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Extrahepatic factor VIII production in transplant recipient of hemophilia donor liver

Charles L. Madeira, Michael E. Layman, Ralph E. de Vera, Paulo A. Fontes and Margaret V. Ragni

To the editor:

Although the liver is the major site of production of factor VIII (FVIII), as demonstrated by correction of hemophilia A by liver transplantation,1 extrahepatic FVIII production has been suspected ever since increased FVIII levels were recognized in end stage liver disease.2,3 Extrahepatic FVII production has been confirmed by FVIII mRNA detection in spleen and kidneys of a pig model of fulminant liver failure,4 the correction of hemophilia in animal models after spleen or lung transplantation,5,6 and normal FVIII levels in normal canine recipients of hemophilia A dog livers.7,8 In humans, FVIII:C levels have been detected in pulmonary endothelial cell supernatants.9 Although obligate carrier donor liver transplantation corrects hemophilia,10 extrahepatic FVIII production in humans has not been demonstrated. We report normal FVIII production after transplantation of a hemophilia A donor liver into a nonhemophilic recipient with alcoholic cirrhosis.

The liver donor was a 47-year-old white man with mild hemophilia A, FVIII:C = 0.05 U/mL, hypertension, and insulin-dependent diabetes mellitus complicated by renal failure and peripheral vascular disease. He experienced recurrent hemarthroses and a Mallory Weiss tear, managed uneventfully with FVIII concentrate. He presented to the emergency room with a gastrointestinal bleed, complicated by hypovolemic shock and diabetic ketoacidosis, and died several days later with irreversible diffuse anoxic brain injury. There was no factor VIII inhibitor.

The liver recipient was a 69-year-old white man with alcoholic cirrhosis and stage 2 hepatocellular carcinoma. His Model for End-Stage Liver Disease (MELD) score was 25, following a 3-month wait on the transplant list. His FVIII level was normal preoperatively and remained so postoperatively (Table 1). The activated partial thromboplastin time (APTT) was subsequently markedly prolonged from heparin therapy for hemodialysis, and both prothrombin time (PT) and APTT were prolonged from vitamin K deficiency due to warfarin therapy for atrial fibrillation, and intravenous antibiotic agents for pneumonia. Postoperatively, his course was complicated by acute respiratory distress syndrome, biliary stricture, encephalopathy, and cytomegalovirus (CMV) viremia, conditions likely accounting for nonspecific elevation of von Willebrand factor (VWF). His graft function was good, with normal total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels and no evidence of liver failure.

Table 1

Coagulation studies before and after orthotopic liver transplantation

This report demonstrates for the first time that transplantation of a human hemophilia A donor liver results in normal FVIII levels after transplantation. The postoperative persistence of normal FVIII levels in the hemostatic range confirms that the source of recipient FVIII production is other than liver tissue. Whether the source is lung, spleen, kidney, or other tissue, however, is not possible to confirm in this recipient. It is of interest that transplantation of spleen or lung has corrected factor VIII deficiency in hemophilia animal models,5,6 and human lung endothelial cells produce FVIII,9 but whether lung tissue compensates for absent hepatic FVIII production remains unanswered.

Together with these reports, these data support the existence of human extrahepatic FVIII production that compensates for missing hepatic FVIII production. Further study will be required to determine which tissues contribute to human extrahepatic FVIII production.

Potential ethical issues regarding the donor and recipient warrant comment. Although liver donors to date have not included persons with hemophilia, increasing evidence in animal models5,6 suggests the success of such an approach in humans. In this case, however, a diagnosis of hemophilia remained unclear before transplantation. Regarding the recipient, liver transplantation is increasingly performed in elderly patients, and the presence of hepatocellular carcinoma (stage 1 or 2) increases priority for transplantation, as survival with transplantation is superior to survival with other forms of treatment.

Authorship

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Margaret V. Ragni, MD, MPH, Professor of Medicine, Department of Medicine, University of Pittsburgh Medical Center, and Director, Hemophilia Center of Western PA, 3636 Boulevard of the Allies, Pittsburgh, PA 15213-4306; e-mail: ragni{at}pitt.edu.

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