INTRODUCTION

During the 1970s, the vast majority of the population with hemophilia and to a lesser extent of the population with von Willebrand disease (vWD) were infected with hepatitis C virus (HCV). This was due to the transfusion of blood products and coagulation factor concentrates. The cumulative incidence of advanced liver disease and hepatocellular carcinoma (HCC) was very similar for patients with hemophilia and those with vWD. According to some studies, around 3-6% of hemophiliacs with HCV-related cirrhosis developed HCC every year ¹. Liver transplantation (LT) became the sole potentially curative treatment available for advanced liver cirrhosis and early-stage HCC.

In 1985, the first LT procedure was successfully carried out in Pittsburgh in a 15-year-old patient with hemophilia A and active chronic hepatitis ². In Spain, the first LT procedure was performed in 1995 at Hospital La Paz, Madrid, in a 5-year-old child with hemophilia A and congenital biliary atresia ³. With regard to vWD, initial LTs performed in 1975 in pigs with the same condition resulted in ephemeral, modest increases in the vWF antigen (vWF:Ag) ⁴. In 1991, Mannucci et al. reported the case of a patient with type-3 vWD who underwent LT due to HCV-associated HCC ⁵. There was no increase in vWF ristocetin cofactor (vWF:RCo) or vWF:Ag activity following transplantation. However, the bleeding episodes subsided considerably, which represented a phenotypic shift to type-1 vWD. Overall, the experience reported in hemophiliacs undergoing LT ^6,7,8 has been satisfactory thus far, both in terms of their congenital coagulopathy and liver disease.

We report about four patients diagnosed with congenital coagulopathy and HCV infection who underwent LT at the Hospital Clínico Lozano Blesa, Zaragoza, Spain. The goal was to assess the clinical and biological course of congenital coagulopathy, to quantify the usage of the deficient factor and blood products perioperatively and to monitor the HCV serology and/or viral load both pre- and post-transplant.

METHODS

This was a retrospective, observational study. All patients diagnosed with congenital coagulopathy who received a liver transplant from December 1998 (start-up of the LT program at our site) to January 2018 at the Hospital Clínico Lozano Blesa, Zaragoza, Spain, were included. Three patients had mild hemophilia A and one had type-3 vWD. Clinical and laboratory data were retrieved from the medical records. Information was collected via telephone contact with patients and the practitioners involved for cases in follow-up in other centers. The presence of anti-FVIII neutralizing antibodies (inhibitors) was ruled out. Inhibitors reduce the efficacy of replacement therapy and result in a higher morbidity.

RESULTS

Four male patients with a mean age of 58 ± 6 years, diagnosed with congenital coagulopathy and HCV-related chronic liver disease, received a liver transplant. None were seropositive for HIV. Patient clinical data (age, sex, liver disease, relapsing tumor, recurrent HCV, survival), laboratory values (pre- and post-transplant coagulation panel) and donor characteristics (age, sex) are listed in Table 1.

Table 1 Characteristics and coagulation studies (pre-transplant and the last follow-up post-transplant) of four patients with congenital coagulopathy that underwent a liver transplant at the Hospital Clínico Lozano Blesa 

*H.A.: hemophilia A; †vWD3: von Willebrand disease, type 3; ‡HCC: hepatocellular carcinoma; §HCV: hepatitis C virus; ǁSv: survival; ¶FVIII:C: coagulating factor VIII; **vWF:Ag: vWF antigen; ††vWF:RCo: vWF ristocetin cofactor. ǁAs of 01/01/2018.

DISCUSSION

LT for liver cirrhosis secondary to infection with HCV was a curative therapy for congenital coagulopathy in all three patients with hemophilia A. Correcting hemophilia A was also a relevant factor for the absence of post-transplant morbidity and the survival of all three cases. These patients still have well-functioning grafts as of today.

With regard to the patient with type-3 vWD who underwent an LT due to HCV-related cirrhosis and HCC, no hemostatic levels of vWF:Ag were detected and bleeding symptoms improved considerably. This allowed prophylactic treatment with Haemate-P(r) to be discontinued. His postoperative period was uneventful and the liver function was normal post-transplant.

A stringent control of perioperative coagulation parameters is required in patients with congenital coagulopathy undergoing surgery for appropriate deficient factor replacement. Dosing regimens for deficient factor concentrates vary among reported studies ⁹. The optimal factor plasma levels and treatment duration required to prevent bleeding complications during invasive procedures are not definitively established. Hermans et al. ¹⁰, on behalf of the European Hemophilia Therapy Standardization Board (EHTSB), reviewed 35 clinical studies regarding replacement therapy for major invasive procedures. In most studies (26/31), target plasma levels for patients with hemophilia A were above 80 U/dl ¹⁰. In our patients with hemophilia A, the perioperative administration of rFVIII concentrates was maintained for an average of 36 hours post-transplant (range: 8-48 h). This is consistent with the experience of other authors ⁶. The average amount of FVIII that was perioperatively administered was 175 IU/kg.

Deficient factor concentrates may be administered using intravenous boluses, continuous infusion or both. Boluses were used in our center, since exogenous factor supply is deemed necessary for just a few hours in the LT setting. Some authors have pointed out that perioperative transfusion requirements in patients with hemophilia A or vWD that undergo LT, regardless of severity, are similar to those of non-hemophiliacs (5), provided that adequate replacement therapy is provided, even though LT is a surgery with a high bleeding risk. Transfusion requirements were not high for our patients, except for case no. 1. High doses of RBCC and FFP were administered in this patient, mainly due to the complex surgery during the hepatectomy phase of the LT.

Previous studies have shown that survival rates in hemophiliacs undergoing LT do not differ from those of non-hemophiliacs ¹¹. In our study, all three patients with hemophilia remained alive at 12 years and 41 and 27 months post-transplant. In one of the scarce Spanish series reported (eleven patients) ⁷, overall survival after transplantation was 91% (eleven patients with hemophilia A or B who underwent LT between 1995 and December 2008 at six Spanish hospitals).

Re-infection with HCV and relapsing HCC shorten survival for LT patients. Overall, liver graft re-infection with HCV is considered as a universal event for all individuals transplanted with a positive viral load. Two of our patients, one with hemophilia A (case no. 1) and the subject with vWD type 3 (case no. 4), had a HCV re-infection of the liver graft. Furthermore, the latter patient had relapsing hepatocellular carcinoma, which caused his demise.

Data reported in the literature on type-3 vWD patients undergoing LT are controversial and limited due to the low prevalence of this congenital coagulopathy (approximately one case per million). This results in a virtually undetectable production of vWF:Ag. Mannucci et al. ⁵ found that a healthy liver only generates a small proportion of the overall vWF:Ag pool, a fraction much smaller than that required to rectify the primary defect. Similarly, Lechler et al. ¹² observed a modest increase (2 IU/dl) in vWF:Ag levels following LT, in a patient with type-3 vWD. There was increase in vWF:Ag and vWF:RCo levels in our patient with type-3 vWD, with values around 3 and 1 IU/dl, respectively. However, the VIIIF:C levels rose from 5 IU/dl to 12 IU/dl at 30 months post-transplant. Prophylaxis treatment with Haemate-P(r) that the patient required before transplantation could finally be discontinued. With regard to the cases reported by Schulman et al. ¹³ and by Ghinolfi et al. ¹⁴, replacement therapy had to be maintained after LT with halved doses of vWF/FVIII. In the published accounts of patients with vWD undergoing LT, short survival primarily resulted from HCV recurrence and/or tumor relapse. Our patient with type-3 vWD died at 63 months after transplantation due to relapsing hepatocellular carcinoma. A multidisciplinary approach is key for an appropriate LT candidate selection and bleeding risk minimization. Optimal doses and dosing intervals to achieve a successful hemostasis have not been established and vary significantly from one site to the next.

To conclude, LT in patients with end-stage liver disease and hemophilia A cures the congenital coagulopathy, which in turn facilitates a favorable course with no bleeding complications post-transplant. Experience with LT in patients with type-3 vWD is very limited. Following LT, patient outcome was modestly favorable from a congenital coagulopathy biologic perspective, while the clinical benefits were substantial, as reflected by a decrease in bleeding events.