Abstract

A 35-year-old female presents with a prolonged activated partial thromboplastin time (aPTT) on routine testing, which is found to be due to a lupus anticoagulant. She has no medical issues, no personal or family history of thrombosis, no history of pregnancy loss, and no symptoms suggestive of an underlying rheumatologic disorder. She is a non-smoker and does not take oral contraceptives. You are asked to provide recommendations regarding the need for primary thromboprophylaxis. As you begin your literature search, you formulate the following clinical question: “In asymptomatic patients with antiphospholipid antibodies, does primary prophylaxis prevent thrombotic complications?”

Antiphospholipid antibodies (aPL) are autoantibodies directed against phospholipid binding proteins, most commonly β2-glycoprotein I. The presence of aPL in the normal healthy population has been estimated to range from 1.0% to 5.6%; in patients with systemic lupus erythematosus (SLE) the prevalence ranges from 11% to 86%.1 Repeated measurements of aPL documented at least 12 weeks apart, including lupus anticoagulant, anticardiolipin antibodies or anti-β2-glycoprotein I antibodies, in conjunction with clinical events of arterial or venous thrombosis or pregnancy morbidity defines the anti-phospholipid antibody syndrome (APS).2 

A PubMed search was performed using the MeSH terms “Antiphospholipid Antibodies” or “Antiphospholipid Syndrome” and “Thrombosis” and “Primary Prevention” (search completed May 26, 2009). A total of 104 citations were retrieved and reviewed for inclusion. We excluded studies enrolling patients who had a history of thrombosis or pregnancy morbidity, children, pregnant women or evaluated pregnancy morbidity as the outcome. A total of 5 studies were identified3,7 (1 duplicate study8), and 2 further studies9,10 were identified by manual review of the reference list of relevant review articles. A total of 7 studies were therefore included in this review (Table 1 ).

Based on the literature review, only one published prospective clinical trial addresses our clinical question of interest. The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a randomized, double-blind, placebo-controlled clinical trial in asymptomatic patients with persistently positive aPL comparing the efficacy of aspirin 81 mg daily versus placebo for the prevention of thrombotic complications.3 A total of 98 study participants with aPL measured on 2 occasions 6 weeks apart (study designed based on the initial consensus criteria for APS) were randomized. Participants in this study were predominantly female, and notably over 60% of patients had SLE. The study was terminated early because of an unexpectedly low rate of thrombotic events, and analyzed after all patients had completed 1 year of follow-up. A total of 3 thrombotic events (arterial or venous) occurred in the aspirin group, and no thrombotic events occurred in the placebo group. Although limited by the small number of patients enrolled and infrequent outcome events, this study demonstrated that in patients with persistently positive aPL, aspirin was no more effective than placebo for the primary prevention of thrombotic events.3 

The other studies addressing our clinical question include cohort studies examining asymptomatic aPL-positive patients and cohort studies of aPL-positive patients with SLE. In asymptomatic aPL-positive patients, thrombo-prophylaxis with aspirin or low molecular weight heparin during high-risk periods (ie, surgery or prolonged immobilization) appears to be effective in reducing thrombotic complications.10 In the APLASA as well as other studies, most of the aPL-positive patients who developed thrombosis had additional thrombotic or cardiovascular risk factors.3,9 However, it is notable that most of these studies included patients with SLE, which is potentially problematic since SLE itself has been shown to be independently associated with thrombosis.11,13 Therefore, the results of these studies may not be entirely applicable to non-SLE populations.

Among asymptomatic aPL-positive patients with SLE, primary prophylaxis with aspirin and hydroxychloroquine appears to reduce the frequency of thrombotic events. In a Markov decision analysis, prophylactic aspirin, oral anticoagulant therapy and observation were compared in asymptomatic aPL-positive patients with SLE.14 Prophylactic aspirin was effective in reducing the number of thrombotic events compared to inducing bleeding episodes.

For the clinician who is faced with a patient who has persistently positive aPL testing but no history of thrombosis or pregnancy morbidity, we recommend an individual assessment of the patient’s thrombotic risk. There is currently no good quality evidence to support the routine use of aspirin for primary thromboprophylaxis in these patients, given that the benefit of aspirin is uncertain and because aspirin does carry a small, but not insignificant risk of bleeding (Grade 2B).15 In asymptomatic patients with SLE, aspirin and hydroxychloroquine may be beneficial based on observational data (Grade 2C). Reversible vascular risk factors should be addressed, and during periods of increased thrombotic risk aggressive thromboprophylaxis appears to be warranted (Grade 2C). The optimal type and duration of thromboprophylaxis remains unknown.

For the patient illustrated in the clinical vignette, given the absence of cardiovascular and thrombotic risk factors and the absence of signs and symptoms of SLE, we suggest that primary prophylaxis with aspirin is not warranted, either alone or in combination with hydroxychloroquine.

Table 1.

Studies addressing primary prophylaxis in asymptomatic patients with antiphospholipid antibodies.

Author, yearStudy designNNumber of aPL measurementsComparison/ interventionResults/conclusions
AIT indicates autoimmune thrombocytopenia; aPL, antiphospholipid antibodies; ASA, aspirin; CI, confidence interval; CTD, connective tissue disease; HCQ, hydroxychloroquine; HR, hazard ratio; LMWH, low molecular weight heparin; N/A, not available; OR, odds ratio; RCT, randomized controlled trial; SLE, systemic lupus erythematosus; TIA, transient ischemic attack. 
*Enoxaparin 1 mg/kg once daily for surgery or immobilization; ASA 325 mg/d during pregnancy; both in combination with counseling and treatment to reduce vascular risk factors 
**52/81 patients received primary prophylaxis (ASA = 50, oral anticoagulants = 1, clopidogrel = 1) 
Asymptomatic aPL patients 
Hereng et al, 20085  Retrospective 103 2; Unknown time interval between measurements ASA (n = 75) vs Observation (n = 28) 
  • -Lower frequency of thrombotic events in ASA group, especially in the subgroup of patients with SLE or AIT

  • -36% of patients had SLE

 
Erkan et al, 20073  RCT with parallel prospective cohort RCT: 98
 Cohort: 74 ≥ 2; 6 weeks apart RCT: ASA 81 mg daily (n = 48) vs
 Placebo (n = 50)
 Cohort: ASA (n = 61) 
  • -HR: 1.04 (95% CI 0.69–1.56)

  • -> 60% of patients in RCT had SLE

  • -ASA not effective in preventing thrombosis compared to placebo

 
Giron-Gonzalez et al, 200410  Prospective 178 ≥ 2; 8–12 weeks apart ASA 325 mg/d or LMWH daily during high risk situations* 
  • -All patients received thromboprophylaxis during high risk situations, no thrombotic events occurred

 
Erkan et al, 20029  Cross-sectional 56 Not specified Logistic regression analysis (ASA and/or HCQ use) 
  • -Probability of thrombotic event decreased in patients taking ASA +/− HCQ (HCQ only in patients with CTD)

  • -78% of patients had CTD

 
SLE patients 
Tektonidou et al, 20097  Retrospective 288; 144 aPL positive ≥ 2; ≥ 12 weeks apart Adjusted survival analysis (ASA 80–100 mg/d, HCQ) 
  • -HR per month: ASA 0.98 (95% CI 0.96–0.99) and HCQ 0.99 (95% CI 0.98–1.00)

  • -Duration of use of ASA and HCQ associated with decreased thrombosis

 
Kaiser et al, 20096  Retrospective 1930; 516 aPL positive Logistic regression analysis (HCQ use) 
  • -OR 0.63 (95% CI 0.48–0.83)

  • -HCQ protective against thrombosis

 
Tarr et al, 20074,8  Prospective 272; 81 aPL positive ≥ 2; 6 weeks apart Prophylaxis (n = 52) vs Observation (n = 29)** 
  • -Lower incidence of thrombosis in prophylaxis group vs observation group (1/52 vs 2/29 had stroke or TIA)

 
Author, yearStudy designNNumber of aPL measurementsComparison/ interventionResults/conclusions
AIT indicates autoimmune thrombocytopenia; aPL, antiphospholipid antibodies; ASA, aspirin; CI, confidence interval; CTD, connective tissue disease; HCQ, hydroxychloroquine; HR, hazard ratio; LMWH, low molecular weight heparin; N/A, not available; OR, odds ratio; RCT, randomized controlled trial; SLE, systemic lupus erythematosus; TIA, transient ischemic attack. 
*Enoxaparin 1 mg/kg once daily for surgery or immobilization; ASA 325 mg/d during pregnancy; both in combination with counseling and treatment to reduce vascular risk factors 
**52/81 patients received primary prophylaxis (ASA = 50, oral anticoagulants = 1, clopidogrel = 1) 
Asymptomatic aPL patients 
Hereng et al, 20085  Retrospective 103 2; Unknown time interval between measurements ASA (n = 75) vs Observation (n = 28) 
  • -Lower frequency of thrombotic events in ASA group, especially in the subgroup of patients with SLE or AIT

  • -36% of patients had SLE

 
Erkan et al, 20073  RCT with parallel prospective cohort RCT: 98
 Cohort: 74 ≥ 2; 6 weeks apart RCT: ASA 81 mg daily (n = 48) vs
 Placebo (n = 50)
 Cohort: ASA (n = 61) 
  • -HR: 1.04 (95% CI 0.69–1.56)

  • -> 60% of patients in RCT had SLE

  • -ASA not effective in preventing thrombosis compared to placebo

 
Giron-Gonzalez et al, 200410  Prospective 178 ≥ 2; 8–12 weeks apart ASA 325 mg/d or LMWH daily during high risk situations* 
  • -All patients received thromboprophylaxis during high risk situations, no thrombotic events occurred

 
Erkan et al, 20029  Cross-sectional 56 Not specified Logistic regression analysis (ASA and/or HCQ use) 
  • -Probability of thrombotic event decreased in patients taking ASA +/− HCQ (HCQ only in patients with CTD)

  • -78% of patients had CTD

 
SLE patients 
Tektonidou et al, 20097  Retrospective 288; 144 aPL positive ≥ 2; ≥ 12 weeks apart Adjusted survival analysis (ASA 80–100 mg/d, HCQ) 
  • -HR per month: ASA 0.98 (95% CI 0.96–0.99) and HCQ 0.99 (95% CI 0.98–1.00)

  • -Duration of use of ASA and HCQ associated with decreased thrombosis

 
Kaiser et al, 20096  Retrospective 1930; 516 aPL positive Logistic regression analysis (HCQ use) 
  • -OR 0.63 (95% CI 0.48–0.83)

  • -HCQ protective against thrombosis

 
Tarr et al, 20074,8  Prospective 272; 81 aPL positive ≥ 2; 6 weeks apart Prophylaxis (n = 52) vs Observation (n = 29)** 
  • -Lower incidence of thrombosis in prophylaxis group vs observation group (1/52 vs 2/29 had stroke or TIA)

 

Disclosures
 Conflict-of-interest disclosure: The authors have no conflicts of interest to declare.
 Off-label drug use: None disclosed.

References

References
1
Petri M. Epidemiology of the antiphospholipid antibody syndrome.
J Autoimmun
.
2000
;
15
:
145
–151.
2
Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost
.
2006
;
4
:
295
–306.
3
Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals.
Arthritis Rheum
.
2007
;
56
:
2382
–2391.
4
Tarr T, Lakos G, Bhattoa HP, Shoenfeld Y, Szegedi G, Kiss E. Analysis of risk factors for the development of thrombotic complications in antiphospholipid antibody positive lupus patients.
Lupus
.
2007
;
16
:
39
–45.
5
Hereng T, Lambert M, Hachulla E, et al. Influence of aspirin on the clinical outcomes of 103 anti-phospholipid antibodies-positive patients.
Lupus
.
2008
;
17
:
11
–15.
6
Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort.
Ann Rheum Dis
.
2009
;
68
:
238
–241.
7
Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies.
Arthritis Rheum
.
2009
;
61
:
29
–36.
8
Tarr T, Lakos G, Bhattoa HP, et al. Clinical thrombotic manifestations in SLE patients with and without antiphospholipid antibodies: a 5-year follow-up.
Clin Rev Allergy Immunol
.
2007
;
32
:
131
–137.
9
Erkan D, Yazici Y, Peterson MG, Sammaritano L, Lockshin MD. A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome.
Rheumatology (Oxford)
.
2002
;
41
:
924
–929.
10
Giron-Gonzalez JA, Garcia del Rio E, Rodriguez C, Rodriguez-Martorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals.
J Rheumatol
.
2004
;
31
:
1560
–1567.
11
Rahman P, Urowitz MB, Gladman DD, Bruce IN, Genest J Jr. Contribution of traditional risk factors to coronary artery disease in patients with systemic lupus erythematosus.
J Rheumatol
.
1999
;
26
:
2363
–2368.
12
Calvo-Alen J, Toloza SM, Fernandez M, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients.
Arthritis Rheum
.
2005
;
52
:
2060
–2068.
13
Bruce IN. ‘Not only . . . but also’: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus.
Rheumatology (Oxford)
.
2005
;
44
:
1492
–1502.
14
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 Med
.
2000
;
160
:
2042
–2048.
15
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
Chest
.
2006
;
129
:
174
–181.

Author notes

1

Department of Medicine, Division of Hematology, Duke University, Durham, NC

2

Department of Medicine, McMaster University, Hamilton, Ontario, Canada

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