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CORRESPONDENCE Factor V (FV) Leiden is the most common genetic defect found in
persons of European descent with venous thromboembolism.1 The 1691G>A transition determines the R506Q
substitution.2 This suppresses a cleavage site for
activated protein C (APC) on FVa, resulting in resistance to
APC in a functional coagulation-based assay.3 FV Leiden
accounts for over 90% cases of APC resistance, but this phenomenon may
also be associated with pregnancy, oral contraceptive use, lupus
anticoagulant, elevated FVIII levels, and rarely mutations other than
FV Leiden.4,5 Although APC resistance may occur in the
absence of FV Leiden, the converse is usually not true. We describe 2 patients who, following bone marrow and liver transplantation
respectively, developed anomalies between APC resistance and FV
Leiden genotype. A 38-year-old female presented with a right-sided iliofemoral deep-vein
thrombosis (DVT) secondary to venous obstruction by inguinal
lymphadenopathy. She was diagnosed to have stage IV low-grade follicular B-cell non-Hodgkin lymphoma (NHL) and received combination chemotherapy. After a second relapse, she underwent sibling allogeneic progenitor cell transplantation with busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) conditioning. After transplantation, she
developed menopausal symptoms and was considered for
hormone-replacement therapy (HRT). Further questioning revealed that,
although her stem cell donor was well, her other sibling had previously
suffered a spontaneous popliteal DVT. In view of this history and the
2- to 4-fold increased risk of venous thrombosis associated with HRT,6 thrombophilia screening was undertaken. Resistance
to APC in FV-deficient plasma was normal. FV Leiden genotyping by PCR
and Hind III restriction enzyme analysis, however,
demonstrated heterozygosity for FV Leiden (G/A). In view of these
unexpected results, mutation analysis of stored pretransplantation DNA
was performed. Because this revealed a normal FV genotype (G/G), we surmised that the mutant allele had originated from the donor, and
given the history of spontaneous DVT, the other sibling was also likely
to be a carrier of FV Leiden. These predictions were confirmed by
testing both siblings (Table 1).
The second patient was a 41-year-old female who had undergone orthotopic liver transplantation (OLT) for cirrhosis secondary to Wilson disease. She became pregnant 1 year after OLT. At 20 weeks' gestation she developed progressive hepatocellular failure, and thrombophilia screening was performed to investigate possible hepatic vaso-occlusion. Although her APC-sensitivity ratio (in FV-deficient plasma) of 1.5 would have been consistent with heterozygosity for FV Leiden, genotyping was normal. But DNA analysis is routinely performed on peripheral blood leukocytes, which may not be representative of donor liver genotype. Analysis of donor-liver biopsy samples for FV Leiden demonstrated heterozygosity (G/A), confirming that the mutant FV giving rise to APC resistance originated from the donor liver. The FV Leiden mutation results in resistance to APC and may be associated with a 3- to 8-fold increased risk of venous thrombosis in heterozygotes and an 80-fold increased risk in homozygotes.1 Screening for FV Leiden involves a combination of coagulation and genetic assays. The conventional APC-resistance assay will detect not only mutant factor V but also several conditions associated with the APC-resistant phenotype that may also pose a thrombotic risk. These conditions may be excluded by use of the modified APC-resistance assay in which samples are prediluted in FV-deficient plasma.7 Confirmatory genetic analysis usually employs DNA extracted from peripheral blood leukocytes. Although these would have the same genotype as hepatic tissue in normal subjects, this might not be the case after transplantation. We highlight this possible discrepancy between genotype and phenotype also previously reported in 2 subjects who, in a reversal of the situation described here, were heterozygous for FV Leiden and received bone marrow and liver transplants, respectively, from FV wild-type donors.8 In humans, circulating FV is synthesized primarily by hepatocytes with a smaller pool originating from megakaryocytes.8,9 In our first patient, circulating FV synthesized by recipient liver would be of wild type, despite heterozygosity for FV Leiden in donor-derived hemopoietic cells. The risk of venous thromboembolism would not, therefore, be significantly increased, and she was able to receive HRT. In contrast, production of mutant FV by donor hepatocytes indicates that the second patient might have an increased risk of thrombosis despite a normal FV Leiden genotype. We therefore elected to give her thromboprophylaxis in the postpartum period. These cases illustrate the difficulties of thrombophilia testing after tissue transplantation and emphasize the need for evaluating both FV phenotype and genotype in order to accurately assess thrombotic risk in such patients.
Jane Parker, Antonio Pagliuca, Taya Kitiyakara, Malcolm Whitehead, Nigel Heaton, John O'Grady, and Roopen Arya
References
1.
Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH.
High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).
Blood.
1995;85:1504-1508 2. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64-67[CrossRef][Medline] [Order article via Infotrieve].
3.
Dahlbäck B, Carlsson M, Svensson PJ.
Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.
Proc Natl Acad Sci U S A.
1993;90:1004-1008 4. Bertina RM, Reitsma PH, Rosendaal FR, Vandenbroucke JP. Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. Thromb Haemost. 1995;74:449-453[Medline] [Order article via Infotrieve].
5.
Williamson D, Brown K, Luddington R, Baglin C, Baglin T.
Factor V Cambridge: a new mutation (Arg306 6. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;344:977-980. 7. Jorquera J, Montoro J, Fernandez M, Aznar JA, Aznar J. Modified test for activated protein C resistance. Lancet. 1994;344:1162-1163[Medline] [Order article via Infotrieve].
8.
Camire RM, Pollak ES, Kaushansky K, Tracy PB.
Secretable human platelet-derived factor V originates from the plasma pool.
Blood.
1998;92:3035-3041 9. Wilson DB, Salem HH, Mruk JS, Maruyama I, Majerus PW. Biosynthesis of coagulation factor V by a human hepatocellular carcinoma cell line. J Clin Invest. 1984;73:654-658.   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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Thr) associated with resistance to activated protein C.
Blood.
1998;91:1140-1144
