ReviewHydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome
Introduction
Despite an efficient anticoagulation therapy the recurrence rates of thrombosis in APS remains elevated.
Recent data reviewed the rate of venous and arterial thrombosis in APS according to type of antiphospholipid antibodies. Therefore, lupus anticoagulant aCL were significantly associated with an increased risk of thrombosis, especially arterial [9].
Aspirin use could be proposed, as suggested by a recent meta-analysis in asymptomatic aPL individuals, patients with SLE or obstetrical APS. However, data from prospective studies as regards the preventive effect in thrombosis in APS lack to show a beneficial effect of aspirin [10].
Nowadays, several data highlight the need of new therapies in APS patients [11], [12].
New guidelines, and among them those recently elaborated at the 14th International Congress on aPL, highlighted current laboratory approach to APS diagnosis and treatment [13], [14], and also reviewed the potential future treatment strategies for aPL-positive patients [15].
Hydroxychloroquine (HCQ) is an anti-malarial drug widely used in rheumatoid arthritis (RP) and systemic lupus erythematosus (SLE) for its immunosuppressive effects [16].
The immunomodulatory properties of HCQ are related to several mechanisms such as reduction of proteolysis and antigen presentation, decrease of some pro-inflammatory cytokine production such as IL-1, IL-6, soluble CD8, and soluble receptors of IL2, T cell receptors (TCR) inhibition, interaction with toll-like receptors, and inhibition of calcium-dependent cellular signaling [17], [18], [19], [20], [21].
Although several effects have been documented in vitro, little is known about its effect in vivo as an anti-thrombotic drug.
Some studies suggested that chloroquine (CQ) and HCQ could potentially be anti-thrombotic. Therefore, HCQ could exert some anti-thrombotic effects through several mechanisms involving platelet adhesion, intravascular aggregation of red blood cells (RBCs), interactions between platelets and coagulation factors and binding of antiphospholipid (aPL) antibodies phospholipid surfaces [22], [23], [24], [25], [26], [27], [28], [29], [30], [31].
Moreover, HCQ reduces cardio-vascular risk factors [32], [33], [34], [35], [36].
Retrospective and prospective studies have pointed out that HCQ diminishes LDL and VDRL cholesterol and increases HDL cholesterol levels [32], [33], [34], [35], [36], and could reduce subclinical atherosclerosis [1].
In the Baltimore SLE cohort, patients who were HCQ users had diminished blood glucose levels compared with patients without HCQ treatment [35].
HCQ lowers disease activity and inflammation in SLE, and it has been reported that early initiation of HCQ delays the onset and progression of disease and ameliorates overall survival [36], [37], [38], [39], [40], [41], [42].
Molad et al. reported that in a SLE cohort HCQ treatment was positively correlated with damage-free survival [37].
In an observational prospective cohort, Ruiz-Irastorza et al. reported a survival benefit related to the use of HCQ [1].
A case–control study within the LUMINA cohort also supported this finding [39].
Moreover, in the longitudinal GLADEL cohort of 1480 SLE patients it has been reported that HCQ exerted beneficial effects on survival [41].
Patients who received a long term treatment with HCQ had a lower mortality compared with patients who were treated for shorter periods [41].
Section snippets
Clinical studies
Although not statistically valid, ancient surgical studies from early seventies suggest the efficacy of HCQ for the prevention of thrombosis [42], [43], [44], [45], [46], [47], [48], [49], [50].
At that time, several studies suggested the usefulness of HCQ as prophylactic antithrombotic therapy during the postoperative period, in particular after total hip replacement [42], [43], [44], [45], [46], [47], [48], [49], [50].
Therefore, Carter et al. reported a reduction in the incidence of venous
HCQ use in patients with SLE
Since the first report of Wallace et al. with respect to a potential thromboprotective effect of HCQ [52], several studies have suggested that hydroxychloroquine could be a prophylactic treatment against thromboses relapse in SLE [1], [2], [3], [4], [5], [6].
In the Hopkins lupus cohort, it had been suggested that HCQ use was protective against thromboses [60].
A study including 272 SLE patients revealed that the incidence of thrombotic events among patients in whom HCQ was administered was lower
HCQ use in patients with APS associated with systemic lupus erythematosus
In the LUMINA observational cohort in 442 SLE patients in whom aPL status was characterized, univariate analysis suggested that HCQ use was thromboprotective [2].
In a longitudinal retrospective case–control study in 144 aPL positive SLE patients matched with other 144 aPL negative SLE patients, HCQ was protective against thromboses in all patients no matter their aPL status (HR per month 0.99 in aPL positive patients and 0.98 per month in aPL negative patients) [5].The length of the period of
APS without SLE
Few data are available in APS without SLE.
Recently, a prospective nonrandomized study in this population suggested a protective role of HCQ for the recurrence of thrombotic events [62].
Therefore, in twenty APS patients treated with HCQ added to oral anticoagulants, compared to twenty others patients with oral anticoagulants alone, no thrombosis recurrence was observed [62].
However, no prospective large scale study is available.
Asymptomatic APL positive individuals
A study comparing APS patients with history of thrombosis with asymptomatic aPL-positive patients brought some supporting evidence for the protective effect of HCQ against thrombosis in asymptomatic aPL-positive individuals [61].
Until now, as no prospective large study had specifically addressed primary thrombosis prevention in asymptomatic aPL positive patients, most patients receive no treatment. However, low dose aspirin (ASA) or HCQ are used in some patients [64]. Among asymptomatic
1a—HCQ inhibits platelet aggregation
The anti-aggregant effect of HCQ and CQ has extensively been described [22], [23].
In a dose-dependent fashion, HCQ and CQ can reduce collagen-induced platelet aggregation and platelet alpha-granule release [24], [25].
HCQ can also reduce ADP-induced and/or ristocetin platelet aggregation [23], [24], as well as arachidonic acid release by activated platelets [26].
This effect seems to be related to the inhibition of phospholipase A2 activation. HCQ is able, in the presence of a thrombin agonist,
Effects on lipid profile
The antilipidaemic effects of HCQ are related to its action at the lipid receptor level to regulate enzyme activity and also possibly through TLRs [32], [33], [34], [35], [36].
A small prospective double blind study in 17 SLE patients confirmed these data [63].
In a retrospective study on 155 RA or SLE patients who were treated with steroids, the subgroup additionally treated with HCQ had lower LDL-cholesterol and triglyceride levels [32]. Similar data were observed in the Hopkins SLE cohort, as
Experimental model of APS
The thrombogenic mechanisms of anticardiolipin antibodies (aCL) have been investigated in an animal model by Pierangeli et al. [71]. A CD1 mouse model enabled the study of the kinetics of formation and dissolution of thrombus as well as the clot area in a dynamic fashion [71].
Authors reported a significant increase in both the size of the thrombus and the duration of time that the clot persists in mice that were injected with IgG and IgM-aCL antibodies obtained from patients with APS when
Take-home messages
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Recurrence rate of thrombosis remains elevated in APS despite efficient anticoagulation
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Hydroxychloroquine could be a new therapy in APS patients.
References (73)
- et al.
Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis
Autoimmun Rev
(2014) - et al.
Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis
Autoimmun Rev
(2014) - et al.
Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies
Autoimmun Rev
(2013) - et al.
Piedmont APS Consortium
Thrombotic recurrences and bleeding events in APS vascular patients: a review from the literature and a comparison with the APS Piedmont Cohort.
Autoimmun Rev
(2013) - et al.
Correct laboratory approach to APS diagnosis and monitoring
Autoimmun Rev
(2013) - et al.
14th International Congress on Antiphospholipid Antibodies Task Force
Report on antiphospholipid syndrome laboratory diagnostics and trends
Autoimmun Rev
(2014) - et al.
14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends
Autoimmun Rev
(2014) Mechanism of action of hydroxychloroquine as an antirheumatic drug
Semin Arthritis Rheum
(1993)- et al.
Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties
Blood
(2000) - et al.
On the inhibitory effect of chloroquine on blood platelet aggregation
Thromb Res
(1994)
Prevention of the platelet alpha-granule release reaction by membrane-active drugs
Thromb Res
Chloroquine inhibits stimulated platelets at the arachidonic acid pathway
Thromb Res
Hydroxychloroquine directly reduces the binding of antiphospholipid antibody—beta2-glycoprotein I complexes to phospholipid bilayers
Blood
Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids
Am J Med
Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis
Am J Med
Hydroxychloroquine and postoperative thromboembolism after total hip replacement
Am J Med
Antiphospholipid syndrome
Lancet
Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients
J Thromb Haemost
Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force
Chest
Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy
Ophthalmology
Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay
Am J Pathol
Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug
Blood
Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus
Lupus
Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII.
Factors predictive of thrombotic events
Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival
Lupus
Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort
Ann Rheum Dis
Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies
Arthritis Rheum
The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus
Arthritis Rheum
Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice
Circulation
Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus
J Rheumatol
ydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial
Ann Intern Med
The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE
Lupus
Mode of action of hydroxychloroquine in RA—evidence of an inhibitory effect on toll-like receptor signaling
Nat Clin Pract Rheumatol
Antimalarial agents: closing the gate on Toll-like receptors?
Arthritis Rheum
Platelet-inhibiting drugs in the prevention of clinical thrombotic disease (third of three parts)
N Engl J Med
Antiaggregation action of chloroquine
Med Trop
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