Keywords
thrombophilia - portal vein thrombosis - anticoagulation - low molecular weight heparin
Portal vein thrombosis (PVT) is a potentially life-threatening aliment stems from
multiple factors, both local and systemic prothrombotic risk factors.[1] Patients may present asymptomatically or within life-threatening intestinal infarction.
Conditions including cirrhosis, malignancy, and abdominal infections may precipitate
thrombus formation, and lead to complications of intestinal ischemia, portal cholangiopathy,
portal hypertension, and death.[2]
The use of anticoagulants in PVT poses a risk to patients with any aliment because
of increased risk of gastrointestinal bleeding with portal hypertension.[3] Current guidelines are unclear on the efficacy of anticoagulant therapy in patients
with PVT.[4]
[5] Exploring the outcomes of all three groups of patients with and without the use
of anticoagulants will highlight the possible effectiveness and safety of this treatment,
helping guide treatment in the future.
Aim
The aim of this study was to understand the differences in clinical outcomes in PVT
patients with cirrhosis, malignancy, and abdominal infections, with or without anticoagulation.
Method
This study was approved by ethics committee (Domain Specific Review Board, Singapore).
Data were collected from inpatient referrals to the Department of Vascular Medicine,
General Medicine, Tan Tock Seng Hospital, for PVT, from 2011 to 2016.
Patients were classified into three groups:
-
PVT with cirrhosis
-
PVT patients with primary or secondary liver malignancy
-
PVT patients with intra-abdominal infections
Patients excluded were those with missing data for primary outcome measures or those
with overlap of PVT for two or more conditions. Demographic data along with various
comorbidities including diabetes, hypertension, previous thrombotic events, and hypercoagulable
states were collected. Data were also collected for extent of PVT occlusion and additional
vein occlusions. Primary outcomes measures collected were clot resolution, bleeding,
recurrence, death in all three groups, and overall with or without anticoagulation.
Frequency, means, and percentages were calculated and the data across each subgroup
were compared with the variables of use of anticoagulant therapy compared with those
who did not receive.
Results
Data were analyzed for 36 patients. Four patients were lost to follow-up, two patients
were excluded as they had both cirrhosis and intra-abdominal infections, and it was
difficult to classify them. In total, 30 patients were analyzed in this study.
Mean age was 60.8 years (range of 30–91 years). There were 19 (63.3%) males and 11
(36.7%) females with ethnicity: 21 (70.0%) Chinese, 2 (6.7%) Malay, 2 (6.7%) Indian,
and 5 (16.7%) other race. Patients developing PVT from malignancy in this group were
13 (43.4%), 13 (43.4%) with infections, and 4 (13.3%) with cirrhosis. Out of 30 patients
overall, 15 received anticoagulation and 15 did not receive anticoagulation. The data
on demographic, comorbidities, investigations, complications, and outcomes are summarized
in [Table 1].
Table 1
Demographic data
|
Overall
|
Anticoagulation
|
No anticoagulation
|
|
Count
|
30
|
15 (50.0%)
|
15 (50.0%)
|
|
Age: mean (y)
|
60.8
|
55.6
|
66.0
|
|
Range (y)
|
30–91
|
30–77
|
45–91
|
|
Gender
|
|
Male
|
19 (63.3%)
|
11 (86.7%)
|
8 (53.3%)
|
|
Female
|
11 (36.7%)
|
4 (26.7%)
|
7 (46.7%)
|
|
Ethnicity
|
|
Chinese
|
21 (70.0%)
|
10 (66/7%)
|
11 (73.3%)
|
|
Malay
|
2 (6.7%)
|
0 (0.0%)
|
2 (13.3%)
|
|
Indian
|
2 (6.7%)
|
1 (6.7%)
|
1 (6.7%)
|
|
Others
|
5 (16.7%)
|
4 (26.7%)
|
1 (6.7%)
|
|
Malignancy
|
13 (43.4%)
|
6 (40.0%)
|
7 (46.7%)
|
|
Infection
|
13 (43.4%)
|
8 (53.3%)
|
5 (33.3%)
|
|
Cirrhosis
|
4 (13.3%)
|
2 (13.3%)
|
2 (13.3%)
|
|
Comorbidities
|
|
Diabetes mellitus
|
8 (26.7%)
|
4
|
4
|
|
Hypertension
|
14 (46.7%)
|
9
|
5
|
|
Previous thrombotic events
|
4 (13.3%)
|
3
|
1
|
|
Hypercoagulable state
|
5 (16.7%)
|
2
|
3
|
Comparing the subgroups of those who received anticoagulation to those who did not
receive anticoagulation, mean age was 55.6 years compared with 66 years. The group
of 15 who received anticoagulation therapy had a higher proportion of intra-abdominal
infection. In PVT group of 15 patients who did not receive anticoagulation, malignancy
was most common cause, either from primary hepatocellular carcinoma or hepatocellular
carcinoma with metastasis ([Table 1]).
The group who received anticoagulation had a lower proportion of patients with hypertension
and history of previous thrombotic events compared with those who did not receive
anticoagulation. Incidence of diabetes was the same in both groups ([Table 1]).
Investigations of PVT occlusion extent, presence of intestinal ischemia, portal hypertension,
portal cholangiopathy, and thrombocytopenia were performed prior to initiation of
treatment. Out of 15 patients in both arms (anticoagulation vs. no anticoagulation),
complete luminal occlusion was seen in 10 out of 15 patients in each group and partial
occlusion was seen in 5 out of 15 patients in each group. Involvement of other veins
such as superior mesenteric, inferior mesenteric, or splenic vein is shown in [Table 2]. Single case of intestinal ischemia was seen in patient who did not receive anticoagulation.
Incidence of portal hypertension was seen in two patients in anticoagulation group
and one patient in the other group.
Table 2
Investigations and complications: overall
|
Overall
|
Anticoagulation
|
No anticoagulation
|
|
Total
|
30
|
15 (50.0%)
|
15 (50.0%)
|
|
Radiology scan
|
|
PVT occlusion: complete
|
20 (66.7%)
|
10 (66.7%)
|
10 (66.7%)
|
|
PVT occlusion: partial
|
10 (33.3%)
|
5 (33.3%)
|
5 (33.3%)
|
|
Additional occlusion: 1 vein (SMV, IMV, SV)
|
8
|
5
|
3
|
|
Additional occlusion: 2 veins (SMV, IMV, SV)
|
7
|
4
|
3
|
|
Additional occlusion: 3 veins (SMV, IMV, SV)
|
2
|
2
|
0
|
|
Intestinal ischemia
|
1
|
0
|
1
|
|
Portal hypertension
|
3
|
2
|
1
|
|
Portal cholangiopathy
|
0
|
0
|
0
|
|
Thrombocytopenia (platelet <100)
|
7
|
4
|
3
|
Abbreviations: IMV, inferior mesenteric vein; SMV, superior mesenteric vein; SV, splenic
vein.
Of the 15 patients who received anticoagulation, there was complete resolution of
thrombus in 5 (33.3%), partial resolution in 1 (6.7%), and no resolution in 9 (60.0%).
Of these 15 patients, there was bleeding in 3 (20.0%), there was no recurrence in
9 (60.0%), and 3 (20.0%) died during the period of follow-up. Of the 15 patients who
did not receive anticoagulation, there was complete resolution of thrombus in 2 (13.3%),
partial resolution in 0 (0.0%), and no resolution in 13 (86.7%). Of these 15 patients,
there was bleeding in 0 (0%), there was recurrence in 2 (13.3%), and 6 (40.0%) died
during the period of follow-up.
Out of the 13 patients with malignancy, 6 patients received anticoagulation and 7
patients did not receive anticoagulation, the mortality rate was 4 (66.7%) out of
6 in anticoagulation group and 4 (57.1%) out of 7 in group who did not receive anticoagulation.
However, the survival time in days (mean) was 291 days (range of 22–981) in anticoagulation
group and 90 days (range of 6–219) in group who did not receive anticoagulation. Out
of the 13 patients with infections, 8 patients received anticoagulation and 5 patients
did not receive anticoagulation. There was no mortality rate in any groups; however,
there was recurrence in one out of five patients in group who did not receive anticoagulation
and no recurrence in the group who received anticoagulation. Out of the four patients
with infections, two patients received anticoagulation and two patients did not receive
anticoagulation. There was no mortality rate in anticoagulation group compared with
50% mortality in the group which did not receive anticoagulation. There was recurrence
in one out of two patients in patient who did not receive anticoagulation.
Anticoagulation therapies of low-molecular-weight heparin (LMWH) or a combination
of LMWH and warfarin were used during the 5-year period. Of the 15 patients who received
anticoagulation, 7 (46.7%) received LMWH, and 8 (53.3%) received the combination of
LMWH and warfarin. Mean target international normalized ratio (INR) in patients receiving
warfarin was 1.67, with a range of 1 to 3.3. Only three of the eight patients were
within this target INR for a period of 60% or more. Mean duration of anticoagulation
use was 66 days, with a range of 2 to 243 days ([Table 3]).
Table 3
Use of anticoagulation
|
Overall
|
Malignancy
|
Infection
|
Cirrhosis
|
|
Overall
|
15
|
6
|
9
|
3
|
|
Regime: LMWH
|
7 (46.7%)
|
5 (83.3%)
|
4 (44.4%)
|
1 (33.3%)
|
|
Regime: LMWH + warfarin
|
8 (53.3%)
|
1 (16.7%)
|
5 (55.6%)
|
2 (66.7%)
|
|
Target INR: mean
|
1.67
|
2.65
|
1.52
|
2.21
|
|
Target INR: range
|
1–3.3
|
1.99–3.31[a]
|
1–2.06
|
2.01–2.4
|
|
INR within therapeutic range 60% of the time
|
3
|
0
|
2
|
3
|
|
Anticoagulation duration: mean duration (d)
|
66
|
75
|
61
|
27
|
|
Anticoagulation duration: range (d)
|
2–243
|
11–122
|
2–243
|
10–45
|
Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight heparin.
a Difficult to titrate due to hepatocellular carcinoma.
Note: LMWH or a combination of LMWH and warfarin was used in patients. No novel anticoagulation
agents, such as rivaroxaban or dabigatran, were used. Target INR for patients on LMWH
and warfarin therapy recorded.
Discussion
The efficacy of anticoagulant therapy in the setting of PVT has been well documented
in the previous studies. In a 2015 meta-analysis of 16 observational studies on cirrhotic
patients with PVT, Qi et al determined a pool rate, the rates of recanalization with
anticoagulation, was significantly higher in the anticoagulated group than in the
nonanticoagulated group (odds ratio = 4.16, 95% confidence interval [CI] = 1.88–9.20,
p = 0.0004).[5] Our data suggest similar results.
Increased mortality rates were identified in PVT patients with cirrhosis.[6] A study by Turnes et al suggests a rate of 87% for 5-year survival of patients receiving
anticoagulation therapy.[7] From our data, mortality rates were lower in PVT patients who received anticoagulation.
Mean survival duration was increased from 90 to 291 days from use of anticoagulants
in patients with PVT and malignancy.
Increased age in PVT is also known to be associated with increased mortality—with
a hazard ratio of 1.02 (95% CI).[6] In our study group, patients who received anticoagulation were 10.4 years younger
compared with those who did not receive anticoagulation. This may account for decreased
mortality rates seen in patients on anticoagulation in our study. The effects of thrombus
extent have been described in the previous study. Greater the extent, poorer the outcomes.[8] In our study, the complete and partial occlusions were similar in both groups.
In a study by Condat et al, 84 of 136 patients were treated with anticoagulant therapy,
a documented incidence rate of gastrointestinal bleeding was recorded as 12.5 per
100 patient-years (95% CI, 10–15).[3] The study concluded by stating that the risk of thrombosis is currently as clinically
significant as the risk of bleeding—with the benefit–risk ratio favoring the use of
anticoagulant therapy. In our study, there was increase bleeding risk of patients
receiving anticoagulation.
A decrease in recurrence and complete thrombosis and increase in recanalization rates
are seen with the use of anticoagulation.[9]
[10]
[11] Similar findings were seen with our study.
The use of anticoagulation in noncirrhotic patients with acute PVT, anticoagulation
therapy is beneficial.[12]
[13]
[14]
[15]
[16] Thrombolysis has also been used in extensive mesenteric vein and PVT.[13] In our study, no patients received thrombolysis. It is also known that use of anticoagulation
therapy to treat PVT in the setting of cirrhosis should be done after a thorough assessment
of the risk of bleeding against the risk of rethrombosis.[17]
All patients with PVT should be investigated for thrombophilic conditions as possible
causes. Cirrhosis is considered as the main cause of PVT and is a fluctuant disease.
Treatment with low-weight heparin should be considered in these patients.[18] Investigating for thrombophilia is not a routine practice in our center.
Anticoagulants are a safe treatment for PVT and partial or complete recanalization
is seen in many patients.[19] In our study, anticoagulation increased the bleeding risk by 20%. The early initiation
of anticoagulation in patients of superior mesenteric vein thrombosis combined with
PVT could minimize the serious complication such as peritonitis due to bowel necrosis
required immediate exploratory laparotomy.[20] Our understanding of the etiology, natural history, and treatment options for extrahepatic
PVT have improved over the past few years. The recognition that multiple risk factors,
including inherited and acquired thrombophilic predispositions, are involved in the
majority of cases merits a methodical search for these, as their identification may
influence management.[21] Rare case of massive upper gastrointestinal bleeding due to pancreatic pseudocyst
rupture into the duodenum, which developed during anticoagulation therapy for acute
pancreatitis associated with PVT has been reported.[22] Thus, bleeding risk on anticoagulation needs to be monitored closely in these patients.
Our study shows that over 5-year period, treatment of PVT with anticoagulation irrespective
of cause, there is a benefit in anticoagulation therapy though there is slight increase
in bleeding risk in these patients with overall improvement in mortality.
However, the study has the following limitations:
-
This is retrospective data analysis.
-
The sample size is small. This is due to the fact that PVT is not very common condition
seen in our population.
Conclusion
Anticoagulation is effective in PVT. It reduces mortality by 50%, helps in resolution
of thrombus, and lower rate of recurrence when compared with those with no anticoagulation.
The rate of recanalization with anticoagulation is three times higher compared with
ones who do not receive anticoagulation. However, anticoagulation is associated with
three times increased risk of bleeding and should be used with caution in patients
with increased bleeding risk.
