PMID- 8823001
OWN - NLM
STAT- MEDLINE
DCOM- 19961217
LR  - 20190623
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 94
IP  - 6
DP  - 1996 Sep 15
TI  - Enhanced thrombolytic and antithrombotic potency of a fibrin-targeted plasminogen 
      activator in baboons.
PG  - 1412-22
AB  - 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.
FAU - Runge, M S
AU  - Runge MS
AD  - Cardiology Division, University of Texas Medical Branch, Galveston 77555-0553, 
      USA.
FAU - Harker, L A
AU  - Harker LA
FAU - Bode, C
AU  - Bode C
FAU - Ruef, J
AU  - Ruef J
FAU - Kelly, A B
AU  - Kelly AB
FAU - Marzec, U M
AU  - Marzec UM
FAU - Allen, E
AU  - Allen E
FAU - Caban, R
AU  - Caban R
FAU - Shaw, S Y
AU  - Shaw SY
FAU - Haber, E
AU  - Haber E
FAU - Hanson, S R
AU  - Hanson SR
LA  - eng
GR  - HL-02414/HL/NHLBI NIH HHS/United States
GR  - HL-31950/HL/NHLBI NIH HHS/United States
GR  - HL-41619/HL/NHLBI NIH HHS/United States
GR  - etc.
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Recombinant Proteins)
RN  - 9001-31-4 (Fibrin)
RN  - EC 3.4.21.- (Plasminogen Activators)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*immunology
MH  - Fibrin/*immunology
MH  - Hemostasis/drug effects
MH  - Male
MH  - Plasminogen Activators/*pharmacology
MH  - Recombinant Proteins
MH  - *Thrombolytic Therapy
MH  - Thrombosis/*prevention & control
MH  - Tissue Plasminogen Activator/pharmacology
MH  - Urokinase-Type Plasminogen Activator/*pharmacology
EDAT- 1996/09/15 00:00
MHDA- 1996/09/15 00:01
CRDT- 1996/09/15 00:00
PHST- 1996/09/15 00:00 [pubmed]
PHST- 1996/09/15 00:01 [medline]
PHST- 1996/09/15 00:00 [entrez]
AID - 10.1161/01.cir.94.6.1412 [doi]
PST - ppublish
SO  - Circulation. 1996 Sep 15;94(6):1412-22. doi: 10.1161/01.cir.94.6.1412.