The Role of TIPS for Portal Vein Patency in Liver Transplant Patients With Portal Vein Thrombosis

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1 LIVER TRANSPLANTATION 12: , 2006 SHORT REPORT The Role of TIPS for Portal Vein Patency in Liver Transplant Patients With Portal Vein Thrombosis Jason Bauer, 1 Stephen Johnson, 1 Janette Durham, 1 Michael Ludkowski, 1 James Trotter, 2 Thomas Bak, 3 and Michael Wachs 3 1 Department of Radiology, Division of Interventional Radiology, 2 Department of Internal Medicine, Division of Hepatology, and 3 Department of Surgery, Division of Liver Transplant, University of Colorado Health Sciences Center, Denver, CO The purpose of this research was to study the efficacy and outcomes of transjugular intrahepatic shunt (TIPS) in end-stage liver disease (ESLD) patients with portal vein thrombosis (PVT) eligible for orthotopic liver transplant. Nine consecutive patients with PVT underwent TIPS as a nonemergent elective outpatient procedure. The primary indication for TIPS was to maintain portal vein patency for optimal surgical outcome. Eight patients underwent contrast enhanced computed tomography (CT) and 1 magnetic resonance imaging diagnosing PVT. Shunt creation was determined by available targets at the time of TIPS and by prior imaging. Patients were followed with portography, ultrasound, CT, or magnetic resonance imaging, and the luminal occlusion was estimated before and after TIPS. Primary endpoints were transplantation, removal from the transplant list, or death. Stabilization, improvement, or complete resolution of thrombosis was considered successful therapy. Failures included propagation of thrombosis or vessel occlusion, and poor surgical anatomy due to PVT. Of 9 patients with PVT, TIPS was successfully placed in all patients without complication or TIPS-related mortality. Eight of 9 patients (88.8%) had improvement at follow-up. One patient failed therapy and re-thrombosed. Two patients (22.2%) were transplanted without complication and had no PVT at the time of transplant. Eight of 9 patients were listed for transplant at the time of their TIPS. Eight of 9 PVTs were nonocclusive. Four of 9 patients (44%) had evidence of cavernous transformation. Two patients expired during follow-up 42 and 44 months after TIPS. Three patients remain on the transplant list. One patient has not been listed due to nonprogression of disease. One patient has been removed from the transplant list because of comorbid disease. In conclusion, TIPS is safe and effective in patients with PVT and ESLD requiring transplant. Patients can be successfully transplanted with optimal surgical anatomy. Liver Transpl 12: , AASLD. Received January 16, 2006; accepted May 18, Portal vein thrombosis (PVT) in the adult population is rare. However, PVT is an accepted common complication of chronic liver disease, reaching as high as 39%, 1,2 and in transplant patients incidence of PVT ranges from 2.1 to 26% preoperatively. 3 In those with end-stage liver disease (ESLD) who are eligible for transplant, PVT can exclude patients from surgery completely or complicate transplantation with poor outcome. Routine screening for liver transplant eligibility will usually uncover PVT. Until recently, the condition was an absolute contraindication to transplant. 4-8 Now, patients with PVT may be transplanted, but the level of difficulty for the surgeon is increased as are the number of postoperative complications Studies have shown that transjugular intrahepatic shunt (TIPS) is technically feasible in patients with PVT, but the studies include a wide range of patients with malignancy, hypercoagulable states, and pancreatitis as the cause of PVT. 14,15 In cirrhotics, TIPS have been placed successfully in patients with portal vein clot for the standard indication of ascites and hemorrhage. To our knowledge, there are few reports of TIPS placement to maintain portal vein patency for transplant. Since 1992, we have performed over 300 TIPS at the Univer- Abbreviations: PVT, portal vein thrombosis; ESLD, end-stage liver disease; TIPS, transjugular intrahepatic shunt; CT, computed tomography; SMV, superior mesenteric vein. Address reprint requests to Dr. Stephen Johnson, A030, 4200 East 9th Ave., Denver, CO Telephone: ; FAX: ; stephen.johnson@uchsc.edu DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 TIPS FOR PORTAL VEIN PATENCY IN LIVER TRANSPLANTATION 1545 Figure 1. Contrast enhanced CT in an ESLD patient without TIPS showing progression of portal vein thrombosis over one year from Grade II to Grade IV, ultimately excluding this patient from transplant at our institution. sity of Colorado. TIPS have been placed in patients with portal vein or splanchnic vein thrombosis. However, beginning in 1999 in conjunction with the Hepatology and the Liver Transplant services, Interventional Radiology has been consulted to place TIPS in patients with PVT to maintain vessel patency in order to maximize surgical outcome. The natural history of untreated PVT in this population is not clear, but in our experience, progression of thrombus is common and has excluded patients from transplantation (Fig. 1A-C). Here, we describe our experience with 9 consecutive patients who received primary TIPS on a nonemergent basis to maintain portal vein patency for future liver transplant. PATIENTS AND METHODS From 1999 through January 2005, 149 primary TIPS were performed at our institution. Nine of 149 (6%) patients who received a primary TIPS for portal vein thrombosis were retrospectively identified. These patients represented a population of ESLD patients who at the time of their TIPS did not require decompression of varices or control of ascites and would not have otherwise required TIPS. These 9 patients represent our study group. All but 1 patient was listed on the liver transplant registry at the time TIPS was performed. Eight patients underwent a dual phase contrast enhanced computed tomography (CT), and 1 patient underwent an magnetic resonance imaging prior to the procedure which diagnosed the thrombosis. Long term follow up of portal vein patency was established with follow up CT, ultrasound, magnetic resonance imaging, or Portography. Data was retrospectively compiled and included the type of PVT as well as extension of thrombus into the superior mesenteric vein (SMV) or the splenic vein. Findings on portography during TIPS placement, whether thrombectomy or thrombolytic therapy was performed, and the anatomy of the TIPS shunt and

3 1546 BAUER ET AL. TABLE 1. Patient Prior to TIPS PT Age Cavernous Transformation PVT SMVT SVT OLT Listed* at TIPS Listed* Now 1 26 Yes Yes Yes No 2 61 No No Yes No 3 45 Yes No Yes No 4 53 No No Yes No 5 28 No No Yes Yes 6 57 Yes No Yes Yes 7 52 Yes No No No 8 50 No Yes Yes No 9 54 No No Yes Yes Abbreviations: PT, patient; PVT, portal vein thrombosis; SMVT, superior mesenteric vein thrombosis; SVT, splenic vein thrombosis; OLT, orthotopic liver transplant, thrombosis present;, thrombosis absent. *Listed for liver transplantation at our institution. TABLE 2. Pre-TIPS Degree of Thrombosis in the Main Portal Vein, SMV, and Splenic Vein PT MPV SMV SV Cavernous Transformation 1 Grade IV Grade II Patent Yes 2 Grade II Grade IV Patent No 3 Grade IV Grade IV Grade II Yes 4 Grade III Grade III Patent No 5 Grade IV Patent Grade II No 6 Grade II Grade II Patent Yes 7 Grade IV Grade III Patent Yes 8 Grade IV Grade IV Grade IV No 9 Grade IV Patent Grade IV No Abbreviations: PT, patient; MPV, main portal vein; SMV, super mesenteric vein; SV, splenic vein. device type used have been recorded for each case. As well, clot burden in portal, mesenteric, and splenic veins at the time of the procedure and at follow-up was estimated (Patent: no detectable thrombus; Grade I: less than 25%; Grade II: 26-50%; Grade III: 51-75%; and Grade IV: % occluded). The outcome of each TIPS, its long-term function, patient survival, and whether patients were transplanted were also recorded (Tables 1, 2, and 3). This retrospective review was approved by the Colorado Multiple Institution Review Board. RESULTS Two of 9 patients were female. Age at the time of TIPS ranged from 26 to 61 years mean age. ESLD resulted from hepatitis and alcohol in 6 patients, autoimmune hepatitis in 1, and cryptogenic in the remaining 2. One patient had documented PVT only. Four patients had PVT and SMV thrombosis. Two patients had portal vein and splenic vein thrombosis, and 2 had thrombus in all 3 vessels. Four patients presented with cavernous transformation of the portal vein. TABLE 3. Post-TIPS Degree of Thrombosis in the Main Portal Vein, SMV, and Splenic Vein PT MPV SMV SV 1 Grade I Grade I Patent 2 Grade I Grade I Patent 3 Grade IV Grade IV Grade II 4 Grade I Grade I Patent 5 Grade II Patent Grade I 6 Grade I Grade I Patent 7 Grade IV Grade III Patent 8 Patent Patent Patent 9 Grade III Patent Grade III NOTE: Luminal occlusion was estimated as follows: Patent (no detectable thrombus), Grade I (1-25% luminal occlusion), Grade II (26-50%), Grade III (51-75%), and Grade IV (76-100%). Abbreviations: PT, patient; MPV, main portal vein; SV, splenic vein. No patient had a diagnosed hepatoma at the time of TIPS. One patient developed a hepatoma during the follow-up period. All TIPS were performed from a right internal jugular vein approach using standard technique. A Ring TIPS set (Cook, Bloomington, IN) was used in all cases. Wedge CO 2 portography was performed in 4 cases and mesenteric angiography in 2 cases. Hepatic to portal vein access was performed blindly under fluoroscopic guidance in the remaining cases. Because of the change in technology during this period, the 3 most recent shunt procedures were performed with the Viatorr stent graft (Gore, Newark, DE ), 1 was performed with a Wallstent (Boston Scientific, Natick, MA), and 3 were performed with the Smart stent (Cordis, New Brunswick, NJ ). Only 1 stent was used in all cases, and none were placed into the main portal vein to decrease the possibility of transplant complication. TIPS was performed from the right hepatic vein to the right portal vein in 5 patients and from the middle

4 TIPS FOR PORTAL VEIN PATENCY IN LIVER TRANSPLANTATION 1547 hepatic vein to the right portal vein in 1 patient. One patient had a shunt created from the left hepatic vein to the left portal vein due to extensive right portal vein clot. All patients survived TIPS placement and were discharged home with no complications. Follow-up ranged from 2 to 45 months. Only 1 patient required shunt revision. While there was no clot identified, narrowing of the shunt from neointimal hyperplasia required angioplasty and stenting at the 3-month follow-up in this patient. Follow-up imaging included a combination of catheter portography, CT, magnetic resonance imaging, and ultrasound. Eight of 9 patients (88.8%) maintained portal vein patency. One patient with extensive chronic PVT and SMV thrombosis as well as cavernous transformation of the portal vein underwent portal vein thrombectomy with an Amplatz device (Microvena, White Bear Lake, MN) and with tissue plasminogen activator (Genentech, South San Francisco, CA ) laced into the clot, on the day of the TIPS and again 2 days following TIPS. This patient received post-procedure Coumadin but never developed a patent portal vein and was considered a failure of therapy. Occlusion was demonstrated on follow-up CT 4 months later and on mesenteric angiogram 41 months later performed for gastrointestinal bleeding. The patient also had a prior splenectomy and inflow into the portal vein was decreased compared to the other 8 patients. This patient died 42 months after TIPS from massive variceal hemorrhage. Another patient (Fig. 1 and 2) with near occlusive thrombosis of the portal vein, SMV, and splenic veins received adjunctive tissue plasminogen activator (20 mg), Angiojet, (Possis Medical, Minneapolis, MN) thrombectomy, and Fogarty thrombectomy (Edwards Life Sciences, Irvine, CA) at the time of TIPS. This successfully recanalized the portal vein, SMV, and splenic veins. On follow-up ultrasound at 2 weeks and portography at 3 months, there was complete resolution of thrombus. This patient was successfully transplanted 6 months after TIPS with a patent portal vein at the time of surgery. In both patients for whom thrombectomy was performed, mechanical techniques were employed before shunt placement in order to minimize pulmonary embolization. One patient with autoimmune hepatitis was transplanted 8 months after TIPS. This patient developed extensive non-occlusive PVT with evidence of cavernous transformation prior to TIPS (Fig. 2A-D). The portal vein was patent at the time of surgery, and the transplant was performed without complication. The patient is alive today and doing well. The remaining 6 patients (66.6%) have not been transplanted. Two patients have died, the first at 44 months after TIPS, and the second at 42 months after TIPS. Of the remaining 5 patients who are alive and without a liver transplant, 3 patients remain on the transplant list, 1 has not been listed because of stable liver disease, and 1 has been removed from the transplant list because of comorbidities (Fig. 3). All of the patients who remain on the transplant list have patent portal veins with improvement or resolution of clot within affected veins (Fig. 4). DISCUSSION As experience has grown with liver transplantation, PVT has become only a relative contraindication. The surgical literature details many techniques for dealing with PVT at the time of transplantation including thrombectomy, portal vein graft, extra-anatomic venous reconstruction, and splenomesenteric or left gastric vein recipient to donor portal vein anastomosis Improved surgical survival and decreased complication rates can be seen with partial vs. complete PVT and with isolated PVT vs. extension in to the splenic and/or superior mesenteric vein. 16 Because of advancing surgical techniques and the development of TIPS as a safe and efficacious procedure, there has been a natural evolution utilizing TIPS to treat PVT and prevent progression of clot in order to maintain candidacy for liver transplant. The pathophysiology of PVT in patients with cirrhosis is not clear but is likely due to increased resistance to flow. Therefore, shunt creation alone leads to improved outflow with autothrombolysis regardless of mechanical or pharmacologic therapy. This has been reported in several small series where TIPS was performed for PVT in patients ultimately undergoing orthotopic liver transplantation and was confirmed in our patients. 17,18 Technical success in these 9 patients was 100% with 85.7% patency of all veins. While a TIPS was successfully placed and functioning in 1 patient with complete PVT and cavernous transformation, the patient s portal vein never recanalized despite mechanical thrombectomy, thrombolytics, and anticoagulation. This result may in part be due to poor inflow from a prior splenectomy as well as more chronic thrombosis. This patient maintained his transplant eligibility until he died from renal failure and overwhelming sepsis 44 months after TIPS. Due to the retrospective nature of the study, post- TIPS imaging and the timeline of these studies are not uniform. As a result, estimation of clot burden following TIPS was not standardized. The routine post-tips follow-up for our department in transplant-eligible patients with PVT has now been standardized to include a 3- and 9- month contrast-enhanced CT in asymptomatic patients, or portography with possible shunt revision in our symptomatic patients. TIPS was safely performed for PVT in our patients with no TIPS-related mortality. However, there are reports of higher complication rates and increased mortality in this population. A recent study by Ganger et al. reported a complication rate of 22%, including an 11% mortality rate in 11 patients with PVT. Nine patients had a TIPS successfully placed, with 4 patients undergoing liver transplantation. 18 Complication and mortality differences may be attributable to acute hemorrhage requiring portal decompression with TIPS, while in our

5 1548 BAUER ET AL. Figure 2. Portography of a patient with autoimmune cirrhosis. (A) Cavernous transformation of the portal vein. (B) Grade IV PVT. (C) Patent TIPS and Grade I portal vein thrombosis one month and (D) five months after TIPS. The patient is alive today after OLTX. small group of patients all procedures were performed on an elective outpatient basis. Wasler et al. reported 20 patients with PVT, and 14 TIPS were successfully placed. Decreased technical success and outcomes were attributable to clot burden and chronicity of PVT. 19 Radosevich et al. were able to place TIPS in 3 of 6 patients through a transjugular approach and in 4 of 4 patients using transhepatic portal vein recanalization followed by TIPS. 14 All of these patients had portal vein occlusion, with subsequent long-term patency at follow-up in 5 of 7 patients. Finally, Blum et al. successfully placed TIPS in 7 patients with partial PVT. There were no immediate complications. 15 Fibrinolytic agents and balloon maceration were used in all patients. Five of 7 patients had complete recanalization, and 2 of 7 experienced partial portal vein recanalization. A diverse approach exists in the literature regarding the recanalization of the portal vein. Two patients with complete thrombosis of the portal vein and/or SMV and splenic veins received adjunctive lytic therapy and mechanical thrombectomy. The remainder had only the TIPS placement. Eight of our patients maintained portal vein patency with improvement in clot. Reports

6 TIPS FOR PORTAL VEIN PATENCY IN LIVER TRANSPLANTATION 1549 Figure 3. A patient with hepatitis C cirrhosis. (A) Contrast enhanced CT showing Grade IV PVT. (B) Showing TIPS with intraluminal clot. (C) Follow up at 3 months with shunt narrowing but no PVT. The shunt was revised. (D) and (E) Gadolinium MRI (TR 150 TE 4.1) showing Grade I portal vein thrombosis 11 months after TIPS. This patient has been removed from the transplant list due to comorbidities.

7 1550 BAUER ET AL. Figure 4. (A) Contrast enhanced CT in a patient with Grade II calcified chronic PVT. (B) CO2 portogram at the time of TIPS. (C) Grade I portal vein thrombosis at 6 month portogram. The patient remains on the transplant list. by Blum et al. and Wasler et al. used thrombectomy techniques in all their patients. This may increase procedure time and cost but may be necessary for patients who have complete PVT and no antegrade flow. There are only a few cases in the literature in which the primary indication for TIPS was to recanalize the portal vein to maintain transplant status. In 2001, Liatsos et al. reported 2 patients, both with PVT and extension into the superior mesenteric vein. 17 Both patients underwent successful TIPS and received orthotopic liver transplant at 31 and 27 days, respectively. Portal veins were patent at the time of transplant, and both patients left the hospital without complication. Other reports were for patients whose primary indication for TIPS was unrelated to maintaining optimal surgical anatomy for transplantation. Patients with ESLD awaiting transplant who have partial PVT do well with TIPS and will likely maintain portal vein patency. ESLD patients with complete PVT and cavernous transformation are technically more challenging, and recanalization of the portal vein may not be feasible. Here, we have presented 9 patients who successfully underwent TIPS for PVT. The procedure is technically feasible, and there was no procedure-related mortality or significant complication in our group of patients. Clot lysis, prevention of clot propagation, and maintenance of portal vein patency seems achievable with timely placement of TIPS following diagnosis of PVT in transplant-eligible patients. Even if clot resolution is incomplete, halting its propagation is also valued for surgical success. With our

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