The Role of Thrombocytopenia as an Independent Predictor of Cardiovascular and Renal Damage in Patients with Systemic Lupus Erythematosus

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1 Med. J. Cairo Univ., Vol. 77, o. 1, March [2]: 65-70, The Role of Thrombocytopenia as an Independent Predictor of Cardiovascular and Renal Damage in Patients with ystemic Lupus Erythematosus MOHAMAD ALAH ABDEL BAKI, M.D.*; IMA AHMAD HAFEZ, M.D.*; IMA EMAT IBRAHIM, M.D.**; REEM ABDEL MOEIM HABIB, M.D.* and GHADA METWALLY ELGOHARY, M.D.* The Departments of Medicine* and Cardiology**, Faculty of Medicine, Ain hams University. Abstract Introduction: ystemic lupus erythematosus (LE) is an autoimmune disorder in which the body's immune system incorrectly attacks the body's own tissues and organs, leading to inflammation and damage. Thrombocytopenia (defined as platelet count less than 100 x 10 9 /liter) is rather common in LE. The incidence ranges from and it represents a predictor of a worse prognosis. Aim of the Work: To study the role of thrombocytopenia as an independent predictor of organ damage (renal and cardiac) in LE patients. Patients and Methods: Our study was conducted on 40 LE Patients from Ain hams University Hospitals, classified into 2 groups; group I including 20 patients with thrombocytopenia and group II including 20 patients without thrombocytopenia. All patients were subjected to medical history, clinical examination, laboratory investigations including, serological markers antinuclear antibody (AA), anti-double stranded DA (anti ds-da), renal biopsy. Transthoracic echocardiography for assessment of cardiac affection, evaluating cardiac function, valvular lesion and presence of any pericardial disease. Results: We found that there was no significant statistical difference between the two groups as regard their ages. Echocardiography was done for all patients, there were significant echocardiographic findings in group I compared to group II (p.value 0.027). As 40 of the patients in group I had pericardial effusion, 35 had mitral regurgitation, 10 had mitral stenosis, 20 had aortic regurgitation and 15 had tricuspid regurgitation. Among the patients in group II, 20 had pericardial effusion, 25 had mitral regurgitation, 10 had tricuspid regurgitation and no one of them had aortic valve disease. As regard renal damage, we found that 50 of thrombocytopenic LE patients had proteinuria >3.5 gm/24h, in contrast to non thrombocytopenic patients in which only 25 of them had proteinuria. Also in thrombocytopenic patients 5 had ERD, while no ERD was found between non thrombocytopenic groups. While comparing the two groups regarding the pathological pattern of kidney affection assessed by renal biopsy according to WHO classification system, we found no significant statistical differences among the two groups (p.value=0.38). Conclusion: We concluded that thrombocytopenia emerged as one of the most important predictors of damage also it is a qualitative marker of impending damage in lupus patients and that thrombocytopenic LE patients are at high risk of developing proteinuria, pericardial and valvular disease. Key Words: ystemic lupus erythematosis Thrombocytopenia Echocardiography Renal disease. Introduction THE role of thrombocytopenia as independent factor related to disease aggressiveness and outcome has been a matter of controversy leading to conflicting reports ultan et al. [1]. Clinical cardiac involvement is relatively common in LE Cardiac manifestations of LE often present as pericarditis that is reported in of the patients, myocarditis, ECG changes, or valvular heart disease in over 50 of patients including the classic cardiac lesion of Libman- acks endocarditis (nonbacterial verrucous endocarditis [2]. Renal involvement in systemic lupus erythematosus varies from asymptomatic proteinuria or microscopic haematuria with normal renal function, to severe nephrotic syndrome or acute renal failure [3]. Aim of the study: The aim of this work is to to study the role of thrombocytopenia as an independent predictor of organ damage(especially renal & cardiac) in systemic lupus erythematosus patient. Patients and Methods The study was carried at Ain hams University Hospitals Patients were selected from Rheumatology Clinic and in patients of Internal Medicine 65

2 66 The Role of Thrombocytopenia in LE Department. The study was performed on 40 LE patients fulfilling the criteria of American College of Rheumatology at the time of diagnosis. The patients were divided into two groups; Group I: 20 LE patients with thrombocytopenia. Group II: 20 LE patients with no thrombocytopenia. Ethical considerations: The nature of the present study was explained to all participants. The laboratory and radiological procedures represent standard care and pose no ethical conflicts. A verbal consent was obtained from all participants. All patients were subjected to the following: Medical history: Including personal history, disease duration, presence of diabetes, hypertension, drug history "including cytotoxic therapy like Endoxan and Immuran which may be a cause of thrombocytopenia" and other symptoms suggestive of other system affection. General examination: Included temperature, blood pressure and pulse and also cardiac, chest abdominal and neurological examination was performed. The disease activity was assessed using systemic lupus activity measure (LAM) score, this score has a rating scale (0 to 3) on 31 items and the total score range from 0 to 84. Routine laboratory investigations & 24 hours urinary protein and creatinine. erological investigations include: Antinuclear antibodys (AA), anti-double stranded DA (anti ds-da), anti-cardiolipin IgG: Pelvi-abdominal ultrasound: Renal biopsy: Was taken if indicated with histiopathological examination according to WHO classification. Transthoracic echocardiography: Was done using M-mode, two dimensional echo, pulse wave, continuous wave and colour flow Doppler. The study was performed in parasternal short and long axis views and apical 2 chambers and 4 chambers views. The machine used was Vivid 5 with 2.5MHz and 3.5 megahertz transducers. Echocardiographic evaluation was in accordance with the guidelines of the American society of echocardiography [4]. tatistical analysis: tatistical presentation and analysis of the present study was conducted, using the mean, standard error, unpaired student t-test, linear correlation coefficient and chi-square using P V12. Results Group I (thrombocytopenic patients): eventeen patients were females (85) and three were males (15), with mean age with D ± years. Their disease duration ranged from 1 month to 7 years with median 2.5 years (Table 1). Group II (non-thrombocytopenic patients): Eighteen patients were females (90) and two patients were males (10), with mean age 27.1 with D ± Their disease duration ranged from 1 month to 8 years with median 4.00 years (Table 1). As regards the clinical manifestations there is a significant statistical difference among the two groups as regard fever (p.value=0.028), oral ulcer (p.value=0.010), fatigue (p.value=0.020), muscle manifestation (p.value=0.002) and active nephritis (p.value=0.001). All these clinical data were higher among the thrombocytopenic group (group I). While comparing the two groups regarding the various laboratory data, there were significant statistical differences between the two groups as regard blood urea nitrogen (p.value=0.041), serum K the (p.value=0.043), AT level (p.value=0.01), ER level (p.value=0.008), 24 hours urinary proteins (p.value=0.01). All these laboratory data were higher in the thrombocytopenic group. There were also significant statistical differences between the two groups as regard white blood cell count (p.value=0.01), haemoglobin level (p.value= 0.003), the platelet count (p.value=0.000) and the Cr.clearance (p.value=0.02). All these laboratory data were lower in the thrombocytopenic group (Table 3). Table (1): Comparison between the two groups as regard age and gender. Group (I) Group (II) Variables p.value ig. o. o. Gender: Females Males Age: <30 years >30 years

3 Mohamad. Abdel Baki, et al. 67 Table (2): Comparison between thrombocytopenic and non-thrombocytopenic cases as regard the clinical manifestations: Clinical Thrombocytopenic group (I) on-thrombocytopenic group (II) Total Fisher's exact test ig. Fever: * Arthritis: Oral ulcer: * Malar rash: Photosenstivity: Lymphodonopatly: Fatigue: * Muscle manifestations: o: Myalgia: * Myositis: Raynauds: europsychological disorders: Table (3): Comparison between the laboratory data of thrombocytopenic and non-thrombocytopenic patients. Variables Creatinine Blood urea nitrogen a K Alb Total proteins ALT AT WBCs Hb PLT ER 24h. urinary protein Thrombocytopenic group (I) Mean ± D 1.420± ± ± ± ± ± ± ± ± ± ± ± ± on-thrombocytopenic group (II) Mean ± D 0.831± ± ± ± ± ± ± ± ± ± ± ± ± t-test or Mann-Whitney test p-value * * * 0.01* 0.003* 0.000* 0.008* 0.01* ignificant p value <0.05. Cr.Clearance: Creatinine clearance. a : odium. ER: Erythrocyte sedimentation rate. ALT : Alanine transaminase. WBCs : White blood cells. PLTs: Platelets. Alb : Albumin. BU: Blood urea nitrogen. T.Proteins : Total proteins. K : Potassium. AT : Aspartate transaminase. Hb : Haemoglobin. ig.

4 68 The Role of Thrombocytopenia in LE Table (4): Description of echocardiographic findings in Group I (thrombocytopenic patients). Variable umber Percent Pericardial effusion: o Yes 8 40 Mitral valve disease: Regurgitation 7 35 tenosis 2 10 Aortic valve disease: Regurgitation 4 20 tenosis 0 0 Tricuspid valve disease: Regurgitation 3 15 tenosis 0 0 Pulmonary valve disease: Regurgitation 1 5 tenosis 0 0 Table (6): Description of renal damage in both groups. Renal damage Thrombocytopenic group (I) Proteinuria >3.5gm/ h End stage renal disease Abdominal pain or serositis: Active nephritis: ignificant p value <0.05. onthrombocytopenic group (II) * The most common echocardiographic findings were pericardial effusion which was present in (40) of patients, mitral regurge in (35), aortic regurge in (20) and tricuspid regurge in (15) of patients (Table 4). Table (5): Description of echocardiographic findings in Group II (non thrombocytopenic patients). Variable umber Percent Pericardial effusion: o Yes 4 20 Mitral valve disease: Regurgitation 5 25 tenosis 0 0 Aortic valve disease: Regurgitation 0 0 tenosis 0 0 Tricuspid valve disease: Regurgitation 2 10 tenosis 0 0 Pulmonary valve disease: Regurgitation 0 0 tenosis 0 0 The most common echocardiographic findings were mitral regurge which was present in (25) of patients, pericardial effusion (20) and tricuspid regurge which was present in (10) of patients (Table 5). There was significant statistical difference among the two groups as regards the echocardiographic abnormalities (p.value=0.027), being more common among thrombocytopenic patients Tables (4,5). Table (7): Comparison between thrombocytopenic and non thrombocytopenic patients as regard WHO classification of renal biopsy. Renal biopsy II III IV V Total Group (I): Group (II): Total: Chi-square: X p-value 0.38 ignificant p value <0.05. Regarding the pathological pattern of kidney affection assessed by renal biopsy according to WHO classification system, we found no significant statistical differences among the two groups (p.value=0.38). Discussion ystemic lupus erythematosus (LE), the prototype of systemic autoimmunity, affects the quality of life and often result in irreversible organ damage and early death [5]. A umber of efforts have been undertaken lately to associate certain epidemiological, clinical characteristic and therapeutic intervention to irreversible organ damage and early demise. Among them increased age and disease duration. C, renal disease and high dose corticosteroid seem

5 Mohamad. Abdel Baki, et al. 69 the most influential damage is also independent predictor of further damage [6]. The role of thrombocytopenia as independent factor related to disease aggressiveness and outcome has been a matter of controversy leading to conflicting reports ultan et al. [1]. Our results revealed that 85 of our thrombocytopenic patients were females and only 15 were males, in contrast to those who are not thrombocytopenic 90 were females and 10 were males. We found no significant statistical difference between the two groups regarding the sex, in contrast to Kaufman et al. [7] study who found that there was higher rate of thrombocytopenia in male LE patients. However in Monica et al. [8] study there was non significant correlation between sex and thrombocytopenia, which is in agreement with our study. Also in our study we found that there was no significant statistical difference between the two groups as regard their ages (In the thrombocytopenic patients the mean of their ages was with D ± years, however the non thrombocytopenic patients the mean of their ages was 27.1 with D ± 9.55 years). Our results were somewhat different from Monica et al. [8] study they found that LE patients with thrombocytopenia tend to be younger. Our patients went through several investigations in order to determine the role of thrombocytopenia as a prognostic factor. Autoimmune markers as anti-nuclear antibodies (AA), anti double stranded DA (anti-ds DA) and anticardiolipin (ACL) were done for both groups and we found that in thrombocytopenic patients 30 of patients were ACL +ve, 100 of patients were AA +ve and 90 of patients were Anti-DA +ve. In nonthrombocytopenic patients: 25 of patients were ACL +ve, 90 of patients were AA +ve and 75 of patients were anti-da +ve. From the above results, we found no significant statistical difference between both groups as regard AA, Anti-DA and anti-cardiolipin antibodies thus there is no association between thrombocytopenia and those antibodies. Our results were somewhat different from those of ultan et al. [1], who found that thrombocytopenia was associated with ACL but not with anti-ds DA. However we are in agreement with Ziakas et al. [9] who found that there was no association between the presence of ACL antibodies and the presence of thrombocytopenia. Also Monica et al. [8] found that Anti-ds DA are more frequent in thrombocytopenic patients. Echocardiography was done for all patients in both groups, where there were significant echocardiographic findings in thrombo-cytopenic LE patients compared to those who are not thrombocytopenic. In thrombocytopenic patients 40 had pericardial effusion, 35 had mitral regurgitation, 10 had mitral stenosis 20 had aortic regurgitation and 15 had tricuspid regurgitation. In comparison to non-thrombocytopenic patients their were 20 had pericardial effusion, 25 had mitral regurgitation, 10 had tricuspid regurgitation and none of them had aortic valve disease. As regard the association of ACL antibodies and valvular lesions, we found that there was no association between the valvular lesion and ACL antibodies These findings are different from Khamashta et al. [10] study in 1990 who found that valvular lesion is the most frequent type of cardiac involvement in LE and the presence of antibodies against phospholipid is associated with higher prevalence of valvular abnormalities in LE patients. However our results were in agreement with Ziakas et al. [5] in their study on fifty-five LE patients who revealed that valvular disease occurred more frequently in thrombocytopenic subjects and the risk persisted after adjusting of anti-cardiolipin antibodies. In our study regarding the clinical features of LE, fever, oral ulcer and fatigue were more frequent among thrombo-cytopenic patients; however there is no any significant statistical difference between the two groups as regard arthritis, photosensitivity and the malar rash. ultan et al. [1] found that there was no significant different between thrombo-cytopenic and non thrombocytopenic as regard alopecia, joint involvement and serositis. Also in Ziakas et al. [5] study there was no any association between malar rash, photosensitivity, oral ulcer and arthritis with the presence of thrombocytopenia. Monica et al. [8] found no statistical difference between thrombocytopenic and nonthrombocytopenic LE patients as regard the clinical features. Miller et al. [11] suggested that thrombocytopenia didn't determine patient s subsequent course but the coexistence of associated feature such as glomerulonephritis and central nervous system involvement was a factor. On the other hand, Ziakas and collaborator [5] studied 150 patients retrospectively, they found that thrombocytopenic and non thrombocytopenic

6 70 The Role of Thrombocytopenia in LE patients differed significantly in the number of end organ damage. As regard organ specific damage; in our study 50 of thrombocytopenic LE patients had proteinuria >3.5gm/24h, in contrast to non thrombocytopenic patients in which only 25 of them had proteinuria. Among thrombocytopenic patients, 5 had ERD, while no ERD was found between the non thrombocytopenic groups. ultan et al. [1] found that there was an association between thrombocytopenia and renal involvement but not with renal failure. While Ziakas et al. [5] study, found that all feature of renal damage are higher among thrombocytopenic patients including proteinuria and end stage renal disease. As regard cardiovascular damage 45 of thrombo-cytopenic LE patients had valvular lesion, while only 20 in non thrombocytopenic patients have valvular lesion, 30 of thrombocytopenic patient had pericarditis while only 15 in non thrombocytopenic group. These results were in agreement with the Ziakas et al. [5] they found that is a higher risk of valvular disease and pericarditis is seen in thrombocytopenic group. In conclusion: Thrombocytopenia marks a subgroup of LE patients, bearing a higher risk of end organ damage throughout their disease course. References 1- ULTA.M., BEGUM. and IEBERG D.A.: Prevalence, pattern of disease and outcome in patients with systemic lupus erythomatosus who develop sever haematological problems. Rheumatology (Oxford), 42: 230-4, GOODO.J. and OLOMO D.H.: The cardiovascular manifestations of rheumatic diseases. Current Opinion in Rheumatology, 18: 5-40, FIEH C., HAJJAR Y. and MUELLER K.: Improved clinical outcome of lupus nephritis during the past decade: Importance of early diagnosis and treatment. Ann. Rheum. Dis., 62: , CHEITLI M.D., ARMTROG W.F., AURIGEMMA G.P., et al.: ACC/AHA/AE Guidelines update for the clinical application of echocardiography-summary article; a Report of the American college of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/AE Committee to update the 1997 guidelines for the Clinical Application of Echocardiography). J. Am. Coll. Cardiol., 42: , ZIAKA P.D., DAFI U.G., GIAOULI., TZIOUFA A.G. and VOULGARELI M.: "Thrombocytopenia in lupus as a marker of adverse outcome seeking Ariadne's thread". Rheumatology, Oxford, ALARCO G.., ROEMA D.M. and MCGWI G.: LUMIA study group systemic lupus erythematosus in three ethinic groups". Damage as a predictor of further damage. Rheumatology, 43: 202, KAUFMA L.D., GOMEZ REIO J.J., HEIICKE M.H. and GOREVIC P.D.: Male lupus: Retrospective analysis of the clinical and laboratory features of 52 patients, with a review of the literature. emin Arthritis Rheum., 18: , MOICA FERADEZ, GRACIELA., ALARCO, MADAR APTE, ROA M., ADRADE and JOH D.: "Reveilles for the LUMIA study group". Arthritis and Rheumatism, ZIAKA P.D., GIAOULI., ZITZARA E., TZIO- UFA A.G. and VOULGARELI M.: Lupus thrombocytopenia: Clinical implications and prognostic significance. Ann. Rheum. Dis., 64: 66-69, KHAMAHTA M.A., CERVERA R. and AHERO R.A.: Association of anibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet, 335: , MILLER M.H., UROWITZ M.B. and GOLDMA D.D.: The significance of thrombocytopenia in systemic lupus erythermatosus Arthritis Rheum., 26: , 1983.