Antithrombotic effects of combining activated protein C and urokinase in nonhuman primates.

Abstract The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double-mutant thrombin (Trp215Ala/Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis specificity.

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1114. Antithrombotic Effects of Endogenous Expressed Activated Protein C (aPC) in Murine Models

Molecular Therapy ◽

10.1016/j.ymthe.2005.07.662 ◽

2005 ◽

Vol 11 ◽

pp. S429

Keyword(s):

Protein C ◽

Activated Protein C ◽

Murine Models ◽

Antithrombotic Effects

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Inhibition of platelet-dependent thrombus formation by human activated protein C in a primate model

Blood ◽

10.1182/blood.v73.3.639.bloodjournal733639 ◽

1989 ◽

Vol 73 (3) ◽

pp. 639-642 ◽

Cited By ~ 1

Author(s):

A Gruber ◽

JH Griffin ◽

LA Harker ◽

SR Hanson

Keyword(s):

Protein C ◽

Thrombus Formation ◽

Activated Protein C ◽

Graft Patency ◽

Scintillation Camera ◽

Primate Model ◽

Baboon Model ◽

Platelet Deposition ◽

Antithrombotic Effects

The in vivo antithrombotic properties of human plasma activated protein C (APC), a natural anticoagulant enzyme, were investigated in a baboon model of thrombus formation on prosthetic vascular grafts. Infusion of 0.25 to 1.1 mg/kg/h purified, human, APC inhibited blood clotting, as measured by the activated partial thromboplastin time (APTT), and reduced vascular graft platelet deposition by 40% to 70%, as determined by the real-time scintillation camera imaging of 111In-labeled platelet deposition. APC infusion also preserved graft patency. Hemostatic plug formation remained normal, as measured by the template bleeding times. These results suggest that APC administration may produce immediate antithrombotic effects under arterial flow conditions.

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Inhibition of platelet-dependent thrombus formation by human activated protein C in a primate model

Blood ◽

10.1182/blood.v73.3.639.639 ◽

1989 ◽

Vol 73 (3) ◽

pp. 639-642 ◽

Cited By ~ 97

Author(s):

A Gruber ◽

JH Griffin ◽

LA Harker ◽

SR Hanson

Keyword(s):

Protein C ◽

Thrombus Formation ◽

Activated Protein C ◽

Graft Patency ◽

Scintillation Camera ◽

Primate Model ◽

Baboon Model ◽

Platelet Deposition ◽

Antithrombotic Effects

Abstract The in vivo antithrombotic properties of human plasma activated protein C (APC), a natural anticoagulant enzyme, were investigated in a baboon model of thrombus formation on prosthetic vascular grafts. Infusion of 0.25 to 1.1 mg/kg/h purified, human, APC inhibited blood clotting, as measured by the activated partial thromboplastin time (APTT), and reduced vascular graft platelet deposition by 40% to 70%, as determined by the real-time scintillation camera imaging of 111In-labeled platelet deposition. APC infusion also preserved graft patency. Hemostatic plug formation remained normal, as measured by the template bleeding times. These results suggest that APC administration may produce immediate antithrombotic effects under arterial flow conditions.

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Activated protein C: the cure for sepsis - again?

Anaesthesia ◽

10.1046/j.1365-2044.2001.02441.x ◽

2001 ◽

Vol 56 (12) ◽

pp. 1133-1135 ◽

Cited By ~ 1

Author(s):

Tariq Hoth ◽

Timothy W. Evans

Keyword(s):

Protein C ◽

Activated Protein C

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Coagulation Factor V Leiden Mutation Was Detected in the Patients with Activated Protein C Resistance in Thailand

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615201 ◽

1998 ◽

Vol 80 (08) ◽

pp. 344-345 ◽

Cited By ~ 2

Author(s):

Pasra Arnutti ◽

Motofumi Hiyoshi ◽

Wichai Prayoonwiwat ◽

Oytip Nathalang ◽

Chamaiporn Suwanasophon ◽

...

Keyword(s):

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Coagulation Factor ◽

Factor V ◽

Activated Protein C Resistance ◽

Factor V Leiden Mutation ◽

Coagulation Factor V

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APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614518 ◽

1999 ◽

Vol 81 (04) ◽

pp. 527-531 ◽

Cited By ~ 114

Author(s):

U. Kjellberg ◽

N.-E. Andersson ◽

S. Rosén ◽

L. Tengborn ◽

M. Hellgren

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Protein C ◽

Activated Protein C ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Reference Level ◽

Soluble Fibrin ◽

Prothrombin Fragment ◽

D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

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Dermatan Sulfate and LMW Heparin Enhance the Anticoagulant Action of Activated Protein C

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614856 ◽

1999 ◽

Vol 82 (11) ◽

pp. 1462-1468 ◽

Cited By ~ 22

Author(s):

José Fernández ◽

Jari Petäjä ◽

John Griffin

Keyword(s):

Molecular Weight ◽

Unfractionated Heparin ◽

Protein C ◽

Dermatan Sulfate ◽

Anticoagulant Activity ◽

Activated Protein C ◽

Factor V ◽

Factor Va ◽

Anticoagulant Action

SummaryUnfractionated heparin potentiates the anticoagulant action of activated protein C (APC) through several mechanisms, including the recently described enhancement of proteolytic inactivation of factor V. Possible anticoagulant synergism between APC and physiologic glycosaminoglycans, pharmacologic low molecular weight heparins (LMWHs), and other heparin derivatives was studied. Dermatan sulfate showed potent APC-enhancing effect. Commercial LMWHs showed differing abilities to promote APC activity, and the molecular weight of LMWHs correlated with enhancement of APC activity. Degree of sulfation of the glycosaminoglycans influenced APC enhancement. However, because dextran sulfates did not potentiate APC action, the presence of sulfate groups per se on a polysaccharide is not sufficient for APC enhancement. As previously for unfractionated heparin, APC anticoagulant activity was enhanced by glycosaminoglycans when factor V but not factor Va was the substrate. Thus, dermatan sulfate and LMWHs exhibit APC enhancing activity in vitro that could be of physiologic and pharmacologic significance.

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