Wenzhu Li1,2, Chase W Kessinger1,3, Makoto Orii1,4, Hang Lee5, Lang Wang1,6, Ido Weinberg7, Michael R Jaff8, Guy L Reed9, Peter Libby10, Ahmed Tawakol1, Peter K Henke11, Farouc A Jaffer1. 1. Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (W.L., C.W.K., M.O., L.W., A.T., F.A.J.). 2. Now with Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (W.L.). 3. Masonic Medical Research Institute, Utica, NY (C.W.K.). 4. Department of Radiology, Iwate Medical University Hospital, Morioka, Japan (M.O.). 5. Biostatistics Center (H.L.), Massachusetts General Hospital, Harvard Medical School, Boston. 6. Cardiovascular Division, Hubei Renmin Hospital, Wuhan University, China (L.W.). 7. Vascular Medicine (I.W.), Massachusetts General Hospital, Harvard Medical School, Boston. 8. Department of Medicine (M.R.J.), Massachusetts General Hospital, Harvard Medical School, Boston. 9. Department of Medicine, University of Arizona, College of Medicine, Phoenix (G.L.R.). 10. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston (P.L.). 11. Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor (P.K.H.).
Abstract
BACKGROUND: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution. METHODS: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes. RESULTS: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days. CONCLUSIONS: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.
BACKGROUND: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution. METHODS: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes. RESULTS: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days. CONCLUSIONS: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.
Authors: Jose A Diaz; Andrea T Obi; Daniel D Myers; Shirley K Wrobleski; Peter K Henke; Nigel Mackman; Thomas W Wakefield Journal: Arterioscler Thromb Vasc Biol Date: 2012-03 Impact factor: 8.311
Authors: Jose A Diaz; Prakash Saha; Brian Cooley; Olivia R Palmer; Steven P Grover; Nigel Mackman; Thomas W Wakefield; Peter K Henke; Alberto Smith; Brajesh K Lal Journal: Arterioscler Thromb Vasc Biol Date: 2019-03 Impact factor: 8.311
Authors: Chase W Kessinger; Jin Won Kim; Peter K Henke; Brian Thompson; Jason R McCarthy; Tetsuya Hara; Martin Sillesen; Ronan J P Margey; Peter Libby; Ralph Weissleder; Charles P Lin; Farouc A Jaffer Journal: PLoS One Date: 2015-02-13 Impact factor: 3.240
Authors: Sravya Kattula; Yaqiu Sang; Gustaaf de Ridder; Anna C Silver; Emma G Bouck; Brian C Cooley; Alisa S Wolberg Journal: J Thromb Haemost Date: 2021-09-06 Impact factor: 5.824
Authors: Samuel Z Goldhaber; Elizabeth A Magnuson; Khaja M Chinnakondepalli; David J Cohen; Suresh Vedantham Journal: Vasc Med Date: 2021-10-04 Impact factor: 4.739