Chronic liver disease is characterized by several hematological derangements resulting in a complex and barely rebalanced haemostatic environment. Thrombocytopenia is the most common abnormality observed in these patients and recent advances have led to researchers focus the attention on the multifactorial origin of thrombocytopenia and on the key role of thrombopoietin (TPO) in its physiopathology. Severe thrombocytopenia (platelet count < 50000/μL) complicates the management of patients with chronic liver disease by increasing the potential risk of bleeding for invasive procedures, which may be therefore delayed or canceled even if lifesaving. In the very last years, the development of new drugs which exceed the limits of the current standard of care (platelet transfusions, either immediately before or during the procedure) paves the way to a new scenario in the management of this population of patients. Novel agents, such as the TPO-receptor agonists avatrombopag and lusutrombopag, have been developed in order to increase platelet production as an alternative to platelet transfusions. These agents have demonstrated a good profile in terms of efficacy and safety and will hopefully allow reducing limitations and risks associated with platelet transfusion, without any delay in scheduled interventions. Altogether, it is expected that patients with chronic liver disease will be able to face invasive procedures with one more string in their bow.

Thrombocytopenia is a consequence of portal hypertension and is the most common hematological manifestation of chronic liver disease (CLD) (ie, cirrhosis). Data indicates the rates of CLD are increasing and, as a result, so will the incidence of this complication. Although bleeding risks are only relevant when elective procedures are performed, this is a frequent concern as these procedures are commonly part of the spectrum of care for patients with cirrhosis. As such, thrombocytopenia remains a pertinent issue. Fortunately, we now have effective and accurate treatment modalities to raise platelet counts before scheduled procedures, known as thrombopoietin receptor agonists. Two drugs in this therapeutic class (avatrombopag and lusutrombopag) are now approved for the treatment of thrombocytopenia in adults with CLD undergoing a procedure and have revolutionized how this is managed. Although there is progress in the field, peer-reviewed literature and expert guidance are lacking. Recognizing these unmet needs, a group of expert hepatologists comprised this review, which summarizes the most current and relevant peer-reviewed literature on thrombocytopenia in CLD and provides clinical expertise on this timely topic.

Patients with chronic liver diseases (CLD) undergo a range of invasive procedures during their clinical lifetime. Various hemostatic abnormalities are frequently identified during the periprocedural work-up; including thrombocytopenia. Thrombocytopenia of cirrhosis is multifactorial in origin, and decreased activity of thrombopoietin has been identified to be a major cause. Liver is an important site of thrombopoietin production and its levels are decreased in patients with cirrhosis. Severe thrombocytopenia (platelet counts < 60-75,000/µL) is associated with increased risk of bleeding with invasive procedures. In recent years, compounds with thrombopoietin receptor agonist activity have been studied as therapeutic options to raise platelet counts in CLD. We reviewed the use of Eltrombopag, Romiplostim, and Avatrombopag prior to various invasive procedures in patients with CLD. These agents seem promising in raising platelet counts before elective procedures resulting in reduction in platelet transfusions, and they also enabled more patients to undergo the procedures. However, these studies were not primarily aimed at comparing bleeding episodes among groups. Use of these agents had some adverse consequences, importantly being the occurrence of portal vein thrombosis. This review highlights the need of further studies to identify reliable methods of safely reducing the provoked bleeding risk linked to thrombocytopenia in CLD.

Platelets are frequently given inappropriately. The accepted indication is symptomatic thrombocytopaenia due to bone marrow failure. In contrast replacement therapy is contraindicated in immune mediated peripheral sequestration because it is almost always ineffective and also aggravates the already rapid rate of the clearance due to superimposed isoimmunisation. Furthermore circulating levels, rather than the clinical situation, customarily trigger the request and would typically be at 20 x 10(9)/l. Usage is under evaluated and, accordingly, current practice has been scrutinised and a guideline proposed that is applicable to user and vendor alike.

Prospectively a consecutive series of eligible cases were selected and, with informed consent, all relevant information recorded. Specific observations were haematologic status, quality of the product and the impact of previous exposure to blood fractions on outcome. Additionally, factors that influence response were documented and included disseminated intravascular coagulation, splenomegaly and concurrent use of intravenous Amphotericin B. The absolute numbers infused, the increase in peripheral value recorded and this ratio which is designated as corrected count index generated in each instance.

The CCI was computed for each of the 85 megaunits given to 29 individuals and subsequently estimated for the entire sample population using regression analysis. Each of the variables was used to test the hypothesis that such a figure might differ depending on patient sub-population. This approach was accurate in 60% of the time and predicates a more rational use of donor characteristics. The cardinal measurement is that supplied by the transfusion service which can be used as a basis for clinically important predictors of anticipated benefit.

This data, in keeping with international practice, leads to the recommendation that commercial and other services routinely measure and specify absolute numbers. The clinicians, reciprocally, should always confirm this figure and then match anticipated to observed outcome. Failure to carry out these simple procedures lead to gross over utilisation of this expensive intervention, risks unnecessary sensitisation and furthers persistence with sub-optimum administration.

Thrombopoietin (TPO) is a hematopoietic growth factor which plays a central role in normal megakaryocytopoiesis and thrombopoiesis. Although the interaction between TPO and its receptor c-Mpl encoded by the c-mpl gene is now known to be implicated in the proliferation and/or differentiation of abnormal myeloid cells and normal hematopoietic stem cells, little is known about a role of the TPO/c-Mpl system in lymphoid leukemia cells. In the present study, we first examined the expression of c-mpl/c-Mpl in 23 human lymphoid leukemic cell lines (T-lineage 4, B-lineage 19) using three distinct methods. The c-mpl mRNA was detectable in as many as 20 cell lines (T-lineage 3, B-lineage 17) by reverse transcriptase-polymerase chain reaction, but its translated product, c-Mpl, was demonstrable by Western blot only in B-lineage cell lines. Flow cytometric analysis revealed the surface c-Mpl expression in 13 of 17 B-lineage cell lines, but its higher expression (>40%) was restricted in nine B-precursor cell lines, eight of which had 11q23 translocation or Philadelphia chromosome (Ph1). We also demonstrated that two of eight cell lines with 11q23 translocation or Ph1 exhibited a significant proliferative response to TPO in the 3H-thymidine uptake and colony-forming assays. Triggering of these cell lines by TPO transiently up-regulated tyrosine phosphorylation of JAK-2 and Shc, indicating that their receptor is functional. Primary leukemia cells separated from patients with B-precursor acute lymphoblastic leukemia with Ph1 or 11q23 translocation also showed the surface c-Mpl expression and a significant responsiveness to TPO. These results suggest that the TPO/c-Mpl interaction may play a physiological role in the growth regulation of B-precursor leukemia cells particularly with specific chromosomal abnormalities.

Thrombopoietin performs an essential role during hematopoiesis by regulating the expansion and maturation of megakaryocytes. In keeping with this function, megakaryocytes, platelets, and their precursors all express the thrombopoietin receptor, Mpl, on their cell surface. However, Mpl is also expressed on primitive, pluripotent hematopoietic progenitors and plays an important role in the regulation of lineages other than megakaryocytes as well as primitive progenitors. Recently, the ability of thrombopoietin to maintain and expand repopulating stem cells has been demonstrated. Thus, thrombopoietin is unique among the hematopoietic cytokines because it is necessary both for terminal maturation and regulation of lineage-specific megakaryocytes and also for maintenance of the most primitive hematopoietic stem cells. Many new strategies are evolving to exploit the activity of thrombopoietin on primitive progenitors. This may lead to faster hematopoietic recovery from marrow-suppressive therapy, effective methods of ex vivo expansion of hematopoietic stem cells, and retroviral transduction of stem cells to facilitate gene therapy.

Thrombopoietin (TPO) is a primary regulator of megakaryocytopoiesis, a process through which megakaryocytes proliferate and mature into platelets. Recombinant human TPO (rhTPO) was expressed in Chinese hamster ovary (CHO) cells and purified from the culture medium. The cDNA encoding full-length TPO, including the native signal peptide sequence, was amplified by PCR from a human fetal liver cDNA library. The product was cloned into a mammalian expression vector under the control of the SV40 early promoter and enhancer. Secreted rhTPO was purified in three conventional chromatography steps. It migrates on SDS-PAGE as a broad band, characteristic of a heavily glycosylated protein, with an average molecular mass of 85 kDa. rhTPO expressed in CHO cells is biologically active in vitro as demonstrated by its ability to stimulate the proliferation of a megakaryocytic cell line and to trigger the JAK/STAT signal transduction pathway. rhTPO also shows activity in vivo as judged by the elevation of platelet count in treated mice.

This article focuses on a selected number of topics among recent developments in the supportive care of hematological malignancies. The first section focuses on the role of hematopoietic growth factors, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, interleukin-11, and keratinocyte growth factor. The following sections discuss the management of fungal and viral infections as well as changes in the current policies of platelet transfusion. The focus of this review is on the clinical utility and economic feasibility of the published findings.