EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Here, we report a case of severe immune thrombocytopenia that occurred after orthotopic liver transplant. On day 16 after transplant, the patient was readmitted to our hospital with a platelet count of 0 cells/mL, with the count remaining at a low level of 1000 to 10 000 cells/mL for 46 days. A diagnosis was made, after exclusion of other causes, of thrombocytopenia. Platelet blood transfusion and high-dose prednisone (1mg/kg/d) combined with intravenous immunoglobulin (0.5g/kg/d) were administered with no improvement. After additional treatments, which included altered use of immunosuppressive agents, changing adefovir to lamivudine and continuous steroid therapy, the patient was discharged with a platelet count of 55 000 cells/mL. Both liver and renal functions generally stayed well during hospitalization. The patient was discharged uneventfully and achieved remission during 10-month follow-up after discharge.

Key words : Cyclosporine

Immune thrombocytopenia is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding, often occurring in response to an unknown stimulus. The estimated incidence in the general population is 100 cases per 1 million people annually, with half of these being children.^1,2 Immune thrombocytopenia is classified as primary for isolation or as secondary to other disorders, including viral infections, drug related, and autoimmune diseases. Moreover, lymphoid tissue and passenger lymphocytes from the graft may cause immune thrombocytopenia after transplant.^3,4 For those liver recipients, immune thrombocytopenia is a rare but fatal complication that requires a quick recognition and treatment. Taylor and associates5 reported 8 patients (0.7%) from a study of 1105 orthotopic liver transplant recipients (from January 1990 to June 2005) who had new-onset immune thrombocytopenia. The patients had a median platelet count of 3500 cells/mL (range, 1000-12 000) at presentation. Steroids combined with intravenous immunoglobulin therapy were effective for 50% of patients, whereas other patients required rituximab or splenectomy for long-term remission.⁵ After orthotopic liver transplant, thrombocytopenia increases the risk of fatal hemorrhage, leading to greater uncertainty in the prognosis of patients who undergo this transplant procedure.

Here, we report a patient with severe immune thrombocytopenia early after orthotopic liver transplant who had a platelet count of 0 cells/mL on readmission. The patient recovered after treatment with altered use of immunosuppressive agents, a change from adefovir to lamivudine, and continuous steroid therapy.

In 2013, a 43-year-old man underwent orthotopic liver transplant for hepatocellular carcinoma associated with cirrhosis due to hepatitis B virus infection with an ABO-identical allograft from donation after cardiac death in our hospital. The donor was a 26-year-old man diagnosed with traumatic subdural hematoma. The consent for organ donation was obtained from his family. The donor had no particular previous medical history. The recipient recovered uneventfully and was discharged in good condition 12 days after transplant. Six days after discharge, the patient was readmitted because of spontaneous mucocutaneous hemorrhage for 2 days, with platelet count found to be 0 cells/mL. However, neither the donor nor the recipient had a history of immune thrombocytopenia. Before transplant, the recipient’s mean platelet count was 132 000 cells/mL (range, 71 000-199 000 cells/mL); after transplant and before discharge, the count was 82 000 cells/mL (range, 50 000-195 000 cells/mL) (Figure 1). The recipient had been taking 10 mg/day adefovir for 2 years, and his hepatitis B virus DNA levels were undetectable before transplant. With no complication after surgery, the patient was discharged 12 days after transplant and prescribed an immunosuppressive regimen of 2 mg tacrolimus every 12 hours, 500 mg mycophenolate mofetil every 12 hours, and 10 mg/day prednisone. The mean whole blood level of tacrolimus was 5.2 ng/mL (range, 3.9-8.0 ng/mL) before readmission.

At readmission, the recipient (height, 1.8 m; weight, 70 kg) was generally well at physical examination. Blood pressure was 105/75 mm Hg, body temperature was 36.7℃, and pulse was 59 beats/minute. In addition, at readmission, the patient had normal results on abdominal and chest examination; however, his laboratory test results revealed a platelet count of 0 cells/mL and white blood cell count of 5080 cells/mL, with 10.8% lymphocytes, 82.0% neutrophils, 4.8% monocytes, 1.5% eosinophils, and 0.9% basophils. Total bilirubin, direct bilirubin, indirect bilirubin, prothrombin time, activated partial thromboplastin time, and fibrinogen and peripheral blood film results were all normal. Alanine aminotransferase level was 160 IU/L (reference level < 50 U/L), aspartate aminotransferase level was 40 IU/L (reference level < 40 IU/L), alkaline phosphatase level was 212 U/L (reference range, 51-160 U/L), γ-glutamyltransferase level was 225 IU/L (reference level < 60 IU/L), and lactate dehydrogenase level was 197 IU/L (reference range, ~72-182 IU/L). Results from the Coombs test and peripheral blood film were both negative, whereas bone marrow aspiration revealed a slightly increased number of megakaryocytes. In addition, serology tests for hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, Cytomegalovirus, human papillomavirus, and human immunodeficiency virus infections were all negative. The recipient’s abdominal ultrasonography also showed no abnormalities.

A diagnosis of immune thrombocytopenia was made after other possible causes for the observed thrombocytopenia were eliminated.^1,2 First, there was no evidence of infection; hematology laboratory evaluations, including bone marrow aspiration, Coombs test, and peripheral blood film results revealed none, although there was a mildly increased number of megakaryocytes. Therefore, based on the clinical and laboratory findings, we were able to exclude other causes, such as thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, disseminated intravascular coagulation, hematologic neoplasms, and aplastic anemia, and thus diagnosed our observation as immune thrombocytopenia.

Platelet blood transfusion was given for the first 3 days after readmission to prevent major hemorrhages: 2 units on day 1 and 1 unit on days 2 and 3. However, the patient did not improve. The diagnosis was made on day 4. With the consideration that existing drugs may cause immune thrombocytopenia, the recipient’s immunosuppressive agents and nucleoside analog agent were consequently changed. Specifically, a new immunosuppressive regimen was devised for the patient with 75 mg cyclosporine (1mg/kg) every 12 hours.^6,7 The patient was also switched from adefovir to 100 mg/day lamivudine at the same time. Prednisone was also increased to 1mg/kg/day, and the intravenous immunoglobulin was altered to 1g/kg/day (Figure 1). Intravenous immunoglobulin was suspended after 5 days of administration, as the agent did not contribute to a change in the platelet count. Despite a low platelet count after 8 days of treatment, symptoms like mucocutaneous hemorrhage were in partial remission. The whole blood trough level of cyclosporine remained around 79.46 ng/mL (range,73.3-87 ng/mL),whereas liver and renal function both stayed generally well during hospitalization. After 46 days of treatment, the patient was discharged with a platelet count of 55 000 cells/L. Afterward, prednisone was tapered 5 mg/week until posttransplant day 90, with 10-month follow-up showing no more thrombocytopenia. In addition, mean platelet count remained around 133 000 cells/mL (range, 81 000-197 000 cells/mL).

Immune thrombocytopenia is an autoimmune disorder characterized by immunologic destruction, which commonly occurs in response to an unknown stimulus. Immune thrombocytopenia is classified as primary or secondary by the cause. Lymphoid tissue and passenger lymphocytes from graft may cause immune thrombocytopenia after transplant. On the basis of relevant literature, hematologic toxicity due to immunosuppressive agents is believed to be associated with thrombocytopenia after solid-organ transplant.^7-9 However, cyclosporine is one of the second-line treatments for immune thrombocytopenia.^1,10 Emilia and associates¹¹ stated that low-dose cyclosporine treatment (2.5-3 mg/kg of body weight/d) of patients with severe, chronic immune thrombocytopenia refractory was safer and more effective than other therapies. In their study, follow-up for the 12 patients was 26.8 months. The group found that 10 patients (83.3%) had clinical improvement and 2 patients had no response. More specifically, 5 of the 10 patients with improvement had a complete response (overall rate of 41.4%), 4 patients had a complete response to maintenance therapy (overall rate of 33.3%), and 1 patient had a partial response (overall rate of 8.3%). Adverse effects, including hypertension and increased creatinine levels, are rare and easily controlled by administration of cyclosporine at a low dose. Also, mycophenolate mofetil-related myelosuppression contributes to the thrombocytopenia in a dose-limiting manner, which seems to be reversible with discontinuation or dose reduction.⁷

A review of the literature showed that nucleoside analog drugs also can lead to thrombocytopenia through an unknown mechanism. Adefovir is a well-tolerated and effective drug for treatment of chronic hepatitis B virus.¹² Stornaiuolo and associates¹³ reported a rare case of immune thrombocytopenia that occurred with adefovir therapy (10 mg/d) in a 56-year-old man with chronic hepatitis B virus infection resistant to lamivudine. This is the only known case in which adefovir therapy led to immune thrombocytopenia, but the mechanism is still underexplored. In our patient, however, we decided that adefovir was not the cause of immune thrombocytopenia. The reason is that he had already started antiviral therapy with adefovir 2 years before transplant, and the hepatitis B virus DNA level was well controlled. However, we did change the patient from adefovir to lamivudine just in case. Evidence showing that immune thrombocytopenia after orthotopic liver transplant is linked to the drugs mentioned remains scarce. Therefore, further research is still needed.

In conclusion, severe thrombocytopenia increases the risk of fatal hemorrhage, worsening the prognosis of patients who undergo orthotopic liver transplant. Exclusion of other causes for thrombocytopenia should be considered first for orthotopic liver transplant recipients who display new-onset immune thrombocytopenia early after transplant. In addition, we suggest that the combined use of low-dose cyclosporine and high-dose steroids may be helpful for orthotopic liver transplant recipients who have severe and refractory immune thrombocytopenia.

Volume: 16 Issue: 1 February 2018

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