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Management of Thrombocytopenia Due to Liver Cirrhosis: a Review

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Management of Thrombocytopenia Due to Liver Cirrhosis: a Review Online Submissions: http://www.wjgnet.com/esps/ World J Gastroenterol 2014 March 14; 20(10): 2595-2605 [email protected] ISSN 1007-9327 (print) ISSN 2219-2840 (online) doi:10.3748/wjg.v20.i10.2595 © 2014 Baishideng Publishing Group Co., Limited. All rights reserved. TOPIC HIGHLIGHT WJG 20th Anniversary Special Issues (11): Cirrhosis Management of thrombocytopenia due to liver cirrhosis: A review Hiromitsu Hayashi, Toru Beppu, Ken Shirabe, Yoshihiko Maehara, Hideo Baba Hiromitsu Hayashi, Toru Beppu, Hideo Baba, Department of including platelet transfusion, interventional partial Gastroenterological Surgery, Graduate School of Life Sciences, splenic embolization, and surgical splenectomy, are Kumamoto University, Kumamoto 860-8556, Japan now available for severe thrombocytopenia in cirrhotic Ken Shirabe, Yoshihiko Maehara, Department of Surgery and patients. Although thrombopoietin agonists and target- Science, Graduate School of Medical Sciences, Kyushu Univer- ed agents are alternative tools for noninvasively treat- sity, Fukuoka 812-8582, Japan ing thrombocytopenia due to liver cirrhosis, their ability Author contributions: Hayashi H identified the concept and to improve thrombocytopenia in cirrhotic patients is wrote the draft of the review paper; Beppu T, Shirabe K and under investigation in clinical trials. In this review, we Maehara Y provided critical revisions for interventional or sur- gical procedures; Baba H organized the paper and approved the propose a treatment approach to thrombocytopenia final version to be published. according to our novel concept of splenic volume, and Supported by Grant-in-Aid for Young Scientists, Ministry of we describe the current management of thrombocyto- Education, Culture, Sports, Science and Technology of Japan, penia due to liver cirrhosis. No. 24791434 (to Hayashi H) and Takeda Science Foundation, Japan (to Hayashi H) © 2014 Baishideng Publishing Group Co., Limited. All rights Correspondence to: Hideo Baba, MD, PhD, FACS, Professor, reserved. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto Key words: Liver cirrhosis; Thrombocytopenia; Throm- 860-8556, Japan. [email protected] bopoietin; Partial splenic embolization; Splenectomy Telephone: +81-96-3735211 Fax: +81-96-3714378 Received: September 23, 2013 Revised: February 9, 2014 Accepted: February 20, 2014 Core tip: The major mechanisms for thrombocytopenia Published online: March 14, 2014 in liver cirrhosis are (1) platelet sequestration in the spleen; and (2) decreased production of thrombopoi- etin in the liver. For thrombocytopenia that is caused by platelet sequestration in the spleen, partial splenic embolization or laparoscopic splenectomy are effec- Abstract tive. Thrombopoietin agonists and targeted agents are Thrombocytopenia is a common complication in liver alternative tools for noninvasively treating thrombocy- disease and can adversely affect the treatment of liver topenia due to decreased thrombopoietin production, cirrhosis, limiting the ability to administer therapy and although their ability to improve thrombocytopenia is delaying planned surgical/diagnostic procedures be- under investigation in clinical trials. In this review, we cause of an increased risk of bleeding. Multiple factors, describe the current management of thrombocytopenia including splenic sequestration, reduced activity of the due to liver cirrhosis, and we propose the novel con- hematopoietic growth factor thrombopoietin, bone cept of using the splenic volume to discern the primary marrow suppression by chronic hepatitis C virus infec- cause of thrombocytopenia due to liver cirrhosis. tion and anti-cancer agents, and antiviral treatment with interferon-based therapy, can contribute to the development of thrombocytopenia in cirrhotic patients. Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Manage- Of these factors, the major mechanisms for thrombo- ment of thrombocytopenia due to liver cirrhosis: A review. cytopenia in liver cirrhosis are (1) platelet sequestra- World J Gastroenterol 2014; 20(10): 2595-2605 Available from: tion in the spleen; and (2) decreased production of URL: http://www.wjgnet.com/1007-9327/full/v20/i10/2595.htm thrombopoietin in the liver. Several treatment options, DOI: http://dx.doi.org/10.3748/wjg.v20.i10.2595 WJG|www.wjgnet.com 2595 March 14, 2014|Volume 20|Issue 10| Hayashi H et al . Management of thrombocytopenia due to liver cirrhosis INTRODUCTION and platelets. Experimentally, when TPO or its recep- tor (c-Mpl) has been “knocked-out” by homologous Thrombocytopenia is a common complication in liver recombination in mice, the megakaryocyte and platelet disease, and liver disease-related thrombocytopenia is masses are reduced to approximately 10% of the normal 9 often defined as a platelet count < 100 × 10 /L, includ- value, even though the animals are healthy and do not 9 ing moderate (less than 100 × 10 /L) and severe (less spontaneously bleed[14-16]. Cirrhotic patients with throm- 9 than 50 × 10 /L) thrombocytopenia. Although clinically bocytopenia have lower circulating TPO levels than do significant spontaneous bleeding does not usually occur cirrhotic patients with normal platelet counts, possibly 9 9 until the platelet count is less than 10 × 10 /L-20 × 10 /L, as a result of diminished TPO production[17]. Interest- cirrhotic patients with or without cancers often require ingly, following successful liver transplantation or splenic numerous medical and/or surgical procedures during embolization, the TPO levels appear to normalize, diagnosis and therapy. The presence of thrombocytope- suggesting that decreased TPO production in the liver nia can aggravate surgical or traumatic bleeding and can may also contribute to thrombocytopenia in cirrhotic also significantly complicate routine patient care, such patients[17-19]. This review describes the current manage- as liver biopsy, antiviral therapy, and medically indicated ment of thrombocytopenia in cirrhotic patients and also or elective surgery for cirrhotic patients, resulting in proposes a treatment approach for thrombocytopenia delayed or cancelled medical management and affect- based on using the splenic volume to distinguish among ing the administration of effective treatment for several the major causes of thrombocytopenia (splenic and conditions (e.g., antiviral therapy for chronic hepatitis C other mechanisms, such as decreased TPO production). virus (HCV) infection or cancer chemotherapy). Indeed, the degree of thrombocytopenia has been shown to be a useful prognostic marker in cirrhotic patients because MANAGEMENT OF the finding of severe thrombocytopenia (< 50 × 109/L) THROMBOCYTOPENIA DUE TO LIVER in liver disease can be associated with significant mor- bidity[1,2]. Additionally, a decreased platelet count can of- CIRRHOSIS ten be a diagnostic clue to unsuspected cirrhosis and to Several treatment options, including platelet transfusion, the presence of esophageal varices[3-6]. Multiple factors, interventional splenic artery embolization, and surgical including splenic sequestration, reduced activity of the splenectomy, are now available for thrombocytopenia hematopoietic growth factor thrombopoietin (TPO), cir- in cirrhotic patients. Therapeutic options to safely and rhotic coagulopathy, cirrhotic bone marrow suppression effectively raise the platelet level can have significant ef- by chronic HCV infection and anti-cancer agents, and fects on the care of cirrhotic patients. Specifically, an in- antiviral treatment with interferon (IFN)-based therapy, crease in platelet levels can significantly reduce the need can contribute to the development of thrombocyto- for platelet transfusions and facilitate the use of IFN- penia in cirrhotic patients. Of these factors, the major based antiviral therapy and other medically indicated mechanisms for thrombocytopenia in liver cirrhosis are treatments in cirrhotic patients. Recently, treatments (1) platelet sequestration in the spleen; and (2) decreased such as interventional management using partial splenic production of TPO in the liver. Historically, thrombo- embolization (PSE) and surgical splenectomy have often cytopenia has been thought to arise from the increased attempted to correct splenomegaly-associated throm- pooling of platelets in an enlarged spleen (splenomegaly). bocytopenia as the only current tool that noninvasively While the normal splenic volume has been reported to improves thrombocytopenia is the administration of range from 50-200 mL[7], splenomegaly sometimes in- platelet infusions. For example, antiviral therapy against creases it to even more than 1000 mL. Platelet sequestra- HCV using peginterferon (Peg-IFN) alfa-2a plus ribavi- tion is seen in congestive splenomegaly due to cirrhosis- rin was discontinued in up to 2.6% of patients because induced portal hypertension and is characterized by a of laboratory abnormalities, including thrombocytope- redistribution of platelets from the circulating pool to nia, and 3%-5% of patients receiving Peg-IFN alfa-2a or the splenic pool[8]. However, the interventional and/or alfa-2b plus ribavirin required dose modification because surgical treatments aimed at reversing portal hyperten- of thrombocytopenia[20,21]. In contrast, the management sion do not always correct thrombocytopenia in the of thrombocytopenia using PSE or splenectomy prior to clinical setting. Indeed, decreased platelet production antiviral therapy successfully enables avoidance of dis- has been noted,
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