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Interventional Treatment for Hepatic Artery Thrombosis after Liver Transplantation
CLINICAL STUDY
Interventional Treatment for Hepatic Artery Thrombosis after Liver Transplantation Hua Zhang, MD, Sheng Qian, MD, PhD, Rong Liu, MD, PhD, Wei Yuan, MD, PhD, and Jian-Hua Wang, MD, PhD ABSTRACT Purpose: To evaluate short-term and long-term effectiveness of interventional treatment for hepatic artery thrombosis (HAT). Materials and Methods: From March 2003 to October 2015, 34 patients (32 male and 2 female; mean age, 45 y; range 7–64 y) with HAT were identified 0–21d (mean 6.5 d ± 6.0) after liver transplantation and underwent interventional treatments. Technical success, clinical success, complications, hepatic artery patency, and survival time were assessed. Results: All 34 patients underwent urokinase thrombolytic treatment. The mean dosage of urokinase was 1,250,000 U ± 1,000,000 (range, 350,000–9,000,000 U). Thrombolysis treatment required 5–120 h (mean 50 h ± 31) for completion. In 21 patients, stents were also implanted during thrombolytic treatment. In 3 patients with splenic artery steal syndrome, proximal splenic artery embolization was performed during thrombolytic treatment. The technical and clinical success rate was 91% (31/34), with treatment failure in 3 children. Hemorrhage was observed in 11 cases. Local necrotic foci in the transplanted liver were found on CT in 5 patients. Complications associated with the interventional procedures occurred in 2 patients. Patency rates of the hepatic artery at 1 y, 2 y, 3 y, and 5 y were 96%, 93%, 83%, and 83%. Overall survival rate at 1 y, 2 y, 3 y, and 5 y were 82%, 73%, 57%, and 57%. Conclusions: Interventional treatment can achieve satisfactory short-term and long-term effectiveness for adult HAT.
ABBREVIATIONS HAT ¼ hepatic artery thrombosis, LT ¼ liver transplantation, PT ¼ prothrombin time
Hepatic artery thrombosis (HAT) is the most common and severe vascular complication and accounts for > 50% of all arterial complications after orthotopic liver transplantation (LT) (1,2). The incidence of HAT as a complication of LT in adults was reported to be 4%–15% (3–6), and HAT was generally more frequent after pediatric LT (3%–9% in adults vs 11%–26% in children) (7–9). Mortality related to HAT has been reported to reach 54.5% (10,11). Early diagnosis and effective treatment for HAT are crucial to organ salvage and patient survival. Generally there are 3 different treatment modalities for HAT: retransplantation, surgical revascularization, and interventional treatment. The most
effective treatment approach remains controversial. Interventional treatments for HAT, such as intraarterial thrombolysis, percutaneous transluminal angioplasty (PTA), and stent placement, have been emerged as a less invasive alternative to surgical intervention (12–16). However, interventional treatment for HAT remains controversial because of potential risk of fatal intraperitoneal hemorrhage (17,18) and uncertain long-term efficacy. In the present study, the short-term and long-term effectiveness of interventional treatment of HAT were evaluated retrospectively.
MATERIALS AND METHODS Patient Information
From the Shanghai Institute of Medical Imaging and Department of Interventional Radiology (H.Z., S.Q., R.L., W.Y., J.-H.W.), Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui, Shanghai 200032, China. Received November 19, 2016; final revision received April 11, 2017; accepted April 30, 2017. Address correspondence to J.-H.W.; E-mail: dr_wangjianhua@126. com None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–7 http://dx.doi.org/10.1016/j.jvir.2017.04.026
Between March 2003 and October 2015, 1,385 LTs (maleto-female ratio 1,162:223; mean patient age, 49.6 y ± 11.7; range, 0–81 y) were performed. Types of transplantation included orthotopic LT (n ¼ 1,325), living donor LT (n ¼ 48), split LT (n ¼ 8), and reduced LT (n ¼ 4). At 0–21 days (mean 6.5 d ± 6.0) after LT, HAT was identified in 34 patients (32 male and 2 female; mean age, 45 y; range, 7–64 y). Underlying diseases included primary hepatic carcinoma (n ¼ 21), end-stage hepatitis B virus–related liver cirrhosis (n ¼ 6), Wilson disease (n ¼ 4), congenital biliary
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atresia (n ¼ 2), and Budd-Chiari syndrome (n ¼ 1), and LT procedures included orthotopic LT (n ¼ 28; 2.1% of 1,325 orthotopic LTs), living donor LT (n ¼ 5; 10.4% of 48 living donor LTs), and split LT (n ¼ 1; 12.5% of 8 split LTs). Endto-end hepatic artery anastomosis was performed without intraoperative complications; types of arterial anastomoses between donors and recipients are listed in the Table. Blood types (ABO) between donors and recipients was identified in all 34 patients. Mean hot, cold, and warm ischemia times were 4.5 minutes (range, 0–5 min), 65 minutes (range, 43–100 min), and 6.5 hours (range, 4–12 h).
Diagnosis of HAT Hepatic artery blood flow was monitored daily by color Doppler ultrasound during the first postoperative week and then every 2 days until patients were discharged. Liver function, kidney functions, and routine blood and coagulation function tests were measured daily. On the basis of color Doppler ultrasound and/or clinical and laboratory findings, 38 patients were suspected to have HAT. Clinical and laboratory findings included fever and hepatalgia (n ¼ 4), and elevated serum alanine transferase and bilirubin (n ¼ 34); 2 patients were asymptomatic. Angiography immediately identified HAT in 34 patients. Among these 34 patients, mean alanine aminotransferase, aspartate aminotransferase, total bilirubin, and conjugated bilirubin levels were 428.5 U/L ± 385.0, 294.4 U/L ± 257.0, 50.9 U/L ± 35.0, and 30.1 U/L ± 22.9. Mean prothrombin time, activated partial thromboplastin time, international normalized ratio, and fibrinogen concentration were 20.5 seconds ± 11.9, 48.49 seconds ± 12.1, 1.4 ± 0.2, and 216.8 mg/dL ± 117.9. Patients with defective coagulation function and the following conditions were excluded from interventional treatment: activated partial thromboplastin time > 3 times the control value, PT > 2.5 times the control value, Table. Types of Arterial Anastomoses (N ¼ 34) LT Procedures
OLT
LDLT
SLT
Type of Arterial Anastomoses
Number of Cases
Donor
Recipient
CHA
CHA
22
CHA
PHA
1
CTA
CHA
4
CTA
PHA
1
RHA RHA
CHA RHA
1 1
RHA
LHA
1
RHA
PHA
1
LHA
CHA
1
LHA
CHA
1
CHA ¼ common hepatic artery; CTA ¼ celiac trunk artery; LDLT ¼ living donor liver transplantation; LHA ¼ left hepatic artery; OLT ¼ orthotopic liver transplantation; PHA ¼ proper hepatic artery; RHA ¼ right hepatic artery; SLT ¼ split liver transplantation.
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international normalized ratio > 3, fibrinogen concentration < 100 mg/dL, and platelet concentration < 30 109/L.
Methods A 5-F RH catheter (Cook, Inc, Bloomington, Indiana) was used for selective catheterization of the hepatic artery via a right femoral artery approach. Heparinization was performed with a weight-adjusted dosage regimen of 60 U/kg followed by 10 U/kg per hour via intravenous injection. A coaxial microcatheter (Progreat; Terumo, Tokyo, Japan) and micro–guide wire were passed to the thrombus. The coaxial microcatheter was advanced to the inside of the thrombus, and 100,000–250,000 U of urokinase (Lizhu Pharmaceutical Co. Ltd, Shanghai, China) was dissolved into 50 mL of normal saline and injected into the coaxial microcatheter during the first 15 minutes (this procedure was performed in all 34 patients with HAT). Another 250,000–750,000 U of urokinase was injected into the coaxial microcatheter during the next 30 minutes in the same way if the thrombolysis was not satisfactory (this procedure was performed in 32 patients with HAT). An additional 50,000–100,000 U was injected in the same way if the thrombolysis was still not satisfactory (this procedure was performed in 2 patients with HAT). After most of the large thrombus was dissolved, the coaxial microcatheter was newly advanced to inside of the residual thrombus, and 250,000 U of urokinase was dissolved into 50 mL of normal saline and perfused continuously by infusion pump at a rate of 6–10 mL/h during the following 12–24 hours in the intensive care unit. Liver function and routine blood and coagulation function tests were done every 5 hours. Arteriography was performed every 8 hours during thrombolytic treatment. The coaxial microcatheter was withdrawn from the RH catheter. Arteriography of the celiac trunk and common hepatic artery was performed through the RH catheter. When the thrombus was dissolved and branches of the hepatic artery were shown clearly, thrombolysis was stopped. The catheter sheath was retained for 2–3 days. Hepatic artery angiography was performed daily. Stents (XIENCE PRIME; Abbott, Abbott Park, Illinois) were implanted if the following conditions occurred during thrombolytic treatment: (a) HAT was accompanied by stenosis or kinking, (b) the residual thrombi were > 70% of cross section inside the hepatic artery 24 hours after thrombolysis (n ¼ 5) or the residual thrombi were > 50% of cross section inside the hepatic artery 48 hours after thrombolysis (n ¼ 6). If splenic artery steal syndrome was observed during the thrombolysis treatment, proximal embolization of the splenic artery with coils (Gianturco coils; Cook, Inc) was performed (Fig 1a–f). Low-molecular-weight heparin, 4,100 U in adults and 1,000 U in children (Fraxiparine; GlaxoSmithKline, Middlesex, UK), was administered for anticoagulation every 12 hours by subcutaneous injection and lasted for 1 week after recanalization of the thrombosed hepatic artery. PT was limited to approximately 25 seconds (normal range, 10–13 s).
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Figure 1. Interventional treatment of HAT. (a) The initial segment of the hepatic artery was kinked and stenosed (arrow). The intrahepatic artery branches are not shown. (b) The thrombus was dissolved in a region distant from the site of thrombus anastomosis after 24 hours of thrombolytic therapy, but thrombus at the anastomotic site still (arrows) was not dissolved. (c) A stent (arrow) with a diameter of 4 mm and length of 38 mm was placed. (d) The hepatic artery kinks and stenosis disappeared. The blood flow of the hepatic artery was patent. (e) Angiography demonstrated complete hepatic artery occlusion, and the large splenic artery (arrow) severely shunted the hepatic artery blood flow. (f) Hepatic artery was patent after 72 hours of thrombolytic therapy, stent placement, and proximal splenic artery embolization.
Analysis and Follow-up Technical and clinical success rates, complications, survival time, and hepatic artery patency were analyzed. Technical success was defined as recanalization of hepatic artery blood flow after interventional treatment. Clinical success was defined as disappearance of signs or symptoms and elevated laboratory values. Complications were assessed according to Society of Interventional Radiology (SIR) Clinical Practice Guidelines (19). Minor complications were defined as complications requiring no therapy, no consequence or nominal therapy, and no consequence, including overnight admission for observation only. Major complications were defined as complications requiring major therapy, unplanned increase in level of care, or prolonged hospitalization (> 48 h), resulting in permanent adverse sequelae or death. Hepatic artery patency was defined as no stenosis and thrombosis during the follow-up period. Color Doppler ultrasound, liver function tests, and routine blood and coagulation function tests were performed monthly. If patients were suspected to have HAT or hepatic artery stenosis on the basis of color Doppler ultrasound and/or clinical and laboratory findings (eg, fever, hepatalgia, elevated serum alanine transferase and bilirubin) during follow-up, computed tomography (CT) or magnetic resonance (MR) imaging was performed immediately. If patients were not suspected to have HAT or hepatic artery stenosis on the basis color Doppler ultrasound and/or clinical and laboratory findings, CT or MR imaging was performed every
6 months. Follow-up ended at the time of death, the last patient visit, or June 5, 2016.
Statistical Analysis The statistical analysis was performed with IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, New York). Continuous variables were expressed as mean ± SD or as median. The hepatic artery patency rate and overall survival rate were determined by the KaplanMeier method.
RESULTS Angiography Outcomes, Technical Success, and Clinical Success The thrombi of the 34 patients all were located at the anastomotic site of the hepatic artery, and in 3 of 34 cases, thrombi were located at the branches of the hepatic artery. The thrombi were 3–30 mm in length. Thrombolytic treatment with urokinase was performed in these 34 patients. The mean dosage of urokinase was 1,250,000 U ± 1,000,000 (range, 350,000–9,000,000 U). Thrombolysis treatment required 5–120 hours (mean 50 h ± 31) for completion. Balloon-expandable stents were implanted in 21 patients during thrombolytic treatment. There were 24 stents implanted (diameter, 2.5–5.0 mm; length, 10–38 mm). Proximal splenic artery embolization was
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performed in 3 patients with splenic artery syndrome during thrombolytic treatment. Recanalization of the hepatic artery was achieved in 31 of 34 patients; recanalization failed in 3 children (age 7, 7, and 14 y). The reason for failure was acute thrombosis in the stents on the day of stent implantation. Repeated thrombolysis was unsuccessful. One child (age 7 y) underwent retransplantation. She survived 4 years and died of multipleorgan failure caused by inferior vena cava and hepatic vein stenosis. Two children (age 7 y and 14 y) without surgical intervention died of multiple-organ failure 6 days and 10 days after stent placement because of no grafts. Clinical success was achieved in 31 of 34 patients. Resolution of signs or symptoms and improvement of laboratory findings were achieved 3–14 days (mean, 7.5 d ± 4.6) after hepatic artery recanalization. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, and conjugated bilirubin levels were decreased to 62.3 U/L ± 58.2, 36.0 U/L ± 29.4, 22.8 U/L ± 13.9, and 14.2 U/L ± 11.4 at 2 weeks after hepatic artery recanalization.
Complications During the thrombolysis, 11 patients experienced bleeding from the abdominal cavity. In 3 of 11 patients, hemoglobin decreased significantly (< 70 g/L), and extravasation of contrast agent at the anastomotic site was identified by angiography. Graft-covered stents (Jo Stents; Abbott Vascular Netherlands BV, Heerlen, Netherlands) were implanted in these 3 patients, and the bleeding was stopped; the patients received blood transfusions and were discharged in good health with a patent hepatic artery. During the follow-up period, 2 of the 3 patients died of causes unrelated to hepatic arteries; survival times were 26 and 80 months, respectively. The third patient was still alive during the follow-up period. No extravasation of contrast agent and decreased hemoglobin were observed in another 8 patients; the bleeding gradually decreased and stopped after decreasing or stopping the urokinase. CT revealed local necrotic foci (minor hypodense ischemic lesions) in the transplanted liver in 5 patients; these foci were observed 0, 4, 8, 10, and 20 days after diagnosis of HAT. Cefoperazone/sulbactam (Sulperazone; Pfizer Pharmaceutical Co, New York, New York) was infused intravenously. Thus, no infection of the necrotic foci and no liver abscess developed in these 5 patients. Complications associated with interventional procedures occurred in 2 patients. One case involved a femoral artery pseudoaneurysm that was treated with a compression bandage. The other case involved extravasation of contrast agent at the anastomotic site caused by the interventional procedure, and a graft-covered stent (Jo Stent) was implanted. HAT recurred in 2 patients at 12 hours and 36 hours after initial recanalization of hepatic artery. Rethrombolysis was performed. The blood flow of the hepatic artery was reestablished successfully at 24 hours and 72 hours after rethrombolysis. A total of 3,250,000 U was
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administered to 1 patient during initial thrombolysis and rethrombolysis. In another patient, 9,000,000 U of urokinase was administered during initial thrombolysis and rethrombolysis.
Follow-Up, Hepatic Artery Patency, and Survival Time Follow-up time ranged from 3 to 135 months. Recurrence of HAT 6 months after initial recanalization of the hepatic artery was observed in 1 patient who underwent retransplantation; the patient died of multiple-organ failure 2 months later. Hepatic artery stenosis was observed in 4 patients at 22, 25, 30, and 32 months after LT; no clinical symptoms were observed, and no further treatment was performed. The 4 patients died during the follow-up period of causes unrelated to hepatic arteries; survival times of these patients were 37, 37, 80, and 94 months. Biliary strictures were observed in 4 patients at 5, 10, 15, and 30 months after LT. Biliary stents were implanted using endoscopic retrograde cholangiopancreatography, and the 4 patients were still alive with normal liver function during the follow-up period. There were 9 patients with patent hepatic arteries who died during the follow-up period of causes unrelated to hepatic arteries. During the follow-up period ranging from 12 to 135 months, 17 patients remained alive in good health with patent hepatic arteries. The patency rates of the hepatic artery at 1 year, 2 years, 3 years, and 5 years were 96%, 93%, 83%, and 83% (Fig 2). The overall survival rates at 1 year, 2 years, 3 years, and 5 years were 82%, 73%, 57%, and 57%. The median survival time was 94 months (Fig 3).
DISCUSSION Interventional selective catheterization of the hepatic artery made intraarterial thrombolytic therapy possible. Hidalgo et al (12) first reported the successful use of intraarterial
Figure 2. Kaplan-Meier estimate of the rate of hepatic artery patency. The patency rates of the hepatic artery at 1 year, 2 years, 3 years, and 5 years were 96%, 93%, 83%, and 83%.
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Figure 3. Kaplan-Meier estimate of the rate of overall survival. The overall survival rates at 1 year, 2 years, 3 years, and 5 years were 82%, 73%, 57%, and 57%. The median survival time was 94 months.
thrombolytic therapy in 2 cases of HAT. Selective thrombolysis has several advantages, such as small thrombolysis dose, high localized concentration, and minimal effect on systemic coagulation. Bjerkvik et al (13) believed that thrombolytic treatment combined with mechanical recanalization using a guide wire and catheter was more effective, with reestablished slow blood flow giving the thrombolytic agent a much better chance to work throughout the arterial tree. Mechanical recanalization with a microcatheter was applied in the present study. Mechanical recanalization with a softer microcatheter was beneficial in decreasing hepatic artery intimal injury; however, artery injury caused by recanalization with a microcatheter occurred in 1 patient. Figueras et al (20) suggested that continuous urokinase therapy would be safer and more effective if the infusion catheter was placed inside the thrombus, and a similar method was used in this group. The coaxial microcatheter was left inside the thrombus. Using a bolus injection of a large dose of urokinase over a relatively short time during the procedure, the thrombus can be dissolved partially, which helps to restore the blood supply and alleviate ischemia quickly. However, in most cases, the hepatic artery may not be opened completely via a single infusion of urokinase during the procedure. Therefore, a continuous infusion with a small amount of urokinase is necessary in the residual thrombus to completely restore hepatic artery blood flow. Clinical safety and efficacy have been demonstrated with different dosages of thrombolytic agent (12,20–22), and the lowest effective dosage and duration have not yet been determined. In the present study, different doses of urokinase were administered. In 1 patient, 9,000,000 U of urokinase was administered without any complications. Another patient in whom 950,000 U of urokinase were administered experienced severe hemorrhage. Therefore, clinically safe and effective dosages of urokinase varied with huge individual differences. It is difficult to determine
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the clinical safety and efficacy of urokinase dosages in thrombolysis treatment. Successful thrombolytic dosages are not easy to achieve in pediatric patients with HATs, recipients of split grafts, and recipients of living donor transplants because smaller and tortuous hepatic arteries are technically difficult in LT and thrombose extensively before interventional procedures, which increases greatly dosage and time of thrombolysis. Increasing urokinase dosage causes more complications. To avoid the prolongation of thrombolysis as well as a lower exposure to bleeding problems, stent placement should be performed; however, stent placement in smaller and tortuous hepatic arteries has a high risk of vascular intimal injury, which can cause more serious thrombosis, and in-stent thrombosis can easily develop after stent placement. Adjunctive anticoagulation with heparin is essential to prevent and treat thrombosis (23,24). Increased dose and duration of thrombolytic agent and adjunctive anticoagulation therapy contributed to increasing risk of hemorrhage (25,26). Hemorrhage was the most common complication in the present study. Careful monitoring of color of drainage in the abdominal cavity, coagulation function, and hemoglobin is necessary during thrombolysis treatment. It is recommended to maintain PT at approximately 25 seconds if there is no anastomotic and intraabdominal bleeding. The catheter sheath should be maintained for 2–3 days after initial recanalization of the hepatic artery so that thrombus recurrence can be detected and rethrombolysis can be performed immediately. In this group, recanalization of the hepatic artery was achieved in 2 patients with thrombus recurrence via the retained catheter sheath. Thrombolysis with restoration of flow without resolving underlying anatomic defects, such as kinking, can lead to rethrombosis and often requires PTA or stent placement (14–16). Orons et al (27) stated that hepatic artery stenosis, if left untreated, has a 65% chance to develop into HAT within 6 months. Yamakado et al (15) found that anastomotic stenosis was usually accompanied by reactive edema early after LT. Additionally, anastomotic stenosis may not be relieved, and risk of arterial rupture may be increased after PTA. Moreover, the restenosis rate can reach 60% after PTA (28). Stent placement can be used as the preferred treatment for early HAT accompanied by stenosis. If the thrombus cannot be dissolved continuously during continuous thrombolytic treatment, stent placement should be performed as soon as possible so that hepatic artery patency can be reestablished to avoid ischemic injury of liver parenchyma and biliary tree. Hepatic artery patency was reestablished in this way in 10 patients. For patients with a thrombosed hepatic artery trunk and nonthrombosed intrahepatic vasculature, stents can achieve recanalization of hepatic artery directly. However, thrombolysis with urokinase still needs to be performed in patients before and after stent placement. Interventional procedures associated with stent placement in the hepatic artery with thrombus have a higher incidence of vascular intimal injury. More serious thrombosis can result if thrombolysis is not
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performed before stent placement. Moreover, in-stent thrombosis can easily develop especially in patients with extensive HAT if thrombolysis is not performed after stent placement. No specific hepatic artery stent is available at the present time. Cotroneo et al (14) reported 4 patients with hepatic artery stenosis or a thrombus who were successfully treated by self-expanding stents. Balloon expandable coronary stents were usually applied as first-choice treatments for stenosis or HAT in the present study. Because coronary stents have an increased radial force and conformability and are sufficiently flexible compared with other peripheral vascular stents, stent placement in tortuous or angulated hepatic artery strictures is easily accomplished (29). However, stents cannot be applied to all hepatic arteries. Very small and tortuous hepatic arteries (eg, pediatric split grafts) would likely be technically difficult and may thrombose. Therefore, the use of stent placement in children with HAT is questionable. Splenic artery steal syndrome after LT was first proposed by Langer et al in 1990 (30) and defined as decreased perfusion of hepatic arteries because of diversion of blood flow into the splenic artery originating from the celiac trunk (31). Splenic artery steal syndrome has a reported morbidity of 3.1%–5.9% (32–34). The shift of hepatic blood flow can cause devastating consequences, such as ischemic biliary tract destruction or graft failure. In patients with other conditions, such as rejection, ischemic injury, and increased intrahepatic resistance, slowing of blood flow can easily cause thrombosis (35). Splenic artery embolization with coils can be an adequate treatment because it can save the graft and it is minimally invasive (31–33). Proximal splenic artery embolization with coils was performed in 3 patients with splenic artery steal syndrome; splenic parenchyma was preserved in all cases, and no symptoms related to splenic artery embolization were identified. Proximal splenic artery embolization allowed collateral arterial perfusion of splenic parenchyma and avoided complications caused by splenic parenchyma injury. This study has some limitations. First, experience of thrombolysis of HAT is still limited, and more effective ways to administer thrombolysis need further exploration. Second, alteplase is a more effective and safer thrombolytic agent than urokinase; however, it was not used as a thrombolytic agent because of its high price. In addition, strict inclusion and exclusion criteria for interventional treatment of HAT were not established because this study was retrospective. In conclusion, interventional treatment can achieve satisfactory short-term and long-term effectiveness in adults with early HAT.
ACKNOWLEDGMENTS This study was supported by the Natural Science Foundation of Zhongshan Hospital for Young Scholars (Grant No. 2015ZSYXGG18), Natural Science Foundation of Shanghai City (Grant No. 15ZR1406700), National Natural Sciences
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Foundation of China (Grant No. 81501562), and National Natural Sciences Foundation of China (Grant No. 81171432).
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30. Langer R, Langer M, Neuhaus P, Scholz A, Felix R. Angiographic diagnosis in liver transplantation. I: Evaluation before transplantation. [German]. Digitale Bilddiagn 1990; 10:62–66. 31. Langer R, Langer M, Scholz A, Felix R, Neuhaus P, Keck H. The splenic steal syndrome and the gastroduodenal steal syndrome in patients before and after liver transplantation. [German]. Aktuelle Radiol 1992; 2:55–58. 32. Uflacker R, Selby JB, Chavin K, Rogers J, Baliga P. Transcatheter splenic artery occlusion for treatment of splenic artery steal syndrome after orthotopic liver transplantation. Cardiovasc Intervent Radiol 2002; 25:300–306. 33. Nussler NC, Settmacher U, Haase R, Stange B, Heise M, Neuhaus P. Diagnosis and treatment of arterial steal syndromes in liver transplant recipients. Liver Transpl 2003; 9:596–602. 34. Geissler I, Lamesch P, Witzigmann H, Jost U, Hauss J, Fangmann J. Splenohepatic arterial steal syndrome in liver transplantation: clinical features and management. Transpl Int 2002; 15:139–141. 35. Troisi R, Hoste E, Van Langenhove P, et al. Modulation of liver graft hemodynamics by partial ablation of the splenic circuit: a way to increase hepatic artery flow? Transplant Proc 2001; 33:1445–1446.
Interventional Treatment for Hepatic Artery Thrombosis after Liver Transplantation Hua Zhang, MD, Sheng Qian, MD, PhD, Rong Liu, MD, PhD, Wei Yuan, MD, PhD, and Jian-Hua Wang, MD, PhD ABSTRACT Purpose: To evaluate short-term and long-term effectiveness of interventional treatment for hepatic artery thrombosis (HAT). Materials and Methods: From March 2003 to October 2015, 34 patients (32 male and 2 female; mean age, 45 y; range 7–64 y) with HAT were identified 0–21d (mean 6.5 d ± 6.0) after liver transplantation and underwent interventional treatments. Technical success, clinical success, complications, hepatic artery patency, and survival time were assessed. Results: All 34 patients underwent urokinase thrombolytic treatment. The mean dosage of urokinase was 1,250,000 U ± 1,000,000 (range, 350,000–9,000,000 U). Thrombolysis treatment required 5–120 h (mean 50 h ± 31) for completion. In 21 patients, stents were also implanted during thrombolytic treatment. In 3 patients with splenic artery steal syndrome, proximal splenic artery embolization was performed during thrombolytic treatment. The technical and clinical success rate was 91% (31/34), with treatment failure in 3 children. Hemorrhage was observed in 11 cases. Local necrotic foci in the transplanted liver were found on CT in 5 patients. Complications associated with the interventional procedures occurred in 2 patients. Patency rates of the hepatic artery at 1 y, 2 y, 3 y, and 5 y were 96%, 93%, 83%, and 83%. Overall survival rate at 1 y, 2 y, 3 y, and 5 y were 82%, 73%, 57%, and 57%. Conclusions: Interventional treatment can achieve satisfactory short-term and long-term effectiveness for adult HAT.
ABBREVIATIONS HAT ¼ hepatic artery thrombosis, LT ¼ liver transplantation, PT ¼ prothrombin time
Hepatic artery thrombosis (HAT) is the most common and severe vascular complication and accounts for > 50% of all arterial complications after orthotopic liver transplantation (LT) (1,2). The incidence of HAT as a complication of LT in adults was reported to be 4%–15% (3–6), and HAT was generally more frequent after pediatric LT (3%–9% in adults vs 11%–26% in children) (7–9). Mortality related to HAT has been reported to reach 54.5% (10,11). Early diagnosis and effective treatment for HAT are crucial to organ salvage and patient survival. Generally there are 3 different treatment modalities for HAT: retransplantation, surgical revascularization, and interventional treatment. The most
effective treatment approach remains controversial. Interventional treatments for HAT, such as intraarterial thrombolysis, percutaneous transluminal angioplasty (PTA), and stent placement, have been emerged as a less invasive alternative to surgical intervention (12–16). However, interventional treatment for HAT remains controversial because of potential risk of fatal intraperitoneal hemorrhage (17,18) and uncertain long-term efficacy. In the present study, the short-term and long-term effectiveness of interventional treatment of HAT were evaluated retrospectively.
MATERIALS AND METHODS Patient Information
From the Shanghai Institute of Medical Imaging and Department of Interventional Radiology (H.Z., S.Q., R.L., W.Y., J.-H.W.), Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui, Shanghai 200032, China. Received November 19, 2016; final revision received April 11, 2017; accepted April 30, 2017. Address correspondence to J.-H.W.; E-mail: dr_wangjianhua@126. com None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–7 http://dx.doi.org/10.1016/j.jvir.2017.04.026
Between March 2003 and October 2015, 1,385 LTs (maleto-female ratio 1,162:223; mean patient age, 49.6 y ± 11.7; range, 0–81 y) were performed. Types of transplantation included orthotopic LT (n ¼ 1,325), living donor LT (n ¼ 48), split LT (n ¼ 8), and reduced LT (n ¼ 4). At 0–21 days (mean 6.5 d ± 6.0) after LT, HAT was identified in 34 patients (32 male and 2 female; mean age, 45 y; range, 7–64 y). Underlying diseases included primary hepatic carcinoma (n ¼ 21), end-stage hepatitis B virus–related liver cirrhosis (n ¼ 6), Wilson disease (n ¼ 4), congenital biliary
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atresia (n ¼ 2), and Budd-Chiari syndrome (n ¼ 1), and LT procedures included orthotopic LT (n ¼ 28; 2.1% of 1,325 orthotopic LTs), living donor LT (n ¼ 5; 10.4% of 48 living donor LTs), and split LT (n ¼ 1; 12.5% of 8 split LTs). Endto-end hepatic artery anastomosis was performed without intraoperative complications; types of arterial anastomoses between donors and recipients are listed in the Table. Blood types (ABO) between donors and recipients was identified in all 34 patients. Mean hot, cold, and warm ischemia times were 4.5 minutes (range, 0–5 min), 65 minutes (range, 43–100 min), and 6.5 hours (range, 4–12 h).
Diagnosis of HAT Hepatic artery blood flow was monitored daily by color Doppler ultrasound during the first postoperative week and then every 2 days until patients were discharged. Liver function, kidney functions, and routine blood and coagulation function tests were measured daily. On the basis of color Doppler ultrasound and/or clinical and laboratory findings, 38 patients were suspected to have HAT. Clinical and laboratory findings included fever and hepatalgia (n ¼ 4), and elevated serum alanine transferase and bilirubin (n ¼ 34); 2 patients were asymptomatic. Angiography immediately identified HAT in 34 patients. Among these 34 patients, mean alanine aminotransferase, aspartate aminotransferase, total bilirubin, and conjugated bilirubin levels were 428.5 U/L ± 385.0, 294.4 U/L ± 257.0, 50.9 U/L ± 35.0, and 30.1 U/L ± 22.9. Mean prothrombin time, activated partial thromboplastin time, international normalized ratio, and fibrinogen concentration were 20.5 seconds ± 11.9, 48.49 seconds ± 12.1, 1.4 ± 0.2, and 216.8 mg/dL ± 117.9. Patients with defective coagulation function and the following conditions were excluded from interventional treatment: activated partial thromboplastin time > 3 times the control value, PT > 2.5 times the control value, Table. Types of Arterial Anastomoses (N ¼ 34) LT Procedures
OLT
LDLT
SLT
Type of Arterial Anastomoses
Number of Cases
Donor
Recipient
CHA
CHA
22
CHA
PHA
1
CTA
CHA
4
CTA
PHA
1
RHA RHA
CHA RHA
1 1
RHA
LHA
1
RHA
PHA
1
LHA
CHA
1
LHA
CHA
1
CHA ¼ common hepatic artery; CTA ¼ celiac trunk artery; LDLT ¼ living donor liver transplantation; LHA ¼ left hepatic artery; OLT ¼ orthotopic liver transplantation; PHA ¼ proper hepatic artery; RHA ¼ right hepatic artery; SLT ¼ split liver transplantation.
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international normalized ratio > 3, fibrinogen concentration < 100 mg/dL, and platelet concentration < 30 109/L.
Methods A 5-F RH catheter (Cook, Inc, Bloomington, Indiana) was used for selective catheterization of the hepatic artery via a right femoral artery approach. Heparinization was performed with a weight-adjusted dosage regimen of 60 U/kg followed by 10 U/kg per hour via intravenous injection. A coaxial microcatheter (Progreat; Terumo, Tokyo, Japan) and micro–guide wire were passed to the thrombus. The coaxial microcatheter was advanced to the inside of the thrombus, and 100,000–250,000 U of urokinase (Lizhu Pharmaceutical Co. Ltd, Shanghai, China) was dissolved into 50 mL of normal saline and injected into the coaxial microcatheter during the first 15 minutes (this procedure was performed in all 34 patients with HAT). Another 250,000–750,000 U of urokinase was injected into the coaxial microcatheter during the next 30 minutes in the same way if the thrombolysis was not satisfactory (this procedure was performed in 32 patients with HAT). An additional 50,000–100,000 U was injected in the same way if the thrombolysis was still not satisfactory (this procedure was performed in 2 patients with HAT). After most of the large thrombus was dissolved, the coaxial microcatheter was newly advanced to inside of the residual thrombus, and 250,000 U of urokinase was dissolved into 50 mL of normal saline and perfused continuously by infusion pump at a rate of 6–10 mL/h during the following 12–24 hours in the intensive care unit. Liver function and routine blood and coagulation function tests were done every 5 hours. Arteriography was performed every 8 hours during thrombolytic treatment. The coaxial microcatheter was withdrawn from the RH catheter. Arteriography of the celiac trunk and common hepatic artery was performed through the RH catheter. When the thrombus was dissolved and branches of the hepatic artery were shown clearly, thrombolysis was stopped. The catheter sheath was retained for 2–3 days. Hepatic artery angiography was performed daily. Stents (XIENCE PRIME; Abbott, Abbott Park, Illinois) were implanted if the following conditions occurred during thrombolytic treatment: (a) HAT was accompanied by stenosis or kinking, (b) the residual thrombi were > 70% of cross section inside the hepatic artery 24 hours after thrombolysis (n ¼ 5) or the residual thrombi were > 50% of cross section inside the hepatic artery 48 hours after thrombolysis (n ¼ 6). If splenic artery steal syndrome was observed during the thrombolysis treatment, proximal embolization of the splenic artery with coils (Gianturco coils; Cook, Inc) was performed (Fig 1a–f). Low-molecular-weight heparin, 4,100 U in adults and 1,000 U in children (Fraxiparine; GlaxoSmithKline, Middlesex, UK), was administered for anticoagulation every 12 hours by subcutaneous injection and lasted for 1 week after recanalization of the thrombosed hepatic artery. PT was limited to approximately 25 seconds (normal range, 10–13 s).
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Figure 1. Interventional treatment of HAT. (a) The initial segment of the hepatic artery was kinked and stenosed (arrow). The intrahepatic artery branches are not shown. (b) The thrombus was dissolved in a region distant from the site of thrombus anastomosis after 24 hours of thrombolytic therapy, but thrombus at the anastomotic site still (arrows) was not dissolved. (c) A stent (arrow) with a diameter of 4 mm and length of 38 mm was placed. (d) The hepatic artery kinks and stenosis disappeared. The blood flow of the hepatic artery was patent. (e) Angiography demonstrated complete hepatic artery occlusion, and the large splenic artery (arrow) severely shunted the hepatic artery blood flow. (f) Hepatic artery was patent after 72 hours of thrombolytic therapy, stent placement, and proximal splenic artery embolization.
Analysis and Follow-up Technical and clinical success rates, complications, survival time, and hepatic artery patency were analyzed. Technical success was defined as recanalization of hepatic artery blood flow after interventional treatment. Clinical success was defined as disappearance of signs or symptoms and elevated laboratory values. Complications were assessed according to Society of Interventional Radiology (SIR) Clinical Practice Guidelines (19). Minor complications were defined as complications requiring no therapy, no consequence or nominal therapy, and no consequence, including overnight admission for observation only. Major complications were defined as complications requiring major therapy, unplanned increase in level of care, or prolonged hospitalization (> 48 h), resulting in permanent adverse sequelae or death. Hepatic artery patency was defined as no stenosis and thrombosis during the follow-up period. Color Doppler ultrasound, liver function tests, and routine blood and coagulation function tests were performed monthly. If patients were suspected to have HAT or hepatic artery stenosis on the basis of color Doppler ultrasound and/or clinical and laboratory findings (eg, fever, hepatalgia, elevated serum alanine transferase and bilirubin) during follow-up, computed tomography (CT) or magnetic resonance (MR) imaging was performed immediately. If patients were not suspected to have HAT or hepatic artery stenosis on the basis color Doppler ultrasound and/or clinical and laboratory findings, CT or MR imaging was performed every
6 months. Follow-up ended at the time of death, the last patient visit, or June 5, 2016.
Statistical Analysis The statistical analysis was performed with IBM SPSS Statistics for Windows version 20.0 (IBM Corp, Armonk, New York). Continuous variables were expressed as mean ± SD or as median. The hepatic artery patency rate and overall survival rate were determined by the KaplanMeier method.
RESULTS Angiography Outcomes, Technical Success, and Clinical Success The thrombi of the 34 patients all were located at the anastomotic site of the hepatic artery, and in 3 of 34 cases, thrombi were located at the branches of the hepatic artery. The thrombi were 3–30 mm in length. Thrombolytic treatment with urokinase was performed in these 34 patients. The mean dosage of urokinase was 1,250,000 U ± 1,000,000 (range, 350,000–9,000,000 U). Thrombolysis treatment required 5–120 hours (mean 50 h ± 31) for completion. Balloon-expandable stents were implanted in 21 patients during thrombolytic treatment. There were 24 stents implanted (diameter, 2.5–5.0 mm; length, 10–38 mm). Proximal splenic artery embolization was
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performed in 3 patients with splenic artery syndrome during thrombolytic treatment. Recanalization of the hepatic artery was achieved in 31 of 34 patients; recanalization failed in 3 children (age 7, 7, and 14 y). The reason for failure was acute thrombosis in the stents on the day of stent implantation. Repeated thrombolysis was unsuccessful. One child (age 7 y) underwent retransplantation. She survived 4 years and died of multipleorgan failure caused by inferior vena cava and hepatic vein stenosis. Two children (age 7 y and 14 y) without surgical intervention died of multiple-organ failure 6 days and 10 days after stent placement because of no grafts. Clinical success was achieved in 31 of 34 patients. Resolution of signs or symptoms and improvement of laboratory findings were achieved 3–14 days (mean, 7.5 d ± 4.6) after hepatic artery recanalization. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, and conjugated bilirubin levels were decreased to 62.3 U/L ± 58.2, 36.0 U/L ± 29.4, 22.8 U/L ± 13.9, and 14.2 U/L ± 11.4 at 2 weeks after hepatic artery recanalization.
Complications During the thrombolysis, 11 patients experienced bleeding from the abdominal cavity. In 3 of 11 patients, hemoglobin decreased significantly (< 70 g/L), and extravasation of contrast agent at the anastomotic site was identified by angiography. Graft-covered stents (Jo Stents; Abbott Vascular Netherlands BV, Heerlen, Netherlands) were implanted in these 3 patients, and the bleeding was stopped; the patients received blood transfusions and were discharged in good health with a patent hepatic artery. During the follow-up period, 2 of the 3 patients died of causes unrelated to hepatic arteries; survival times were 26 and 80 months, respectively. The third patient was still alive during the follow-up period. No extravasation of contrast agent and decreased hemoglobin were observed in another 8 patients; the bleeding gradually decreased and stopped after decreasing or stopping the urokinase. CT revealed local necrotic foci (minor hypodense ischemic lesions) in the transplanted liver in 5 patients; these foci were observed 0, 4, 8, 10, and 20 days after diagnosis of HAT. Cefoperazone/sulbactam (Sulperazone; Pfizer Pharmaceutical Co, New York, New York) was infused intravenously. Thus, no infection of the necrotic foci and no liver abscess developed in these 5 patients. Complications associated with interventional procedures occurred in 2 patients. One case involved a femoral artery pseudoaneurysm that was treated with a compression bandage. The other case involved extravasation of contrast agent at the anastomotic site caused by the interventional procedure, and a graft-covered stent (Jo Stent) was implanted. HAT recurred in 2 patients at 12 hours and 36 hours after initial recanalization of hepatic artery. Rethrombolysis was performed. The blood flow of the hepatic artery was reestablished successfully at 24 hours and 72 hours after rethrombolysis. A total of 3,250,000 U was
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administered to 1 patient during initial thrombolysis and rethrombolysis. In another patient, 9,000,000 U of urokinase was administered during initial thrombolysis and rethrombolysis.
Follow-Up, Hepatic Artery Patency, and Survival Time Follow-up time ranged from 3 to 135 months. Recurrence of HAT 6 months after initial recanalization of the hepatic artery was observed in 1 patient who underwent retransplantation; the patient died of multiple-organ failure 2 months later. Hepatic artery stenosis was observed in 4 patients at 22, 25, 30, and 32 months after LT; no clinical symptoms were observed, and no further treatment was performed. The 4 patients died during the follow-up period of causes unrelated to hepatic arteries; survival times of these patients were 37, 37, 80, and 94 months. Biliary strictures were observed in 4 patients at 5, 10, 15, and 30 months after LT. Biliary stents were implanted using endoscopic retrograde cholangiopancreatography, and the 4 patients were still alive with normal liver function during the follow-up period. There were 9 patients with patent hepatic arteries who died during the follow-up period of causes unrelated to hepatic arteries. During the follow-up period ranging from 12 to 135 months, 17 patients remained alive in good health with patent hepatic arteries. The patency rates of the hepatic artery at 1 year, 2 years, 3 years, and 5 years were 96%, 93%, 83%, and 83% (Fig 2). The overall survival rates at 1 year, 2 years, 3 years, and 5 years were 82%, 73%, 57%, and 57%. The median survival time was 94 months (Fig 3).
DISCUSSION Interventional selective catheterization of the hepatic artery made intraarterial thrombolytic therapy possible. Hidalgo et al (12) first reported the successful use of intraarterial
Figure 2. Kaplan-Meier estimate of the rate of hepatic artery patency. The patency rates of the hepatic artery at 1 year, 2 years, 3 years, and 5 years were 96%, 93%, 83%, and 83%.
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Figure 3. Kaplan-Meier estimate of the rate of overall survival. The overall survival rates at 1 year, 2 years, 3 years, and 5 years were 82%, 73%, 57%, and 57%. The median survival time was 94 months.
thrombolytic therapy in 2 cases of HAT. Selective thrombolysis has several advantages, such as small thrombolysis dose, high localized concentration, and minimal effect on systemic coagulation. Bjerkvik et al (13) believed that thrombolytic treatment combined with mechanical recanalization using a guide wire and catheter was more effective, with reestablished slow blood flow giving the thrombolytic agent a much better chance to work throughout the arterial tree. Mechanical recanalization with a microcatheter was applied in the present study. Mechanical recanalization with a softer microcatheter was beneficial in decreasing hepatic artery intimal injury; however, artery injury caused by recanalization with a microcatheter occurred in 1 patient. Figueras et al (20) suggested that continuous urokinase therapy would be safer and more effective if the infusion catheter was placed inside the thrombus, and a similar method was used in this group. The coaxial microcatheter was left inside the thrombus. Using a bolus injection of a large dose of urokinase over a relatively short time during the procedure, the thrombus can be dissolved partially, which helps to restore the blood supply and alleviate ischemia quickly. However, in most cases, the hepatic artery may not be opened completely via a single infusion of urokinase during the procedure. Therefore, a continuous infusion with a small amount of urokinase is necessary in the residual thrombus to completely restore hepatic artery blood flow. Clinical safety and efficacy have been demonstrated with different dosages of thrombolytic agent (12,20–22), and the lowest effective dosage and duration have not yet been determined. In the present study, different doses of urokinase were administered. In 1 patient, 9,000,000 U of urokinase was administered without any complications. Another patient in whom 950,000 U of urokinase were administered experienced severe hemorrhage. Therefore, clinically safe and effective dosages of urokinase varied with huge individual differences. It is difficult to determine
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the clinical safety and efficacy of urokinase dosages in thrombolysis treatment. Successful thrombolytic dosages are not easy to achieve in pediatric patients with HATs, recipients of split grafts, and recipients of living donor transplants because smaller and tortuous hepatic arteries are technically difficult in LT and thrombose extensively before interventional procedures, which increases greatly dosage and time of thrombolysis. Increasing urokinase dosage causes more complications. To avoid the prolongation of thrombolysis as well as a lower exposure to bleeding problems, stent placement should be performed; however, stent placement in smaller and tortuous hepatic arteries has a high risk of vascular intimal injury, which can cause more serious thrombosis, and in-stent thrombosis can easily develop after stent placement. Adjunctive anticoagulation with heparin is essential to prevent and treat thrombosis (23,24). Increased dose and duration of thrombolytic agent and adjunctive anticoagulation therapy contributed to increasing risk of hemorrhage (25,26). Hemorrhage was the most common complication in the present study. Careful monitoring of color of drainage in the abdominal cavity, coagulation function, and hemoglobin is necessary during thrombolysis treatment. It is recommended to maintain PT at approximately 25 seconds if there is no anastomotic and intraabdominal bleeding. The catheter sheath should be maintained for 2–3 days after initial recanalization of the hepatic artery so that thrombus recurrence can be detected and rethrombolysis can be performed immediately. In this group, recanalization of the hepatic artery was achieved in 2 patients with thrombus recurrence via the retained catheter sheath. Thrombolysis with restoration of flow without resolving underlying anatomic defects, such as kinking, can lead to rethrombosis and often requires PTA or stent placement (14–16). Orons et al (27) stated that hepatic artery stenosis, if left untreated, has a 65% chance to develop into HAT within 6 months. Yamakado et al (15) found that anastomotic stenosis was usually accompanied by reactive edema early after LT. Additionally, anastomotic stenosis may not be relieved, and risk of arterial rupture may be increased after PTA. Moreover, the restenosis rate can reach 60% after PTA (28). Stent placement can be used as the preferred treatment for early HAT accompanied by stenosis. If the thrombus cannot be dissolved continuously during continuous thrombolytic treatment, stent placement should be performed as soon as possible so that hepatic artery patency can be reestablished to avoid ischemic injury of liver parenchyma and biliary tree. Hepatic artery patency was reestablished in this way in 10 patients. For patients with a thrombosed hepatic artery trunk and nonthrombosed intrahepatic vasculature, stents can achieve recanalization of hepatic artery directly. However, thrombolysis with urokinase still needs to be performed in patients before and after stent placement. Interventional procedures associated with stent placement in the hepatic artery with thrombus have a higher incidence of vascular intimal injury. More serious thrombosis can result if thrombolysis is not
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performed before stent placement. Moreover, in-stent thrombosis can easily develop especially in patients with extensive HAT if thrombolysis is not performed after stent placement. No specific hepatic artery stent is available at the present time. Cotroneo et al (14) reported 4 patients with hepatic artery stenosis or a thrombus who were successfully treated by self-expanding stents. Balloon expandable coronary stents were usually applied as first-choice treatments for stenosis or HAT in the present study. Because coronary stents have an increased radial force and conformability and are sufficiently flexible compared with other peripheral vascular stents, stent placement in tortuous or angulated hepatic artery strictures is easily accomplished (29). However, stents cannot be applied to all hepatic arteries. Very small and tortuous hepatic arteries (eg, pediatric split grafts) would likely be technically difficult and may thrombose. Therefore, the use of stent placement in children with HAT is questionable. Splenic artery steal syndrome after LT was first proposed by Langer et al in 1990 (30) and defined as decreased perfusion of hepatic arteries because of diversion of blood flow into the splenic artery originating from the celiac trunk (31). Splenic artery steal syndrome has a reported morbidity of 3.1%–5.9% (32–34). The shift of hepatic blood flow can cause devastating consequences, such as ischemic biliary tract destruction or graft failure. In patients with other conditions, such as rejection, ischemic injury, and increased intrahepatic resistance, slowing of blood flow can easily cause thrombosis (35). Splenic artery embolization with coils can be an adequate treatment because it can save the graft and it is minimally invasive (31–33). Proximal splenic artery embolization with coils was performed in 3 patients with splenic artery steal syndrome; splenic parenchyma was preserved in all cases, and no symptoms related to splenic artery embolization were identified. Proximal splenic artery embolization allowed collateral arterial perfusion of splenic parenchyma and avoided complications caused by splenic parenchyma injury. This study has some limitations. First, experience of thrombolysis of HAT is still limited, and more effective ways to administer thrombolysis need further exploration. Second, alteplase is a more effective and safer thrombolytic agent than urokinase; however, it was not used as a thrombolytic agent because of its high price. In addition, strict inclusion and exclusion criteria for interventional treatment of HAT were not established because this study was retrospective. In conclusion, interventional treatment can achieve satisfactory short-term and long-term effectiveness in adults with early HAT.
ACKNOWLEDGMENTS This study was supported by the Natural Science Foundation of Zhongshan Hospital for Young Scholars (Grant No. 2015ZSYXGG18), Natural Science Foundation of Shanghai City (Grant No. 15ZR1406700), National Natural Sciences
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Foundation of China (Grant No. 81501562), and National Natural Sciences Foundation of China (Grant No. 81171432).
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