Platelet Abnormalities in Hepatobiliary Diseases*

ARMAND B. GLASSMAN, M.D.

National Reference Laboratory, Nashville, TN 37217

ABSTRACT Platelet abnormalities associated with hepatobiliary diseases include increased (thrombocytosis) and decreased (thrombocytopenia) numbers of platelets as well as abnormalities in function (thrombocytopathy or throm basthenia). Hepatic diseases that are accompanied by platelet abnormali ties include hepatitis, cirrhosis, portal hypertension, and neoplastic dis orders both benign and malignant. The objective of this work is to examine the platelet abnormalities that occur with a variety of hepatobi liary disorders. Thrombocytosis is seen as a reactive entity following sple nectomy. Thrombocytopenia is associated with hypersplenism, dyspro- teinemias and liver disease related disseminated intravascular coagulation (DIC). Qualitative platelet abnormalities are found in hepatic failure, liver diseases associated with high or low levels of lipid, and with medications given for a variety of hepatocellular diseases. Clinically common and sig nificant platelet abnormalities associated with liver disease are thrombo cytopenia secondary to portal hypertension and the thrombasthenias fol lowing metabolic changes and/or therapeutic interventions of liver disease.

Introduction HBD are associated with a combination of more than one platelet abnormality. The entire range of platelet abnormali The most common hepatic diseases ties can be found in association with associated with platelet abnormalities hepatobiliary diseases (HBD). Thrombo- include hepatitis, cirrhosis, portal cythemia can occur rarely with primary hypertension, hypersplenism, vascular or secondary liver tumors. Thrombocy and other tumors of the liver. The plate topenia occurs in association with portal let abnormalities related to hepatocellu hypertension and hypersplenism. lar disease may occur with or without Thrombasthenias are noted in associa other clinical manifestations of hepatic tion with advanced hepatic failure. Some disease such as jaundice, cutaneous changes, portal hypertension, hepatic * Send reprint requests to Armand B. Glassman, coma and precoma, impaired hepatic M.D., Vice President and Director, National Refer ence Laboratory, 1400 Donelson Pike, Nashville, TN detoxification, or altered lipid and 37217 immunoglobulin metabolism. 119 0091-7370/90/0300-0119 $00.60 © Institute for Clinical Science, Inc. 120 GLASSMAN

The relationship of thrombocythemia, severe thrombocytopenia in some indi thrombocytopenia, thrombasthenia, and viduals.3,5 The contributing factors of combinations of platelet abnormalities folate and other nutritional deficiencies that are seen in a variety of HBD will be and hypersplenism that may be present examined. in patients who are ethanol abusers do not have to be present for the thrombo Methods cytopenia to occur. In those instances where the thrombocytopenia is directly Thrombocytopenia, thrombocytosis, related to alcohol and there are no other and thrombasthenia occur in association underlying problems, platelet counts with HBD (table I).1 Thrombocytopenias may recover within one week after the will be examined in light of consump cessation of alcohol and the provision of tion, sequestration, and immune phe proper nutrients and vitamins. nomena. Thrombocytopenia associated with Thrombocytosis will be reviewed increased peripheral destruction and/or related to status postsplenectomy and sequestration of platelets with or without malignant hepatic neoplasms. a nutritional component is common in Thrombasthenias are assessed in light liver disease. Cirrhosis, particularly if of hepatic failure, lipid abnormalities, associated with portal hypertension and and medications taken by patients with hypersplenism, is a well recognized hepatobiliary disease. cause of thrombocytopenia.2 Other hepatic disorders, such as hemangiomas Results and hemangioblastomas, may sequester and destroy platelets as well. Hepatic Thrombocytopenias may be secondary disease with alterations of immunoglobu to decreased production or increased lins, other proteins and lipids can result consumption (or sequestration), and may in decreased platelet counts either be separated into immune and non- through changes of platelet membrane immune types in association with HBD. binding sites, aggregation and clumping Hepatobiliary diseases associated with of platelets with subsequent removal, or thrombocytopenia include the aplastic sequestration and destruction. anemia which sometimes follows hepati Thrombocytosis is most often encoun tis, viral infections of the liver, therapeu tered as a secondary or reactive phenom tic agents taken in conjunction with liver enon.6 The platelet count rarely exceeds diseases, and vitamin deficiencies asso 1,000 X 109 per L (one million platelets ciated with nutritional abnormalities of per millimeter3). The spleen is the major the liver.4,7 Alcohol is associated with site for removal of platelets. At any moment, approximately one-third of the total number of circulating platelets may T A B L E I be within the geographic confines of the Platelet Abnormalities in Hepatobiliary Diseases spleen. Splenectomy results in a prompt 48 hour to one week increase in the Thrombocytopenia : Decreased production Increased consumption platelet count. Thrombocytosis following Combination splenectomy is usually self-correcting Thrombocytosis : R e a c t i v e with platelet counts returning to normal Malignancy associated over six to 12 weeks. Platelet morphol Thrombasthenia : Secondary to medications Toxic-metabolic effects ogy in reactive thrombocytosis is usually normal as are platelet function tests. PLATELET ABNORMALITIES IN HEPATOBILIARY DISEASES 121

Thrombocytosis associated with hepa ties. These include thrombocytopenia, tocellular tumors is unusual. Malignan thrombasthenia or thrombocytopathy, cies of hepatocellular and canalicular cel and thrombocytosis. A common clinical lular types have been reported to be disorder associated with mild to moder associated with thrombocytosis. A dis ate thrombocytopenia is viral associated tinction is made of thrombocythemia hepatitis. Clinically significant thrombo from thrombocytosis. Thrombocytosis is cytopenia is found associated with defined as a mild to moderate usually hepatic cirrhosis, portal hypertension, short-lived and symptomless elevation of and hypersplenism. Thrombocytopathies the platelet count which occurs second are most often associated with the medi ary to some other clinical condition. cations given to people with liver dis Thrombocythemia is defined as a marked ease. Aspirin is the most common and persistent elevation in the platelet offender. Hepatic failure and abnormal count as a result of a myeloproliferative lipids and/or proteins have also been disorder. In those instances where the implicated in thrombocytopathies. thrombocytosis is secondary to hepato Thrombocytosis is an infrequent cellular malignancy, the condition may accompaniment of liver disease. It is have a natural history which is consistent seen in its reactive form after the with an unremitting rise in the platelet removal of the spleen or secondary to count. regenerative responses following some Thrombocytopathies or qualitative liver disease associated anemias. Post platelet abnormalities occur associated splenectomy thrombocytosis occurs with hepatic failure or secondary to med within 48 hours to one week. Usually, ications given for the underlying hepato the platelet count returns to normal by biliary disease. The causes of throm- the end of two months. Rarely, tumors basthenias in hepatic failure are thought involving the liver are associated with to be related to abnormalities of platelet thrombocytosis probably through the metabolism secondary to excess lipids or mechanism of the production of a mega toxic metabolic end product accumula karyocyte growth stimulating factor elab tions seen in severe hepatic decompen orated by the tumor. sation. Medications taken by people with Conclusion hepatic disease can result in quantitative and/or qualitative platelet abnormalities. Hepatobiliary diseases are associated These medications include aspirin, other with a myriad of quantitative and qualita nonsteroidal anti-inflammatory agents, tive platelet abnormalities. Advanced heparin, high doses of penicillin, and liver disease associated with portal chemically related antibiotics, clofibrate, hypertension results in thrombocyto propranolol, hydroxychloroquine, and penia and thrombocytopathy. Although alcohol. Many other medications which thrombocytopenia is clinically the entity may be taken by patients with liver dis most often associated with hepatobiliary ease have been reported to interfere disease, thrombocytopathies and throm with platelet function. bocytosis do occur.

Discussion Acknowledgment

Hepatobiliary diseases of many types Thanks are extended to Ms. Maxine Goldstein for are associated with platelet abnormali her typing and assistance. 122 GLASSMAN

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