The treatment with fondaparinux is the effective and safe anticoagulant therapy in liver transplant patient on immunosuppressive therapy with arterial thrombosis, and it seems able to reduce liver fibrosis. Although this treatment is not generalizable, further prospective large studies need to confirm this case report

Cafolla, Arturo

Gentile, Giuseppe

Clinical Case Reports

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PubMed

Arturo Cafolla

Giuseppe Gentile

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Anticoagulant therapy with fondaparinux in a liver transplant patient with thrombosis and liver fibrosis: a case report

CAFOLLA, Arturo

GENTILE, Giuseppe

Archivio della ricerca- Università di Roma La Sapienza

CASE REPORTAnticoagulant therapy with fondaparinux in a livertransplant patient with thrombosis and liver fibrosis: a casereportArturo Cafolla1 & Giuseppe Gentile21Department of Cellular Biotechnologies and Hematology, Thrombosis Centre, Sapienza University of Rome, Rome, Italy2Department of Cellular Biotechnologies and Hematology, Infectious Diseases Unit, Sapienza University of Rome, Rome, ItalyCorrespondenceArturo Cafolla, Department of CellularBiotechnologies and Hematology, ThrombosisCentre, Sapienza University of Rome, Via R.Fucini 204- Roma 00137, Italy.Tel: 00390685795300;Fax: 00390644241984;E-mail: cafolla@bce.uniroma1.itFunding InformationNo sources of funding were declared for thisstudy.Received: 18 December 2015; Revised: 25July 2016; Accepted: 5 December 2016Clinical Case Reports 2017; 5(3): 342–345doi: 10.1002/ccr3.820Key Clinical MessageThe treatment with fondaparinux is the effective and safe anticoagulant therapyin liver transplant patient on immunosuppressive therapy with arterial throm-bosis, and it seems able to reduce liver fibrosis. Although this treatment is notgeneralizable, further prospective large studies need to confirm this case report.KeywordsFondaparinux, liver fibrosis, liver transplant patient, thrombosis.IntroductionThe treatment of deep vein thrombosis (DVT) is wellestablished, and evidence-based guidelines [1] are regu-larly updated, whereas the management of vein/arterythrombosis in patients with liver fibrosis and/or cirrhosishas not yet been validated.The incidence of thrombosis among patients undergo-ing orthotopic liver transplantation (OLT) is approxi-mately 9%; the majority of events tend to occur withinthe first 3 months after the transplant [2]. A recent studyof liver transplant patients reported a greater incidence ofhepatic artery and portal vein thrombosis in patients trea-ted with a reduced dose of immunosuppressive therapy[3]. The hepatic artery thrombosis was observed in 4.6%of 1000 primary liver transplants, and it was one offrequent factors for retransplants [4].Anticoagulation therapy (AT) with low-molecularweight heparin (LMWH) followed by the administrationof a vitamin K antagonist has been reported to be a use-ful treatment in the management of patients waiting forliver transplantation [5]. LMWH appears to be safe andeffective in achieving recanalization of the portal vein inpatients with cirrhosis [6]. A disadvantage of LMWH inpatients with cirrhosis is that the drug efficacy dependson antithrombin. Indeed, antithrombin levels can be sig-nificantly reduced in cirrhotic patients. Recently, warfarinanticoagulation was proposed as a treatment for liverfibrosis in patients undergoing liver transplantation forhepatitis C [7].Since 2003, physicians have been using fondaparinux.Fondaparinux is a synthetic indirect factor Xa inhibitor,which mediates its effects indirectly through antithrombinbut, unlike heparin, is selective for factor Xa [8].Case ReportA 53-year-old woman presented with left renal arterythrombosis in July 2012. The patient, who was seronega-tive for HCV, HBV, and HIV, underwent liver transplan-tation for Caroli’s syndrome in 2005 and started onimmunosuppressive therapy with tacrolimus. Caroli’s342 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use anddistribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.syndrome is a combination of Caroli’s disease (bouts ofcholangitis, hepatolithiasis, and gallbladder stones) withcongenital hepatic fibrosis (portal hypertension). Clinicalprogression and presentation of Caroli’s syndrome arehighly variable, and symptoms may appear early or lateduring life [9].Ultrasound (US)–Doppler, and angio-magnetic reso-nance imaging (MRI) were performed in October 2006and showed no sign of a hepatic disorder. Liver functionwas preserved, and transaminases were within the normalrange. These findings were confirmed by subsequent US–Doppler and blood tests, which were regularly performedduring the five-year follow-up period (Table 1). In March2009, after 39 months from the liver transplant, thepatient exhibited hypertension related to left renal arterystenosis. The treatment for the stenosis consisted of stent-ing and drug therapy with dipyridamole (75 mg/day). Atthis time, the immunosuppressive therapy was adjustedaccording to the patient’s renal function.In July 2012, after 78 months from the liver transplant,the US–Doppler imaging suggested that the liver hadundergone fibrosis. Stiffness was evaluated by AcousticRadiation Force Impulse (ARFI) and was equal to16.85 m/sec. The mean value of ARFI measurements innormal individuals was 1.15  0.21 m/sec [10]. In addi-tion, the imaging technique showed a thrombotic eventin the left renal artery. The patient’s clinical characteris-tics at the time of this thrombotic event are shown inTable 2.The patient had no family history of thrombosis. Shearrived at the Thrombosis Centre of Hematology andunderwent blood tests, which ruled out the presence ofinherited conditions such as protein C, protein S, andantithrombin deficiencies or G20210A, G1691A, andJAK2 mutations. The presence of acquired prothromboticsystemic factors was also excluded.Although the patient did not have any visible varicoseesophageal veins and the creatinine clearance was 46 mL/min, physicians decided to treat the artery thrombosiswith 2.5 mg/daily of fondaparinux for 12 months. Thistreatment is considered off-label, although a large studyshowed the efficacy and safety of treatment with fonda-parinux 2.5 mg/daily in patients with acute coronary syn-dromes (ACS) which is considered an arterial thrombosis[11].No pharmacological interference between fondaparinuxand the drugs taken by the patient, which included tacro-limus, ursodeoxycholic acid, and a beta-blocker, werenoted.In July 2013, after 12 months from the start of thetherapy, the patient underwent abdominal US–Doppler,kidney scintigraphy, and blood tests (Table 2). Imagingtechniques and blood tests showed both recanalization ofthe left renal artery and an increase in the portal veinspeed, which was associated with a reduction in liverfibrosis. The authors decided to stop the AT and moni-tored the patient every 4 months with US–Doppler andbiochemical parameters.In January 2015, the patient was on immunosuppres-sive therapy with a low dose of tacrolimus in order toobtain a plasmatic concentration of 2.6 ng/mL. At thistime, the patient developed two new thrombotic events:one involved the left renal artery, and the other involvedthe common iliac artery. These two events were diagnosedby abdominal X-ray computed tomography. At the sametime, US–Doppler imaging showed that the liver fibrosiswas equal to 1.7 m/sec. The extent of fibrosis was evalu-ated using ARFI.The patient underwent further therapy with fonda-parinux at 2.5 mg/daily, and after 5 months, both throm-boses were completely resolved the second time. Inaddition, US–Doppler imaging showed a reduction inTable 1. Clinical parameters of the patient during the five years afterliver transplantation.Parameters 2006 2008 2010Albumin gr/dL 3.6 3.7 4.5GPT (U/L) 21 20 29GOT (U/L) 24 21 33GGT (U/L) 18 15 19Creatinine (mg/dL) 1.1 1.0 1.0Tacrolimus (FK506) ng/mL 7.0 6.1 3.6Fibrosis (Metavir) F0 F0 F0-1Portal vein* (mm) 10.4 12.4 11.0Portal flow† (cm/sec) 19.5 13.6 12.6*Vessel diameter.†Blood speed.Table 2. Clinical parameters before and after anticoagulant therapywith fondaparinux.July 2012 (Beforefondaparinux)July 2013 (Afterfondaparinux)Age (years) 53 54Weight (kg) 68 65Creatinine clearance (mL/min) 46 64Factor VIII (%) 178 130Homocysteinemia (lmol/mL) 17 13Liver stiffness (ARFI) 16.85 5.71Fibrosis (Metavir) F4 F0-1Portal vein* (mm) 8.2 13.4Portal flow† (cm/sec) 14.8 22.7Reference range: Factor VIII = 65–130%. Homocysteinemia =8–15 lmol/mL.*Diameter.†Speed.ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 343A. Cafolla & G. Gentile Fondaparinux therapy for thrombosis and liver fibrosisliver fibrosis to 1.4 m/sec; this value was lower than thatobserved after the first treatment with fondaparinux.Currently, the patient continues to be on anticoagulanttherapy with fondaparinux. The aim is to reduce thethrombotic risk, as the tacrolimus plasmatic concentra-tion (2.6 ng/mL) was also reduced according to clinicalcriteria.DiscussionThe management of vein/artery thrombosis in patientswith liver fibrosis and/or cirrhosis is not evaluated. Astudy reported the safety and effectiveness of LMWH inachieving recanalization of the portal vein in patients withcirrhosis [6]. One disadvantage when using LMWH inpatients with cirrhosis may be the unpredictable efficacyof this drug, given that LMWH requires antithrombin toexert its anticoagulation function.A retrospective study reported an incidence of 27 DVTsafter liver transplantation (LT) among 304 patients whowere followed at a single institution from 2005 to 2012[2]. Among patients with and without DVT, there was nosignificant difference in the following preoperative riskfactors: age, sex, platelet count, INR value, and the pres-ence of infections and/or cancer. The risk of DVT wasrelated to both the difference in mobility and the periop-erative use of factor VII. The risk of developing a DVTafter liver transplantation was 9% even with mechanicalDVT prophylaxis [2]; the risk is higher in the first3 months after a liver transplant.Recently, warfarin anticoagulation was proposed forpatients with liver fibrosis undergoing liver transplanta-tion for hepatitis C [7].Francoz et al. [5] assessed the usefulness of anticoagu-lation therapy with LMWH followed by administration ofa vitamin K antagonist in patients waiting for liver trans-plantation.The arterial thrombosis observed in our patient couldbe considered as late thrombosis, which was not relatedto the liver transplantation but due to concomitantevents, including the change in immunosuppressive ther-apy and the stent insertion.Battinelli et al. [12] showed that platelets, whenexposed to heparin, tended to release a significantly smal-ler amount of vascular endothelial growth factor inresponse to adenosine 50-diphosphate. The microparticlereleased from these platelets contained less proangiogenicproteins. In addition, these platelets exhibited decreasedangiogenic potential. Fondaparinux showed a similareffect on the platelet angiogenic potential. Moreover, fon-daparinux seems to inhibit the generation of thrombin byactivated monocytes and monocyte-derived microparticles(MMPs) via tissue factor; this inhibition is known to bedose-dependent. Monocytes and MMPs play a major rolein ACS. Indeed, the efficacy of fondaparinux at a dailydose of 2.5 mg in ACS patients appears to be related toits inhibitory effect on MMPs [13].In addition, Abe et al. [14] reported that LMWH,such as dalteparin sodium, up-regulates serum hepaticgrowth factor to prevent proliferation of hepatic stellatecells (HSC) and down-regulates the transforming growthfactor levels in rats exposed to carbon tetrachloride foran extended period of time. Therefore, our hypothesis isthat fondaparinux could exert antifibrogenic effects bydirect inhibition of HSC proliferation. Indeed, these cellsplay a key role in liver fibrinogenesis which could beinhibited by the reduced amount of thrombin secondaryto the administration of both LMWHs and fondaparinux[15].As is the case for any LMWH, fondaparinux is metabo-lized by the kidney; therefore, caution is required whenadministering fondaparinux to patients with impairedkidney function, which is defined by a creatinine clear-ance below 30 mL/min. Caution is needed because thebleeding risk is increased in these patients.This report suggests that fondaparinux appears to beeffective and safe in the anticoagulant treatment ofpatients with thrombosis and liver fibrosis. Given that thetreatment with fondaparinux is uncommon for livertransplant patients, other unknown factors may haveplayed a role in the resolution of arterial thrombosis andliver fibrosis of our patient. Although this treatment isnot generalizable, further prospective studies on a largecohort of patients are needed to confirm this case report.AuthorshipAC: designed the study and wrote the report. GG: ana-lyzed the data and revised the manuscript.Conflict of InterestThe authors declare that they have no conflict of interest.References1. Pruthi, R. K. 2013. Review of the American College ofChest Physicians 2012 Guidelines for anticoagulationtherapy and prevention of thrombosis. Semin. Hematol.50:251–258.2. Annamalai, A., I. Kim, V. Sundaram and A. Klein. 2014.Incidence and risk factors of deep vein thrombosis afterliver transplantation. Transplant. Proc. 46:3564–3569.3. Asrani, S. K., R. H. Wiesner, J. F. Tratter, G. Klintmalm,E. Katz, E. Maller, et al. 2014. De novo sirolimus andreduced dose tacrolimus versus standard dose tacrolimus344 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Fondaparinux therapy for thrombosis and liver fibrosis A. Cafolla & G. Gentileafter liver transplantation: the 2000-2003 phase IIprospective randomized trial. Am. J. Transplant. 14:356–366.4. Jain, A., A. Shingal, P. Fontes, G. Mazariegos, M. E.deVera, T. Cacciarelli, et al. 2011. One thousandconsecutive primary liver transplants under tacrolimusimmunosuppression: a 17- to 20-year longitudinal follow-up. Transplantation 91:1025–1030.5. Francoz, C., J. Belghiti, V. Vilgrain, D. Sommacale, V.Paradis, B. Condat, et al. 2005. Splanchnic vein thrombosisin candidates for liver transplantation: usefulness ofscreening and anticoagulation. Gut 54:691–697.6. Amitrano, L., M. A. Guardascione, A. Menchise, R.Martino, M. Scaglione, S. Giovine, et al. 2010. Safety andefficacy of anticoagulation therapy with low-molecular-weight-heparin for portal vein thrombosis in patients withliver cirrhosis. J. Clin. Gastroenterol. 44:448–451.7. Dharemail, A., E. Tschotazis, R. Brown, P. Manousou, C.Millson, M. Aldersley, et al. 2015. Warfarin anticoagulationfor liver fibrosis in patients transplanted for hepatitis(WAFT-C): results at one year. J. Hepatol. 62:S263–S864.8. Samama, M. M., and G. T. Gerotziafas. 2003. Evaluation ofthe pharmacological properties and clinical results of thesynthetic pentasaccharide (fondaparinux). Thromb. Res.109:1–11.9. Yonem, O., and Y. Bayraktar. 2007. Clinical characteristicsof Caroli’s syndrome. World J. Gastroenterol. 13:1934–1937.10. Popescu, A., I. Sporea, R. Sirli, S. Bota, M. Focsa, M.Danila, et al. 2011. The mean values of liver stiffnessassessed by Acoustic Radiation Force Impulse elastographyin normal subjects. Med. Ultrason. 13:33–37.11. Fifth Organization to Assess Strategies in Acute IschemicSyndromes Investigators, Yusuf, S., S. R. Mehta, S.Chrolavicius, R. Afzal, J. Pogue, C. B. Granger, et al. 2006.Comparison of fondaparinux and enoxaparin inacute coronary syndromes. N. Engl. J. Med. 354:1464–1476.12. Battinelli, E. M., B. A. Markens, R. A. Kulenthirarajan, K.R. Machlus, R. Flaumenhaft, and J. E. Italiano. 2014.Anticoagulation inhibits tumor cell–mediated release ofplatelet angiogenic proteins and diminishes plateletangiogenic response. Blood 123:101–112.13. Ben-Hadj-Khalifa-Kechiche, S., N. Hezard, S. Poitevin,M. G. Remy, B. Florent, T. Mahjoub, et al. 2010. Differentialinhibitory effect of fondaparinux on the procoagulantpotential of intact monocytes and monocyte-derivedmicroparticles. J. Thromb. Thrombolysis 30:412–418.14. Abe, W., K. Ikejima, T. Lang, K. Okumura, N. Enomoto,T. Kitamura, et al. 2007. Low molecular weight heparinprevents hepatic fibrinogenesis caused by carbontetrachloride in the rat. J. Hepatol. 46:286–294.15. Anstee, Q. M., A. Dhar, and M. R. Thursz. 2011. The roleof hypercoagulability in liver fibrogenesis. Clin. Res.Hepatol. Gastroenterol. 35:526–533.ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 345A. Cafolla & G. Gentile Fondaparinux therapy for thrombosis and liver fibrosis

Anticoagulant therapy with fondaparinux in a liver transplant patient with thrombosis and liver fibrosis: a case report

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