The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis also termed primary, secondary and tertiary hemostasis. From the platelet transcriptome 6000 mRNA species and represent receptors, ion channels, signalling molecules, kinases, phosphatases, and structural, metabolic and regulatory proteins. This abundance of regulatory proteins points towards the importance of signal transduction in platelet function. First platelets adhere to collagen, this induces activation signals such as TXA(2) that induces further Ca(2+) increase. Consecutively, fibrinogen binds to the integrin alpha(IIb)beta(3) resulting in aggregation.This self-amplifying process is controlled by signals, from endothelial cells, to restrict the platelet plug to the site of vessel injury. Secondary hemostasis (coagulation) consists of an extrinsic and intrinsic pathway. Thrombin is generated via Factor Xa resulting from the extrinsic tenase reaction that is turned of by tissue factor pathway inhibitor. While thrombin generation is maintained via positive feedback mechanisms activating factors V, VIII and XI. Excess thrombin is inhibited by antithrombin or by autodownregulation via activation of protein C. Since minor injuries are common, platelets and plasma clotting factors constantly produce clots to stop bleeding. If clots remained after the tissue healing, the vascular bed would become obstructed with clots therefore this is regulated by fibrinolysis, tertiary hemostasis. Tissue-type plasminogen activator synthesised by the endothelium, converts plasminogen to plasmin, the clot lysis enzyme. Plasmin clears the blood vessels by degrading fibrin. Fibrinolysis is controlled by plasminogen activators inhibitor (PAI-1), alpha2-antiplasmin and alpha2-macroglobulin, and thrombin-activatable fibrinolysis inhibitor (TAFI).

Heparin is the standard treatment of deep vein thrombosis; the aim of this treatment is to prevent further thrombus growth, although minimal thrombolysis may be expected. In an animal thrombosis model, 1 ' 2 a significant reduction of the size of the thrombus has been obtained with low molecular weight heparins (LMWH), suggesting that these products may be of value in the curative treatment of thrombosis. A recent comparative study of standard heparin and LMWH showed a similar thrombolytic effect of both drugs but with the latter having no side effect. 3 In order to explain the reduction of the size of the thrombus obtained with heparin or LMWH, several studies attempted to demonstrate a profibrinolytic effect of these drugs. Investigations mainly concerned an effect on the release of tissue-type plasminogen activator (t-PA) by endothelial cells. The results of these studies are controversial.After a single injection of heparin or LMWH in human volunteers, an increase in euglobulin fibrinolytic activity (EFA) was observed 2 and 4 hours after the injection of LMWH, 1,4 and in one study the level of t-PA antigen was shown to be elevated after the injection. 5 However, the increase in EFA could have resulted from circadian fluctuations of the fibrinolytic activity with decrease of the PA inhibitor level in the early afternoon hours. 6 ' 7The observation of an increase in EFA in the eluate of organs perfused with heparin or LMWH 1,8 suggested an effect on the release of t-PA by the vascular bed.The same conclusion was suggested by Arnesen et al, 9 who showed that patients receiving heparin during the pre-and postoperative periods exhibited a larger increase in t-PA activity and t-PA antigen after venous occlusion the third day after surgery than patients not receiving heparin.In patients with deep vein thrombosis receiving high dose of the LMWH CY 222 (Choay, Paris, France), we looked for a relationship between the thrombolytic effect of CY 222 and the change in plasma fibrinolytic parameters: 10 a good thrombolytic effect evaluated by phlebography was obtained after 7 days of treatment but no change in EFA, t-PA antigen, and PA inhibitor occurred during treatment. These results were not consistent with the stimulating effect of CY 222 on the release of t-PA by endothelial cells, or with an effect on PA inhibitor. However, a direct effect of LMWH on the patient's own fibrinolytic system could be involved. To test this hypothesis, we looked for a direct effect of the LMWH CY 222 on t-PA activity and single chain urokinase PA (scu-PA) activity in animal studies: 11 in a model of jugular vein thrombosis in which rabbits received t-PA or scu-PA and standard heparin or LMWH, we found that CY 222 potentiated the thrombolytic effect of t-PA and to a lesser extent of scu-PA. THROMBOLYSIS AND PLASMA FIBRINOLYTIC PARAMETERS IN PATIENTS TREATED WITH CY 222Thirty patients with recently diagnosed (less than 7 days) deep vein thrombosis who had given their informed consent were randomized into three treatment groups and received 4...

No abstract