Portal Hypertension in Patients with Hemophilia

Hemophilia is a congenital disorder that affects the blood's ability to clot properly. The condition predisposes patients to experience spontaneous bleeds, particularly into joints, or excessive bleeding following trauma or other insult. ¹ Hemophilia is a hereditary x-linked recessive disorder that primarily occurs as one of two types. Type A occurs due to a deficiency in clotting factor VIII, while type B occurs due to a deficiency in clotting factor IX. ¹ Hemophilia A and B are the most common of the severe hereditary hemorrhagic disorders. ¹ There is a type C hemophilia, however, it is quite rare. Hemophilia afflicts roughly 400,000 people worldwide with hemophilia A accounting for greater than 80% of all hemophilia cases. ^{2 3} Historically, patients with hemophilia have been treated with transfusions of clotting factor VIII or IX concentrates to correct their coagulopathy. The inability to pasteurize factor concentrates prior to the late 1980s led to many hemophiliacs contracting blood-borne viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). ⁴ As a result, there is an increased prevalence of viral hepatitis, chronic liver disease, cirrhosis, and, subsequently, portal hypertension in this patient population. ⁵

Etiology and Epidemiology of Portal Hypertension in Hemophiliacs

During the 1970s and the 1980s, hemophiliacs were treated with routine intravenous infusions of clotting factor concentrates, specifically factors VIII and IX. ⁶ Virally inactivated concentrates did not become widely available until 1987. ^{4 6} As a result, many hemophiliacs treated before 1987 contracted blood-borne viruses such as HBV, HCV, and HIV. ^{4 6} In 1990, Makris et al performed a radioimmunoassay to detect antibodies to HCV in 154 hemophiliacs. They found that the prevalence of anti-HCV antibodies was associated with level of exposure to clotting factor concentrates. In addition, they found that overall 59% of hemophiliacs who had received factor VIII or IX had anti-HCV antibodies. They also found that 76% of hemophiliacs who required over 10,000 units of factor concentrate annually had anti-HCV antibodies compared with 46% of hemophiliacs who required less factor concentrate and 0% of patients who had never received factor concentrate. ⁷ Also noted was a strong positive correlation between anti-HCV antibodies and antibodies against HBV and HIV. ⁷ In the study by Makris et al, ⁷ 35 patients with chronic liver disease also underwent liver biopsy. Histologically, features associated with posttransfusion hepatitis were found in 24 patients, all of whom showed anti-HCV antibodies, demonstrating that HCV is the major predisposing factor to hepatitis and chronic liver disease in hemophiliacs. ⁷ In a study by Goedert et al, ⁶ a total of 1,816 HCV-seropositive hemophiliacs were followed up over a 16-year period to quantify the risk of developing HCV-related end-stage liver disease (ESLD). ESLD was defined as the development of esophageal varices, hepatic encephalopathy, refractory ascites, or death related to liver disease. They found that in hemophiliacs coinfected with HCV and HIV, there was a 16-year cumulative incidence of ESLD of 14%. However, there was a cumulative incidence of 2.6% in patients with HCV alone. ⁶ This finding signified that coinfection with HIV is a significant risk factor for development of HCV-related ESLD in the hemophilia population. ⁶ They also noted that risk of ESLD increased dramatically with age. ⁶ Consequently, cirrhosis, portal hypertension, and upper gastrointestinal varices are not uncommon in this population and can be expected to increase in incidence as this patient population ages.

Treatment of Portal Hypertension in Hemophiliacs

The treatment of portal hypertension in hemophiliacs is more complex than in the non-hemophiliac population because the patient's underlying coagulopathy must be taken into account. Patients with hemophilia are less likely to undergo liver biopsy to histologically diagnose cirrhosis due to the increased risk of bleeding; however, after pretreatment with clotting factors the procedure can be performed safely if needed. ⁶ There are instances in which intervention becomes medically imperative, such as transjugular intrahepatic portosystemic shunt (TIPS) creation for hemophiliacs with cirrhosis, portal hypertension, and resultant varices or refractory ascites. The safety and efficacy of TIPS creation in patients with hemophilia has been reported previously. Beirne et al reported a series of four patients with hemophilia A who underwent TIPS creation. ⁸ Three of the patients underwent TIPS creation to treat variceal bleeding and one to treat refractory ascites. In each case, hematology was consulted to assist with management and all patients received periprocedural factor VIII administration per the recommendation of the hematologist. In all four patients, TIPS creation was successful and without associated bleeding complications. ⁸ A case report by Singh et al described successful TIPS creation in a single patient with hemophilia to treat variceal hemorrhage. ⁹ Currently, TIPS creation is supported in patients who have a history of acute variceal bleeding and are at high risk for treatment failure or in patients with refractory ascites. ¹⁰ At present, prophylactic TIPS creation is not supported by literature. However, given the increased risk of catastrophic variceal hemorrhage in the hemophiliac population, prophylactic TIPS creation may be prudent if not life-saving in these patients.

Historically, patients with hemophilia A and B have been treated with concentrate of factors VIII and IX, respectively. While the patients in previous reports of TIPS creation in hemophiliacs generally received periprocedural factor VIII concentrate to ward against bleeding complications in patients with hemophilia A, other agents exist which are now used for the same indication. Currently, recombinant factor VIIa is widely used to treat and prevent bleeding complications, including in patients who are undergoing a procedure or surgery. Patients with hemophilia can develop alloantibodies that neutralize factors VIII and IX, limiting their effectiveness when they are administered to control or prevent bleeding. ¹¹ Recombinant factor VIIa is a bypassing agent that can be used in instances where a patient has developed inhibitors to other factors. ¹¹

Case Presentation

A 45-year-old man with a past medical history of hemophilia A, HCV, cirrhosis, and esophageal varices presented with primary complaints of dental pain and a left arm hematoma. The patient was admitted for the management of arm hematoma. The patient had no history of variceal hemorrhage or ascites. Subsequent workup was remarkable for FibroSURE elastography demonstrating F4 cirrhosis, confirmed on CT of the abdomen, which also showed gastroesophageal varices, splenomegaly, a patent portal vein, and no ascites ( Fig. 1 ). Upper endoscopy was performed during which large (>5 mm) esophageal varices with no stigmata of bleeding ( Fig. 2 ), type 1 gastroesophageal varices just distal to the GE junction, and portal hypertensive gastropathy were noted. Given the patient's history of hemophilia and its associated risk of hemorrhage, variceal band ligation was not performed. The established associated complications of esophageal variceal ligation, including rebleeding varices and postbanding ulcers that are prone to bleeding, were thought to outweigh the benefits of banding in the presence of hemophilia. Interventional radiology consultation was recommended for evaluation for TIPS creation to prevent future variceal bleeding which could be catastrophic given the patient's history of hemophilia A.

Fig. 1.

( a and b ) Images from CT of the abdomen with contrast showing a cirrhotic liver with a nodular contour, a patent portal vein (arrow), large gastroesophageal varices (circle), splenomegaly, and a lack of ascites.

Fig. 2.

( a ) Grade III esophageal varices without stigmata of recent bleeding appreciated during upper endoscopy. ( b ) Digital subtraction angiography image obtained during TIPS creation showing large gastroesophageal varices arising from the left gastric vein (arrow).

The case was discussed in multidisciplinary fashion. The hematology service agreed with the indication for TIPS and recommended a perioperative regimen to allow the procedure to be safely performed. As the patient had a history of severe hemophilia A with evidence of a high-titer inhibitor of factor VIII since childhood, he would not respond to routine factor VIII replacement. Instead, he required a factor VIII bypassing agent to safely proceed. Hematology recommended a recombinant factor VIIa product, NovoSeven, which has an average half-life of approximately 2.3 hours. He was given NovoSeven 90 μg/kg IV once immediately prior to the start of the procedure and an additional dose halfway through the procedure. NovoSeven 90 μg/kg was then administered every 4 hours over the next 24 hours before being tapered off once it was felt that adequate hemostasis was achieved.

The TIPS procedure was performed under general anesthesia. Shunt creation was uneventful and the tract was covered with two overlapping 8 to 10 mm × 8 cm VIATORR-controlled expansion covered stents (W.L. Gore, Flagstaff, AZ; Fig. 3 ). The stents were dilated to 8 mm. The portosystemic gradient before TIPS portosystemic was 11 mm Hg and was reduced to 4 mm Hg after shunt creation. Large gastroesophageal varices were identified ( Fig. 2 ), but embolization was not performed since the patient did not have previous bleeding episodes. The patient tolerated the procedure well. He was admitted to the intensive care unit overnight after the procedure to monitor for signs of hemorrhage. His hemoglobin level was stable and the patient was transferred to floor level care the following morning. He was discharged to home in stable condition. The patient had a clinic follow-up 2 weeks after TIPS. His liver function is stable and the shunt is patent.

Fig. 3.

Completion digital subtraction angiography following TIPS creation showing preferential flow of portal venous blood through the shunt (arrows) composed of two overlapping 8–10 mm × 8 cm VIATORR controlled expansion covered stents.

Conclusion

Patients with hemophilia and transfusion-acquired viral hepatitis represent a unique population with high risk of developing ESLD, especially if hepatitis is associated with HIV infection. As these patients age, they are at higher risk of developing decompensated portal hypertension. Standards for the management of portal hypertension may be different for these patients and it is important for the interventional radiologist to be aware of this problem, which may become more prevalent. To the best of our knowledge, this is the only case reported where a prophylactic TIPS was performed in a patient with hemophilia. The management guidelines and indications for TIPS may be different in this patient population. With the appropriate administration of clotting factors in the periprocedural setting, interventions, including TIPS creation, can be safely performed.