Evaluation of Fibrinolysis for Deep Vein Thrombosis

Lozier, Jay

Abstract

In FY2008 thirteen subjects with a first lower extremity deep vein thrombosis (DVT) of less than two weeks duration were enrolled and treated with low dose tPA given by pulse spray catheter delivery directly into the clot. This brought the total accrual for the study from 10 subjects (since the inception of the study in 2004) to 23 subjects out of a maximum accrual limit of 25. For each subject on the protocol venographic and ultrasound studies were used to document the presence of a DVT. tPA was administered at a maximum daily dose of up to 10 mg for up to four consecutive days (maximum total dose 40 mg).Venographic studies were done at the end of the inpatient hospitalization and showed restored patency in all subjects.? ? Demographics of subjects enrolled to this date show 16 male and 7 female subjects with a mean age of 48.6 years (range 19 to 61 year). One third (34.7%) had underlying prothrombotic mutations of coagulation factor V (6/23 FVLeiden) or prothrombin (2/23 prothrombin 20210). Other prothrombotic states (deficiency of ATIII, proteins C or S) were not seen in our study population. ? ? Baseline laboratory studies showed mean pre-treatment functional tPA of 0.94 IU/mL, and mean PAI-1 levels of 9.2 IU/mL. At the close of the first thrombolytic treatment, the mean tPA reached a peak of 81.0 IU/mL and mean PAI-1 levels were 0.1 IU/mL. By 1 hour post-procedure, the mean tPA level was 3.9 and the mean PAI-1 level was 4.3 IU/mL. Subsequent time points for tPA showed mean levels of 0.7 IU/mL, 0.4 IU/mL, and 0.2 IU/mL at 2, 4, and 8 hours, respectively. Subsequent time points for tPA showed mean levels of 9.4, 14.5, and 32.5 IU/mL at 2, 4, and 8 hours, respectively. The data indicate that the tPA levels were largely gone by 1 hour post-Rx, and gone entirely by 2 hours post-Rx. PAI-1 levels disappeared coincident with peak tPA levels, and were half-recovered by one hour post-Rx, and back to baseline by 2 hrs post-Rx. Interestingly, PAI-1 levels were 157% of baseline at 4 hours post-Rx, and 353% of baseline 8 hours post-Rx, indicating an overshoot after administration of tPA.? ? Results of venography show 100% patency at discharge and at 6 weeks in all subjects studied; one 36 year old subject who died less than six weeks after treatment, due to a very aggressive gastrointestinal malignancy, was not evaluated for patency of vessels after initial treatment. One subject with factor V Leiden and an incompetent perforator vein ipsilateral to his original DVT had recurrent DVT six months after treatment of his first DVT.No patients had bleeding attributable to the tPA treatment.? ? In summary, low dose tPA administered via pulse-spray catheter to subjects with a first acute DVT had uniformly good outcomes with respect to immediate patency of treated vessels, and had no bleeding complications attributable to tPA administration. The apparent safety of this approach is likely due in part to the relatively low doses of tPA employed and perhaps to the affinity of tPA for fibrin clot.? ? Future plan: We anticipate that this study will accrue the approved limit of 25 patients early in FY2009, at which point we will describe the findings and conclusions of our work. We contemplate future studies of tPA at time points later than 2 weeks after symptoms, or treatment with the thrombolytic enzyme plasmin itself to extend the interval in which treatment can be initiated.