SUPPLEMENTARY MATERIAL
Supplementary Table 1. Other aspects of the management of non-malignant portal
vein thrombosis in cirrhosis
Question *
All professionals
(n=135)
Hepatology
(n= 93)
Non-Hepatology
(n=42) p ‡
Type of thrombophilia testing (Q 6.2) (N=83)† 0.127
Decided by Haematology 51 (61.4) 35 (56.5) 16 (76.2)
Not decided by Haematology 32 (38.6) 27 (43.5) 5 (23.8)
Deficiencies of protein C, S, and AT 30 (93.8) 26 (96.3) 4 (80.0) 0.292
FV Leiden and prothrombin gene mutation 30 (93.8) 27 (100) 3 (60.0) 0.020
Antiphospholipid syndrome 29 (90.6) 25 (92.6) 4 (80.0) 0.410
Celiac disease 9 (28.1) 9 (33.3) 0 (0) 0.288
JAK2 ± calreticulin mutations 23 (71.9) 23 (85.2) 0 (0) <0.001
PNH 8 (25.0) 8 (29.6) 0 (0) 0.296
MTHFR gene mutations 0 (0) 0 (0) 0 (0)
PAI-1 gene mutations 8 (25.0) 7 (25.9) 1 (20) 1
TIPS in acute PVT (Q 6.7) (N=102)† 0.453
I do not perform TIPS in acute PVT 25 (24.5) 16 (22.2) 9 (30.0)
I do consider TIPS in acute PVT 77 (75.5) 56 (77.8) 21 (70.0)
Progression of PVT 44 (57.1) 34 (60.7) 10 (47.6) 0.316
Complications of ACT 47 (61.0) 35 (62.5) 12 (57.1) 0.794
Severe PH-related complications 65 (84.4) 46 (82.1) 19 (90.5) 0.494
ACT in chronic PVT with cavernomatosis (Q 6.8)
(N=110)†0.725
I do not administer anticoagulant therapy 10 (9.1) 8 (10.0) 2 (6.7)
I do administer anticoagulant therapy if: 100 (90.9) 72 (90.0) 28 (93.3)
Presence of thrombophilia 74 (74.0) 54 (75.0) 20 (71.4) 0.801
Progression of thrombosis 91 (91.0) 67 (93.1) 24 (85.7) 0.262
Intestinal infarction 54 (54.0) 43 (59.7) 11 (39.3) 0.077
Type of anticoagulant therapy if INR<2 and
platelet count ≥ 50000/μl (Q 6.9) (N=109)†0.145
Vitamin K antagonists 75 (68.8) 57 (73.1) 18 (58.1)
LMWH 32 (29.4) 19 (24.4) 13 (41.9)
Fondaparinux 0 (0) 0 (0) 0 (0)
Direct oral anticoagulants 2 (1.8) 2 (2.6) 0 (0)
Type of anticoagulant therapy if INR≥2 and
platelet count ≥ 50000/μl (Q 6.10) (N=104)†0.685
No anticoagulation in this scenario 8 (7.7) 5 (6.7) 3 (10.3)
Vitamin K antagonists 38 (36.5) 26 (34.7) 12 (41.4)
LMWH 54 (51.9) 40 (53.3) 14 (48.3)
Fondaparinux 1 (1.0) 1 (1.3) 0 (0)
Direct oral anticoagulants 3 (2.9) 3 (4.0) 0 (0)
Type of anticoagulant therapy if INR<2 and
platelet count < 50000/μl (Q 6.11) (N=100)†0.296
No anticoagulation in this scenario 7 (7.0) 4 (5.4) 3 (11.5)
Vitamin K antagonists 54 (54.0) 44 (59.5) 10 (38.5)
LMWH 36 (36.0) 24 (32.4) 12 (46.2)
Fondaparinux 0 (0) 0 (0) 0 (0)
Direct oral anticoagulants 3 (3.0) 2 (2.7) 1 (3.8)
Type of anticoagulant therapy if INR≥2 and
platelet count < 50000/μl (Q 6.12) (N=96)†0.189
No anticoagulation in this scenario 25 (26.0) 19 (27.1) 6 (23.1)
Vitamin K antagonists 27 (28.1) 20 (28.6) 7 (26.9)
LMWH 40 (41.7) 30 (42.9) 10 (38.5)
Fondaparinux 2 (2.1) 1 (1.4) 1 (3.8)
Direct oral anticoagulants 2 (2.1) 0 (0) 2 (7.7)
Anti-factor Xa monitoring in LMWH (Q 6.13)
(N=78)†0.156
I do not use it 51 (65.4) 38 (64.4) 13 (68.4)
At the beginning of therapy 9 (11.5) 5 (8.5) 4 (21.1)
If haemorrhagic/thrombotic complications occur 18 (23.1) 16 (27.1) 2 (10.5)
* Qualitative variables are expressed as absolute values and proportions.
† The total number of answers to each question, excluding those whose answer was “I do not know/no opinion”
‡ Comparisons between groups of hepatology and non-hepatology were performed with unpaired Student´s t-test, or Fisher's
exact test.
Abbreviations: Q: question; PVT: portal vein thrombosis; AT: antithrombin; FV: Factor V; JAK2: janus kinasa 2; PNH:
paroxysmal nocturnal hemoglobinuria; PAI-1: plasminogen activator inhibitor-1; MTHFR: methylene tetrahydrofolate
reductase; LT: liver transplantation; INR: international normalized ratio; TIPS: transjugular intrahepatic portosystemic shunt;
PH: portal hypertension; LMWH: low-molecular-weight heparins
Supplementary Figure 1. Flow chart of the design and distribution of the survey.
Questions were selected based on current guidelines and expert reviews on each topic.
The first draft was sent to other colleagues of our Digestive Diseases department to
ascertain whether the questions were well understood. After their feedback and an
internal discussion process, the definitive survey was created as an online survey and
sent by email through the Spanish Association for the Study of the Liver (AEEH) and
the Spanish Society of Digestive Pathology (SEPD). A total of 135 responses were
anonymously collected.
Supplementary Figure 2. Map of Spain highlighting the 33 provinces that participated in the survey (in grey) and the absolute number of participants in each province.
Annex 1: FULL COPY OF THE QUESTIONNAIRE
Explanatory notes:
1. The design of the questions and their answers was conceived in order to know, in
the most specific way possible, the usual clinical practice of each of the
professionals surveyed. This specificity attempts to reflect the general actuation and
not individualized clinical practice for more complex patients.
2. The questions refer to patients with compensated and decompensated liver cirrhosis
WITHOUT acute on chronic liver failure, or another type of congenital or acquired
coagulopathy or thrombopathy.
3. The answer "do not know/no opinion" should be selected when the professionals
surveyed do not know their management choice because it is beyond the scope of
their usual clinical practice. Therefore, it does not refer to lack of scientific evidence
in that field.
4. The platelet count is expressed in 10*3/μL. For example, if your threshold is 90,000
or 120,000 platelets per μL, write 90 and 120, respectively.
AFFILIATION1. Date of birth: |___|___|-|___|___|-|___|___|___|___|
2. Sex:
o Female
o Male
3. Subspecialty:
o General digestive disease physician
o Hepatology
o Gastroenterology
o Gastrointestinal endoscopy
o Other: ________________________________________________
4. How many years have you been treating patients with liver disease (excluding years
of Residency)?
o Less than 5 years
o Between 5-15 years
o More than 15 years
5. In which type of health care facility do you work?
o Tertiary-level hospital
o Secondary-level hospital
o Primary-level hospital
o Outpatient clinic
6. In which province do you work?
o _________________________________________________________
7. In your usual clinical practice, how many patients with liver cirrhosis do you treat
directly or indirectly per month (whether in hospital, emergency department, doctor
´s office or endoscopic unit)?
o Less than 10 patients
o Between 10-30 patients
o More than 30 patients
REBALANCED HEMOSTASIS
1. Are you familiar with the concept of "rebalanced haemostasis" associated with liver
cirrhosis?
o No
o Yes
2. If the latter answer is affirmative, has it changed your management of haemostatic
alterations in patients with liver cirrhosis?
o No
o Yes, it has made me use a more restrictive transfusion strategy
o Yes, it has made me use a more liberal transfusion strategy
o Other:
_________________________________________________________________
INVASIVE PROCEDURES
Explanatory note: the questions refer to what you would do, NOT to what for different
reasons, is finally done due to the indication of other specialists (e.g. anaesthetists or
intensivists).
1. In cirrhotic patients who will undergo an invasive procedure with LOW risk of
bleeding (<3%, e.g. paracentesis, thoracentesis, central venous cannulation, or
biopsies taken in gastrointestinal or respiratory endoscopy), what is the threshold of
INR above which you administer blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
2. In cirrhotic patients who will undergo an invasive procedure with MODERATE
risk of bleeding (3-10%, e.g. endoscopic variceal ligation, endoscopic
polypectomy, percutaneous liver biopsy, ERCP with sphincterotomy, or minor
surgery), what is the threshold of INR above which you administer blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
3. In cirrhotic patients who will undergo a MAJOR SURGERY (e.g. hepatic resection
or surgical oncology), what is the threshold of INR above which you administer
blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
4. In case of transfusing blood products to correct the prolongation of the INR, what
type of blood product do you use most frequently before SCHEDULED invasive
procedures?
o Fresh frozen plasma
o Prothrombin complex concentrate
o Recombinant factor VIIa
o Cryoprecipitate
5. In the case of transfusing blood products to correct the prolongation of the INR,
what type of blood product do you use most frequently before URGENT invasive
procedures?
o Fresh frozen plasma
o Prothrombin complex concentrate
o Recombinant factor VIIa
o Cryoprecipitate
6. In the case of transfusing blood products to correct the prolongation of the INR, do
you verify its correction with a post-transfusion analysis?
o No
o I systematically/generally verify the correction of INR prolongation
o I only verify the correction of INR prolongation before invasive procedures with
moderate risk of bleeding or before major surgery.
o I only verify the correction of the INR prolongation before major surgery.
o I use global coagulation tests (thromboelastography or thromboelastometry) to
evaluate the haemostatic effect of the transfusion
7. In cirrhotic patients who will undergo an invasive procedure with LOW risk of
bleeding (<3%, e.g. paracentesis, thoracentesis, central venous cannulation, or
biopsies taken in gastrointestinal or respiratory endoscopy), what is the threshold of
PLATELETS below which you administer blood products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
8. In cirrhotic patients who will undergo an invasive procedure with MODERATE
risk of bleeding (3-10%, e.g. endoscopic variceal ligation, endoscopic
polypectomy, percutaneous liver biopsy, ERCP with sphincterotomy, or minor
surgery), what is the threshold of PLATELETS below which you administer blood
products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
9. In cirrhotic patients who will undergo a MAJOR SURGERY (e.g. hepatic resection
or surgical oncology), what is the threshold of PLATELETS below which you
administer blood products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
10. In the case of transfusing platelets, do you verify the platelet increase with a post-
transfusion analysis?
o No
o I systematically/generally verify the improvement in thrombocytopenia
o I only verify the post-transfusion platelet increase before invasive procedures
with moderate risk of bleeding or before major surgery
o I only verify the post-transfusion platelet increase before major surgery
o I use global coagulation tests (thromboelastography or thromboelastometry) to
evaluate the haemostatic effect of the transfusion
PREVENTION OF VENOUS THROMBOEMBOLISM (VTE)
1. In patients with liver cirrhosis admitted to the hospital WITH risk factors for VTE
(e.g. immobility ≥ 3 days) and WITHOUT a contraindication to anticoagulation,
what is the threshold of INR above which you do not prescribe pharmacological
prophylaxis (e.g. low molecular weight heparin)?
o I do not prescribe any type of pharmacological prophylaxis
o I do not prescribe any type of pharmacological prophylaxis, but use mechanical
prophylaxis (i.e. compression stockings or intermittent pneumatic compression
systems)
o Do not know/No opinion
o INR Figure (if you prescribe pharmacological prophylaxis regardless of the INR
value write “0”): __________________
2. In patients with liver cirrhosis admitted to the hospital WITH risk factors for VTE
(e.g. immobility ≥ 3 days) and WITHOUT a contraindication to anticoagulation,
what is the threshold of PLATELETS below which you do not prescribe
pharmacological prophylaxis (e.g. low molecular weight heparin)?
o I do not prescribe any type of pharmacological prophylaxis
o I do not prescribe any type of pharmacological prophylaxis, but use mechanical
prophylaxis (i.e. compression stockings or intermittent pneumatic compression
systems)
o Do not know/No opinion
o Platelet Figure (if you prescribe pharmacological prophylaxis regardless of the
platelet count write “0”): __________________
3. In the case of prescribing pharmacological prophylaxis, what type of anticoagulant
drug do you use the most?
o Low-molecular-weight heparins
o Unfractionated heparins
o Fondaparinux
o Direct oral anticoagulants (e.g. apixaban, dabigatran, or rivaroxaban)
o Do not know/No opinion
4. In patients with liver cirrhosis admitted to the hospital WITH risk factors for VTE
(e.g. immobility ≥ 3 days) and WITH a contraindication to anticoagulation (e.g.
first days after a severe bleeding of any origin), do you use mechanical
prophylaxis (i.e. compression stockings or intermittent pneumatic compression
systems)
o No
o Yes
o Do not know/No opinion
5. In patients WITHOUT a personal or family history that suggests an underlying
thrombophilia, and who develop deep vein thrombosis and/or pulmonary
thromboembolism, do you test for thrombophilia if they have risk factors for its
development (e.g. immobility ≥3 days)?
o No
o Yes, regardless of age
o Yes, if the patient is under 50 years
o Do not know/No opinion
VARICEAL AND NON-VARICEAL GASTROINTESTINAL BLEEDING
Explanatory note: the questions refer to cirrhotic patients with gastrointestinal
bleeding not taking anticoagulants or antiplatelet therapy, and without suspicion of
vitamin K deficiency
1. In cirrhotic patients hospitalized for MILD VARICEAL bleeding (i.e. drop in
haemoglobin <2 gr/dL, transfusion of <2 packed red blood cells, and no
hemodynamic instability), what is the threshold of INR above which you administer
blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
2. In cirrhotic patients hospitalized for SEVERE VARICEAL bleeding (i.e. drop in
haemoglobin >2 gr/dL, transfusion of ≥2 packed red blood cells, and/or
hemodynamic instability), what is the threshold of INR above which you administer
blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
3. In cirrhotic patients hospitalized for MILD NON-VARICEAL bleeding (i.e. drop
in haemoglobin <2 gr/dL, transfusion of <2 packed red blood cells, and no
hemodynamic instability), what is the threshold of INR above which you administer
blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
4. In cirrhotic patients hospitalized for SEVERE NON-VARICEAL bleeding (i.e.
drop in haemoglobin >2 gr/dL, transfusion of ≥2 packed red blood cells, and/or
hemodynamic instability), what is the threshold of INR above which you administer
blood products?
o I do not correct the INR
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for blood products
o INR Figure: __________________
5. In case of transfusing blood products to correct the prolongation of the INR, what
type of blood product do you use the most?
o Fresh frozen plasma
o Prothrombin complex concentrate
o Recombinant factor VIIa
o Cryoprecipitate
6. In cirrhotic patients hospitalized for MILD VARICEAL bleeding (same criteria as
in question 1), what is the threshold of platelets below which you administer blood
products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
7. In cirrhotic patients hospitalized for SEVERE VARICEAL bleeding (same criteria
as in question 2), what is the threshold of platelets below which you administer
blood products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
8. In cirrhotic patients hospitalized for MILD NON-VARICEAL bleeding (same
criteria as in question 1), what is the threshold of platelets below which you
administer blood products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
9. In cirrhotic patients hospitalized for SEVERE NON-VARICEAL bleeding (same
criteria as in question 2), what is the threshold of platelets below which you
administer blood products?
o I do not transfuse platelets
o I use global coagulation tests (thromboelastography or thromboelastometry) to
guide the need for platelet transfusion
o Platelet Figure: __________________
MANAGEMENT OF NON-MALIGNANT PORTAL VEIN THROMBOSIS IN
CIRRHOSIS
1. In patients with cirrhosis WITHOUT a personal or family history that suggests an
underlying thrombophilia and regardless of their candidacy for liver transplantation,
do you test for thrombophilia after the development of acute or chronic portal
vein thrombosis?
o Yes
o No
o Do not know/No opinion
2. In the case of testing for thrombophilia, what tests do you perform? (you can
select several options)
o Deficiencies of protein C, S, and antithrombin
o Factor V Leiden and prothrombin gene mutation
o Antiphospholipid syndrome: anticardiolipin (ELISA) and lupus anticoagulant
o Celiac disease: anti-tissue transglutaminase antibody serology. Duodenal
biopsies if the latter is positive.
o Myeloproliferative neoplasms: JAK2 mutations, and if the latter are discarded,
test for calreticulin mutations
o Paroxysmal nocturnal hemoglobinuria: flow cytometry
o Methylene tetrahydrofolate reductase (MTHFR) gene mutations
o Plasminogen activator inhibitor-1 (PAI-1) gene mutations
o The laboratory investigation of thrombophilia is decided by the Hematologist.
3. In potential candidates for liver transplantation who develop ACUTE portal vein
thrombosis and WITHOUT an associated thrombophilic disorder, when do you
prescribe anticoagulant therapy if there is no contraindication for its administration?
o I do not administer anticoagulants
o When the thrombus affects more than 50% of the portal vein (including
complete thrombosis), with or without minimal extension into the superior
mesenteric vein (Yerdel II)
o When the portal vein thrombosis is complete and extends to the superior
mesenteric vein (Yerdel III and IV)
o Always, regardless of the degree of thrombosis
o Do not know/No opinion
o Other:
________________________________________________________________
4. In cirrhotic patients who are NOT ELIGIBLE for liver transplantation and who
develop ACUTE portal vein thrombosis WITHOUT an associated thrombophilic
disorder, when do you use anticoagulant therapy if there is no contraindication for
its administration?
o I do not administer anticoagulants
o When the thrombus affects more than 50% of the portal vein (including
complete thrombosis), with or without minimal extension into the superior
mesenteric vein (Yerdel II)
o When the portal vein thrombosis is complete and extends to the superior
mesenteric vein (Yerdel III and IV)
o Always, regardless of the degree of thrombosis
o Do not know/No opinion
o Other:
________________________________________________________________
5. In potential candidates for liver transplantation WITHOUT an associated
thrombophilic disorder who achieve a complete recanalization of the portal vein
thrombosis after 6 months of anticoagulation, how much longer do you prolong the
anticoagulant therapy?
o After 6 months of anticoagulation and verifying its complete recanalization, I
withdraw the anticoagulant therapy
o 6 months more (12 in total)
o I continue anticoagulant therapy indefinitely or until liver transplantation
o Do not know/No opinion
o Other:
________________________________________________________________
6. In cirrhotic patients who are NOT ELIGIBLE for liver transplantation and
WITHOUT an associated thrombophilic disorder, how much longer do you prolong
the anticoagulant therapy if a complete recanalization of the portal vein thrombosis
is achieved after 6 months of anticoagulation?
o After 6 months of anticoagulation and verifying its complete recanalization, I
withdraw the anticoagulant therapy
o 6 months more (12 in total)
o I continue anticoagulant therapy indefinitely or until liver transplantation
o Do not know/No opinion
o Other:
________________________________________________________________
7. In which clinical scenarios do you consider the insertion of a transjugular
intrahepatic portosystemic shunt (TIPS) to treat patients with acute portal vein
thrombosis? (You can select several options)
o I do not perform TIPS in patients with acute portal vein thrombosis
o Progression of thrombosis despite anticoagulation
o Development of complications of anticoagulant therapy
o Presence of several portal hypertension-related complications (e.g. previous
variceal bleeding and ascites)
o Do not know/No opinion
o Other:
________________________________________________________________
8. In cirrhotic patients who develop CHRONIC non-malignant portal vein
thrombosis with portal cavernoma, when do you use anticoagulant therapy if there
is no contraindication for its administration? (You can select several options)
o I do not administer anticoagulants in any case
o Presence of thrombophilia
o Radiological or clinical progression of thrombosis (e.g. episodes of abdominal
pain suggestive of ischemic origin)
o Development of intestinal infarction.
o Do not know/No opinion
o Other:
________________________________________________________________
9. In cirrhotic patients with baseline INR <2 and platelet count ≥50 000 IU/ml, what
type of anticoagulant do you use preferentially to treat portal thrombosis after the
initial phase of anticoagulation with heparin?
o Vitamin K antagonists (e.g. acenocumarol)
o Low-molecular-weight heparins
o Fondaparinux
o Direct oral anticoagulants (e.g. apixaban, dabigatran, or rivaroxaban)
o Do not know/No opinion
10. In cirrhotic patients with baseline INR ≥2 and platelet count ≥50 000 IU/ml, what
type of anticoagulant do you use preferentially to treat portal thrombosis after the
initial phase of anticoagulation with heparin?
o I do not use anticoagulant therapy in patients with INR ≥2
o Vitamin K antagonists (e.g. acenocumarol)
o Low-molecular-weight heparins
o Fondaparinux
o Direct oral anticoagulants (e.g. apixaban, dabigatran, or rivaroxaban)
o Do not know/No opinion
11. In cirrhotic patients with baseline INR <2 and platelet count <50 000 IU/ml, what
type of anticoagulant do you use preferentially to treat portal thrombosis after the
initial phase of anticoagulation with heparin?
o I do not use anticoagulant therapy in patients with platelet count <50 000 IU/ml
o Vitamin K antagonists (e.g. acenocumarol)
o Low-molecular-weight heparins
o Fondaparinux
o Direct oral anticoagulants (e.g. apixaban, dabigatran, or rivaroxaban)
o Do not know/No opinion
12. In cirrhotic patients with baseline INR ≥2 and platelet count <50 000 IU/ml, what
type of anticoagulant do you use preferentially to treat portal thrombosis after the
initial phase of anticoagulation with heparin?
o I do not use anticoagulant therapy in patients with INR ≥2 and/or platelet count
<50 000 IU/ml
o Vitamin K antagonists (e.g. acenocumarol)
o Low-molecular-weight heparins
o Fondaparinux
o Direct oral anticoagulants (e.g. apixaban, dabigatran, or rivaroxaban)
o Do not know/No opinion
13. In cirrhotic patients on anticoagulant therapy with low-molecular-weight heparins
and WITHOUT another indication for anti-factor Xa monitoring (i.e. obesity,
chronic renal failure stage ≥4, pregnancy), when do you use this type of monitoring?
o I do not measure anti-factor Xa activity to guide treatment with low-molecular-
weight heparins
o I systematically/generally measure anti-factor Xa activity for dosage adjustment
at the beginning of low-molecular-weight heparin therapy
o I measure anti-factor Xa activity for dosage adjustment only if haemorrhagic or
thrombotic complications occur
o Do not know/No opinion