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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)


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



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



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 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 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 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.


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


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?





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?





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


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”): __________________


(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


systems)


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)



(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


systems)

o No

o Yes


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


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 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


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


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


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 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?





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?





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






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






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


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 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 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 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 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 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 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 Fondaparinux



10. In cirrhotic patients with baseline INR ≥2 and platelet count ≥50 000 IU/ml, what



o I do not use anticoagulant therapy in patients with INR ≥2



o Fondaparinux



11. In cirrhotic patients with baseline INR <2 and platelet count <50 000 IU/ml, what



o I do not use anticoagulant therapy in patients with platelet count <50 000 IU/ml



o Fondaparinux



12. In cirrhotic patients with baseline INR ≥2 and platelet count <50 000 IU/ml, what



o I do not use anticoagulant therapy in patients with INR ≥2 and/or platelet count

<50 000 IU/ml



o Fondaparinux



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


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