Clopidogrel-induced Thrombotic Microangiopathy in a Patient with Hypocomplementemia

Transcription

1 CASE REPORT Clopidogrel-induced Thrombotic Microangiopathy in a Patient with Hypocomplementemia Kazuhiro Tada, Kenji Ito, Aki Hamauchi, Koji Takahashi, Renya Watanabe, Ai Uchida, Yasuhiro Abe, Tetsuhiko Yasuno, Katsuhisa Miyake, Yoshie Sasatomi and Hitoshi Nakashima Abstract Clopidogrel was administered to a 67-year-old Japanese man to prevent the recurrence of cerebral infarction. Twelve weeks later, he was admitted to our hospital with acute renal failure, hemolytic anemia and thrombocytopenia, and was diagnosed with clopidogrel-induced thrombotic microangiopathy. Clopidogrel was immediately discontinued and corticosteroid and plasma exchange therapy were administered simultaneously. Thereafter, the patient s condition gradually improved. The patient had a decreased serum complement C3 level. This suggests that the activated alternative pathway is related to thrombotic microangiopathy (TMA). TMA is a critical drug-associated adverse reaction that clinicians should always be vigilant about, because clopidogrel is widely prescribed. Key words: thrombotic microangiopathy, clopidogrel, thrombotic thrombocytopenic purpura, plasma exchange, atypical hemolytic uremic syndrome, alternative pathway (Intern Med 55: , 216) (DOI: /internalmedicine ) Introduction Moschcowitz (1924) was the first person to describe thrombotic microangiopathy (TMA) (1), which is clinically characterized by the presence of microangiopathic hemolytic anemia along with schizocytes, thrombocytopenia and multiple organ injury (2). The pathological features are arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel walls (3). The most common types of TMA are thrombotic thrombocytopenic purpura (TTP), which is a TMA mediated by the deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (2) and hemolytic uremic syndrome (HUS), which is actually Shiga toxin-mediated TMA (4). However, the clinical manifestations are extraordinarily diverse because of various pathogeneses other than ADAMTS13 deficiency and Shiga toxin. An adverse reaction to drugs is one of the most common causes of TMA. About one-fifth of TMA cases are associated with pharmaceuticals (5). Ticlopidine, a thienopyridine derivative, is one of the most commonly reported drugs (6), and the estimated rate of TMA incidence is about one per 1,6 to 5, ticlopidine-treated patients (7, 8). Neutropenia is also frequently observed in ticlopidine-treated patients. Therefore, ticlopidine has largely been replaced by clopidogrel, a newer and safer thienopyridine derivative (9). We herein report a case of clopidogrel-induced TMA that was treated with drug interruption, corticosteroid administration and plasma exchange (PE) therapy. The patient gradually recovered and hemodialysis was discontinued; however, renal insufficiency persisted. Case Report A 67-year-old Japanese man was admitted to our hospital because of severe nausea, fatigue, edema and macrohematuria. He had no personal or familial history of TMA. Three months before admission, he had developed a cerebral infarction of the posterior limb of the internal capsule. Hence, Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Japan Received for publication May 7, 215; Accepted for publication July 29, 215 Correspondence to Dr. Kenji Ito, kito@adm.fukuoka-u.ac.jp 969

2 Intern Med 55: , 216 DOI: /internalmedicine Table. Laboratory Data on Admittion. <urinary exam.> <hematology> <biochem.> specific gravity 1.15 WBC 1192 / L TP 4.6 g/dl ph 6.5 RBC / L Alb 2.4 g/dl Hb 6.3 g/dl UN 11 mg/dl RBC >1 /HPF Ht 18.3 % Cr 8.94 mg/dl WBC 1-4 /HPF MCV 87 fl T-Bil 2 mg/dl oval fat body MCH 28.6 pg D-Bil.5 mg/dl fatty cast MCHC 34.4 % AST 88 IU/L Plt / L ALT 26 IU/L Protein 1.1 g/day Ret 23.1 LDH 223 IU/L 2-MG.6 mg\l ALP 239 IU/L NAG 33.2 U/L <Coagulation> -GTP 24 IU/L PT-INR 1.14 Na 144 meq/l <Immunology> aptt 27.1 Sec K 4.1 meq/l CRP 1.41 mg/dl Fbg 34 mg/dl Cl 113 meq/l IgG 89 mg/dl D-dimer 28.6 g/ml BS 15 mg/dl IgA 175 mg/dl FDP 17.5 g/ml haptoglobin 4 mg/dl C3 33 mg/dl ADAMTS-13 MPO-ANCA <.5 EU C4 2.2 mg/dl activity 61.5 % PR3-ANCA <.5 EU CH5 27 U/mL inhibitor (-) ANA <4 dil RBC: red blood cell, WBC: white blood cell, 2-MG: 2-microglobulin, NAG: N-acetyl- -Dglucosaminidase, CRP: C-reactive protein, Ig: immunoglobulin, C: complement, CH5: 5%hemolytic unit of complement, ANA: anti-nuclear antibody, Hb: Hemoglobin, Ht: Hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, Plt: Platelet, Ret: reticulocyte, PT-INR: prothrombin time-international normalized ratio, aptt: activated partial thromboplastin time, Fbg: fibrinogen: FDP: fibrin degradation product, ADAMTS-13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif: member 13, TP: total protein, Alb: albumin, UN: urea nitrogen, Cr: creatinine, T-bil: total bilirubin, D-bil: direct bilirubin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkalin phosphatase, -GTP: -glutamyl trans peptitase, Na: sodium, K: potassium, Cl: chlorine, BS: blood suger, MPO: myeloperoxidase, ANCA: antineutrophil cytoplasmic antibody, PR-3: proteinase-3 Figure 1. A microscopic examination of a peripheral blood smear. The arrows point to schizocytes. The magnification is 4 times. clopidogrel administration was initiated at a dose of 75 mg/ day to prevent the recurrence of cerebral infarction. At this time, the level of serum creatinine was 1.1 mg/dl. Two months later, the patient experienced appetite loss and nausea, and his condition deteriorated gradually. Red urine, oliguria and systemic edema were observed in the patient a week before hospitalization. On admission, the patient was conscious, but complained of severe fatigue, and found it difficult to move. His blood pressure was 17/98 mmhg, while his pulse rate was 8 bpm and regular and his respiratory rate was 18/min. Blood oxygenation was slightly poor, with a saturation level of 96% for room air. The patient s body temperature was 36.9 C. A physical examination revealed anemic and icteric conjunctiva, and edema and purpura of the extremities. His breath sounds were vesicular and no murmurs were audible. No abnormalities were observed during the abdominal and neurologic examinations. The results of a pathological examination completed during admission are shown in Table. The urinary examination revealed hematuria, proteinuria and bilirubinuria. The results of a blood test indicated severe renal failure, hemolytic anemia and thrombocytopenia. Some schizocytes were observed on the peripheral blood smear (Fig. 1). The results of blood coagulation tests were within normal limits and they did not indicate disseminated intravascular coagulation. Plain chest radiographs and computed tomography images showed slight cardiomegaly, pleural effusion and ascites. Thrombotic microangiopathy was suspected based on the physical, pathological and laboratory findings. Serum ADAMTS13 activity was within normal limits and the serum ADAMTS13 inhibitor test was negative. The drug-induced lymphocyte stimulation test for clopidogrel was also negative. The serum complement C3 level and CH5 activity showed very low levels at 33 mg/dl (normal range, 86 to 16 mg/dl) and 27 U/mL (normal range, 3 to 5 U/mL), respectively, as opposed to a normal C4 level. 97

3 Intern Med 55: , 216 DOI: /internalmedicine Hb (g/dl) Clopidogrel m-psl 1g Hb PE HD (3 times/w) Prednisolone 5mg 15mg LDH Figure 2. A timeline of clinical events. A line graph shows the serum levels of hemoglobin (Hb), platelets (Plt), lactate dehydrogenase (LDH) and creatinine (Cr). Treatments are represented with different colored bars. PE: plasma exchange, HD: hemodialysis, m-psl: methyl-prednisolone 5, 4, 3, 2, 1, (week) LDH (IU/L) Plt 4 15 Cr (/ ) Plt 3 Cr (mg/dl) Ticlopidine Clopidogrel Figure 3. The incidence of antiplatelet agent-induced thrombotic microangiopathy in Japan. These numbers were reported to the Pharmaceuticals and Medical Devices Agency. The patient s clinical course is shown in Fig. 2. He did not display malignant hypertension, signs of infection or evidence of connective tissue disease. Clopidogrel administration was immediately discontinued because it was suspected to be the cause of the TMA. Intravenous methylprednisolone was administered at a dose of 1, mg/day for three days, and subsequently, oral prednisolone was administered at a dose of 5 mg/day. Hemodialysis was simultaneously performed three times a week. The patient s systemic status and clinical parameters did not improve, and therefore PE was performed three times a week (a total of 1 times). Thereafter, the serum lactate dehydrogenase level decreased and the hemoglobin level and platelet count also gradually improved. The urine volume increased and hemodialysis was discontinued 48 days after admission to the hospital. The oral prednisolone administration was decreased gradually, and the patient was discharged without a TMA relapse 12 days after admission. One year after being discharged from the hospital, the patient s serum C3 level (58 mg/dl) was still lower than the normal limit. Discussion Thienopyridine derivatives are the primary antiplatelet agents currently in use, and are also the most commonly implicated drugs responsible for drug-induced TMA. In 1989, ticlopidine, a very efficient thienopyridine derivative, was the first of its kind to be introduced on the market. Unfortunately, ticlopidine treatment was not included in the 211 American Heart Association guidelines (1) because of its frequent harmful adverse effects, such as neutropenia and TMA. Currently, clopidogrel has largely replaced ticlopidine as the drug of choice for patients who need antiplatelet therapy because of superior efficacy and safety (9). The TMA incidence rate for clopidogrel is much lower than that of ticlopidine; the notifications on the packaging include incidence estimates of one per 83, patients for clopidogrel and one per 5, patients for ticlopidine (11). However, the first case of clopidogrel-mediated TMA was reported in 2 (12), and some other reports have followed (13). Recently, the database of the Japanese Pharmaceuticals and Medical Devices Agency identified clopidogrel as the most common drug to be associated with TMA (13) (Fig. 3), because it is being prescribed more widely. A comparison between ticlopidine-induced and clopidogrel-induced TMA cases showed the following differential characteristics: ticlopidine-associated TMA cases were more likely to occur after >2 weeks of drug administration, to be severely thrombocytopenic, and to have a normal renal function. The proportion of cases with <15% ADAMTS13 activity levels was significantly higher in ticlopidine-induced TMA than in clopidogrel-induced TMA (11, 14). The survival rate for cases with PE was sig- 971

4 Intern Med 55: , 216 DOI: /internalmedicine nificantly higher than that of cases without PE. With respect to ADAMTS13 activity, the clinical and laboratory findings of thienopyridine derivative-induced TMA are similar to those reported previously for idiopathic TTP cases (15, 16). In contrast, three-quarters of the clopidogrel-associated TMA cases develop after 2 weeks of clopidogrel use. These patients have mild thrombocytopenia and renal insufficiency at diagnosis, and ADAMTS13 activity levels >15%. The survival rates for cases with and without PE were similar (14). In our case, renal function was severely damaged requiring the use of hemodialysis, and the ADAMTS13 activity remained in the normal range. Moreover, the drug-induced lymphocyte stimulation test for clopidogrel was also negative. These results are similar to those previously reported for clopidogrel-induced TMA. In contrast, TMA developed three months after drug initiation, and therefore the latent period was considerably longer than that reported in previous studies. The efficacy of PE was unclear; it seemed to be effective because hemolysis improved after the initiation of PE. The unique characteristic of this case was a decreased serum C3 level in contrast to a normal serum C4 level, and a low serum C3 level was generally observed in cases where the patient had a C3 deficiency or overactive alternative complement pathway. Previous reports indicated that patients with a C3 deficiency generally have a history of frequent infection and develop systemic lupus erythematosuslike symptoms (17-19). Their serum C3 level is often undetectable because it is very low, and their serum CH5 activity is 1 U/mL (17, 18). Our patient did not display the aforementioned symptoms, and the serum C3 level and CH5 activity were higher than in typical cases of C3 deficiency. Therefore, we believed that the alternative complement pathway is activated and uncontrolled in this case, even though disorders of the complement system have not been reported for clopidogrel-induced TMA. Complement-mediated TMA accounts for 5 to 6% of TMA cases, excluding HUS and TTP (2). It is thought that large amounts of deposits of activated complement components in the glomeruli and arterioles during acute disease are consistent with the activation of complement and local C3 consumption. It is also believed that C9 staining in the glomeruli and small arteries with intimal proliferation and thrombosis documents activation up to the final lytic C5b-9 membrane-attack complex (21). Various abnormalities in the proteins involved in the alternative complement pathway have been identified, including inactivating mutations in the genes encoding regulatory proteins of the alternative pathway C3 convertase, factor H, factor I, membrane cofactor protein, thrombomodulin (2) and antifactor H antibodies (22). Less than 2% of them developed familially, and the frequency of genetic mutations between the sporadic and familial forms was not significantly different (23, 24). Forty percent of the patients developed TMA before the age of 18, and only 2% after the age of 6 (23). The efficacy of PE has not been established, but it is reportedly effective in almost 3 to 6% of complement-mediated TMA cases depending on the type of genetic mutation (2). Unfortunately, gene mutations and autoantibodies for complement regulators could not be evaluated in this case, and had not been evaluated before the onset of TMA. However, the patient s serum C3 level was lower than the normal limit at the onset and remained lower than the normal limit after remission. Hence, we suggest that in this case, complement activation and consumption may have been present for a long time, and the patient might have been an asymptomatic carrier until the onset of TMA that was triggered by the administration of clopidogrel. Chapin et al. (25) first reported a case of ticlopidine-induced TMA that involved a complement factor H mutation. Some cancer drugs are postulated to initiate TMA events in predisposed patients with genetic defects in the complement cascade (26). This mechanistic hypothesis is compatible with the possibility of PE being effective in this case. In conclusion, clopidogrel-induced TMA is a very rare but critical drug-associated adverse event, and the underlying mechanism is still unclear. Clopidogrel is one of the most commonly prescribed drugs in Japan and other countries. Clinicians should therefore be vigilant and carefully inform patients about the risk of TMA development, even if more than two weeks have passed since the initiation of clopidogrel administration. The authors state that they have no Conflict of Interest(COI). References 1. Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc NY Pathol Soc 24: 21-24, Moake JL. Thrombotic microangiopathies. N Engl J Med 347: 589-6, Laszik ZG, Silva FG. Hemolytic uremic syndrome, thrombotic thrombocytopenia purpula, and other thrombotic microangiopathies and coagulopathies. In: Heptinstall s Pathology of the Kidney. 6th ed. Jennett J, et al, Eds. Lippincott Williams & Wilkins, Philadelphia, 27: Javett SN, Senior B. Syndrome of hemolysis, thrombopenia and nephropathy in infancy. Pediatrics 29: , Andersohn F, Bronder E, Klimpel A, Garbe E. Proportion of drugrelated serious rare blood dyscrasias: estimates from the Berlin Case-Control Surveillance Study. Am J Hematol 77: , Zakarija A, Bandarenko N, Pandey DK, et al. Clopidogrelassociated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration. Stroke 35: , Bennett CL, Kiss JE, Weinberg PD, et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 352: , Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA 281: 86-81, Berger PB, Bell MR, Rihal CS, et al. Clopidogrel versus ti- 972

5 Intern Med 55: , 216 DOI: /internalmedicine clopidine after intracoronary stent placement. J Am Coll Cardiol 34: , Levine GN, Bates ER, Blankenship JC, et al. 211 ACCF/AHA/ SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 82: E266-E355, Jacob S, Dunn BL, Qureshi ZP, et al. Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 2-year review from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost 38: , Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342: , Pharmaceuticals and Medical Devices Agency [Internet]. [cited 214 Jan. 3]. Available from: new/jsp/menu_fukusayou_base.jsp 14. Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RA- DAR Project. J Am Coll Cardiol 5: , Furlan M, Robles R, Galbusera M, et al. von Willebrand factorcleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339: , Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 13: , Reis ES, Falcao DA, Isaac L. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand J Immunol 63: , Ghannam A, Pernollet M, Fauquert JL, et al. Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells. J Immunol 181: , Matsuyama W, Nakagawa M, Takashima H, Muranaga F, Sano Y, Osame M. Identification of a novel mutation (Tyr181Ter) in sisters with hereditary component C3 deficiency and SLE-like symptoms. Hum Mutat 17: 79, Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 361: , Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L. Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr 138: , Jozsi M, Licht C, Strobel S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/ CFHR3 deficiency. Blood 111: , Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8: , Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial ahus and their impact on clinical phenotype. Clin J Am Soc Nephrol 5: , Chapin J, Eyler S, Smith R, Tsai HM, Laurence J. Complement factor H mutations are present in ADAMTS13-deficient, ticlopidine-associated thrombotic microangiopathies. Blood 121: , Izzedine H, Perazella MA. Thrombotic microangiopathy, cancer, and cancer drugs. Am J Kidney Dis 66: , The Japanese Society of Internal Medicine 973