Department of Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA
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Abstract |
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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.
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Introduction |
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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.
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Materials and methods |
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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 (19992000 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 MannWhitney 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.
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Results |
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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 4). The number of APS patients with combinations of additional thrombotic risk factors is shown in Table 5
. 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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During our chart review, we observed some other possible trigger factors which were not originally included in the data collection (Table 6).
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Discussion |
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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 5075%, but with ASA in combination with subcutaneous heparin the chance of full-term delivery increases to 7080% [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.
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Notes |
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References |
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