The antithrombotic effect of dextran-40 in man is due to enhanced fibrinolysis in vivo.
BACKGROUND
Dextran-40 is effective in reducing postoperative Doppler-detectable embolization in patients undergoing carotid endarterectomy (CEA). Dextrans are thought to have antithrombotic and antiplatelet effects. The mode of action is unclear. In rats, dextran blocks uptake of tissue plasminogen activator (tPA) by mannose-binding receptors. Because this would have the effect of enhancing endogenous fibrinolysis, we explored this effect of dextran-40 on fibrinolysis in man.


METHODS
Twenty patients undergoing endovascular stenting for abdominal aortic aneurysm were randomized to receive 100 mL of 10% dextran-40 or saline, over 1 hour, during their operation in addition to heparin. Blood samples were taken preoperatively, intraoperatively (immediately after operative procedure), and 24 hours postoperatively. Thrombi were formed in a Chandler loop and used to assess endogenous fibrinolysis over 24 hours, measured as the fall in thrombus weight, and the release of fluorescently labelled fibrinogen from the thrombus. Plasma samples were analyzed for markers of fibrinolysis; plasmin-antiplasmin (PAP), PAI-1, and t-PA, and for functional von Willebrand factor (vWF). Platelet response to thrombin and other agonists was measured by flow cytometry.


RESULTS
Thrombi formed ex vivo from the intraoperative blood samples from the dextran-treated patients exhibited significantly greater fibrinolysis vs preoperative samples, seen both as a significantly greater percentage reduction in thrombus weight (from 34.7% to 70.6% reduction) and as an 175% increase in the release of fluorescence (P < .05). Fibrinolysis returned to baseline levels the next day. No change was seen in the saline-treated group. Plasma levels of PAP and PAI-1 increased significantly postoperatively in the dextran-treated group vs the saline group (P < .05). The postoperative level of functional VWF was significantly lower in the dextran-treated group vs controls. A specific reduction occurred in the platelet response to thrombin, but not to other agonists, in the intraoperative samples from the dextran-treated group (11.1% vs 37.1%; P = .022), which was not seen in the controls.


CONCLUSIONS
These data are consistent with a rise in plasmin due to dextran blockade of tPA uptake in vivo, leading to enhanced fibrinolysis, cleavage of vWF and of the platelet protease-activated receptor-1 (PAR-1) thrombin receptor. This suggests that dextran exerts a combined therapeutic effect, enhancing endogenous fibrinolysis, whilst also reducing platelet adhesion to vWF and platelet activation by thrombin. The proven antithrombotic efficacy of low-dose dextran in carotid surgery may be applicable to wider therapeutic use.
Jones
Chris I
CI
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
Payne
David A
DA
Hayes
Paul D
PD
Naylor
A Ross
AR
Bell
Peter R F
PR
Thompson
Mathew M
MM
Goodall
Alison H
AH
D000368:Aged; D000369:Aged, 80 and over; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003911:Dextrans / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D011446:Prospective Studies; D015607:Stents; D013917:Thrombin / Q000378:metabolism; D013923:Thromboembolism / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000097:blood; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures / Q000009:adverse effects / Q000295:instrumentation; D000979:alpha-2-Antiplasmin / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D003911:Dextrans; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D000979:alpha-2-Antiplasmin; C037742:plasmin-plasmin inhibitor complex; D014841:von Willebrand Factor; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin