30-05_Acquired factor V inhibitor after liver transplantation.pdf

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Please cite this article in press as: Sun L-Y, et al. Acquired factor V inhibitor after liver transplantation. Clin Res HepatolGastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.007

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CLINRE-573; No. of Pages 3

Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxxxxx

Available online at

ScienceDirect

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CASE REPORT

Acquired factor V inhibitor after liver

transplantation

Li-Ying Suna, Zhi-Jun Zhua,, Zhi-Gui Zeng a, Wei Qu a,Lei Zhangb, Meng-Su Tianb, Xiao-Ye Sun c, Wei Rao c,Wei Gao c, Lin Weia

a Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road,XiCheng District, Beijing 100050,

Peoples Republic ofChinab Institute ofHematologyandBloodDiseases Hospital, CAMS andPUMC, Tianiin, 300020, Chinac Organ Transplantation Center, Tianjin First CenterHospital, 24 Fukang Road, Nankai, Tianjin 300192,

Peoples Republic ofChina

Summary Acquired inhibitors against coagulation factor V (FV) occur rarely, the clinical symp-

toms vary to a great extent, from asymptomatic laboratory abnormalities to life-threatening

bleeding. Coagulation factor V (FV) is a plasma-cofactor mostly existing in the plasma, and

approximately 2025% (Tracy et al. (1982), Kane (2006)) of FV exist in platelet granules.Patients reaction is the prolonging of prothrombin time (PT) and activated partial thrombo-

plastin time (APTT), but there is no exact reason, and that can not be corrected after normal

plasma transfusion (Morris and Curris (2009), Lucia and Aguilar (2005)). We report here a case of

the occurrence ofFV inhibitors after orthotopic liver transplantation (OLT). With gastrointesti-

nal bleeding, patients haemostatic response was not achieved after using fresh frozenplasma

(FFP), platelet concentrates (PC), prothrombin complex concentrates (PCC) or recombinant

activated FVII (rFVIIa). After using high-dose intravenous immunoglobulin (IVIg) and change of

immunosuppressant from tacrolimus (FK506) to cyclosporine, the bleeding stopped and better

laboratory examination results was achieved thereafter.

2014 Elsevier Masson SAS. All rights reserved.

A 54-year-old man was admitted to our hospital with cirrosis,past medical history showed that he was diagnosed hepatitisB 9 years ago. In the last 3 years, the patient was hospital-ized repeatedly due to the progressive deterioration ofliver

Corresponding author. Tel.: +86 10 63138350;fax: +86 10 63138350.

E-mail address: [email protected] (Z.-J. Zhu).

function and gastrointestinal bleeding. Thereby, transplan-tation was recommended. Before transplantation, plateletwas 263109/L, the prothrombin time (PT) was 13.2 s (nor-mal, 1115 s), activated partial thromboplastin time (APTT)was 35.5 s (normal, 2840 s). The operation course wasuneventful; the portal vein thrombos was removed dur-ing surgery. Also, 1000 mL plasma, 4830 mL red blood cellswere used interoperation and no bovine thrombin or fib-rin glue was used during the operation. From the first

http://dx.doi.org/10.1016/j.clinre.2014.03.0072210-7401/ 2014 Elsevier Masson SAS. All rights reserved.
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2 L.-Y. Sun et al.

Table 1 Laboratory parameters ofcoagulation studies.

Postoperative day

1 7 12 14 20 25 30 44 54 65 72 79

PT (s) 20.9 13.7 43.6 120 53.7 51.7 48.4 48.6 47 33.5 14.4 12.1

APTT (s) 50.4 43.6 71.3 180 180 180 180 180 180 87.2 32.8 33.6

PT% 45 92 16 10 13 13 15 14 15 23 83 122

FV% 0.6 7.9 86.6Anti-FV (BU) 9 1.7

TT (s) 22.6 15.1 16.3 15.3 15.3 15.4 15.4 15.1 15 16.8 17.6 15.9

PLT (10*9/L) 76 127 450 526 628 400 182 476 404 450 362 420

day after transplantation, the patient received Meropenen

1 g iv.q8h, Methylprednisolone 25 mg iv.q6h and was con-tinuously administrated in a tapering dose of 8 mg dailysince the seventh day, and the immunosuppressive drugFK506 (Fujisawa Japan) 2 mg q12h oral. On the 6th dayafter transplantation, he started to receive warfarin anti-coagulation to prevent thrombosis. On the 7th day, PTwas 13.7 s, INR was 1.05, APTT was 43.6 s, platelet was

180109/L. On the 12th day, routine coagulation evalua-tion showed that PT was 43.6 s, INR was 4.84, APTT was71.3 s, thrombin time was normal, platelet count increasedto 450109/L (Table 1), and the patient received FFP(fresh frozen plasma) intermittently with no laboratoryexpense. On the 24th day, he had gastrointestinal bleed-ing and the performance of blood in the stool was testedpositive. In order to locate the bleeding site, the patientsunderwent gastroscopy, colonoscopy and capsule endoscopy,which revealed mild esophageal varies erosive gastritis, coli-tis, colon polyps and suspected jejunal bleeding. The patientreceived FFP (fresh frozen plasma), Vitamin K, Prothrom-bin complex, NovoSeven (recombinant human coagulation

factor VIIa for injection) repeatedly. Despite the therapyadopted, gastrointestinal bleeding was still developing andthe laboratory results showed no improvement. So we sus-pected the presence of clotting factors that interferedcoagulation process. On the 44th day, assays for all thefactors levels were obtained. The factor V level was 0.6%(normal, 50150%), factor II was 57.1%, factor VII was 45.6%,factor was VIII 88.2%, factor IX was 47.5%, factor X was42.4%, and factor XI was 43.8%. The factor V inhibitor levelwas found to be 9 Bethesda units/mL (Table 1). By refe-rence to anti-factor VIII inhibitor titration, the anti-factorV inhibitor titer was estimated at Bethesda units. The fac-tor V inhibitor was assessed in vitro by incubating equalamounts of dilutions of the patients plasma with normal

plasma. Residual factor V activity was measured after 2 h ofincubation at 37 C.

On the 52nd postoperative day, we changed the immuno-suppressant from FK506 to CsA, laboratory parametersshowed no obvious improvement. On 63rd postoperative day,the patient was treated with IVIg (Boya Bio-PharmaceuticalCo., Ltd, Jiangxi, China) at a dose of 400 mg/kg whichwas administered slowly over 7 consecutive days. On the65th postoperative day (after two days of initiation of IVIgtherapy), the patients PT and APTT decreased, FV levelincreased, whereas the factor V inhibitor level decreased to1.7 BU/mL (Table 1, Fig. 1). And clinical bleeding symptomwas gradually resolved. On the 72nd postoperative day, the

PT, APTT and FV levels continued to improve, with a normalPT was 14.4 s, APTT was 32.8 s, and FV was 86.6% (Table 1,Fig. 1). Factor V inhibitor could not be tested at the lastlaboratory examination (Table 1, Fig. 1). The patient wasdischarged on the 80th postoperative day, he had no furtherabnormal coagulation or episodes of bleeding reported inthe next month.

Acquired FV inhibitors has been associated with the pres-

ence of relatively risk factors, including bovine thrombinadministered during surgical procedures, antibiotic admin-istration (especially the lactam group), blood transfusions,cancers and autoimmune disorders [15]. However, it isdifficult to prove the reason or their relationship in manycases. It is either related to the development of inhibitorsor to their role in bleeding, and it is possible that manycases arise in complex multifactorial process [2]. In thereview by Massimo and Giuseppe [6], except for patientswith acquired factor V inhibitors after exposure to bovinethrombin, 78 cases were analyzed, 42% ofthe cases (33/78)had documented in using of antibiotics such as b-lactams,aminoglycosides, cephalosporins, tetracyclines and quino-

linones (especially ciprofloxacin). Surgical procedures andinfections were recorded respectively in 24 cases (31%) and18 cases (23%). Autoimmune disorders were presented in 10of the 78 cases (13%), and 17 cases (22%) were associatedwith cancer.

There are only five cases of FV inhibitors occurrenceafter liver transplantation, reported by a large numberof literature search results [711]. One of them achievesgood results through IVIg treatment. The patient in thiscase has some related factors, including the use of surgery,antibiotics, warfarin, tacrolimus. But we cannot deter-mine what kind of reason causes the formation of the FVinhibitors. The post-transplanted patient has conspicuouscoagulation dysfunction and gastrointestinal bleeding. FV

inhibitors existence was proved in laboratory examina-tions. The patient was cured by high dose of intravenousimmunoglobulin and conversion immunosuppressant fromtacrolimus to cyclosporine. However, IVIG have probablybeen more efficacious for the resolution of this case thanthe conversion from tacrolimus to cyclosporine, since:

the resolution occurred 48 h after IVIG perfusion, whereasconversion had no effect for more than 10 days;

IVIG have been successfully used previously; cyclosporine and tacrolimus have similar effects on the

immune response.
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Acquired factor V inhibitor after liver transplantation 3

Figure 1 PT, APTT and factor V levels during the post-transplant and treatment course. FV activity was very low on the 44th day

postoperation, it was increasing after treatment with IVIG and others. The length ofthe blue strip indicates the length of time of

the medicine used.

Disclosure ofinterest

The authors declare that they have no conflicts of interestconcerning this article.

References

[1] Lucia JF, Aguilar C. A case of an asymptomatic idiopathicinhibitor to coagulation factor V. Haemophilia 2005;11:17880.

[2] Morris CJ, Curris N. Acquired factor V inhibitor in a critically illpatient. Anaesthesia 2009;64:10147.

[3] Miesbach W, Voigt J, Peetz D, et al. Massive bleeding symptomsin two patients with factor V inhibitor and antiphospho-

lipid antibodies after treatment with ciprofloxacin. Med Klin2003;98:33943.

[4] Takahashi H, Fuse I, Abe T, et al. Acquired factor V inhibitoromplicated by Hashimotos thyroditis, primary biliary cirrho-sis and membranous nephropathy. Blood Coagul Fibrinolysis2003;14:8793.

[5] Koyama JA, Saito T, Kusano T, et al. Factor V inhibitor associ-ated with Sjogrens syndrome. Br J Haematol 1995;89:8936.

[6] Massimo F, Giuseppe L. Acquired factor V inhibitors: a system-atic review. J Thromb Thrombolysis 2011;31:44957.

[7] Guglielmone H, Jarchum G, Minoldo S. Successful treatmentwith intravenous immunoglobulin (IVIg) in a patient with anacquired factor V inhibitor after liver transplantation. ThrombHaemost 2011;106(5):9856.

[8] Lian EC, Tzakis AG, Andrews D. Response of factor V inhibitorto rituximab in a patient who received liver transplantation forprimary biliary cirrhosis. Am J Hematol 2004;77:3635.

[9] Leroy-Matheron C, Mallat A, Duvoux C, et al. Inhibitor againstcoagulation factor V after liver transplantation. Transplanta-tion 1999;68:10546.

[10] Smith JD, Sindhi R, Rogers R, et al. Factor V inhibitor in a livertransplant patient associated with porcine xenoperfusion. AnnClin Lab Sci 1998;28:2802.

[11] Gordon B, Haire W, Duggan M, et al. Factor V inhibitor develop-

ing after liver transplantation in a 3-year-old child. Pediatrics1991;88:1569.

Further reading

Tracy PB, Eide LL, Bowie EJ, et al. Adioimmunoassay of factor V inhuman plasma and platelets. Blood 1982;60:5963.

Kane WH. Factor V in hemostasis and thrombosis: basic principlesand clinical practice. 5th ed. Philadelphia: J.B. Lippincott Company;2006. p. 17792.
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