Current use of anticoagulants in cirrhosis: a prospective study.

Cirrhosis represents irreversible destruction of the liver parenchyma which
occurs in response to multiple conditions and diseases. Due to persistent cell
damage, liver function is impaired (1). One of the central roles of the liver
is to provide a balanced hemostastic system by manufacturing coagulation
proteins and factors. Consequently chronic liver failure, i.e. cirrhosis,
results into profound changes in this hemostatic system, which leads to a new
but delicate balance. As a resultant of this delicate balance there is an
increased susceptibility to bleeding as well as thrombotic events (2, 3), with
a twofold increase in relative risk for venous thromboembolisms in cirrhosis
compared to matched controls (4). Portal vein thrombosis, in particular, has a
reported incidence of up to 40% in end stage cirrhosis (5).

Historically, patients with cirrhosis were considered to be *auto-
anticoagulated* as evidenced by an increased INR and reduced platelet count.
Large epidemiological studies have definitevely shown that patients with liver
disease are not protected from thrombotic disease, but are rather at increased
risk. Nevertheless many physicians are still reluctant to use antithrombotic
therapy in these patients, due to a (perceived) bleeding risk, despite
accumulating evidence that antithrombotic therapy in patients with cirrhosis
has a favorable safety profile. The lack of guidelines focusing on the optimal
anticoagulant treatment in cirrhosis precipitates cautious prescribing.

Until recently vitamin K antagonists (VKA) have been the preferred drugs in the
treatment of venous thrombo-embolisms in patients without liver disease. Since
several years, VKAs have been abandonded as first line treatment for the
prevention of cerebrovascular events in non-valvular atrial fibrillation.
Currently direct oral anticoagulants (DOAC) are the recommended anticoagulant
treatment for these specific indications mainly due to the significantly
reduced risk of intracranial hemorrhage (6-13). Unfortunately patients with
impaired liver function were excluded from large phase 2 and 3 trials in which
safety and efficacy of DOAC were tested compared to traditional anticoagulant
therapy.

Correct dosing and monitoring of VKA is regulated by means of INR. Standard
treatment is adjusted to a prespecified target range, which is unclear in
patients with cirrhosis, due to the already prolonged INR (14). The use of
LMWH is relatively safe for patients with cirrhosis in the treatment and
prevention of portal vein thrombosis or venous tromboembolism (15-18)
However the mode of administration, subcutaneous injections twice a day, is
strenuous and might impair long term use and adherence.
Next to the INR, the traditional coagulation tests, prothrombin time (PT) and
activated partial thromboplastin time (APTT) are a poor reflection of the true
hemostatic profile of patients with cirrhosis. Thrombin generation testing in
the presence of thrombomodulin, which assesses the real balance of pro- and
anticoagulant factors, provides a reliable measurement on the effects of drugs
on the hemostatic profile of patients with cirrhosis (19-21).
There is still little data on the use of all (traditional and DOAC)
anticoagulant drugs in patients with cirrhosis. They are presented with
different advantages and disadvantages, which complicates the treatment of
thrombosis even more. In this study, the efficacy of current anticoagulant
therapy in cirrhotics is assessed by thrombin generation tests before and
after administration of a single dose of the prescribed drug compared to
matched healthy controls.

Primary Objective: To assess whether the current use and dosing in cirrhosis of
anticoagulation is as effective in inhibiting ex vivo thrombin generation
compared to the treatment of patients with competent liver function

This study has a case controlled observational design in which patients with
cirrhosis will be subsided to two venous punctures at two time points during
recently initiated anticoagulation therapy in the context of routine care. We
will include consecutive patients meeting inclusion criteria during a time
frame of two years and compare their results to age, gender, therapy and
in-outpatient status matched controls. Blood samples will be taken before and
after the start of anticoagulant treatment (prophylactic or therapeutic).

This study could possibly lead to essential information in order to perform
future studies concerning the choice and dosage of anticoagulation in
cirrhosis. The intervention of this study contains the collection of two blood
samples and is considered negligible.