Low-dose, once-daily, intraclot injections of alteplase for treatment of acute deep venous thrombosis

Abstract

Purpose: To evaluate the safety and efficacy of once-daily intraclot injections of low doses (≤ 10 mg) of tissue plasminogen activator (tPA) for thrombolysis of venous thrombosis.

Materials and methods: In prospective studies, 33 patients with subclavian, jugular, and central venous thrombosis (SJ-CVT) (all but two cases associated with central catheters) were treated once a day with ≤ 4 mg/day of tPA, and 30 patients with acute deep vein thrombosis of the lower extremity (DVT-LE) < 14 days old were treated once a day with ≤ 10 mg/leg/day of tPA by intraclot "lacing" of thrombus without continuous infusions of tPA.

Results: Patency was restored in 26 (79%) of 33 patients with SJ-CVT using an average total dose of 7.1 mg of tPA/per patient and average of 2.1 treatments or days of therapy. Five patients received thrombolytic therapy for SJ-CVT as outpatients. Initial patency was restored in 29 (97%) of 30 patients with acute DVT-LE using an average total dose of 20 mg of tPA per patient over an average of 2.7 treatments/or days per patient. Follow-up imaging examinations at 6 months showed continued patency in 27 (96%)/of 28 patients. There were no major bleeding complications, and no patient required a blood transfusion.

Conclusions: Intraclot injection of low doses of alteplase is effective for acute venous thrombosis, and pharmacokinetic data suggest potentially greater safety.

Conflict of interest statement

Conflicts of Interest:

The contributors have no conflicts of interest to report.

Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.

Figures

Fig 1

64 WF with lymphoma (patient # 24 in Tables 1,2), developed right basilic, axillary, and subclavian thrombosis, only 1week after placement first right arm (basilic vein) PICC line: 1A: Pre-treatment venogram shows thrombosed (filling defects, white arrows) basilica vein. 1B: Pre-treatment venogram shows diversion of contrast into collateral veins because of occluded axillary and subclavian veins. 1C, D: post treatment venogram obtained 1day after pulse spray injection of 4 mg of r-tPA, shows clearance of thrombi and no evidence of strictures.

Fig 2

ABC: 19yo WM (patient 20) with Factor V-Leiden (FV-L) referred for acute DVT left leg. A) Lower end of thrombosis: Left leg venogram shows thrombosis of peroneal veins (arrows) down to ankle; posterior tibial veins do not opacify due to occlusive thrombosis at mid calf level. B) Upper end of thrombosis: IVCgram shows IVC occluded by thrombosis below renal veins (arrows, right renal vein), unsuspected because initial diagnosis was made by ultrasound examination only. C) Asymptomatic right leg: Chronic thrombosis of right common iliac vein demonstrated by right femoral venogram shows narrow recanalized right common iliac vein (small white arrows) and collateral venous drainage from internal iliac vein to paravertebral collateral veins bypassing obstructed IVC (large open white arrows). DEFG: 19yo WM with FV-L: Acute DVT left leg/IVC thrombosis received 3 treatments (10mg/10mg/8mg tPA). D) Using retrograde femoral vein access, guidewire and 4 french glidecatheter (arrows) was passed down into clotted peroneal veins to allow intraclot injection of tPA. Note, thrombosis of proximal posterior tibial vein (open arrow). E) Follow up leg venogram at 1 month shows patency of calf veins; patency also recovered in left popliteal, femoral and iliac veins (not shown). F) IVC occlusion treated with pulse spray injections of tPA and double balloon dilatation (10 mm balloon introduced via right jugular vein, and 8 mm balloon from left femoral vein) of partially organized thrombus. Note presence of stricture in IVC (white arrows, 8mm balloon catheter). G) Brisk flow restored in left external, left common iliac vein (mildly narrowed, arrows), and small IVC at 1 month. HIJK: 19 yo WM with FV-L: treatment chronic DVT right iliac vein and 6 month venograms. H) Narrowed right common iliac vein (arrows) was dilated with 10 mm balloon 1 month after treatment of acute DVT left leg and received 2 (6mg/ 6mg) treatments with tPA. I) At 6 month follow up, despite mild narrowing (arrows), right common iliac vein is again the dominant pathway for venous return. J) IVC patent (arrows, transient reflux into left renal vein) at 6 months. K) Left femoral, external iliac and common iliac vein at 6 months. Left Common iliac vein (arrows) caliber has improved since 1 month study (see Fig. 2G).

Fig 2

ABC: 19yo WM (patient 20) with Factor V-Leiden (FV-L) referred for acute DVT left leg. A) Lower end of thrombosis: Left leg venogram shows thrombosis of peroneal veins (arrows) down to ankle; posterior tibial veins do not opacify due to occlusive thrombosis at mid calf level. B) Upper end of thrombosis: IVCgram shows IVC occluded by thrombosis below renal veins (arrows, right renal vein), unsuspected because initial diagnosis was made by ultrasound examination only. C) Asymptomatic right leg: Chronic thrombosis of right common iliac vein demonstrated by right femoral venogram shows narrow recanalized right common iliac vein (small white arrows) and collateral venous drainage from internal iliac vein to paravertebral collateral veins bypassing obstructed IVC (large open white arrows). DEFG: 19yo WM with FV-L: Acute DVT left leg/IVC thrombosis received 3 treatments (10mg/10mg/8mg tPA). D) Using retrograde femoral vein access, guidewire and 4 french glidecatheter (arrows) was passed down into clotted peroneal veins to allow intraclot injection of tPA. Note, thrombosis of proximal posterior tibial vein (open arrow). E) Follow up leg venogram at 1 month shows patency of calf veins; patency also recovered in left popliteal, femoral and iliac veins (not shown). F) IVC occlusion treated with pulse spray injections of tPA and double balloon dilatation (10 mm balloon introduced via right jugular vein, and 8 mm balloon from left femoral vein) of partially organized thrombus. Note presence of stricture in IVC (white arrows, 8mm balloon catheter). G) Brisk flow restored in left external, left common iliac vein (mildly narrowed, arrows), and small IVC at 1 month. HIJK: 19 yo WM with FV-L: treatment chronic DVT right iliac vein and 6 month venograms. H) Narrowed right common iliac vein (arrows) was dilated with 10 mm balloon 1 month after treatment of acute DVT left leg and received 2 (6mg/ 6mg) treatments with tPA. I) At 6 month follow up, despite mild narrowing (arrows), right common iliac vein is again the dominant pathway for venous return. J) IVC patent (arrows, transient reflux into left renal vein) at 6 months. K) Left femoral, external iliac and common iliac vein at 6 months. Left Common iliac vein (arrows) caliber has improved since 1 month study (see Fig. 2G).

Fig 2

ABC: 19yo WM (patient 20) with Factor V-Leiden (FV-L) referred for acute DVT left leg. A) Lower end of thrombosis: Left leg venogram shows thrombosis of peroneal veins (arrows) down to ankle; posterior tibial veins do not opacify due to occlusive thrombosis at mid calf level. B) Upper end of thrombosis: IVCgram shows IVC occluded by thrombosis below renal veins (arrows, right renal vein), unsuspected because initial diagnosis was made by ultrasound examination only. C) Asymptomatic right leg: Chronic thrombosis of right common iliac vein demonstrated by right femoral venogram shows narrow recanalized right common iliac vein (small white arrows) and collateral venous drainage from internal iliac vein to paravertebral collateral veins bypassing obstructed IVC (large open white arrows). DEFG: 19yo WM with FV-L: Acute DVT left leg/IVC thrombosis received 3 treatments (10mg/10mg/8mg tPA). D) Using retrograde femoral vein access, guidewire and 4 french glidecatheter (arrows) was passed down into clotted peroneal veins to allow intraclot injection of tPA. Note, thrombosis of proximal posterior tibial vein (open arrow). E) Follow up leg venogram at 1 month shows patency of calf veins; patency also recovered in left popliteal, femoral and iliac veins (not shown). F) IVC occlusion treated with pulse spray injections of tPA and double balloon dilatation (10 mm balloon introduced via right jugular vein, and 8 mm balloon from left femoral vein) of partially organized thrombus. Note presence of stricture in IVC (white arrows, 8mm balloon catheter). G) Brisk flow restored in left external, left common iliac vein (mildly narrowed, arrows), and small IVC at 1 month. HIJK: 19 yo WM with FV-L: treatment chronic DVT right iliac vein and 6 month venograms. H) Narrowed right common iliac vein (arrows) was dilated with 10 mm balloon 1 month after treatment of acute DVT left leg and received 2 (6mg/ 6mg) treatments with tPA. I) At 6 month follow up, despite mild narrowing (arrows), right common iliac vein is again the dominant pathway for venous return. J) IVC patent (arrows, transient reflux into left renal vein) at 6 months. K) Left femoral, external iliac and common iliac vein at 6 months. Left Common iliac vein (arrows) caliber has improved since 1 month study (see Fig. 2G).

Fig 3

Pharmacokinetics of intraclot tPA injection. Systemic tPA levels measured immediately after cessation of intraclot injection (Time point “0 Hours”) are elevated over pre-treatment baseline (Time point “-1 hour”) level but cessation of injection allows rapid clearance of circulating tPA (within 1–2 hours) at all dose levels due to its short half life (T1/2 ~ 5 minutes). Reduction in dose from 50mg down to 10mg and 4 mg results in a roughly proportional reduction (average “0 hour” or immediate post injection systemic levels of tPA : fall from 568, 75, to 40 IU/mlrespectively) in systemic exposure to tPA. Reduction in overall dose and avoiding prolonged tPA infusions allows reduction in amount and duration of systemic exposure to circulating tPA.