A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome

D. Erkan, Y. Yazici, M. G. Peterson, L. Sammaritano and M. D. Lockshin

Department of Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. Antiphospholipid antibodies (aPL) are major risk factors for thrombosis. Other clinical factors exist in antiphospholipid syndrome (APS) patients which may have an additive or preventive effect on thrombosis. We therefore performed a cross-sectional study to analyse additive clinical thrombotic risk factors and possible preventive treatments in APS patients, and to compare the results with those obtained in asymptomatic aPL-positive (no history of vascular thrombosis or pregnancy morbidity) patients.

Methods. We identified 77 APS patients with non-gravid thrombotic events (group A) and 56 asymptomatic aPL-positive patients (group B). The study periods were defined as 6 months prior to the time of first vascular event in group A and 6 months prior to the patient's last visit in group B. Medical records were reviewed to evaluate the incidence of hypertension, diabetes mellitus, hypercholesterolaemia, regular cigarette smoking, oral contraceptive use or hormone replacement therapy, surgical procedures, pregnancy with or without an APS-related event, malignancy and infections. In addition, any history of thrombocytopenia or the use of aspirin, hydroxychloroquine, corticosteroids or immunosuppressives during the study periods was recorded. Bivariate statistical analysis and logistic regression tests were performed to compare groups.

Results. In group A, 75% (n=58) of patients and in group B 48% (n=27) of patients had at least one of the additional risk factors during the study periods. In the bivariate analysis, pregnancy (P=0.005) and surgical procedures (P=0.04) were significantly more frequent in group A, while aspirin (P<0.001), hydroxychloroquine (P<0.001) and corticosteroids (P=0.002) were used significantly more frequently in group B. In logistic regression, the probability of an event was decreased by taking aspirin and/or hydroxychloroquine. In women only, the probability of an event was increased with thrombocytopenia and pregnancy or surgical procedures. The incidences of hypertension and smoking and the presence of more than one risk factor were significantly associated with arterial thrombosis but not venous thrombosis.

Conclusion. While traditional risk factors were similar between groups, pregnancy and surgical procedures increased the risk of thrombosis. Hypertension and smoking were associated with arterial events. Possessing a combination of risk factors may increase the occurrence of arterial thrombosis but not venous thrombosis. Use of aspirin and/or hydroxychloroquine may be protective against thrombosis in asymptomatic aPL-positive individuals.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The antiphospholipid syndrome (APS) is a distinct clinical syndrome consisting of vascular thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL), most commonly lupus anticoagulant (LAC) or anticardiolipin antibodies (aCL) [1]. The presence of aPL in the absence of clinical complications does not indicate APS. Current literature suggests that asymptomatic aPL-positive (no history of vascular thrombosis or pregnancy morbidity) individuals have a high risk of developing thrombosis and that the high titre of aCL is a significant predictor of thrombosis [24]. However, thrombotic complications of APS are unpredictable and triggering factors are unknown.

Well-defined clinical risk factors for thrombosis exist in individuals without hereditary hypercoagulable states, including pregnancy, the perioperative period, oral contraceptive use, hormone replacement therapy, malignancies and immobilization. A ‘second trigger’ event may be needed for an asymptomatic aPL-positive patient to develop a vascular event, or the prothrombotic state induced by aPL may be followed by a trigger factor which is otherwise not sufficient to cause thrombosis [5]. Support for this theory comes from studies on catastrophic APS patients. Infections, certain medications, surgical procedures and the postpartum period can trigger catastrophic APS, although the mechanism is not clear [6].

To date no prospective large-scale study has specifically addressed primary thrombosis prevention in asymptomatic aPL-positive patients. Thus, while most patients receive no treatment, low-dose aspirin (ASA) or hydroxychloroquine (HCQ) are used in some patients [7, 8].

The primary objective of this cross-sectional study was to analyse additive clinical thrombotic risk factors in APS patients as second triggers. We also examined the differences between APS patients with venous and arterial events and possible preventive treatments in APS.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
APS patients
We identified 162 APS patients from the APS registry of the Hospital for Special Surgery (HSS). Patients who had had only pregnancy events (n=45), transient ischaemic attacks (TIA) (n=15) and patients with incomplete data (n=25) were excluded (the mechanism and the character of a pregnancy event may differ from a vascular event, patients with TIA do not fulfil the Sapporo criteria for APS, and the diagnosis of TIA can be inconsistent). Thus, 77 APS patients with non-gravid thrombotic events (group A) were included in the study. The preliminary Sapporo classification criteria for the APS [1] (a medium to high titre of aCL and/or a positive LAC test in the presence of vascular thrombosis and/or pregnancy morbidity) were to confirm the diagnosis. The study period was 6 months prior to the time of first vascular event.

Asymptomatic aPL-positive patients
We identified 56 asymptomatic aPL-positive patients (medium to high titre of aCL and/or a positive LAC test but no history of vascular or pregnancy events) (group B) from our systemic lupus erythematosus (SLE) registry and screening through the HSS Immunology Laboratory's aPL database (1999–2000 results). Asymptomatic aPL-positive patients without any connective tissue disorder (CTD) were generally identified during work-up for an elevated activated partial thromboplastin time (e.g. during presurgical screening). In addition, patients who did not fulfil the Sapporo criteria for APS but had probable manifestations of APS, such as thrombocytopenia, haemolytic anaemia, livedo reticularis, cardiac valve disease, multiple sclerosis-like syndrome, chorea and migraine [1], were also included in this group. In group B, the study period was 6 months prior to the patient's last hospital visit.

Data collection
We classified initial APS-related clinical events into the following categories: (i) arterial thrombosis (cerebral, retinal, renal, hepatic, mesenteric, coronary, pulmonary or peripheral arteries); (ii) venous thrombosis [deep venous thrombosis (DVT) of the lower extremities, pulmonary emboli and retinal, renal, hepatic, mesenteric or superficial vein thrombosis]; (iii) a catastrophic event; and/or (iv) thrombocytopenia (platelet count less than 150000x109/l). We reviewed medical records systematically to evaluate for hypertension requiring anti-hypertensive medication (HTN), diabetes mellitus requiring anti-diabetic agents (DM), hypercholesterolaemia requiring cholesterol-lowering agents, regular cigarette smoking, oral contraceptive use or hormone replacement therapy (OC/HRT), surgical procedures (requiring hospitalization), pregnancy with or without an APS-related event, malignancy, and infections requiring antibiotics. In addition, we recorded any history of thrombocytopenia and the use of ASA, HCQ, corticosteroids (CS) and immunosuppressive agents (IS) during the study periods. Immobilization and obesity were not included in the data collection as it would be difficult to define these parameters accurately during the chart review. We interviewed patients for missing data. The cross-sectional nature of the study did not allow us to identify other hypercoagulable states systematically.

Laboratory testing
At our institution, lupus-anticoagulant was determined by simplified dilute Russell's Viper Venom Time test (DVVtest; American Diagnostica, USA) and confirmed by a modified platelet neutralization procedure (DVVconfirm; American Diagnostica: Greenwich, CT, USA). Standardized enzyme-linked immunosorbent assay (ELISA) was considered positive (medium to high titre) for IgG and IgM aCL with any value greater than 40 units. However, some of our patients were tested for aPL at outside laboratories at the time of their first vascular event and they were later referred to our institution.

Statistical analysis
The associations between clinical events and clinical risk factors were examined using Fisher's exact test, contingency table analysis, t-tests and the Mann–Whitney test as appropriate. Logistic regression was performed, with the APS-related vascular event as the dependent variable and those clinical risk factors whose association with the event was statistically significant in the preceding analysis as the independent variables. Alpha was set to 0.05.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We compared 77 APS patients in group A with 56 asymptomatic aPL-positive patients in group B. Table 1Go shows the clinical and demographic characteristics of both groups. Overall, 87% (n=58) of patients with the diagnosis of CTD had SLE and 13% (n=9) had other CTDs (rheumatoid arthritis, six; psoriatic arthritis, two; mixed CTD, one). The distribution of APS-related initial vascular events in group A was as follows: arterial thrombosis, 42 patients (stroke, 27; peripheral arteries, eight; retinal, renal, hepatic, mesenteric, coronary and pulmonary arteries, one patient each; one patient developed intracardiac thrombosis); venous thrombosis, 34 patients (DVT of lower extremities, 22; DVT with pulmonary emboli, eight; retinal and superficial veins, one patient each; two patients had internal jugular vein thrombosis); (c) catastrophic event, one (iliac vein, retinal and pulmonary artery); and (d) thrombocytopenia, 13 patients.


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TABLE 1.  Clinical and demographic characteristics of APS patients (group A) and asymptomatic aPL-positive patients (group B)

 
In group A, 75% (n=58) of patients had at least one of the additional risk factors at the time of the event (one risk factor, 47%; two risk factors, 23%; three risk factors, 5%), whereas 48% of the patients in group B (n=27) had at least one of the risk factors (one risk factor, 21%; two risk factors, 21%; three risk factors, 5%). Patients with additional risk factors, the distribution of these factors and a statistical comparison between groups are shown in Table 2Go. In the bivariate analysis, pregnancy (P=0.005) and surgical procedures (P=0.04) were significantly more frequent in group A.


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TABLE 2.  Patients with additional thrombotic risk factors

 
Smoking and OC/HRT use were more common in group A, although the difference between the two groups did not reach statistical significance. When we compared 64 female patients in group A (mean age 33.6±13.1 yr) with 51 female patients in group B (mean age 45.3±14.4 yr), 13 (20%) and five (10%) patients were using OC/HRT in group A and B respectively (Table 3Go). Of six APS patients who were using OC/HRT and cigarettes, four developed arterial events, one a catastrophic event, and only one DVT. Of five APS patients who did not have any other additional risk factors, all developed venous events but not arterial events. When we analysed five patients in group B, we observed that one patient was on OC and four patients were on HRT (Table 3Go).


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TABLE 3.  OC/HRT use in APS and asymptomatic aPL-positive patients

 
In group A, one patient was using ASA, four were using HCQ, 14 were using CS and nine were using IS. In group B, 18 patients were using ASA, 21 were using HCQ, 25 were using CS and eight were using IS. In both groups, all patients receiving HCQ had been diagnosed with a CTD. One patient who had had stroke while on ASA was 65 yr old, had hypertension, and also developed a further recurrent event while on a therapeutic dose of warfarin. In the bivariate analysis, the use of ASA (P<0.001), HCQ (P<0.001) and CS (P=0.002) was significantly more frequent in group B.

In logistic regression analysis, the probability of an event was decreased by taking ASA and/or HCQ. In women only, the probability of an event increased with thrombocytopenia and the presence of either pregnancy or surgical procedures.

In group A, 34 patients had venous and 43 had arterial events. The mean age at diagnosis was not different (34.5±13.1 and 35.0±13.6 yr respectively). There was no significant difference between groups with respect to the incidence of DM, hypercholesterolaemia, OC/HRT use, surgical procedures, pregnancy, malignancy, infections or thrombocytopenia. However, the incidences of HTN and smoking were significantly higher in the group of patients with arterial events (Table 4Go). The number of APS patients with combinations of additional thrombotic risk factors is shown in Table 5Go. Possession of more than one risk factor was significantly associated with arterial thrombosis (P=0.016). At the time of the arterial event, one patient was using ASA, four were using HCQ, nine were using CS and six were using IS. At the time of the venous event, none of the patients was using ASA or HCQ, five were using CS and three were using IS.


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TABLE 4.  Additional thrombotic risk factors in APS patients with venous and arterial events

 

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TABLE 5.  Numbers (%) of APS patients with combinations of additional thrombotic risk factors

 
When APS patients younger than 40 yr were compared with patients older than 40 yr, there was no statistically significant difference among the risk factors studied. We also compared primary APS patients with secondary APS and found that only the incidence of hypercholesterolaemia was significantly higher in secondary APS patients (P=0.01).

During our chart review, we observed some other possible trigger factors which were not originally included in the data collection (Table 6Go).


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TABLE 6.  Possible trigger factors for thrombosis

 


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our cross-sectional study demonstrates that while traditional thrombotic risk factors are similar in APS patients and asymptomatic aPL-positive patients, pregnancy and surgical procedures increase the risk of thrombosis. Hypertension and smoking are more commonly associated with arterial events, but not venous events. Furthermore, the use of ASA and/or HCQ may protect against thrombosis in asymptomatic aPL-positive individuals.

The elevated oestrogen level during pregnancy is associated with increased risk of thrombosis, even in the absence of aPL. Branch et al. [9] reported 19 APS patients (86% of patients with a history of thrombosis) who had suffered one or more thrombotic events during pregnancy, in the postpartum period or while using OC. Aspirin plus subcutaneous heparin is the standard prophylactic therapy during pregnancy for APS patients fulfilling the Sapporo criteria. However, the management of pregnancy in aPL-positive patients in the absence of previous pregnancy or vascular events is controversial; while some physicians favour low-dose ASA, others do not. Our study demonstrates that pregnancy can trigger a non-gravid vascular event in aPL-positive asymptomatic patients.

The increased risk of thrombosis during the perioperative period is well recognized not only for APS patients [10] but also for patients with other hereditary hypercoagulable states [11]. Patients with APS are classified in the very high-risk category for venous thromboembolism during the postoperative period [12]. Perioperative thromboses occur due to: (i) withdrawal of warfarin [13]; (ii) increased hypercoagulability despite ongoing, optimal warfarin or heparin therapy [14]; and (iii) catastrophic exacerbation of APS [15]. Our data strongly support the proposition that surgical procedures can trigger an acute thrombotic event in asymptomatic aPL-positive patients.

Thrombocytopenia due to APS does not protect against thrombosis. In logistic regression analysis, we found that pregnancy or surgical procedures in the presence of thrombocytopenia increases the risk of an APS-related event. We speculate that the presence of thrombocytopenia may represent a more severe disease state or less use of prophylactic regimens during the perioperative period.

Hypertension, hyperlipidaemia and elevated homocysteine levels increase the risk of thrombosis in patients with aPL [16]. Verro et al. [17] reported that cerebrovascular events with high-titre immunoglobulin (Ig) G aCL (>100 GPL) are associated with smoking and hyperlipidaemia. Levine et al. [18] studied cerebrovascular and neurological disease associated with aPL in 48 cases and demonstrated that recurrent events are significantly more common among regular cigarette users and hyperlipidaemics. Asherson et al. [19] showed that hypertensive patients had multiple strokes more often than normotensive patients. Hansen et al. [34] demonstrated that hypertension, smoking, hyperlipidaemia and diabetes mellitus are the most important predictors of arterial thrombosis. Our findings are similar to those of all these studies; we demonstrated that hypertension and smoking are associated with arterial events, but not venous events, in APS patients.

OCs increase the risk of both venous and arterial thrombosis even in patients without hypercoagulable states. Furthermore, OC pills increase the risk of a first episode of venous thromboembolism (VTE) eight-fold in patients with antithrombin deficiency (and probably cause a similar increase in patients with protein S and C deficiencies) and four-fold in carriers of factor V Leiden [20]. Similarly, HRT increases the risk of developing a first VTE two-fold [21]. The use of oestrogens in patients with aPL is thought to be highly thrombogenic by physicians [22, 23]. We observed that approximately one-fifth of our APS patients developed their first vascular event in the presence of OC/HRT use, although this proportion did not reach statistical significance when compared with asymptomatic aPL-positive patients. Furthermore, we noted that the use of OC/HRT appeared to increase the risk of arterial thrombosis in the presence of smoking.

Malignant diseases may cause aPL production or APS [24]. Infections can trigger a thrombotic event; this is well documented, especially in catastrophic APS patients [6]. Neither malignancies nor infections were statistically significant in our cohorts.

A recent overview of four randomized trials concluded that ASA prevents the first myocardial infarction and any vascular event [25]. The role of ASA in preventing recurrent pregnancy losses in APS has been well demonstrated. Patients with aPL have a chance of fetal loss of about 50–75%, but with ASA in combination with subcutaneous heparin the chance of full-term delivery increases to 70–80% [26, 27]. Although ASA is not administered universally for the primary prevention of thrombosis in aPL-positive patients, there have been recent reports that emphasize the prophylactic role of ASA and the lack of large-scale prospective studies [2830]. HCQ has been used as a prophylactic agent against DVT in hip surgery patients [31] and reduces the risk of thrombosis in both SLE patients and animal models of APS [31, 32], and possibly decreases the titre of aPL [31]. We found that ASA and/or HCQ use may be protective against thrombosis in asymptomatic aPL-positive individuals. It is important to note that only patients with the diagnosis of a CTD were receiving HCQ and large-scale prospective studies are needed to confirm and generalize these findings.

One study demonstrated that the younger an individual, the more risk factors are required to precipitate thrombosis; therefore ageing itself appears to be a strong risk factor for thrombosis [33]. Our study showed that possessing a combination of risk factors in addition to aPL may increase the occurrence of thrombosis, although this was found for arterial thrombosis but not venous thrombosis. However, on the basis of age, we did not find any difference in the incidence of thrombotic risk factors or the location of the thrombosis.

The cross-sectional nature of our study is its major limitation. There were too few males for us to have the power to detect anything but very robust associations for some of the clinical risk factors. The definition of the study periods may account for some of the differences in the baseline characteristics of the groups (i.e. group B was older and had more patients with other CTDs, which may have affected the comparison) and the incidence of risk factors. The fact that our hospital is a tertiary referral centre biases the results towards more severe patients. Furthermore, the clinical effect of aPL is probably enhanced by procoagulant polymorphisms of plasma proteins such as factor V Leiden, G20210A mutant prothrombin and methyltetrahydrofolate reductase [34, 35]. The cross-sectional nature of the study did not allow us to evaluate genetic hypercoagulable states.

In summary, our data can be used to generate hypotheses to explain why some patients develop thrombosis and some do not. Prospective studies are needed to confirm our findings. The presence of additional risk factors may be considered a marker in the risk assessment plan and may help physicians decide if a patient needs prophylactic treatment.


    Notes
 
Correspondence to: D. Erkan, Division of Rheumatology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum1999;42:1309–11.[ISI][Medline]
  2. Ginsburg KS, Liang MH, Newcomer L et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med1992;117:997–1002.[ISI][Medline]
  3. Vaarala O, Mantarri M, Manninen V et al. Anticardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation1995;91:23–7.[Abstract/Free Full Text]
  4. Finazzi G, Brancaccio V, Moia M et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med1996;100:530–6.[ISI][Medline]
  5. Jacobs BS, Levine SR. Antiphospholipid antibody syndrome. Curr Treat Options Neurol2000;2:449–58.[Medline]
  6. Asherson RA, Cervera R, Piette JC et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore)1998;77:195–207.[ISI][Medline]
  7. Petri M. Hydroxychloroquine use in the Baltimore lupus cohort: effects on lipids, glucose, and thrombosis. Lupus1996;5(Suppl.):S16–S22.[ISI][Medline]
  8. Myones BL, McCurdy D. The antiphospholipid syndrome: Immunologic and clinical aspects. Clinical spectrum and treatment. J Rheumatol2000;27(Suppl. 58):20–8.
  9. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol1992;80:614–20.[Abstract]
  10. Erkan D, Leibowitz E, Berman J, Lockshin MD. Perioperative medical management of antiphospholipid syndrome: Hospital for Special Surgery experience, review of the literature and recommendations. J Rheumatol2002;29:843–9.[ISI][Medline]
  11. Martlew VJ. Peri-operative management of patients with coagulation disorders. Br J Anaesth2000;85:446–55.[Abstract/Free Full Text]
  12. Geerts WH, Heit JA, Clagett GP et al. Prevention of venous thromboembolism. Chest2001; 119(Suppl. 1):132S–75S.[Free Full Text]
  13. Asherson RA, Chan JK, Harris EN, Gharavi AE, Hughes GR. Anticardiolipin antibody, recurrent thrombosis, and warfarin withdrawal. Ann Rheum Dis1985;44:823–5.[Abstract]
  14. Bick RL, Arun B, Frenkel EP. Antiphospholipid-thrombosis syndromes. Haemostasis1999;29:100–10.[ISI][Medline]
  15. Yamamoto T, Ito M, Nagata S et al. Catastrophic exacerbation of antiphospholipid syndrome after lung adenocarcinoma biopsy. J Rheumatol2000;27:2035–7.[ISI][Medline]
  16. Petri M. Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol1996;25:191–3.[ISI][Medline]
  17. Verro P, Levine SR, Tietjen GE. Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke1998;29:2245–53.[Abstract/Free Full Text]
  18. Levine SR, Deegan MJ, Futrell N, Welch KM. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology1990;40:1181–9.[Abstract]
  19. Asherson RA, Khamashta MA, Gil A et al. Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med1989;86:391–9.[ISI][Medline]
  20. Kearon C, Crowther M, Hirsh J. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med2000;51:169–85.[ISI][Medline]
  21. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. J Am Med Assoc1998;280:605–13.[Abstract/Free Full Text]
  22. Petri M. Pathogenesis and treatment of the antiphospholipid antibody syndrome. Med Clin North Am1997;81:151–77.[ISI][Medline]
  23. Girolami A, Zanon E, Zanardi S, Saracino MA, Simioni P. Thromboembolic disease developing during oral contraceptive therapy in young females with antiphospholipid antibodies. Blood Coagul Fibrinolysis1996;7:497–501.[ISI][Medline]
  24. Asherson RA. Antiphospholipid antibodies, malignancies, and paraproteinemias. J Autoimmun2000;15:117–22.[ISI][Medline]
  25. Hebert PR, Hennekens CH. An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease. Lancet2000;160:3123–7.
  26. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol1996;174:1584–9.[ISI][Medline]
  27. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies. Br Med J1997;314:253–7.[Abstract/Free Full Text]
  28. Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome—effective prophylaxis with aspirin. Arthritis Rheum2001;44:1466–7.[ISI][Medline]
  29. Malaviya AN, Mourou M. Should low-dose aspirin also be a background therapy for all patients with systemic lupus erythematosus (SLE)? Lupus2000;9:561–2.[ISI][Medline]
  30. Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis. Arch Intern Med2000;160:2042–8.[Abstract/Free Full Text]
  31. Petri M. Hydroxychloroquine: past, present, future. Lupus1998;7:65–7.[ISI][Medline]
  32. Edwards MH, Pierangeli S, Liu X et al. Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation1997;96:4380–84.[Abstract/Free Full Text]
  33. Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost1997;78:1–6.[ISI][Medline]
  34. Hansen KE, Kong DF, Moore KD, Ortel TL. Risk factors associated with thrombosis in patients with antiphospholipid antibodies. J Rheumatol2001;28:2018–24.[ISI][Medline]
  35. Qushmaq K, Esdaile J, Devine DV. Thrombosis in systemic lupus erythematosus: the role of antiphospholipid antibody. Arthritis Care Res1999;12:212–9.[ISI][Medline]
Submitted 29 January 2002; Accepted 22 March 2002