What are the prospects for antiplatelet agents for thromboprophylaxis in antiphospholipid syndrome?

KEYWORDS:

• Platelets
• lupus anticoagulant
• antiprothrombin
• aspirin
• clopidogrel
• rivaroxaban
• warfarin

Antiphospholipid syndrome (APS) is the most frequent-acquired thrombophilia. Recent studies estimate that around 10% of individuals with stroke, myocardial infarction, or venous thromboembolism are positive for antiphospholipid antibodies (aPL) [1]. The mechanisms by which aPL cause thrombosis are not fully elucidated, however much has been clarified over the last years. A ‘two-hit’ model has been proposed, in which over a procoagulant state induced by aPL, a second hit (other prothrombotic conditions, inflammation, complement activation, etc.) results in clot formation [2]. aPL are capable of creating a thrombogenic environment by a number of mechanisms involving different cell lines as well as clotting factors [2]. One of the most important ones is enhancing the production of tissue factor (TF) by activated monocytes and endothelial cells. Interference with natural regulators such as protein C, antithrombin, and tissue plasminogen activator, increasing production of von Willebrand factor by endothelial cells, and promoting platelet activation have all been demonstrated [2]. Regarding the latter, it is a proven fact that platelets are a main actor in arterial thrombosis in the general population, with solid evidence of a central role also played in the pathogenesis of arterial thrombosis in APS [3]. aPL are able to upregulate plasma levels of active VWF and promote platelet activation [3]. Under high shear forces, antibodies reacting with β₂ glycoprotein I (β₂GPI) can bind to the surface of stimulated platelets and trigger platelet activation [4], which may lead to the subsequent activation of the endothelium, resulting in fibrin generation and thus making platelet activation a primary mechanism of aPL-mediated arterial thrombosis [5]. With all the above in mind, it would be thus expected that antiaggregant drugs will be protective against arterial thrombotic manifestations of APS.

Primary thromboprophylaxis with low-dose aspirin (LDA) in asymptomatic (i.e. without thrombotic events) carriers of aPL has been shown to be effective [6]. Therefore, LDA is generally recommended for such individuals after taking into account a number of personal circumstances. Among these, the repeated positivity for lupus anticoagulant (LA), particularly with the concomitant presence of anticardiolipin (aCL) and anti-β2GPI antibodies (the so-called triple positive patients), the diagnosis of APS secondary to systemic lupus erythematosus, and/or presenting additional cardiovascular risk factors, particularly smoking [7], are considered high-risk thrombotic factors and thus require a more proactive approach [8].

After the empirical observation that immunosuppression did not change the course of the disease, several antithrombotic regimens, mainly LDA and vitamin K (VK) inhibitors at different intensities of anticoagulation, were tried in patients with APS and thrombosis. The observational study by the group of St. Thomas’ Hospital offered the first data in a sizable number of 147 patients (46% with arterial events) distributed in several groups: no therapy, LDA, warfarin at regular intensity (target INR < 3.0), and warfarin at high intensity (INR > 3), both latter groups with or without associated LDA [9] The final conclusions of the study were that the risk of recurrences in untreated patients was unacceptably high and that high-intensity warfarin was the most effective regime, with or without LDA. It is noteworthy that the recurrence rate in the 17 patients treated with combined anticoagulant-antiplatelet therapy was zero. Unfortunately, there was no sub-analysis of patients with arterial events.

This study paved the way for the general use of high-intensity warfarin in the secondary thromboprophylaxis, in general, of APS, at least until the publication of two clinical trials, in 2003 [10] and 2005 [11], both showing no differences between standard and high-intensity anticoagulation, although both studies had the very relevant limitation of the low numbers of patients with arterial disease. Within the next decade, easy agreement was reached for the secondary thromboprophylaxis of venous thromboembolic disease in international consensus in 2011 [12] and 2019 [8], since VK inhibitors given at a target INR 2.0–3.0, like in the general population, are effective in the vast majority of patients with APS.

Secondary thromboprophylaxis of arterial disease was, however, a fully different story. A systematic review published in 2007 showed the higher risk of recurrences of patients with arterial thrombosis treated with standard intensity anticoagulation, frequently in the same vascular bed [13]. In the 2011 consensus document, a target INR > 3.0 was recommended for this group of patients, although no agreement among the members of the panel was reached [12]. In addition, for the first time, the combination of VK inhibitors at an INR 2.0–3.0 with antiaggregants showed up as an alternative to high-intensity anticoagulation (without full consensus either). Such recommendation was based on a small Japanese clinical trial of 20 young patients with APS and stroke, in which combined therapy with warfarin (target INR 2.0–3.0) plus LDA was statistically more effective than LDA alone, with a low frequency and severity of bleeding in both groups [14].

These results were later confirmed by an international observational study of 139 patients with APS and arterial thrombosis, in whom combined anticoagulant/antiplatelet therapy showed the highest efficacy in preventing recurrent thrombosis compared with monotherapy with any of them [15]. Patients on dual therapy with LDA plus VK inhibitors (most of them at an INR 2.0–3.0) had a reduced rate of recurrent events of 6.9% compared to 23.7% and 37.2% in patients on anticoagulant and antiplatelet therapy alone, respectively. The time to recurrence of thrombosis was 16.3 years in the combination group, compared to 7.3 and 3.4 years in the anticoagulant and antiplatelet therapy groups [15]. After this second work, the 2019 EULAR consensus also included the combination of VK inhibitors/LDA as an alternative to oral anticoagulation [8].

Following this line, another Japanese observational study found significantly higher protection against recurrent arterial thrombosis in APS patients treated with antiaggregants plus warfarin compared with those receiving warfarin alone [16], with respective recurrence rates of 3.7 vs. 11.6 per 100 patient-years. However, the group of patients who did best were those treated with double antiaggregation with LDA and clopidogrel, with 1.8 events per 100 patient-years. Albeit retrospective, this is the first study showing the utility of combined antiaggregant therapy in APS.

The aim to overcome the dependence on VK inhibitors has led to several clinical trials with direct oral anticoagulant drugs [17]. Despite the encouraging results of the RAPS trial, comparing thrombin generation in patients with APS and venous thromboembolism treated with rivaroxaban or warfarin [18], the ensuing studies revealed a higher risk of recurrent arterial thrombosis among patients treated with rivaroxaban [19]. Such increased occurrence of mainly cerebrovascular events in the rivaroxaban group led to the early termination of the TRAPS trial [20] and to the modification in the protocol of the apixaban vs. warfarin (ASTRO) trial, by excluding patients with previous arterial thrombosis [21]. As a result, the current 2019 recommendations are against the use of rivaroxaban in patients with triple aPL positivity and of direct oral anticoagulant drugs, in general, in APS patients with arterial events [8].

These apparently unexpected results take the issue again back to platelets, which may play a major role in the possible explanation for the increased frequency of arterial thrombosis in rivaroxaban-treated triple aPL-positive patients. aPL with lupus anticoagulant activity is able to induce platelet aggregation [22], frequently mediated by antiphosphatidylserine/prothrombin antibodies (aPS/PT). Such an activation is dependent on the circulating levels of prothrombin, which are reduced by warfarin but not by direct factor Xa inhibitors [22]. Therefore, since platelet aggregation could play a central role in the occurrence of arterial thrombosis in rivaroxaban-treated patients, the concomitant use of antiplatelet drugs would make sense. Unfortunately, this option has not yet been studied, and, to our knowledge, there are no ongoing studies with a combined direct factor Xa inhibitor/antiaggregant arm. Only one trial (rather a subgroup analysis) has studied dabigatran, a direct prothrombin inhibitor, in APS patients. Unfortunately, all of them had a history of venous but not arterial thromboembolic disease [23].

Taking all the above into account, what is our view regarding the role of antiplatelet drugs for treating arterial thrombosis in APS patients? The combination of VK antagonist at a target INR 2.0–3.0 plus LDA is currently our first option for the secondary thromboprophylaxis of stroke. This is based on the lower efficacy of any of these agents alone, on the difficulty of attaining stable INR levels >3.0 over the time, and last but not least, on the need for effective platelet inhibition given their importance in the pathogenesis of arterial events in APS [2,3]. In patients with coronary heart disease, prolonged double therapy with LDA and clopidogrel could be a good alternative to the VK inhibitors/LDA combination. In selected patients in whom VK inhibitors are not well tolerated or who do not achieve stable levels of INR, combining a direct factor Xa inhibitor with LDA could be an option to consider, despite the lack of more than anecdotal experience. Finally, in patients at high risk for life-threatening bleeding, such as those with extensive periventricular small vessel lesions, we empirically used triple therapy with LDA, statins, and hydroxychloroquine. Hydroxychloroquine has well-proven antithrombotic effects and has been recently found to be a major protective factor against arterial thrombosis in SLE patients with aPL from the Lupus-Cruces cohort [24] and also in patients with primary APS [25]. Statins may also play a role as antithrombotic drugs beyond their lipid-lowering effects in patients with aPL in the clinical setting [26], following the effects shown in experimental studies of decreasing the expression of TF by monocytes [27].

Future treatments for arterial thrombosis in APS will certainly include new drugs. The option of inhibiting the mammalian target of rapamycin complex (mTORC) with drugs such as sirolimus looks promising [4], particularly for patients with non-thrombotic aPL-related vasculopathy (like APS nephropathy), in which this pathway may play a prominent role [4,28]. However, we must not stop implementing further research on new combinations of the current therapeutic armamentarium (VK inhibitors, DOACs, LDA, clopidogrel, hydroxychloroquine, and statins), which, along with new therapies, will hopefully result in more tailored, more effective, and safer approaches to prevent this devastating manifestation of APS.

Declaration of interest

M Khamashta is an employee of GSK and holds stocks and shares in the company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.