Deceased liver donors may have any of several inheritable disorders that are not recognized at the time of donation. Livers from these donors can transmit clinical diseases to the recipient when transplanted. Our case concerns a patient who experienced multiple intrahepatic vascular thromboses after receiving a transplanted liver later determined by DNA studies to have heterozygous factor V Leiden mutation. This patient’s situation was further complicated by a failed transjugular intrahepatic portosystemic shunt attempt at thrombectomy/thrombolysis, which caused an intrahepatic hematoma and intra-abdominal bleeding with an abdominal compartment syndrome. The patient had a successful outcome after treatment with long-term anticoagulation therapy.

Many of the factors important to the coagulation process are synthesized in the liver, including factor V. A point mutation of the factor V gene, called factor V Leiden mutation, is the most frequently inherited thrombophilic disorder and is not uncommon among the general population.¹The inability of activated protein C to degrade the abnormal factor V creates a thrombophilic diathesis.

Because there are a number of genetic disorders a potential organ donor could have, testing for all of them would be cost-prohibitive. Therefore, deceased liver donors are not routinely checked for factor V Leiden mutation or other thrombophilic disorders. It is imperative that the organ transplant team retain a high level of suspicion when evaluating organs from donors.

Case report
A 46-year-old woman with hepatitis C virus (HCV)—induced cirrhosis was awaiting liver transplantation. She was a nurse anesthetist who had worked in the operating room before her liver disease was diagnosed. The patient’s liver disease was complicated by ascites and pleural effusions, and she was treated with a combination of interferon and ribavirin for 16 months until she achieved an undetectable HCV viral load. After 6 months on the waiting list, she was offered a blood-type—compatible liver. The donor was a 37-year-old man who had died from anoxic brain injury following cardiac arrest. The donor had undergone an emergency triple vessel bypass, failed to regain consciousness after surgery, and progressed to brain death. He had a history of hyperlipidemia but no personal or family history of hypercoagulopathy. The donor’s liver, kidneys, and lungs were recovered for transplantation. Of note, during procurement, an organized clot was observed along the length of the posterior wall of the inferior vena cava. There was no visible evidence of pathology in any other abdominal organ. Frozen sections of the clot showed benign organized thrombus only, and it was decided to proceed with the transplant. During back-table preparation of the liver allograft, the clot was removed from the donor’s vena cava. Examination and probing of the donor’s hepatic veins did not identify any further clot.

At the time of transplantation, the patient had a total bilirubin of 22.6 mg/dL (normal, 0.2—1.3 mg/dL), a prothrombin time of 26.3 seconds (normal, 9.4— 11.8 seconds) with an International Normalized Ratio of 2.6, and a creatinine of 1.4 mg/dL (normal, 0.6—1.1 mg/dL). Preoperative imaging found no evidence of hepatic vascular thromboses.

The transplant procedure itself was uneventful; the patient underwent a standard bicaval anastomosis orthotopic transplant operation. The donated liver was anastomosed to the recipient’s supra and infrahepatic vena cavas, the portal vein, and the hepatic artery. The recipient showed no evidence of portal vein thrombosis. The liver reperfused well, with immediate bile production. The patient underwent a duct-to-duct biliary anastomosis.

The patient was extubated the day after surgery, and Doppler ultrasonography of her new liver showed patent vasculature. Her liver exhibited excellent recovery, and laboratory tests from postoperative day 4 showed a total bilirubin of 4.2 mg/dL, prothrombin time of 14.1 seconds with an International Normalized Ratio of 1.3, aspartate aminotransferase (AST) of 87 U/L (normal, 8—39 U/L), alanine aminotransferase (ALT) of 214 U/L (normal, 9—52 U/L), and creatinine of 1.2 mg/dL. An immunosuppressive regimen consisting of tacrolimus, mycophenolate, and steroids was initiated.

Laboratory tests on postoperative day 5 showed elevated aminotransferase levels (AST, 245 U/L; ALT, 330 U/L). Repeat Doppler ultrasonography of the patient’s liver showed thrombosis of the intrahepatic portion of her right hepatic vein with reversal of flow in the right portal vein (Figure 1). We were unsure of the etiology of this finding and initiated a therapeutic anticoagulation regimen using heparin. Following the initiation of anticoagulation therapy, the patient’s partial thromboplastin times (PTT) were maintained between 55 and 60 seconds and her aminotransferases declined.

On postoperative day 7, the patient became extremely somnolent and exhibited other features of encephalopathy. Her AST was 104 U/L, ALT was 214 U/L, and total bilirubin was 4.7 mg/dL. Doppler ultrasonography of her liver showed the portal vein to be thrombosed while the right hepatic vein demonstrated some flow. These findings were confirmed using magnetic resonance imaging.

Based on the patient’s unusual pattern of thrombosis despite anticoagulation therapy, we suspected a medical cause for her prothrombotic activity and ordered a hematology consult to rule out a hypercoagulable disorder. Additionally, white blood cells (WBCs) harvested from the donor’s lymph nodes and spleen during procurement of the liver were isolated for genetic testing.

After consultation with interventional radiology, thrombolysis using a transjugular intrahepatic portosystemic shunt (TIPS) with placement of a catheter in the portal vein was attempted. Despite several tries, it was not possible to cannulate the portal vein from the hepatic veins (Figure 2). The patient was then taken to the operating room for a portal vein thrombectomy, which restored blood flow through the portal vein. Several subcapsular hematomas were observed on the underside of the liver, presumably resulting from the failed TIPS procedure. There appeared to be no active bleeding from these hematomas.

Hematologic studies showed a low protein C activity of 60% (normal, 74%— 116%), a low protein S activity of 41% (normal, 72%—149%), and a low activated protein C resistance ratio (APCRR) of 1.52 (normal, 1.95—2.89). The low activity of proteins C and S was felt to be caused by the patient’s liver disease and consumption secondary to the acute thrombotic event; however, the low APCRR indicated a possible mutation of factor V Leiden. DNA polymerase chain reaction studies of the donor’s WBCs confirmed heterozygous factor V Leiden mutation in the donated liver.

The patient remained on a heparin drip. Over the next 48 hours, she experienced intraperitoneal bleeding, evidenced by bloody output from her abdominal drains. During this time, she required 12 units of packed red blood cells to maintain her hematocrit above 24%. Her total bilirubin increased to 10.5 mg/dL. On postoperative day 10, she was noted to have a tense abdomen with sudden onset of oliguria, and her serum creatinine peaked at 2.2 mg/dL. An abdominal compartment syndrome was suspected, and she was taken back to the operating room, where 6 L of bloody fluid was aspirated. The bleeding originated from one of the subcapsular hematomas noted on the prior exploration. There was no evidence of blood clot within the abdomen. The heparin drip was reduced, and the hematoma site was packed with thrombogenic material. The patient’s skin was closed, with the fascia left open to reduce intra-abdominal pressure.

The heparin drip was adjusted to maintain the patient’s PTT values between 40 and 45 seconds. Thereafter, no more bleeding was noted. She was switched to therapeutic oral anticoagulation with warfarin. Her total bilirubin peaked at 20 mg/dL, and her creatinine peaked at 3.3 mg/dL before returning to normal over the subsequent 2-month period. During that time, imaging studies revealed an intrahepatic hematoma, which was assumed to have arisen after the TIPS procedure attempt (Figure 3). This hematoma was secondarily infected with vancomycin-resistant Enterococci. It was successfully treated with 8 weeks of intravenous antibiotics after initial curative attempts using percutaneous drainage failed. Eight months posttransplant, the patient’s hematoma had largely resolved and she showed no indication of infection or hepatic dysfunction. She remains on oral anticoagulation therapy, and subsequent serial biopsies show no sign that her HCV has recurred.

Discussion
Thrombosis of the hepatic vasculature is a known complication of liver transplantation. While the etiologies of this complication include surgical technique and pre-existing hypercoagulopathies in the recipient, a thrombotic diathesis transmitted from a donor liver must be considered. Portal vein thrombosis after liver transplantationhas been reported in less than 1% of recipients. To our knowledge, there are no previous reports of intrahepatic thrombosis of a single hepatic vein as a complication of liver transplantation.

Factor V Leiden mutation is a commonly inherited thrombophilic disorder. Its worldwide prevalence is estimated to be between 1% and 8.5%.¹ Factor V is produced predominantly in the liver, with smaller amounts produced in megakaryocytes and vascular endothelium.² This mutation is associated with a 6- to 8-fold increased risk of venous thromboembolism in heterozygote carriers and an 80-fold increased risk in homozygous carriers.³ Donors discovered to have factor V Leiden mutation usually had a history of multiple vascular thromboses. Finding the intracaval thrombus in our patient’s donor should have prompted us to consider this possibility. In the coagulation cascade, activated factor V used for thrombin generation is inactivated by activated protein C. Inability to degrade the mutated factor V causes activated protein C–resistance. Factor V Leiden mutation is the most common cause of activated protein C–resistance.^4,5

There have been previous reports of donor livers transmitting factor V Leiden mutation to transplant recipients and causing venous thromboses in those patients.^4-7 In most instances, such cases were limited to extrahepatic venous thromboses only. In a retrospective study, Hirshfield and colleagues reported a thrombotic event in 6 of 41 liver transplant recipients and, specifically, hepatic vascular thromboses in 4 of 31 recipients whose donor had factor V Leiden mutation.⁴In Hirshfield’s study, hepatic vascular thromboses always led to graft loss or death. Overall, studies recommend lifelong anticoagulation for recipients of livers with factor V Leiden mutation.

Patients with liver failure often exhibit abnormalities on routine coagulation tests. They are known to have reduced levels of anticoagulation factors, including protein C.⁸These abnormalities may take a few days to correct after liver transplantation, which is why the first week after transplantation poses the greatest risk for vascular thromboses. Theoretically, this could have influenced our patient’s timing of clot formation. However, the finding of a low APCRR in our patient suggested a factor V Leiden deficiency of unknown origin.

We were able to conclude that the factor V Leiden deficiency originated from the donor by conducting DNA polymerase chain reaction studies of WBCs preserved from the donor’s lymphocytes. This could have been further confirmed by finding no evidence of factor V Leiden mutation in the recipient’s WBCs.

The standard of care for an early posttransplant portal venous thrombosis is operative thrombectomy. Using a TIPS procedure with local thrombolysis has been reported as successful treatment for early posttransplant portal vein thrombosis. Ciccarelli and colleagues report a positive outcome for a recipient who had early portal vein thrombosis and underwent a TIPS procedure with 12 hours of local infusion of recombinant tissue plasminogen activator.⁹ The authors’ stated advantages to this procedure include the ability to perform it under local anesthesia and the convenient access it allows to the portal system for repeat therapeutic and diagnostic studies.⁹

We elected to try a TIPS procedure because our patient had separate areas of clot (portal and right hepatic vein) that we did not think we could clear with surgical intervention alone. Performing a TIPS procedure in such a patient can be complicated because the portal system is clotted off and difficult to locate to create the shunt. Lateral rotation of the liver, which may be seen immediately posttransplant, can also contribute to the difficulty. In retrospect, our patient suffered complications as a result of the TIPS procedure attempt.

Conclusion
Given the prevalence of factor V Leiden mutations, it may be prudent to keep it in mind when procuring organs from a donor who has a personal or family history of thrombotic disorders. Suspect donors could undergo DNA testing of their blood or tissues to identify this disorder. Because the liver is the main source of the mutated factor, it should receive increased attention. Thrombotic complications in the recipient may be life-threatening, but they are avoidable with timely initiation of anticoagulation prophylaxis.

References
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2. Camire RM, Pollak ES, Kaushansky K, et al. Secretable human platelet–derived factor V originates from the plasma pool. Blood. 1998;92(9):3035-3041.

3. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med. 2001;135(5): 367-373.

4. Hirshfield G, Collier JD, Brown K, et al. Donor factor V Leiden mutation and vascular thrombosis following liver transplantation. Liver Transpl Surg. 1998;4(1):58-61.

5. Leroy-Matheron C, Duvoux C, Van Nhieu JT, et al. Activated protein C resistance acquired through liver transplantation and associated with recurrent venous thrombosis. J Hepatol. 2003;38(6): 866-869.

6. Willems M, Sterneck M, Langer F, et al. Recurrent deep-vein thrombosis based on homozygous factor V Leiden mutation acquired after liver transplantation. Liver Transpl. 2003;9(8):870-873.

7. Gillis S, Lebenthal A, Pogrebijsky G, et al. Severe thrombotic complications associated with activated protein C resistance acquired by orthotopic liver transplantation. Haemostasis. 2000; 30(6):316-320.

8. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553-558.

9. Ciccarelli O, Goffette P, Laterre PF, et al. Transjugular intrahepatic portosystemic shunt approach and local thrombolysis for treatment of early posttransplant portal vein thrombosis. Transplantation.2001;72(1): 159-161.