89 nmol/kg AFA-scuPA produced thrombolysis that was comparable to that obtained with much higher doses of TPA (14.2 nmol/kg) and rscuPA (28.5 nmol/kg). When steady-state plasma concentrations are normalized, AFA-scuPA lyses thrombi sixfold more rapidly than scuPA and TPA (P < .001) and reduces the rate of formation more than comparable doses of rscuPA (P < .0001). At equivalent thrombolytic doses, AFA-scuPA produced fewer antihemostatic effects than either rTPA or rscuPA. Template bleeding time measurements were shorter (3.5 +/- 0.12 minutes for AFA-scuPA versus 5.3 +/- 0.36 and 5.2 +/- 0.04 minutes for rTPA and rscuPA, respectively; P < .05), alpha 2-antiplasmin consumption was less (P < .05), and D-dimer generation was lower (P < .05). CONCLUSIONS: We conclude that antibody targeting of scuPA to fibrin increases thrombolytic and antithrombotic potencies with less impairment of hemostasis compared with rTPA and rscuPA.

Animals↗