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Review Article: Thrombocytopenia in Chronic Liver Disease F Alimentary Pharmacology & Therapeutics Review article: thrombocytopenia in chronic liver disease F. POORDAD Cedars-Sinai Medical Center, Center SUMMARY for Liver Disease and Transplantation, Los Angeles, CA, USA Background Thrombocytopenia is a common finding in advanced liver disease. It is Correspondence to: Dr F. Poordad, Chief of Hepatology, predominantly a result of portal hypertension and platelet sequestration Cedars Sinai Medical Center, Center in the enlarged spleen, but other mechanisms may contribute. The liver for Liver Disease and Transplantation, is the site of thrombopoietin (TPO) synthesis, a hormone that leads to 8635 W. Third Street, Suite 590W, Los proliferation and differentiation of megakaryocytes and platelet forma- Angeles, CA 90048, USA. E-mail: [email protected] tion. Reduced TPO production further reduces measurable serum platelet counts. Publication data Aim Accepted 28 August 2007 This paper describes the scope of thrombocytopenia in chronic liver dis- ease and assesses the clinical impact in this patient population. Methods A medline review of the literature was performed pertaining to throm- bocytopenia and advanced liver disease. This data is compiled into a review of the impact of low platelets in liver disease. Results The incidence of thrombocytopenia, its impact on clinical decision mak- ing and the use of platelet transfusions are addressed. Emerging novel therapeutics for thrombocytopenia is also discussed. Conclusions Thrombocytopenia is a common and challenging clinical disorder in patients with chronic liver disease. New therapeutic options are needed to safely increase platelet counts prior to invasive medical procedures as well as to counteract therapies that further exacerbate low platelets, such as interferon. An ideal compound would be orally available and safe, with rapid onset of action. Aliment Pharmacol Ther 26 (Suppl 1), 5–11 ª 2007 The Author 5 Journal compilation ª 2007 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2007.03510.x 6 F. POORDAD INTRODUCTION INCIDENCE OF THROMBOCYTOPENIA Patients with chronic liver disease including advanced Patients with advanced chronic liver disease frequently fibrosis and cirrhosis commonly experience thrombo- experience thrombocytopenia with increasing inci- cytopenia. In the United States, approximately 8 mil- dence correlating with severity of liver disease.5 In cir- lion units of platelets are transfused each year to rhotic patients, thrombocytopenia occurs in up to 64% reduce the risk of bleeding.1 Thrombocytopenia associ- of patients and is independent of the cause of cirrho- ated with chronic liver disease has been reported in sis.2 Patients with more advanced end-stage disease 15–70% of patients with advanced fibrosis and portal tend to have a higher degree of thrombocytopenia hypertension, depending on the stage of disease and than those with compensated chronic liver disease.15 the platelet cut-off level used to define thrombocyto- Platelet counts of <150 000 ⁄ lL are more frequently penia.2, 3 Thrombocytopenia may be caused by hepati- observed in patients with cirrhosis compared to tis C virus (HCV) directly,4, 5 or it may result from patients without cirrhosis (64% vs. 6%, respectively);2 interferon (IFN)-based anti-viral therapy that affects approximately one-quarter to one-half of cirrhotic platelet number or function, either directly or by sup- patients have counts <100 000 ⁄ lL.2, 16 Platelet counts pression of thrombopoiesis in the bone marrow.6, 7 <50 000 ⁄ lL occur in approximately 1% of patients Although thrombocytopenia is typically low grade and with chronic HCV infection.2 not life-threatening, extended or severe thrombocyto- penia is associated with a poor clinical outcome IMPACT OF THROMBOCYTOPENIA ON because it increases the risk of bleeding from invasive CLINICAL MANAGEMENT procedures,8, 9 complicates therapy6, 10 and increases the risk of mortality.3 The inability to initiate or maintain planned treat- Standard therapy for thrombocytopenia consists of ments because of low platelet counts may lead to platelet transfusions. Although advances have been increased morbidity or mortality, and can significantly made in platelet collection, storage and transfusion, impact patient care. Many doctors will not initiate patients are still at risk for complications including HCV anti-viral therapy if platelet counts are low. Post- infection, alloimmunization and febrile non-haemo- ponement of treatment due to thrombocytopenia can lytic reactions.11, 12 Other methods for treatment of result in diminished sustained virological response and thrombocytopenia, including splenic artery emboliza- the need for additional therapies.17 Recently issued tion, transjugular intrahepatic portosystemic shunts treatment guidelines by the American Gastroentero- (TIPS) and splenectomy, are also associated with sig- logical Association suggest that patients with severe nificant risks.13, 14 Moreover, these approaches are thrombocytopenia should not receive IFN-based anti- invasive, costly and not always suitable for patients viral therapy.10 Initiation of anti-viral therapy is gen- with advanced liver disease. erally contraindicated when platelet counts are below Effective management of thrombocytopenia may 75 000–100 000 ⁄ lL,18 although actual clinical practice help prevent the postponement or cancellation of other may vary. Product labels for pegylated (PEG)-IFN rec- medically necessary procedures from risk of bleeding ommend dose reductions for patients with platelet complications, and may allow initiation of HCV anti- counts between 50 000 and 100 000 ⁄ lL and suspend- viral therapy. Effectively managing thrombocytopenia ing therapy if platelet counts fall below 25– may also reduce healthcare costs for patients with 50 000 ⁄ lL.10 In addition, treatment with PEG-IFN has chronic liver disease and improve patient outcomes. been shown to reduce platelet counts by up to 33%.19 Because of the limitations of platelet transfusions in Patients with chronic liver disease frequently undergo the treatment of thrombocytopenia, novel therapeutic medical procedures for diagnosis and treatment, some approaches are being evaluated. In this review, the of which are invasive. Thrombocytopenia can compli- scope and impact of thrombocytopenia in chronic liver cate or postpone routine care by increasing the risk disease are highlighted. Traditional therapies and their of bleeding from such procedures. These proce- limitations in this type of patient population are also dures include liver biopsies (percutaneous, laparoscopic discussed. and transjugular);1, 9, 20, 21 banding; paracentesis and ª 2007 The Author, Aliment Pharmacol Ther 26 (Suppl 1), 5–11 Journal compilation ª 2007 Blackwell Publishing Ltd REVIEW: THROMBOCYTOPENIA IN CHRONIC LIVER DISEASE 7 thoracentesis for ascites;22–24 liver transplantation;25 transfusion (50 000 ⁄ lL), neonatal alloimmune throm- central line insertion; endoscopy; prostate biopsy and bocytopenia (50 000 ⁄ lL), invasive procedures in elective surgery. Some studies have found no increase cirrhotic patients (50 000 ⁄ lL) and liver biopsy in the risk of bleeding in patients with platelet counts (50 000–100 000 ⁄ lL).35 However, in many cases, for- above 50 000 ⁄ lL undergoing these procedures.26–30 mal guidelines are lacking, and the safety of these Many doctors may avoid or postpone procedures until procedures in patients with substantially lower platelet platelet counts increase to near-normal levels on counts (<20 000 ⁄ lL) has not been established. It is account of the questionable safety of these procedures also not always possible to predict which patients will in chronic liver disease patients with reduced platelet develop severe thrombocytopenia periprocedurally. counts and the concern over haemorrhage.3, 9 Dental Moreover, the relevance of these guidelines for procedures, such as extraction, may also be rescheduled patients with chronic liver disease is unclear. Because due to fear of potential bleeding in patients with of the lack of formal guidelines for patients with severe thrombocytopenia.8 The risk of bleeding com- chronic liver disease and the increased risk of bleeding plications can cause postponement of necessary proce- with concomitant coagulopathy in this population, all dures and therapy, interfere with planned medical chronic liver disease patients could potentially benefit care, significantly add to healthcare costs in these from therapies that would increase platelet levels to patients. >100 000 ⁄ lL. TRIGGER FOR PLATELET TRANSFUSION IN STANDARD TREATMENT OF THROMBOCYTOPENIA THROMBOCYTOPENIA Prophylactic platelet transfusion is often performed for Platelet transfusion has generally been considered the thrombocytopenic patients who are at increased risk of ‘gold standard’ for treatment of thrombocytopenia as bleeding during planned invasive procedures. The it can correct low platelet counts and reduce the risk platelet count at which transfusions are indicated is of bleeding. Though widely used, this approach has controversial, especially in patients with chronic liver several limitations, particularly for patients with disease. For uncomplicated patients (without liver dis- chronic liver disease. Transfusion does not always ease) with platelet counts >20 000 ⁄ lL, platelet transfu- ensure maintenance of haemostatic platelet levels.34 sion is generally not necessary.31 For patients with While advances have been made in platelet collection, platelet counts <20 000 ⁄ lL, platelet transfusions are storage
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