|Year : 2013 | Volume
| Issue : 1 | Page : 15-18
Analysis of 14 young cerebrovascular accident cases with positive anti-phospholipid antibody
Hosseinian Amiri Aref1, Shirani Fatemeh2
1 Department of Rheumatology, Imam Khomeini Hospital, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
2 Department of Rheumatology, Rasoul Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
|Date of Web Publication||17-Aug-2013|
Hosseinian Amiri Aref
Department of Rheumatology, Imam Khomeini Hospital, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari
Source of Support: None, Conflict of Interest: None
Aims and Objectives: To study of clinical and laboratory findings of 14 young (< 45 years) patients with cerebro vascular accident who were positive for anti-phospholipid antibodies (aPLs). Materials and Methods: The clinical, laboratory, and radiologic findings in 14 young patients with cerebrovascular accident and positive tests for aPLs referred to Shohada Hospital were studied. The analysis for aPLs included estimation of lupus anticoagulant (LA) test, anticardiolipin (aCL) antibodies and anti beta2 glycoprotein 1 antibodies. Other relevant tests included anti-nuclear antibody, human immunodeficiency virus, Venereal Diseases Research Laboratory, platelet count, echocardiography and carotid Doppler. aPL positive strokes were those cases where either the immunoglobulin G (IgG) and/or immunoglobulin M (IgM) were raised or LA or anti beta2 glycoprotein 1 antibodies was positive and other known causes were excluded. Results: Levels of IgG aCL antibody was raised in nine cases and IgM aCL antibody was elevated in 11 cases. Three cases were positive for LA test. Only one patient was positive for anti beta2 glycoprotein 1 test. Seven patients showed small multiple bilateral cerebral infarcts on computerized tomography (CT) scan. Four patients had a history of recurrent strokes. Hemiparesis was more frequent than hemiplegia. One of patient presented with dense hemiplegia. Eleven patients recovered to normal functional capacity and did not have a recurrence on drugs. Conclusion: Cerebrovascular accident in young patients with positive tests for aPL showed certain clinical and radiological features, mild to moderate stroke, pre-treatment recurrences, and multiple smaller infarcts on CT, which could be clustered in a subgroup of stroke in young. These patients showed a better prognosis in terms of long-term outcome.
Keywords: Anti beta 2 glycoprotein 1 test, Anti-cardiolipin antibody, Cerebro vascular accident, Lupus anticoagulant test
|How to cite this article:|
Aref HA, Fatemeh S. Analysis of 14 young cerebrovascular accident cases with positive anti-phospholipid antibody. J Med Soc 2013;27:15-8
|How to cite this URL:|
Aref HA, Fatemeh S. Analysis of 14 young cerebrovascular accident cases with positive anti-phospholipid antibody. J Med Soc [serial online] 2013 [cited 2021 Jul 29];27:15-8. Available from: https://www.jmedsoc.org/text.asp?2013/27/1/15/116625
| Introduction|| |
Anti-phospholipid antibodies (aPLs) are a group of heterogeneous circulating serum polyclonal immunoglobulins (IgG, IgM or IgA) that bind negatively charged or neutral phospholipid component of cell membranes and cause increased tendency to venous or arterial thrombosis.  There has been an interest in aPL positivity and associated clinical findings such as focal ischemic cerebrovascular diseases.  They are probably present in up to 50% of the young persons with the stroke and perhaps even in higher prevalence with recurrent ischemic and diseases such as systemic lupus erythematosous (SLE).  Due to unexplained etiology in a large number of young stroke patients without any known conventional predisposing risk factors such as hypertension, diabetes, atherosclerosis etc., the importance of aPLs estimation may increase many fold.
Fourteen young patients of cerebrovascular accident with positive tests for aPLs were assessed in detail to analyze whether they form an independent subgroup having specific pattern of occlusive disease.
| Materials and methods|| |
Sixty three young patients (<45 years) with the stroke admitted in Neurology Department of Shohada Hospital of Lorestan between March 2008 and June 2011 were studied. Apart from computerized tomography (CT) and magnetic resonance imaging (MRI) (where ever necessary) all the routine and related specific investigations such as complete blood count and differentiation including platelet count, activated partial thromboplastin time, prothrombin time, chest X-ray, electrocardiogram, liver function and renal function tests, lipid profile, ultrasonography, echocardiography, carotid Doppler studies, anti-nuclear antibody, Venereal Diseases Research Laboratory, human immunodeficiency virus (HIV) were carried out. In forty (63%) cases, etiology was established with the clinical evaluations. These included cerebral venous thrombosis (CVT) related with pregnancy and puerperium, hemorrhagic stroke due to HT and/or aneurysm, and thrombo-embolic stroke associated with hypertension, diabetes mellitus, and valvular heart disease. In the remaining 23, (37%) patients where the etiology could not be established, aPL were tested by anticardiolipin (aCL) antibodies, lupus anticoagulant (LA) test, and anti beta2 antibody glycoprotein 1 estimation  on admission (3 rd -10 th day of stroke). aCL antibody was tested by enzyme linked immunosorbent assay. Solid phase enzyme immune essay technology was used to measure the titer of antibodies. aCL antibody titers were categorized into negative (< 40 MPL or GPL units) and positive (> 40 MPL or GPL units).  LA test was estimated by dilute Russell viper venom technique. Anti beta2 glycoprotein 1 antibody was tested by enzyme linked immunosorbent assay. In seven patients, aCL antibodies (both IgG and IgM) were found to be positive and in three patient LA test was positive. Another one of the patient was positive for anti beta2 glycoprotein 1 antibody in positive titer. This subgroup of 14 aPL positive cases was subsequently analyzed. Various causes of secondary aPLs such as SLE, adult/juvenile rheumatoid arthritis, auto-immune thrombocytopenic purpura, dermatomyositis, polymyositis, syphilis, leprosy, tuberculosis, HIV infections, and drugs such as chlorpromazine, phenothiazine, phenytoin etc., were excluded by relevant history and investigations. Anti-ds-deoxyribonucleic acid, anti-RO, and anti-LA antibody were carried out for all of these fourteen patients of positive aPL.
| Results|| |
The salient features are shown in [Table 1]. Although IgG was raised in nine cases, IgM was elevated in the 11 cases. Three of the cases were positive for LA test. Seven patients showed small multiple bilateral cerebral infarcts on CT scan. Four patients had a history of recurrent strokes. Hemiparesis was a more frequent occurrence than hemiplegia. One of patient presented with dense hemiplegia. None of cases had a positive history of pregnancy problems such as abortion and fetal loss. Some cases had CVA with cortical infarcts. Eleven patients responded well to treatment with anti-platelets, aspirin or ticlopidine and anticoagulants (in cases of recurrent strokes).
| Discussion|| |
aPLs have been reported in 1-46% of stroke patients and 1-4% in normal controls depending on the manifestations and criteria of studies and the age distribution of the patients. ,, Nagaraja et al. in a study of 60 cases of cerebro vascular accident in young patients found elevated aCL antibody in 23% patients.  The aPLs in stroke study indicated average incidence of 10%.  The mean age in the present study was 38.2 years, which is about 20 years younger than average age of thromboembolic patients. The predisposing risk factors for stroke such as hypertension, diabetes, atherosclerosis, and hyperlipidemia were absent in these patients. Similar low prevalence of recognized risk factors has also been reported in stroke patients with aPL in other studies.  The available data suggest that aPL should be suspected in young stroke patients with a history of previous thrombotic event including deep venous thrombosis, thrombocytopenia, livedoid reaction, and women with a history of pregnancy complications including recurrent fetal loss. 
Levine suggested that IgG is the aCL most commonly seen with aPL positive stroke although in the present study, level of aCL both IgG and IgM were raised.  In the study by Tuhrim et al., aCL antibodies conferred a four-fold increased risk of ischemic stroke.  Young stroke patients tend have positive levels of aPL and multiple infarcts than general stroke population.  Whether elevated aCL antibody titer is an independent risk factor is still not conclusive. , Patients with migraine headache with or without aura have had aPL and some of these patients had cerebral infarcts.  None of the patients in the present study had thrombocytopenia. Four patients in the present series had multiple (two or more) infarcts and in one patient CVT were found. Nagaraja et al. did not observe any case of venous thrombosis although in a study conducted by Mehndiratta et al. one out of seven patients had venous stroke. , Feldmann and Levinein 1995 also suggested that high titers of aPL are associated with a relatively high-risk of recurrent thrombotic events, especially stroke.  Five patients in our series had recurrent strokes, but its correlation with high titers of aPL could not be established. On comparing, the aPL positive and aPL negative stroke patients in the present study, we found aPL positive stroke group had an average age of 36.8 years, which was younger than average age for aPL negative group. More over multiple strokes/TIA episodes were more frequent in aPL positive group than the aPL negative group. These findings are similar with other studies. 
aPL leads to a hypercoagulable state by different mechanisms such as endothelial anticoagulant dysfunction, prostacyclin abnormalities, anti-thrombin III activity, placental ischemia, protein C and protein S, and complement activation any of which would lead to thrombosis.  In addition, various studies have shown that beta 2-glycoprotein 1 may be the key immunogen in the aPL. LA also requires a co-factor identified as lipid bound prothrombin to interact with negatively charged phospholipids.  LA recognizes an epitope that becomes exposed upon calcium mediated binding of prothrombin to phospholipid. The LA by reacting with proteins at these or other sites may interfere with the normal hemostatic system and contribute to a prothrombotic environment by binding to thrombin activated platelets inhibiting thrombin mediated endothelial cell prostacycline release or inhibitory protein C activation.
Treatment modalities in patients with stroke and positive aPL include antithrombotics and immune based treatments. Antithrombotics include anticoagulants, subcutaneous heparin or low molecular weight heparin and antiplatelet agent's aspirin and ticlopidine. Immune based therapies include corticosteroids and immunosuppressant.  In our series, patients with the first episode of stroke were put on aspirin or ticlopidine and were followed with total blood counts. Patients with recurrent events were put on oral anticoagulant. All patients recovered to normal functional capacity and did not have a recurrence. Our findings are in agreement with other study by Khamashta et al.  It is difficult to make any recommendation about preferred therapy as the number of cases with follow-up is too small. Besides drug therapy, recent studies have indicated that calcium intake in dairy milk has an inverse relation with risk for ischemic stroke.  There are clear recommendations about the duration of therapy for lifelong treatment with antiplatelet drugs or anticoagulants to prevent recurrences.  Though, the study comprises of a small sample, the anti-phospholipid positive young stroke cases may constitute an independent subgroup with certain clinical, investigatory and prognostic predictors. Thus, they have mild to moderate strokes, more often multiple smaller infarcts on CT/MRI, history of pretreatment recurrences and relatively better, immediate and long-term outcome.
| References|| |
|1.||Levine SR, Brey RL, Joseph CL, Havstad S. Risk of recurrent thromboembolic events in patients with focal cerebral ischemia and antiphospholipid antibodies. The antiphospholipid antibodies in stroke study group. Stroke 1992;23 Suppl 2:I29-32. |
|2.||Feldmann E, Levine SR. Cerebrovascular disease with antiphospholipid antibodies: Immune mechanisms, significance, and therapeutic options. Ann Neurol 1995;37 Suppl 1:S114-30. |
|3.||Coull BM, Levine SR, Brey RL. The role of antiphospholipid antibodies in stroke. Neurol Clin 1992;10:125-43. |
|4.||Harris EN. Serological detection of antiphospholipid antibodies. Stroke 1992;23 Suppl 2:I3-6. |
|5.||Ejaz ahmed. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. The antiphospholipid antibodies in stroke study (APASS) group. Neurology 1993;43:2069-73. |
|6.||Brey RL, Hart RG, Sherman DG, Tegeler CH. Antiphospholipid antibodies and cerebral ischemia in young people. Neurology 1990;40:1190-6. |
|7.||Montalbán J, Rio J, Khamastha M, Davalos A, Codina M, Swana GT, et al. Value of immunologic testing in stroke patients. A prospective multicenter study. Stroke 1994;25:2412-5. |
|8.||Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, et al. The "primary" antiphospholipid syndrome: Major clinical and serological features. Medicine (Baltimore) 1989;68:366-74. |
|9.||Nagaraja D, Christopher R, Manjari T. Anticardiolipin antibodies in ischemic stroke in the young: Indian experience. J Neurol Sci 1997;150:137-42. |
|10.||Levine SR, Brey RL, Sawaya KL, Salowich-Palm L, Kokkinos J, Kostrzema B, et al. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol 1995;38:119-24. |
|11.||Panagariya A, Makkar RK. APLA and stroke. S Asian J Prev Cardiol 1999;3:6-7. |
|12.||Levine SR. Most commonly asked questions about antiphospholipid antibodies. Neurologist 1996;2:79-84. |
|13.||Tuhrim S, Rand JH, Wu XX, Weinberger J, Horowitz DR, Goldman ME, et al. Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999;30:1561-5. |
|14.||Ahmed E, Stegmayr B, Trifunovic J, Weinehall L, Hallmans G, Lefvert AK. Anticardiolipin antibodies are not an independent risk factor for stroke: An incident case-referent study nested within the MONICA and Västerbotten cohort project. Stroke 2000;31:1289-93. |
|15.||Mehndiratta MM, Bhattacharya A, Gupta M, Khawaja GK, Puri V. Antiphospholipid antibodies syndrome in 'Stroke in young'. Neurol India 1999;47:122-6. |
|16.||Levine SR, Deegan MJ, Futrell N, Welch KM. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology 1990;40:1181-9. |
|17.||Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988;72:512-9. |
|18.||Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993-7. |
|19.||Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, Colditz GA, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999; 30:1772-9. |