Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy.
OBJECTIVE
This study was performed to determine the effectiveness of recombinant P-selectin glycoprotein ligand Ig (rPSGL-Ig) pretreatment to decrease thrombosis and inflammation in experimental venous thrombosis. rPSGL-Ig, a unique mucin-like glycoprotein, has a high affinity for P-selectin.


METHODS
Twelve juvenile baboons underwent inferior vena cava (IVC) thrombosis with temporary 6-hour IVC balloon occlusion. Before balloon placement, the animals received rPSGL-Ig (4 mg/kg; n = 8) or saline solution for control (n = 4). The animals underwent evaluation with duplex ultrasound scan imaging, magnetic resonance venography (MRV), phlebography, coagulation profile, and tissue analysis at death for cytokines and vein wall leukocyte morphometrics. With the MRV results, thrombus development, thrombus resolution, and inflammation (gadolinium; square millimeters of enhancement) were assessed.


RESULTS
Each animal provided two time points for evaluation (days 2 and 6 after balloon occlusion). A significant decrease in IVC thrombosis between balloons was found in the rPSGL-Ig animals (1 of 16) versus the control animals (5 of 8; P <.01). The MRV results showed significantly less enhancement in the rPSGL-Ig animals at days 2 and 6 (P <.05). Spontaneous thrombus resolution (including balloon sites) was significantly greater from day 2 to day 6 in the rPSGL-Ig animals versus the control animals (23% vs 2%; P <.001), without pulmonary embolism. Lower interleukin-8, platelet factor IV, and monocyte chemotactic protein-1 levels were found in rPSGL-Ig vein walls without significant differences in vein wall leukocyte morphometrics. There were significantly lower D-dimer levels in the rPSGL-Ig-treated animals (P <.05), but there were no differences in measurements of coagulation. Adequate circulating rPSGL-Ig levels were documented.


CONCLUSIONS
Pretreatment with rPSGL-Ig results in: (1) a significant inhibition of thrombosis and vein wall inflammation; (2) a decrease in vein wall cytokine expression; and (3) a promotion of thrombus resolution. Inflammatory inhibition by rPSGL-Ig without anticoagulation therapy provides effective venous thrombosis prophylaxis in experimental venous thrombosis.
Wakefield
T W
TW
Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109-0329, USA.
Strieter
R M
RM
Schaub
R
R
Myers
D D
DD
Prince
M R
MR
Wrobleski
S K
SK
Londy
F J
FJ
Kadell
A M
AM
Brown
S L
SL
Henke
P K
PK
Greenfield
L J
LJ
D000818:Animals; D000925:Anticoagulants; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D008024:Ligands; D018810:Magnetic Resonance Angiography; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D009077:Mucins / Q000037:antagonists & inhibitors*; D019007:P-Selectin / Q000378:metabolism*; D010215:Papio; D011859:Radiography; D011994:Recombinant Proteins / Q000627:therapeutic use; D014463:Ultrasonography; D014682:Vena Cava, Inferior / Q000000981:diagnostic imaging / Q000473:pathology; D020246:Venous Thrombosis / Q000097:blood / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D000925:Anticoagulants; D008024:Ligands; D008562:Membrane Glycoproteins; D009077:Mucins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011994:Recombinant Proteins