Modification of von Willebrand Disease after Liver Transplantation

Liver transplantation leads to cure of haemophilia A and B, since coagulation factor VIII and IX, respectively, are synthesised by the hepatocytes (1). The von Willebrand Factor (vWF) is produced by endothelial cells (2) and megakaryocytes (3). In a single case report of a patient with von Willebrand Disease (vWD) type 3 (severe form) and transplantation of the liver no increment of the vWF activity was demonstrated (4). Liver transplantation in pigs with vWD resulted in a slight and transient increase of the vWF activity with a duration of only 2 weeks (5). We wish to report another case with a different outcome. The patient was a 52-year old Caucasian female with vWD type 3, no detectable levels of vWF:antigen (vWF:Ag) in electroimmunoassay and 0.05 IU/mL in an ELISA test, no detectable ristocetin cofactor (vWF:RcoF) or vWF multimers, factor VIII 0.03 IU/mL and a template bleeding time of >900 s. The underlying genetic defect was double heterozygosity for a nonsense mutation in exon 15 and another one in exon 32. She suffered from chronic hepatitis C virus (HCV) infection after transmission via non-heated factor VIII-vWF concentrates more than 20 years ago. In 1989 she started developing signs of liver cirrhosis with repeated bleeding from oesophageal varices and decreasing levels of the vitamin K-dependent coagulation factors. An attempt to eliminate the HCV infection in 1998 with interferon alpha and ribavirin for 6 months resulted in viral response, which was not sustained at 6 months after end of treatment. At that point -fetoprotein increased from 24 to 88 mg/L and a computed tomography scan of the abdomen showed a 9 cm large tumour with two smaller satellite tumours in the right lobe of the liver. Biopsy confirmed the diagnosis of hepatocellular cancer. Orthotopic liver transplantation was performed on August 17, 2000 and the haemostatic treatment consisted of a factor VIII-vWFconcentrate, Haemate P (Aventis Behring, Marburg, Germany) in continuous infusion, and tranexamic acid. There were no signs of extrahepatic spread of the cancer, neither on preoperative investigation, nor at inspection during surgery. The postoperative course was uneventful, immunosuppression was given with prednisone and tacrolimus and the replacement with factor concentrate was slowly tapered to the prophylactic dose of 1000 IU twice a week, that she previously had been on mainly for frequent epistaxis. At follow-up 3 months after surgery, the patient reported absence of bleeding tendency, both spontaneous and after trauma. Blood samples were obtained 5 days after a previous dose of 1000 IU Haemate P, before and at two time points after a subcutaneous injection of desmopressin, 0.2 g/kg (Table 1). The vWF level was detectable already at baseline but did not increase after desmopressin. Analysis of vWF multimers showed a low concentration of high molecular weight bands. On the basis of these results the prophylaxis with Haemate P was reduced to 500 IU once a week and 2 months later discontinued without any reoccurrence of the bleeding tendency. Unfortunately, the patient had an aggressive relapse of the hepatocellular carcinoma in the spring of 2001 and succumbed to it. It seems from the laboratory data and clinical picture as if our patient had a modification of the vWD from type 3 to a moderately severe type 1 after the liver transplantation. The fact that she received a dose of factor concentrate 5 days prior to the blood sampling should not have resulted in residual measurable levels of vWF, since the incremental recovery and half-life before surgery had been consistently 2.1%/IU/kg and 11 h respectively, which is typical of patients with vWD (6). It does not seem plausible that the liver transplantation should have resulted in a pronounced decrease of the clearance of vWF. Neither can it be expected that the hepatocellular carcinoma cells produced vWF, since they are not endothelial and the vWF level was undetectable before surgery. Thus, it may be speculated that the endothelium of the vascular tree of the transplanted liver was responsible for a production corresponding to about 10 percent of the entire vascular tree. This level is usually sufficient to eliminate spontaneous bleeding and to drastically reduce the need for replacement therapy. This concentration was also sufficient to maintain a normal level of factor VIII by protecting it from proteolysis. Liver transplantation may therefore confer secondary benefits, not only to patients with haemophilia, but sometimes also to those with vWD type 3. Whether the absence of a rise of the vWF-level after desmopressin is due to defective storage of vWF in the Weibel-Palade bodies of the endothelial cells in the transplanted liver (7) or absence on these cells of the receptors, presumably V2-receptors, (8) on which desmopressin acts, cannot be answered by our observations.