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Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study
  1. A Ruffatti1,
  2. T Del Ross1,
  3. M Ciprian1,
  4. M Nuzzo2,
  5. M Rampudda1,
  6. M T Bertero3,
  7. R Bergia3,
  8. P Caramaschi4,
  9. D Biasi4,
  10. F Capsoni5,
  11. L Montaguti6,
  12. R Ruffini6,
  13. A Brucato7,
  14. U Picillo8,
  15. V Fanelli9,
  16. V Riccieri10,
  17. A Piccoli11,
  18. G Valesini10,
  19. A Doria1,
  20. P L Meroni9,
  21. A Tincani2
  1. 1
    Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
  2. 2
    Rheumatology and Clinical Immunology Units, University of Brescia, Brescia, Italy
  3. 3
    Clinical Immunology and Allergology Units, Mauriziano Hospital, Turin, Italy
  4. 4
    Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy
  5. 5
    Rheumatology Unit, IRCCS Galeazzi, University of Milan, Milan, Italy
  6. 6
    Rheumatology Unit, Bufalini Hospital, Cesena, Italy
  7. 7
    Department of Internal Medicine, Hospital of Bergamo, Bergamo, Italy
  8. 8
    Institute of Clinical Medicine, II University of Naples, Naples, Italy
  9. 9
    Department of Internal Medicine, Auxologico Institute, University of Milan, Milan, Italy
  10. 10
    Rheumatology Unit, Department of Clinical Medicine and Medical Therapy, University La Sapienza, Rome, Italy
  11. 11
    Nephrology Unit, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy
  1. Professor A Ruffatti, Rheumatology Unit, Policlinico Universitario, Via Giustiniani, 2–35128 Padova, Italy; amelia.ruffatti{at}unipd.it

Abstract

Objectives: To asses risk factors for a first thrombotic event in antiphospholipid antibody (aPL) positive carriers and evaluate the efficacy of prophylactic treatments.

Methods: Recruitment criteria were age 18–65 years, no history of thrombosis, positivity for lupus anticoagulant and/or IgG/IgM anticardiolipin antibody (aCL) on ⩾2 occasions at least 6 weeks apart. Demographic, laboratory and clinical parameters were collected at enrolment and at the time of the thrombotic event.

Results: 370 patients/subjects (mean (SD) age 34 (9.9) years) were analysed retrospectively for a mean (SD) follow-up of 59.3 (45.5) months. Thirty patients (8.1%) developed a first thrombotic event during follow-up. Hypertension and medium/high levels of IgG aCL were identified by multivariate logistic regression analysis as independent risk factors for thrombosis. Thromboprophylaxis during high-risk and long-term periods was significantly protective.

Conclusions: Hypertension or medium/high titres of IgG aCL are risk factors for a first thrombotic event in asymptomatic aPL carriers and primary prophylaxis is protective.

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Antiphospholipid syndrome (APS) is defined by the persistent presence of moderate/high serum levels of antiphospholipid antibodies (aPL) in association with thrombotic events or pregnancy morbidity, or both.1 Several studies have recently endeavoured to identify the predictors of vascular events, but it is difficult to draw conclusions owing to the substantial differences in study designs, patient selection criteria, aPL profiles and the risk factors considered.27

This is a report on a multicentre, retrospective, follow-up study carried out to evaluate the possible predictors of a first thrombotic event and the efficacy of primary prophylactic treatments in a large number of aPL positive carriers.

PATIENTS AND METHODS

Study group

The study included patients/subjects from 11 rheumatological departments within the framework of the APS Study Group of the Italian Society of Rheumatology. The study group was selected from patients/subjects tested for aPL for the following reasons: previous pregnancy morbidity, systemic lupus erythematosus (SLE) or other autoimmune diseases, familiar aPL or APS, before starting oral contraceptives or hormone replacement therapy, long activated partial thromboplastin time or false-positive tests for syphilis. The clinical inclusion criteria were age 18–65 years and no history of any type of vascular thrombosis. The laboratory criteria were at least two consecutive positive results for lupus anticoagulant (LA) and/or IgG/IgM anticardiolipin antibodies (aCL) carried out more than 6 weeks apart.8 Women with APS-related pregnancy morbidity, classified according to the Sapporo criteria,8 were also included. Tables 1 and 2 list the variables, analysed at enrolment and at the time of the first thrombotic event.

Table 1 Baseline clinical characteristics of aPL carriers
Table 2 Results of autoantibody assays in the aPL carriers

The type of prophylactic treatment employed, such as long-term low-dose aspirin (LDA, 100 mg), long-term warfarin or LDA/heparin given during high-risk periods (pregnancy/puerperium, immobilisation and surgery), was recorded. Long-term LDA was initiated arbitrarily for at least one of the following reasons: SLE, other autoimmune diseases, obstetric APS, or LA positivity. Warfarin was given for thrombophylic conditions such as pulmonary hypertension, atrial fibrillation or post-traumatic tetraplegia.

The subjects were withdrawn from the study when a vascular thrombosis, defined in accordance with the last consensus paper,1 took place.

aPL detection

aCL of IgG and IgM isotypes were measured in five centres by inhouse ELISA procedures. Results were expressed as immunoglobulin G phospholipid (GPL) or immunoglobulin M phospholipid (MPL) units using international reference material. Upper normal values varied between 8.3 and 10 GPL and 9.6 and 10 MPL, respectively, and the cut-off value for medium/high titres was ⩾20 GPL and ⩾20 MPL in all the laboratories. The six other centres measured IgG and IgM aCL using commercial kits following the manufactures’ recommendations. LA was identified in platelet-poor plasma samples by a series of coagulation tests following internationally accepted guidelines.9

Statistics

Statistical analysis was performed using a χ2 test with Yates’s correction, Fisher exact test, univariate and multivariate logistic regression analyses. A stepwise forward conditional procedure was used for the logistic regression analysis including all the significant risk factors obtained from the univariate analysis. Estimated probabilities of thrombosis were assessed using a combination of the odds ratios. Missing data were included as an additional category in the analysis.

RESULTS

Baseline data

A cohort of 370 Italian subjects (344 women and 26 men with a mean (SD) age of 34 (9.9) years (range 18–65)) were studied for a mean (SD) follow-up of 59.3 (45.5) months (range 5–239). Table 1 lists for the aPL carriers, clinical characteristics, risk factors for thrombosis and prophylactic treatments.

In particular, prophylaxis was given for 906.1 patient-years, while 921.6 patient-years were without prophylactic treatment. No study participants developed serious adverse events, including major bleeding, during prophylaxis. Table 2 lists the results of the autoantibody assays.

First thrombotic event

Thirty patients (8.1%), 26 women and four men with a mean (SD) age of 38.2 (12.1) years (range 22–66) experienced their first thrombotic event during a mean follow-up of 56.1 months (thrombosis incidence rate 1.64 per 100 patients per year). There were 12 venous (11 deep vein thromboses and one retinal thrombosis) and 18 arterial thromboses (12 strokes, two retinal thromboses, two intestinal infarctions, one myocardial infarction and one lower limb thrombosis). Seven events (23.3%) developed during high-risk periods (puerperium, pill or surgery) and eight (26.7%) during prophylactic treatment (LDA or heparin).

Clinical and laboratory profiles (including thrombosis risk factors) at the time of the thrombotic event were not significantly different from those at baseline.

Analysis of the risk factors for thrombosis

Demographic, clinical and laboratory features at enrolment, as indicated in tables 1 and 2, were statistically analysed in order to assess any association with thrombotic events. Hypertension and primary prophylaxis administered for long intervals and during high-risk periods had the highest association with thrombosis (p = 0.003) and its prevention (p = 0.000), respectively. Medium/high levels of IgG aCL, diagnosis of autoimmune diseases, anti-dsDNA and high total cholesterol were associated, to a lesser extent, with the first thrombotic event (p = 0.026, p = 0.024, p = 0.016, p = 0.048, respectively). For autoimmune diseases, only autoimmune thrombocytopenia was associated with thrombosis (p = 0.039). Univariate and multivariate models analysed all clinical and laboratory characteristics, including thrombosis risk factors, as indicated in tables 1 and 2. Crude odds ratio analysis confirmed previous results. Multivariate logistic regression analysis showed that only hypertension and medium/high titres of IgG aCL were independent risk factors (table 3). Moreover, when long-term and high-risk period prophylaxes were analysed together, it was still identified as an independent, protective factor against thrombosis (table 3). No significant association was, however, found when they were analysed separately.

Table 3 Results of the stepwise logistic regression analysis

Subjects/patients with hypertension and medium/high levels of IgG aCL and receiving prophylaxis have a 9.2% probability of developing a thrombotic event, compared with a 61% probability when no prophylaxis was being administered. Finally, analysis of the relationship between each variable (including hypertension, medium/high IgG aCL levels and prophylaxis) and venous or arterial thrombosis, separately considered, showed no significant association.

DISCUSSION

Hypertension and medium/high titres of IgG aCL were found to be independent predictors of thrombosis in a large cohort of aPL carriers studied retrospectively. Moreover, a long-term and high-risk period of thromboprophylaxis was found to be an independent protective factor against thrombosis only when considered together.

LA was homogeneously identified by each attending centre following the International Society of Thrombosis and Haemostasis guidelines.9 As a variety of inhouse ELISA aCL procedures and commercial kits were used in the different centres, our study truly reflects a “real life” situation in clinical practice.

Thirty first-time thrombotic events during the follow-up period were retrospectively recorded. The number was low but similar to that reported in other studies.27 10 The finding at multivariate regression analysis that arterial hypertension is an independent factor associated with thrombosis is not, then, a surprising one. A comparable association has been reported in patients with APS and with arterial thrombosis.11

In agreement with other reports,58 our study demonstrates that medium/high IgG aCL titres are associated with an increased risk of thrombosis in aPL carriers even after adjustment for other variables. In contrast with other reports,12 however, LA was not found to be predictive of thrombosis. The discrepancy probably arises because LA was not investigated in all the patients/subjects studied, and, as a result, the final numbers were not sufficiently powerful for statistical analysis. The lack of association might also be due to the wide use of prophylactic treatment by our LA carriers (61.7%), and prophylaxis in SLE and in pregnant aPL carriers as well as in patients with APS might have been a confounding factor when risk of thrombosis was being evaluated.

Using prophylactic treatment in aPL carriers with no history of thrombosis continues to be a controversial practice.2 10 11 13 A recent prospective randomised controlled trial demonstrated that asymptomatic, persistently aPL-positive subjects/patients do not benefit from continuous LDA use.14 That study differs from ours in its prospective nature, the number of participants, the exclusion of obstetric APS and the risk stratification on the basis of the patients’ aPL profile. Nevertheless, its conclusions are in keeping with our own, showing that long-term prophylaxis, when considered alone, does not play a protective role. Moreover, in our study both long-term and high-risk period prophylaxis managements were taken into consideration. Although they do not reach statistical significance when they are considered separately, they have been found to be an independent, protective factor against thrombosis when they are analysed together using a multivariate regression model. Taken as a whole, our findings are the first to indicate the importance of thromboprophylaxis to prevent a first thrombotic event in aPL carriers.

In conclusion, our study suggests that aPL carriers with arterial hypertension and/or medium/high IgG aCL titres have a high probability (61%) of developing thrombosis in the absence of antithrombotic prophylaxis. Our study may, however, contain selection and information biases owing to its retrospective and observational nature. Patient compliance with long-term prophylactic treatment is, moreover, an unknown entity and may result in misclassification. A prospective study has already been started to verify the findings presented here.

REFERENCES

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Footnotes

  • Competing interests: None.

  • The authors are members of the APS Study Group of the Italian Society of Rheumatology.

  • Ethics approval: Ethics committee approval obtained.

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