Selective thrombolysis in acute deep vein thrombosis: evaluation of adjuvant therapy in vivo.
OBJECTIVE
To evaluate in a porcine model of acute deep vein thrombosis (DVT) the efficacy of dalteparin and antithrombin with respect to heparin for local adjuvant therapy during selective thrombolysis, and the utility of nitroglycerin and iloprost as heparin supplements.


METHODS
DVT was induced in both hind limbs using a previously described technique (n = 20). Thirty minutes later, the animal was heparinized (2500 IU IV), and bilateral sequestrated thrombolysis was performed using 8 mg alteplase: both external iliac veins were endoluminally occluded with Swan-Ganz catheters, and a multi-sideport infusion wire coaxially introduced through each catheter and advanced into the ipsilateral popliteal vein. In the control limbs, tissue plasminogen activator (tPA) 8 mg was injected as 0.8-ml boluses at 3-min intervals for 2 hr as a 0. 25-mg/ml solution containing heparin 50 IU/ml (n = 20). On the contralateral side, heparin was substituted with either dalteparin 50 IU/ml (n = 5) or antithrombin 12.5 IU/ml (n = 5), or supplemented with either nitroglycerin 0.075 mg/ml (n = 5) or iloprost (150 ng/ml) (n = 5). Blood samples were taken at predetermined intervals to measure the activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen concentration. At autopsy, the thrombus mass in the iliofemoral veins was measured, and the extent of residual thrombosis in the venous tributaries graded at four sites.


RESULTS
Bilateral thrombolysis was successfully completed in all animals. The median thrombus mass in the iliofemoral veins after thrombolysis was 0.48 g (range 0.06-1.58 g), 0.95 g (0.59-1.29 g), 0. 74 g (0.52-0.96 g), and 0.29 g (0.0-0.77 g) for dalteparin, antithrombin, iloprost, and nitroglycerin respectively, as compared with 0.53 g (0.18-0.88 g) (p = 0.69), 0.97 g (0.46-1.15 g) (p = 0. 69), 0.53 g (0.48-1.10 g) (p = 0.69), and 0.18 g (0.13-1.04 g) (p = 0.5) for the respective controls. Likewise, the severity of residual thrombosis in the venous tributaries was not affected by the constituents of adjuvant therapy. Nitroglycerin induced a small drop in blood pressure, which was transient. The temporal change in aPTT was similar in all four groups. Invariably PT progressively shortened during thrombolysis (p = 0.0001); this effect was somewhat blunted with antithrombin. Fibrinogen levels demonstrated a time-dependent increase (p = 0.004) that was not influenced by the adjuvant therapy used.


CONCLUSIONS
Dalteparin or antithrombin demonstrated no appreciable advantage over heparin as local adjuvant therapy for selective venous thrombolysis. Supplementation of heparin with iloprost or nitroglycerin also had virtually no effect on thrombolytic efficacy.
Roy
S
S
Institute for Surgical Research, National Hospital, Pilestredet 32, N-0027 Oslo, Norway.
Brosstad
F
F
Sakariassen
K S
KS
D000818:Animals; D017024:Chemotherapy, Adjuvant; D017985:Dalteparin / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D007084:Iliac Vein; D016285:Iloprost / Q000627:therapeutic use; D005996:Nitroglycerin / Q000627:therapeutic use; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D018709:Statistics, Nonparametric; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000188:drug therapy*
D005343:Fibrinolytic Agents; D014665:Vasodilator Agents; D006493:Heparin; D010959:Tissue Plasminogen Activator; D005996:Nitroglycerin; D016285:Iloprost; D017985:Dalteparin