Thrombocytopenia, defined as platelet counts (PLTs) below 150 × 10⁹/L, is one of the most common complications of liver cirrhosis. This condition is present in almost 80% of patients with advanced chronic liver disease and is conventionally classified into mild (< 150 × 10⁹/L), moderate (< 100 × 10⁹/L), and severe (< 50 × 10⁹/L). Thrombocytopenia, from a pathophysiological perspective, is the result of: a) increased splenic sequestration due to portal hypertension, b) decrease in thrombopoietin production because of reduced liver synthesis capacity, and c) suppression of megakaryocytopoiesis [1, 2]. Thrombocytopenia, together with changes in platelet function and the coagulative/fibrinolytic system, is the basis of a complex hemostasis disorder frequently seen in subjects suffering from advanced liver disease. Unlike the healthy subject, in the cirrhotic patient, the hemostasis system presents a labile balance. This equilibrium can be destabilized, both in the hemorrhagic and thrombotic outcome, by various triggering factors (e.g., infections, bleeding of esophageal varices, refractory ascites, and invasive diagnostic-therapeutic procedures) [3].

There is a limited number of tests available to study the coagulative status in liver cirrhosis. Those used in clinical practice are: international normalized ratio (INR) which, if lengthened, correlates with a reduction in the plasma concentration of coagulative factors synthesized by the liver; PLT which gives us information on the number of platelets, but not in their function, and a reduction of the count is considered an indicator of increased bleeding risk [3, 4]. In clinical practice, subjects with advanced liver disease have increased INR values (between 1.5–2.0) and a PLT below 50 × 10⁹/L. These subjects, not infrequently, have to undergo repeated invasive procedures such as esophageal variceal band ligation (EVBL), loco-regional treatments of hepatocellular carcinoma (HCC), liver biopsies, and others [5]. In the literature, there aren’t prospective studies, in patients with liver cirrhosis, showing the minimum platelets’ cut-off to reduce the risk of bleeding when the most common diagnostic and therapeutic procedures need to be performed [6]. Since there are only retrospective studies on the minimum cut-off PLT to reduce the risk of bleeding, guidelines from various scientific societies state that platelet transfusion can be considered in patients with low PLTs prior to an invasive procedure [4, 6]. Consequently, the indication for prophylactic platelet transfusion in patients with counts below 50 × 10⁹/L is personalized and based both on the bleeding risk of the procedure and the patient’s clinical condition [6].

In recent years, platelet transfusion can be avoided by treating patients with the second generation thrombopoietin receptor (TpoR) agonists (TpoR, lusutrombopag, and avatrombopag) [1]. These drugs have the ability to stimulate the bone marrow to produce platelets, resulting in a transient increase in PLT [4]. Specifically, lusutrombopag is a drug to be taken orally at a dosage of 3 mg/day for 7 days [3]. The pivotal studies of this drug show that the median peak PLT and maintenance, above the threshold, is on day 12 and 19 from the start of administration, respectively [3]. Therefore, in patients undergoing elective invasive procedures, the need for platelet transfusion is unnecessary. Furthermore, the drug showed no safety concerns on thrombotic events, in particular with regard to the development of portal vein thrombosis. These studies evaluated the efficacy in reducing the need for platelet transfusions in subjects with advanced liver disease and severe thrombocytopenia undergoing invasive procedures [7]. Unfortunately, there is no information, even in real life, on the efficacy and tolerability of TpoR drugs in repeated use or in the case of multiple procedures following a single therapeutic cycle [7, 8].

In this paper, the cases of two patients undergoing repeated invasive procedures after single or multiple courses of lusutrombopag therapy are described.

The second generation TpoR provides a tool that allows to avoid platelet transfusion in patients with chronic liver disease who require invasive diagnostic or therapeutic procedures [4]. Platelet transfusion, indeed, is an expensive and complex operation as it must be performed a few hours before the procedure and, above all, not without complications for the patient [9]. Specifically, the main adverse reactions are represented by transfusion-related reactions, such as hemolysis in case of incompatibility of the AB0 blood groups between the donor and recipient [10], anaphylactic shock or allergic reactions [11], and infectious risk given by the presence of viruses or bacteria in the transfused platelet pool which, in rare cases, can even lead to death [11]. Furthermore, the transfused platelets have both a limited temporal action, as they are degraded more rapidly than those produced by the subject, and a reduced function, as the non-self platelets lose their ability to form the platelet plug [12, 13]. Platelet transfusion, however, remains the gold standard in patients who need urgent procedures [4].

In this paper, two emblematic case reports are described where a subject was treated with a single course of lusutrombopag and subjected to two different invasive procedures, while another received repeated courses of the drug before 5 rounds of EVBL.

In the first case, there is evidence that after a single treatment with lusutrombopag, the number of platelets remains above 50 × 10⁹/L for several days before returning to baseline values, allowing to carry out more procedures with a single treatment. This opportunity has a positive impact on planning hospital admissions as well as preventing the risk of adverse events and/or reduced efficacy of close platelet transfusions. Furthermore, the efficacy and tolerability of lusutrombopag in 83-year-old patient are reported. About this topic in the registration studies, the mean age of enrolled subjects was lower and respectively 55.2, 55.7, and 68.9-year-old [7, 8]. Considering that many of the cirrhotic subjects in the world are of advanced age, we believe that data on the safety and efficacy of lusutrombopag in older populations are welcome for a generalized use of this drug.

In the second case, it was demonstrated that repeated treatments with lusutrombopag continue to maintain an excellent efficacy, in terms of PLT, and are associated with a high safety profile. In this latter regard, thrombotic events in the abdominal venous system have never occurred.

To date, literature presents few data related to the use of second generation TpoR. However, there is a general consensus about the excellent response in terms of PLT increase, with a high safety profile both using single and multiple treatments [14–16]. There is, however, no agreement from scientific societies on the use of platelet transfusions or TpoRs in subjects with chronic liver disease and severe thrombocytopenia that are candidates for invasive procedures [4, 6, 17–20]. This disagreement is due to the fact that to date we do not have: a) randomized controlled trials on the risk of bleeding among patients treated with platelet transfusion or TpoR compared with an untreated control group, b) available tests that allow us to stratify the bleeding risk during and after invasive procedures. In the latter, viscoelastic tests are being studied, but at the moment there are insufficient data to demonstrate their effectiveness. Due to the lack of these data, the recent indications of the European Association for the Study of the Liver (EASL) postpone the decision based on the evaluation of clinical conditions and haemocoagulation profile of the individual patient [6]. The results of this experience are limited, retrospective, and not adequate to make up for the discordant guidelines of scientific societies but they can be a useful reference in the management of patients for whom it may be difficult to identify the most appropriate treatment.

In conclusion, given the absence of tools that define the risk of bleeding, TpoR can represent the treatment of choice for the prophylaxis of cirrhotic patients with severe thrombocytopenia, who must electively undergo invasive procedures at a high risk of bleeding. This approach permits to avoid platelet transfusion and overall related risks [21].