A retrospective study of systemic lupus erythematosus patients with prolonged bleeding time

Transcription

1 Formosan Journal of Rheumatology 2008;22:37-42 Original Article A retrospective study of systemic lupus erythematosus patients with prolonged bleeding time Kuei-Ying Su,2, Shih-Tzu Tsai 2, Huei-Ting Lee, Wei-Sheng Chen, De-Feng Huang,3 Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital 2 Buddhist Tzu Chi General Hospital, Hualien 3 Department of Medicine, National Yang-Ming University, Taiwan Objective: The prolongation of bleeding time (BT) in systemic lupus erythematosus (SLE) may be due to a variety of factors, including thrombocytopenia, the existence of autoantibodies, renal or hepatic dysfunction, or usage of special medications. In this study, we investigated and analyzed the possible causes of prolonged BT in SLE patients. Methods: We retrospectively reviewed medical records of 253 SLE patients who had received BT tests from January 2004 to September We collected data on the clinical characteristics, current medications, and laboratory data. Results: Thirty-seven SLE patients had prolonged BT and 26 patients were normal. There were significant differences in both groups in terms of serum level of hemoglobin (0.9 ± 2.2 vs. 2.2 ±.7 g/dl, p<0.005); platelet count (78,200 ± 4,200 vs. 238,900 ± 5,200/cumm, p<0.005); the frequency of INR prolongation (0.8% vs. %, p<0.00); APTT prolongation (6.2% vs. 4.6%, p<0.02); frequencies of serum antiphospholipid antibodies (43.2% vs. 8.%, p<0.005); increasing serum level of Cr (29.7% vs..6%, p<0.00); and overt proteinuria (56.8% vs. 32.9%, p=0.005). Fifty-one patients underwent renal biopsy with predominant lupus nephritis, especially ISN/RPS class IV and V. Significance in the usage of medications in the prolonged BT and normal groups was noted, with methylprednisolone pulse therapy and anti-tb agents: 8% vs. 2%, and 2% vs. 0 (p=0.032 for pulse therapy, and p=0.00 for anti-tb agents). The usage of other medications was not significant. Conclusion: BT prolongation in SLE is a complex clinical problem. In this study, we found that many factors are associated with BT abnormality, including anemia, thrombocytopenia, renal dysfunction and the presentation of antiphospholipid autoantibody. A further cohort study of platelet function and the existence of other autoantibodies should be performed in SLE patients with prolonged BT. Key words: Bleeding time, systemic lupus erythematosus, antiphospholipid autoantibody Introduction Corresponding author: De-Feng Huang, M.D. Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital. 20, Shih-Pai Road, Section 2, Taipei 2, Taiwan. TEL: ext 3375, FAX: dfhuang@vghtpe.gov.tw Received: May 29, 2008 Revised: August 20, 2008 Accepted: September 5, 2008 The prolongation of bleeding time (BT) in systemic lupus erythematosus (SLE) patients may be due to a variety of factors, including thrombocytopenia, the existence of autoantibodies, renal and hepatic dysfunction, or usage of special medications. Thrombocytopenia-associated BT prolongation often occurs if platelet counts are less than 75,000/μL (positive predictive value PPV 95.5%, negative predictive value NPV 69.2%) [], which is related to abnormal primary hemostasis. Liver dysfunction is also associated with 37

2 Prolonged bleeding time in SLE abnormal primary hemostasis, reduced platelet counts, peripheral vasodilation and the severity of liver diseases [2]. Renal dysfunction impairs primary hemostatic function owing to acquired platelet dysfunction and disturbance of the platelet-platelet and platelet-vessel wall interaction [3]. Acute reduction in hematocrit also produces platelet dysfunction [4,5] The phenomenon of hemostatic dysfunction has been observed in SLE patients with antiphospholipid syndrome (APS). Some authors have suggested that prolonged BT was another manifestation presenting in APS; but determining the true mechanism of BT prolongation in APS still requires further investigation [6]. Whenever SLE patients have the paradox of prolonged activated partial thromboplastin time (APTT) and thrombosis, anti-phospholipid antibodies (APA) profiles should be checked for the presentation of APS. In addition to APA, there are varieties of autoantibodies in SLE which could also influence primary hemostasis; such as anti-cd40 ligand antibody (Ab), anti-von Willebrand factor (vwf) Ab, and anti-platelet Ab [7-9]. The aim of this study was to investigate and analyze the possible causes of prolonged BT in SLE patients. Patients and Methods Patients We retrospectively reviewed the medical records of 253 patients who fulfilled the 977 American College of Rheumatology SLE criteria [0], and who had received BT tests in the Division of Allergy, Immunology and Rheumatology in Taipei Veterans General Hospital from January 2004 to September Clinical and laboratory data We collected data on the clinical characteristics of these subjects, including age, gender, status of renal function, and medications. Medication records included prednisolone, immunosuppressants, drugs that may affect the hemostasis, and other special agents. Laboratory data included BT, creatinine (Cr), albumin, aspartate aminotransferase (AST), complete blood counts, the International Normalized Ratio (INR), prolongation of APTT, anti-phospholipid antibodies, namely anti-cardiolipin, anti-phospholipid or anti-beta2 glycoprotein- antibodies, and urinalysis. Platelet counts <75,000/cumm, which influence BT, were evaluated []. The definition of prolonged INR and APTT were based on the laboratory control, as INR >. and APTT >35.5 sec. Abnormal serum Cr was also recorded, with the definition of serum Cr less than.5 mg/dl based on the lab reference level. Overt proteinuria ( +++, or 0.5 g/day) is one of the manifestations of lupus nephritis, and was also recorded. BT was measured by the traditional IVY method, and was defined as prolonged when it was 2 standard deviations (SD) above the mean of the control. If patients had received renal biopsy, the classifications followed those of the International Society of Pathology/Renal Pathology Society (ISN/ RPS) classification []. Statistical analysis Data were presented as mean ± SD. Independent t-tests were performed using the SPSS software program for Windows (version 5.0). A p value <0.05 was considered statistically significant. Results Table summarizes the demographic features of the 253 SLE (F:M = 203:3) patients. Among them, 37 patients (F:M = 35:2) had BT prolongation and 26 patients (F:M = 203:3) had normal BT (p=0.8). The mean age of the BT-prolonged and BT-normal patients was 36. years and 38.5 years, respectively (p=0.38). The average white blood cell counts were 552/cumm and 5982/cumm for the BT-prolonged and BT-normal patients, respectively (p=0.069); hemoglobin was significantly lower in the BT-prolonged than BT-normal group (0.9 ± 2.2 vs. 2.2 ±.7 g/dl, p<0.005); platelet counts were significantly lower in the BT-prolonged patients (78,200 ± 4,200 vs. 238,900 ± 5,200/cumm, p<0.005). The frequency of platelet counts less than 75,000/cumm was 0.8% vs. % in the BT-prolonged and BT-normal groups, respectively (p<0.00). There were significant differences in the frequency of INR and APTT prolongation: 0.8% vs. %, and 6.2% vs. 4.6% in the two groups, respectively (p<0.00 for prolonged INR, and <0.02 for prolonged APTT). The frequency of serum anti-phospholipid antibodies was significantly higher in the BT-prolonged patients than in the BTnormal patients (43.2% vs. 8.%, p<0.005). An increased serum level of Cr was more prevalent in the BT-prolonged group than in the BT-normal group (29.7% vs..6%, p<0.00). Among the BT-prolonged patients, had serum creatinine greater than.5 mg/dl; four of the had the status of end-stage renal disease under regular hemodialysis. Overt proteinuria (urine protein +++, or 0.5 g/day) was 56.8% vs. 32.9% in the BT-prolonged and BT-normal groups, respectively 38

3 Su et al Table. Demographic features of SLE patients with bleeding time tests. BT-prolonged BT-normal n = 37 n = 26 p Age (year) 36. ± ± Sex (Female/Male) 35/2 203/ WBC (/cumm) 552 ± ± Hb (g/dl) 0.9 ± ±.66 <0.00* Platelet (K/cumm) 78.2 ± ± 5.2 <0.00* Platelet counts <75 K/cumm, No. ( %) 4 (0.8%) 2 (%) <0.00* Creatinine (mg/dl) 2.37 ± ± 0.08 <0.00* Renal dysfunction 23 (62%) 97 (44.9%) <0.00* Creatinine.5 mg/dl, No. ( %) (29.7%) 25 (.6%) <0.00* Proteinuria +++, or 0.5 g/day, No. ( %) 2 (56.8%) 7 (32.9%) 0.005* Albumin (g/dl) 3.29 ± ± * AST (U/L) 24.0 ± ± International Normalized Ratio 0.98 ± ± INR >., No. ( %) 4 (0.8%) 2 (%) <0.00* Active partial thromboplastin time, APTT(sec) 29. ± ± * APTT >35.5 sec, No. ( %) 6 (6.2%) 0 (4.6%) 0.02* Anti-dsDNA Ab (IU/mL) 02.2 ± ± Positivity of anti-phospholipid antibodies, No. ( %) 6 (43.2%) 39 (8.%) 0.00* Renal pathology, No. ( %) 4 (37.8%) 37 (7.%) 0.004* Class II 0.56 Class III Class IV * Class V FSGS 0.56 Diabetic nephropathy *p<0.05, significant (p=0.005). Fifty-one patients from both groups received a renal biopsy. Most of them had lupus nephritis; especially ISN/RPS class IV and V. Two patients had focal segmental glomerulosclerosis, and one had diabetic nephropathy. There was no significant difference in the serum level of anti-dsdna antibodies in either group: 02.2 ± 9.2 IU/mL and 20.4 ± 8.9 IU/mL, respectively. The serum AST level showed no significant difference in these 2 groups, either. The current medications during the BT tests are summarized in Table 2. Significance was noted in methylprednisolone pulse therapy and anti-tb agents: 8% vs. 2%, and 2% vs. 0% in the BT-prolonged and BTnormal groups, respectively (p=0.032 for pulse therapy, and p=0.00 for anti-tb agents). The usage of other medications was not significant in either group. Among the group of prolonged BT patients, 30 were under prednisolone treatment (ranging from 5 to 60 mg/day). Twenty-three patients were taking immunosuppressants: 0 with azathioprine, 9 with hydroxychloroquine, 2 with cyclophosphamide, and with mycophenolate. No patient was taking NSAIDs during the period of BT testing. Seven patients used aspirin, and 2 used warfarin. Three patients took other drugs: 2 of them received anti- Table 2. Number of patients with special medications during BT tests BT-prolonged n = 37 BT-normal n = 26 Prednisolone 3 (84%) 6(75%) mg 5 (4%) 40 (9%) ~0 mg 0 (27%) 5 (24%) ~30 mg 4 (38%) 63 (29%) ~60 mg 2 (6%) 6 (2%) Methylprednisolone 3 (8%) 4 (2%) 0.032* pulse therapy Azathioprine (30%) 56 (26%) Hydroxychloroquine 9 (24%) 44 (20%) Cyclophosphamide 2 (5%) 8 (4%) Mycophenolate (3%) (%) 0.56 Aspirin 7 (9%) 34 (6%) Warfarin 2 (5%) 9 (4%) NSAID 0 4 (2%) Propylthiouracil (3%) (%) 0.56 (PTU) Thyroxine 0 5 (2%) 0.35 Anti-TB agents 2 (5%) * *p<0.05, significant p 39

4 Prolonged bleeding time in SLE tuberculosis therapy and received propylthiouracil (PTU) for hyperthyroidism. Discussion In this study, we found that renal dysfunction was the most common, and APA, the second most common factor that was associated with BT-prolong in our SLE patients. Renal dysfunction can impair primary hemostasis through two main mechanisms platelet dysfunction and impaired platelet-vessel wall interaction. Platelet dysfunction in uremic patients is partially caused by the uremic toxins in circulation [2,3]. Anemia, thrombocytopenia, prolonged INR, prolonged APTT, and APS were also significant. Anemia is a vital cause of bleeding tendency [5]; the hemostatic effects of RBC are to clean endothelial cell nitric oxide which inhibits platelet function, to provide arachidonic acid and adenosine diphosphate which promote platelets producing thromboxane, and to increase the shear stress in bleeding sites. The reason for the higher frequency of usage of methylprednisolone pulse therapy in the BTprolonged group may be related to the severity of the renal disease and SLE activity. In four patients, there were no obvious causes of prolonged BT. Further diagnostic tests for platelet dysfunction may be needed in this condition. BT is one of the screening tests for platelet function in primary hemostasis; another is the platelet function analyzer (PFA)-00. The PFA-00 has better specificity and sensitivity than BT, but still has limitations. Special tests are needed to define the defects in platelet function, including platelet aggregation, adenine nucleotides, flow cytometry and electron microscopy [4,5]. Also, autoantibodies should be checked in patients with unknown causes of BT prolongation. There is a variety of Abs in SLE patients which can influence platelet number or function in a number of ways leading to bleeding or a prothrombotic tendency. Autoantibody to CD40 ligand is associated with thrombocytopenia but not thromboembolism [8]. Autoantibodies, which inhibit von Willebrand factor (vwf)/factor VIII complex, suppress platelet function and prolong BT in SLE patients [9]. Acquired von Willebrand syndrome in SLE, unlike a primary deficiency, responds poorly to supplements, but can be treated via controlling SLE activities with prednisolone and immunosuppressants. APS and hyperhomocysteinemia can cause prothrombotic events [6,7]. BT is prolonged in APS, and is a paradoxical manifestation of thrombosis which needs further study. One interesting patient had concomitant APS, hyperthyroidism and thrombocytopenia. It was difficult to clarify the main cause of prolonged BT in this patient. Hyperthyroidism increases platelet plug formation by heightening vwf levels [8], which shortens BT. Hyperthyroidism in this patient was irrelevant to BT prolongation, but may be an innocent bystander in an autoimmune condition. On the other hand, hypothyroidism may take place in immune-mediated thrombocytopenia [9]. References. McDonagh RJ, Ray JG, Burrows RF, Burrows EA, and Vermeulen MJ. Platelet count may predict abnormal bleeding time among pregnant women with hypertension and preeclampsia. Can J Anesth 200;48: Shu WC, Lee FY, Lee SD, Tsai YT, Lin HC, Lin RS, et al. Prolonged bleeding time in cirrhotic patients: Relationship to peripheral vasodilation and severity of cirrhosis. J Gastroenterol Hepatol 2008;9: Noris M, Remuzzi G. Uremic bleeding: Closing the circle after 30 years of controversies? Blood 999; Valeri CR, Cassidy G, Pivacek LE, Ragno G, Lieberthal W, Crowley JP, et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion 200;4: Valeri CR, Khuri S, Ragno G. Nonsurgical bleeding diathesis in anemic thrombocytopenic patients: role of temperature, red blood cells, platelets, and plasma-clotting proteins. Transfusion 2007;47(4 Suppl):206S-248S. 6. Urbanus RT, de Laat HB, de Groot PG, Derksen RH. Prolonged bleeding time and lupus anticoagulant: a second paradox in the antiphospholipid syndrome. Arthritis Rheum 2004;50: Green D. Spontaneous inhibitors to coagulation factors. Clin Lab Haematol 2000;22 Suppl : Nakamura M, Tanaka Y, Satoh T, Kawai M, Hirakata M, Kaburaki J, et al. Autoantibody to CD40 ligand in systemic lupus erythematosus: association with thrombocytopenia but not thromboembolism. Rheumatology (Oxford) 2006;45: Michiels JJ, Schroyens W, van der Planken M, Berneman Z. Acquired von Willebrand syndrome in systemic lupus erythematodes. Clin Appl Thromb Hemost 200;7: Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 997;40:725.. Markowitz GS, D'Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int 2007;7:

5 Su et al 2. Kaw D, Malhotra D. Platelet dysfunction and end-stage renal disease. Semin Dial 2006;9: Review. 3. Brophy DF, Martin EJ, Carr SL, Kirschbaum B, Carr ME Jr. The effect of uremia on platelet contractile force, clot elastic modulus and bleeding time in hemodialysis patients. Thromb Res 2007;9: Michaelson A. Platelets. 2nd ed. New York: Academic Press; Shah U, Ma AD. Tests of platelet function. Curr Opin Hematol 2007;4: Von Feldt JM, Scalzi LV, Cucchiara AJ, Morthala S, Kealey C, Flagg SD, et al. Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus. Arthritis Rheum 2006;54: Nascif AK, Hilário MO, Terreri MT, Ajzen SA, D'Almeida V, Plavnik FL, et al. Endothelial function analysis and atherosclerotic risk factors in adolescents with systemic lupus erythematosus. Int J Adolesc Med Health 2007;9: Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 2007;92: Schleinitz N, Camoin L, Pharm D, Bernit E, Reviron E, Veit V, Harlé JR. Monoclonal antibody immunospecific platelet assay in patients with lupus anticoagulant and prolonged bleeding time: Comment on the article by Urbanus et al. Arthritis Rheum 2005;52:

6 Prolonged bleeding time in SLE 全身性紅斑性狼瘡患者出血時間延長之回溯分析研究,2 蘇桂英 2 蔡世滋 李惠婷 陳瑋昇,3 黃德豐 台北榮民總醫院內科部過敏免疫風濕科 2 花蓮佛教慈濟綜合醫院 3 國立陽明大學醫學系 目的 : 出血時間延長發生於全身性紅斑性狼瘡的原因很多, 包括血小板數目降低 存在自體抗體 肝腎功能不全 或使用特殊藥物等, 本實驗研究及分析全身性紅斑性狼瘡病人出血時間延長的相關影響因子 方法 : 我們回溯性地查閱在 2004 年 月至 2007 年 9 月當中於台北榮總 253 位曾接受出血時間測試的全身性紅斑性狼瘡的病例, 我們進一步分析相關臨床資料, 包括年齡 性別 用藥 實驗室檢查等 結果 : 共 37 位全身性紅斑性狼瘡病人有出血時間延長,26 位出血時間正常 有顯著差異的因子包含血色素值 (0.9 ± 2.2 vs. 2.2 ±.7 g/dl, p<0.005); 血小板數目 (78,200 ± 4,200 vs. 238,900 ± 5,200/cumm, p<0.005);inr 及 APTT 時間延長的頻率 ; 抗凝脂抗體的存在 (43.2% vs. 8.%, p<0.005); 血中肌酸酐上升 (29.7% vs..6%, p<0.00); 及是否有尿蛋白 (56.8% vs. 32.9%, p=0.005) 共有 5 位病人接受腎臟切片檢查, 除了一位病人的腎切片為糖尿病腎病變及 2 位局部性腎絲球硬化症外, 全都顯示有狼瘡性腎炎 出血時間延長的紅斑性狼瘡病人所使用的藥物, 除了較高比例的脈衝類固醇使用 (8% vs. 2%, p=0.032) 及抗結核藥物 (2% vs. 0%) 外, 其餘藥物於兩組並無顯著差異 結論 : 全身性紅斑性狼瘡患者合併出血時間延長是一複雜的情況, 應注意病人是否有貧血 血小板數目低下 腎功能不全 抗磷脂抗體的存在 而進一步的檢查包括血小板功能測定及各式自體抗體也是未來研究的重點 關鍵詞 : 出血時間 全身性紅斑性狼瘡 抗磷脂抗體 42