Key words : Liver transplant, Liver graft survival, Thrombotic complications, Thrombus

Hepatic artery thrombosis (HAT) after living donor liver transplant (LDLT) is a severe complication that may cause acute allograft loss and patient mortality in the immediate postoperative period.^1,2 In recent years, perioperative care has significantly improved for LDLT recipients and reduced the incidence of early HAT after liver transplant (LT). However, despite these improvements, the rates of early HAT for LDLT recipients still range between 2% and 25%.^3,4 A disturbance in the blood flow of the hepatic artery substantially influences the prognosis after LDLT, making HAT the Achilles’ heel of adult LT.

Two types of HAT may be distinguished: early HAT and late HAT.^2,4,5 Early HAT presents shortly after LDLT with an obstructed hepatic artery, which causes biliary ischemia and graft dysfunction and may culminate in graft insufficiency and loss.⁶ Patients with early HAT may clinically present with symptoms of bile duct necrosis, followed by fulminant sepsis in immunocompromised recipient populations. This may quickly escalate to high postoperative patient morbidity and mortality.⁷ Indicators of early HAT may be of biliary (eg, leak or stricture) or hepatic kind (eg, liver abscess).⁸ In comparison, the clinical presentation of late HAT is more variable and may include signs of acute cholangitis with or without strictures and abscesses, as well as bile leaks. However, late HAT may also proceed without obvious clinical signs, with or without laboratory evidence of further impaired liver function.² Because initial symptoms and/or alterations of laboratory parameters may be delayed, daily routine Doppler ultrasonography screening (DUS) for HAT is imperative.⁴

In the past, surgical circumstances (eg, strong discrepancy between donor and recipient artery sizes) were considered risk factors for the development of HAT.⁷ Presently, we know that ischemia-reperfusion damage, graft preservation, coagulatory and immu­no­logical causes, infections, and previous episodes of rejection are equally relevant to the etiology of HAT.^3,4,9 Genetic factors may affect the predisposition for or against vascular complications such as HAT in organ recipients.¹⁰

Immediate intervention is essential to prevent acute graft loss as a result of HAT. Retransplant is the favored option, albeit it is clearly limited by both organ availability and patients’ clinical conditions.¹¹ Reports on surgical revascularization (ie, anastomotic revision), endovascular thrombolysis, percutaneous transluminal angioplasty, and stent placement have shown favorable outcomes.^5,11,12 However, some groups have claimed rates of revascularization failure that exceed 30%.¹³ Furthermore, there is the serious risk of hemorrhage at the surgical site.¹⁴ Presently, conservative “wait-and-see” approaches with best supportive care are described, especially after failed interventional and surgical recanalization and in cases for which retransplant is not feasible.¹

Herein, we report our 13-year experience with early HAT after adult LDLT and present outcomes of 5 patients treated at our LT center at Jordan Hospital, with emphasis on different approaches for surgical, interventional, and conservative vessel management

From April 2004 to December 2020, we performed 155 LDLTs in adults with end-stage liver failure, of which 3% developed early HAT. The Child-Pugh score and the Model for End-stage Liver Disease (MELD) score were used to document patients’ health conditions before LT. In this study, we evaluated their demographic characteristics and perioperative data, as well as postoperative complications and outcomes. The following epidemiological data were collected: age, sex, underlying disease, body weight, and origin of liver donation.

Approval for this study was obtained from the Jordan Hospital ethics committee. Written informed consent was obtained from all patients for the publication of this report.

The mean patient age was 49 years; 2 patients were female (40%) (Table 1). All patients presented with severe liver disease with a class C Child-Pugh score and a mean MELD score of 32 (range, 29-37). Causes of end-stage liver diseases in our study population included hepatitis B (40%) and hepatitis C viral infection (40%) and cryptogenic liver cirrhosis (20%). Results of prerequisite medical assessments showed no contraindications for LT. After evaluation and exclusion of an average of 4 to 5 potential donor candidates per patient, suitable donors from among each patient’s immediate kin were eventually selected. Our local ethical committee, psychiatric team, and the institutional LT board established an agreement to proceed with liver donation in all of the selected patients.

Each graft was transplanted after a total recipient hepatectomy with preservation of the inferior vena cava, as previously described by Tsui and colleagues.¹⁵ Similarly, hepatic artery reconstruction was performed with magnifying loupes and 8-0 or 6-0 Prolene (Johnson and Johnson) via end-to-end anastomosis between the donor right hepatic artery and recipient right, left, or common hepatic artery.

The mean graft weight was 972 g, the mean patient weight was 77 kg, and the mean graft-to-recipient weight ratio was 1.398 (Table 2). During the procedures, all patients required fresh frozen plasma (average, 14 U) and packed red blood cells (average, 9 U) (Table 2). The average cold ischemia time was 88 minutes (Table 2).

In the immediate postoperative period, intra­venous anticoagulation was initiated for all patients by heparin infusion (targeted activated partial throm­boplastin time, 45-50 seconds) and by daily intake of 100 mg of acetylsalicylic acid. All patients received a tacrolimus-based immunosuppressive therapy.

After the diagnosis of early HAT in our first patient, surgical revision of the narrowed anastomosis was performed. Subsequently, a recurrent, intralu­minal hepatic artery thrombus was detected via DUS 2 days after surgical intervention and confirmed via computed tomography (CT) (Figure 1A and Figure 1B). Therefore, the preexisting systemic anticoagulation was declared insufficient to prevent HAT in this case. Because the surgical revision of anastomosis proved unsuccessful, we decided to treat all other patients, who displayed HAT, interventionally via catheter-based technology. We proceeded with local throm­bolysis via femoral artery; recombinant tissue plasminogen activator was applied directly to the site of the clot. After intervention in the catheter laboratory, all patients experienced a recurrence of HAT. Potential clinical deterioration was thoroughly monitored at all times. Throughout hospitalization, all patients remained fully conscious and displayed no evidence of impaired intellectual or neuromuscular functioning. No cognitive, psychomotor deficits, or personality changes were observed. Since urine output remained adequate throughout the hospital stay and liver enzyme levels were not further disrupted, liver failure and hepatic encephalopathy were ruled out with certainty.

Subsequently, a wait-and-see policy was imple­mented, which included precise observation of vital and hepatic parameters, regular DUS, and, if needed, contrast-enhanced angiographic CT. Patients were strongly advised to attend monthly follow-up appointments, at which all patients displayed acoustic intrahepatic signals (detected via DUS) as early as 2 weeks after LDLT, which were attributed to liver graft neovascularization (Figure 2). In the further course, 3 patients received endoscopic retrograde cholangiopancreatography with papillotomy; biliary stents were inserted in 2 patients to treat symptomatic stenoses. Notably, DUS revealed spontaneous recanalization of the hepatic artery in 1 patient at 6 months after LDLT (Figure 3).

Hitherto, 2 patients have died; 1 patient died from fatal pneumonia with sepsis on day 47 after LDLT, and 1 patient died from a lethal myocardial infarct 5.5 years after LT. The median follow-up period was approximately 9 years, and the cumulative 1-year, 5-year, and 10-year survival rates were 80%, 80%, and 60%, respectively (Table 1).

Hepatic artery thrombosis is a potentially lethal complication of LDLT that is a common cause of acute patient death and graft loss.^1,2 Despite enhancements in perioperative care, rates of HAT remain between 2% and 25%.³ Two types of HAT are known, ie, early HAT and late HAT, which differ in acuteness and clinical presentation.^2,4-6 These differences may include symptoms of bile duct necrosis, biliary leak or stricture, abnormal hepatic function tests, or fulminant sepsis and death.⁷ Late HAT may proceed without onset of clinical symptoms.² The etiology of early HAT remains a matter of debate, although both surgical and nonsurgical grounds are hypothesized to cause disturbances in the blood flow of the hepatic artery.⁵

Definitions of the time period for the early form of HAT are inconsistent and range from 2 weeks¹⁶ to 100 days¹⁷ after LT. Kayahan and colleagues have suggested a novel classification of HAT, ie, thromboses within the first postoperative week after LT are considered early HAT, whereas thrombotic events beyond the first week after transplant are considered late HAT.4 During our post-LDLT regimen with daily DUS, within the first postoperative week all of our patients demonstrated flow patterns typical of early HAT. In accordance with the proposed classification by Kayahan and colleagues,4 early HAT was diagnosed in all of our selected patients.

The regimen of primary prevention with anticoagulation begins on the first postoperative day with systemic heparinization by infusion therapy and daily acetylsalicylic acid. If HAT is suspected, then multidetector CT with 3-dimensional angiography is performed to confirm the diagnosis.

Early diagnosis and prompt intervention are crucial for graft and patient rescue, as stated by Kayahan and colleagues.⁴ Options to prevent acute graft loss include surgical revascularization, endovascular thrombolysis, percutaneous transluminal angioplasty, stents, or retransplant. As previously described by Bekker and colleagues,¹ sufficient hepatic artery perfusion and good survival rates are possible with conservative wait-and-see approaches, such as cautious obser-vation, best supportive care, and regular and recurrent use of Doppler sonography to detect arterial collaterals.

In their 20-year experience with pediatric LDLT, Seda-Neto and colleagues have reported that surgical recanalization bears not only the risk of bleeding but also displays high rates of failure.¹⁸ We share this concern, as surgical and interventional attempts to recanalize proved unsuccessful in our cases. Consequently, a catheter-based, interventional ap­proach was implemented for all patients. This procedure is commonly associated with an increased risk of hemorrhage at the surgical site, as described by Singhal and colleagues.¹⁴ Therefore, at our institution, interventional recanalization is performed with careful supervision of the drainage, and patients and teams are fully prepared to enter surgery in response to uncontrolled bleeding. After catheter intervention, all patients experienced rethrombosis, which has been managed conservatively ever since.

Our experience at Jordan Hospital shows that LDLT patients may achieve long-term survival, despite persistent or recurrent obstruction of the hepatic artery. Wozney and colleagues have suggested that these survival rates are explained by the development of arterial collaterals. Diagnosis by DUS or CT has confirmed that these neovascular formations originate most often from phrenic arteries.¹⁹ Moore and colleagues have further confirmed that neovascularizations toward the liver are clearly associated with higher rates of recovery.²⁰ From cases of traumatic liver ruptures with therapeutic ligation of the hepatic artery, we know that the interruption of arterial blood flow in the hepatic artery does not necessarily result in bile duct necrosis.^21,22 Because the vascularization of the bile ducts is entirely dependent on blood supply from the hepatic artery, it was concluded that hepatic collaterals prevent necrosis and thereby avert serious negative outcomes of HAT.^23-25 Although often initially absent, arterial collaterals may be observed in angiography as early as 2 weeks after LDLT¹⁹ (Figure 2). Furthermore, these details provide a possible explanation for the generally self-limiting courses of complications in patients with prevalent HAT.²⁶ We confirmed this, since all of the patients in our study displayed neovascular formations and have presented with satisfactory survival rates to the present day. One patient developed spontaneous recanalization at 6 months after catheter intervention, which further emphasizes the possibility of benign courses despite persistent HAT (Figure 3).

The clinical stability of our patients and all laboratory results disfavored emergency retransplant, which is otherwise limited by insufficient access to donor organs in Jordan. Similarly, living donor retransplant from immediate kin is difficult to implement, since patient workup before LT generally involved the exclusion of 4 to 5 relatives per patient (these exclusions were mostly in response to problematic anatomic conditions, fatty liver, or severe obesity). Sevmis and colleagues have suggested that arterial thrombolysis and intraluminal stent placement should be the favored therapeutic approaches in patients with early HAT.²⁷ They recommended surgical exploration or retransplant in cases of failed interventional approaches and percutaneous translu­minal angioplasty and interventional stent placement in cases of severely narrowed hepatic artery.²⁸

Owing to the circumstances of local health policies, retransplant was not feasible, although we still consider retransplant to be the favored therapeutic option in countries with sufficiently developed deceased organ donation programs.

Limitations of our study include an inherent bias of retrospective study designs, as well as the modest number of patients, which could be enlarged to identify additional risk factors associated with the development of early HAT. However, we provided data that can contribute to the improvement of conservative vessel management after LT, which is crucial for physicians in countries with limited opportunities for retransplant. Furthermore, our findings bear substantial health care implications, as Jordan Hospital is a major regional health care provider for numerous Middle Eastern countries.

In summary, interventional catheter-based approaches with local application of thrombolytic agents are recommended. If patients experience recurrent thromboses but remain clinically stable, then we encourage de adoption of a wait-and-see approach for as long as hepatic failure can be ruled out with certainty. During the course of events, endoscopic retrograde cholan­giopan­creatog­raphy with papillotomy or biliary stent placement may be necessary. Special attention should be directed to arterial collateralization, which is known to be beneficial for both graft and patient survival.

Despite our favorable results, we hope that retransplant will become a feasible option for urgent cases of early HAT, since it has been favored over conservative and interventional approaches in the past.

Our findings show that benign courses of early HAT after LDLT are possible, despite persistent obstructions of the hepatic artery. In Jordan and other countries where organ scarcity may impede the feasibility of retransplant, physicians must rely heavily on interventional strategies and best supportive care for the management of persistent HAT.

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