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transplantation. Clin Res Hepatol

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CASE REPORT
Acquired factor V inhibitor after liver
transplantation
Li-Ying Sun
a
, Zhi-Jun Zhu
a,
, Zhi-Gui Zeng
a
, Wei Qu
a
,
Lei Zhang
b
, Meng-Su Tian
b
, Xiao-Ye Sun
c
, Wei Rao
c
,
Wei Gao
c
, Lin Wei
a
a
Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, XiCheng District, Beijing 100050,
Peoples Republic of China
b
Institute of Hematology and Blood Diseases Hospital, CAMS and PUMC, Tianiin, 300020, China
c
Organ Transplantation Center, Tianjin First Center Hospital, 24 Fukang Road, Nankai, Tianjin 300192,
Peoples Republic of China
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 of FV 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 hepatitis
B 9 years ago. In the last 3 years, the patient was hospital-
ized repeatedly due to the progressive deterioration of liver

Corresponding author. Tel.: +86 10 63138350;

fax: +86 10 63138350.
E-mail address: zhu-zhijun@medmail.com.cn (Z.-J. Zhu).
function and gastrointestinal bleeding. Thereby, transplan-
tation was recommended. Before transplantation, platelet
was 263 10

9/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 was
uneventful; the portal vein thrombos was removed dur-
ing surgery. Also, 1000 mL plasma, 4830 mL red blood cells
were used interoperation and no bovine thrombin or b-
rin glue was used during the operation. From the rst
http://dx.doi.org/10.1016/j.clinre.2014.03.007
2210-7401/ 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Sun L-Y, et al. Acquired factor V inhibitor after liver transplantation. Clin Res Hepatol
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2 L.-Y. Sun et al.
Table 1 Laboratory parameters of coagulation 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 86.6
Anti-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 daily
since the seventh day, and the immunosuppressive drug
FK506 (Fujisawa Japan) 2 mg q12h oral. On the 6th day
after transplantation, he started to receive warfarin anti-
coagulation to prevent thrombosis. On the 7th day, PT
was 13.7 s, INR was 1.05, APTT was 43.6 s, platelet was
180 10

9/L. On the 12th day, routine coagulation evalua-

tion showed that PT was 43.6 s, INR was 4.84, APTT was
71.3 s, thrombin time was normal, platelet count increased
to 450 10

9/L (Table 1), and the patient received FFP

(fresh frozen plasma) intermittently with no laboratory
expense. On the 24th day, he had gastrointestinal bleed-
ing and the performance of blood in the stool was tested
positive. In order to locate the bleeding site, the patients
underwent gastroscopy, colonoscopy and capsule endoscopy,
which revealed mild esophageal varies erosive gastritis, coli-
tis, colon polyps and suspected jejunal bleeding. The patient
received FFP (fresh frozen plasma), Vitamin K, Prothrom-
bin complex, NovoSeven (recombinant human coagulation
factor VIIa for injection) repeatedly. Despite the therapy
adopted, gastrointestinal bleeding was still developing and
the laboratory results showed no improvement. So we sus-
pected the presence of clotting factors that interfered
coagulation process. On the 44th day, assays for all the
factors 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 was
42.4%, and factor XI was 43.8%. The factor V inhibitor level
was found to be 9 Bethesda units/mL (Table 1). By refe-
rence to anti-factor VIII inhibitor titration, the anti-factor
V inhibitor titer was estimated at Bethesda units. The fac-
tor V inhibitor was assessed in vitro by incubating equal
amounts of dilutions of the patients plasma with normal
plasma. Residual factor V activity was measured after 2 h of
incubation at 37

C.
On the 52nd postoperative day, we changed the immuno-
suppressant from FK506 to CsA, laboratory parameters
showed no obvious improvement. On 63rd postoperative day,
the patient was treated with IVIg (Boya Bio-Pharmaceutical
Co., Ltd, Jiangxi, China) at a dose of 400 mg/kg which
was administered slowly over 7 consecutive days. On the
65th postoperative day (after two days of initiation of IVIg
therapy), the patients PT and APTT decreased, FV level
increased, whereas the factor V inhibitor level decreased to
1.7 BU/mL (Table 1, Fig. 1). And clinical bleeding symptom
was gradually resolved. On the 72nd postoperative day, the
PT, APTT and FV levels continued to improve, with a normal
PT 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 last
laboratory examination (Table 1, Fig. 1). The patient was
discharged on the 80th postoperative day, he had no further
abnormal coagulation or episodes of bleeding reported in
the next month.
Acquired FV inhibitors has been associated with the pres-
ence of relatively risk factors, including bovine thrombin
administered during surgical procedures, antibiotic admin-
istration (especially the lactam group), blood transfusions,
cancers and autoimmune disorders [15]. However, it is
difcult to prove the reason or their relationship in many
cases. It is either related to the development of inhibitors
or to their role in bleeding, and it is possible that many
cases arise in complex multifactorial process [2]. In the
review by Massimo and Giuseppe [6], except for patients
with acquired factor V inhibitors after exposure to bovine
thrombin, 78 cases were analyzed, 42% of the cases (33/78)
had documented in using of antibiotics such as b-lactams,
aminoglycosides, cephalosporins, tetracyclines and quino-
linones (especially ciprooxacin). Surgical procedures and
infections were recorded respectively in 24 cases (31%) and
18 cases (23%). Autoimmune disorders were presented in 10
of the 78 cases (13%), and 17 cases (22%) were associated
with cancer.
There are only ve cases of FV inhibitors occurrence
after liver transplantation, reported by a large number
of literature search results [711]. One of them achieves
good results through IVIg treatment. The patient in this
case 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 FV
inhibitors. The post-transplanted patient has conspicuous
coagulation dysfunction and gastrointestinal bleeding. FV
inhibitors existence was proved in laboratory examina-
tions. The patient was cured by high dose of intravenous
immunoglobulin and conversion immunosuppressant from
tacrolimus to cyclosporine. However, IVIG have probably
been more efcacious for the resolution of this case than
the conversion from tacrolimus to cyclosporine, since:
the resolution occurred 48 h after IVIG perfusion, whereas
conversion had no effect for more than 10 days;
IVIG have been successfully used previously;
cyclosporine and tacrolimus have similar effects on the
immune response.
Please cite this article in press as: Sun L-Y, et al. Acquired factor V inhibitor after liver transplantation. Clin Res Hepatol
Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.03.007
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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 of the blue strip indicates the length of time of
the medicine used.
Disclosure of interest
The authors declare that they have no conicts of interest
concerning this article.
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Further reading
Tracy PB, Eide LL, Bowie EJ, et al. Adioimmunoassay of factor V in
human plasma and platelets. Blood 1982;60:5963.
Kane WH. Factor V in hemostasis and thrombosis: basic principles
and clinical practice. 5th ed. Philadelphia: J.B. Lippincott Company;
2006. p. 17792.