Antithrombotic Treatment in Antiphospholipid Syndrome: A Review

Abstract

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid-binding proteins. APS is an autoimmune disorder associated with recurrent thrombosis of arterial or venous vessels and/or recurrent obstetric complications as miscarriages. APS can be divided into primary or secondary clinical syndrome because of the possible association with other autoimmune systemic diseases as systemic lupus erythematosus (SLE). Vitamin K antagonists remain the mainstay of treatment for most patients with APS and, based on current data, appear superior to the more targeted direct oral anticoagulants. However, the choice of the type of antithrombotic drug is based on the anamnesis of affected patients: patients with previous arterial or venous thrombosis may benefit from anticoagulants, while patients with previous obstetric diseases may benefit from aspirin, but several clinical exceptions may be evaluated. This short review is dedicated to underlining the main clinical evidence for patients affected by APS or CAPS (catastrophic antiphospholipid syndrome) in order to prevent recurrent thrombosis.

1. Introduction

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid-binding proteins [1]. APS is an autoimmune disorder associated with recurrent thrombosis of arteriolar venous vessels and/or recurrent obstetric complications as miscarriages [2]. APS can be divided into primary or secondary clinical syndrome because of the possible association with other autoimmune systemic diseases as systemic lupus erythematosus (SLE) [3]. Sometimes it may appear as a catastrophic antiphospholipid syndrome (CAPS) with poor response to medical treatment [3]. Although antiphospholipid syndrome was first recognized in patients with SLE, the presentation as primary antiphospholipid syndrome is at least equally common. Overall, the diagnosis appears to affect at least one in 2000 people [4,5]. Vitamin K antagonists remain the mainstay of treatment for most patients with APS and, based on current data, the role of direct oral anticoagulants should be better investigated. However, the choice of the type of antithrombotic drug is based on the anamnesis of affected patients: patients with previous arterial or venous thrombosis may benefit from anticoagulants, while patients with previous obstetric diseases may benefit from aspirin, but several clinical exceptions may be evaluated.

The estimated population prevalence of antiphospholipid syndrome is between 40 and 50 cases per 100,000 [4,5]. Antiphospholipid syndrome is typically diagnosed in relatively younger individuals, with just 12.7% of patients diagnosed after the age of 50 in one study of 1000 patients [6]. The epidemiology of antiphospholipid syndrome remains understudied, and population-based studies of patients with diverse ages and ethnic backgrounds are needed. This short review is dedicated to underlining the main clinical evidence for patients affected by APS or CAPS in order to prevent recurrent thrombosis.

2. Diagnosis

APS can manifest in its original form (primary APS) or in conjunction with other autoimmune illnesses, primarily systemic lupus erythematosus (SLE) [7,8,9,10,11,12]. The Sapporo categorization criteria for APS were revised in 2006 during the Eleventh International Congress on Antiphospholipid Antibodies in Sydney [7,13]. Patients must meet both clinical and laboratory criteria in order to be diagnosed with APS. Moreover, they must encompass obstetric morbidity, which includes an unexplained death of one or more morphologically normal fetuses at or after the 10th week of gestation, three or more unexplained, consecutive spontaneous abortions before the 10th week of gestation, and the premature birth of one or more morphologically normal neonates before the 34th week of gestation [7,8,9,10,11,12,13]. The most frequent venous events are pulmonary embolism, lower-extremity deep vein thrombosis, or both, whereas the most frequent arterial events are transient ischemic attack and stroke. The Sydney classification scheme states that the laboratory criteria include the following: an LA detected in accordance with the International Society on Thrombosis and Hemostasis guidelines [14,15], antibodies (IgG or IgM) that are greater than 40 IgG or IgM antiphospholipid units, or anti-β2GPI antibodies (IgG or IgM) that are measured by an enzyme-linked immunosorbent assay (ELISA) at levels greater than the 99th percentile. Additionally, it is advised to conduct assays twice, at least twelve weeks apart, to reduce the possibility of diagnosing transient APLA [14,15]. Patients who test positive for APLA, however, might not exhibit any associated symptoms. These patients are typically found when they are being evaluated for other issues such systemic autoimmune illnesses, early miscarriages, and an elevated activated partial thromboplastin time.

3. Aspirin

Low doses of aspirin are usually the first choice for secondary prevention of thrombosis in patients with SLE and associated APS without anamnesis of previous thrombotic events [16]. In this clinical setting, in fact, there is evidence that aspirin slows down the appearance of the first thrombotic event. Yet, the same role of aspirin for primary prevention of thrombotic events in primary APS is still a matter of discussion [17]. Retrospective studies suggest that this preventive role has been found while prospective studies did not confirm this role [18].

On the other hand, low doses of aspirin are the first choice of treatment for APS in patients with a clinical history of obstetric complications (OAPS). In particular, pregnant women with previous evidence of antiphospholipid antibodies and a history of recurrent miscarriages found benefit if treated with aspirin [19]. In this clinical setting, low doses of aspirin may need to be changed in case of further miscarriage during treatment or in case of previous thrombosis. The change may be based on increased doses of aspirin or on the association of aspirin with heparins [19,20]. Furthermore, increased doses of aspirin may be useful in women with associated SLE and/or clinical evidence of only obstetric troubles (early miscarriages, late fetal death, intrauterine growth restriction) [20]. The association of aspirin and heparin needs to be considered, also, for pregnant patients with previous thrombosis ongoing oral anticoagulation (warfarin or DOACs) that is less useful during pregnancy. Regarding doses of heparins, a specific paragraph will be dedicated to this topic. Furthermore, in the case of aspirin intolerance, clopidogrel may be used for the antithrombotic prevention of any type of APS but not for OAPS, and in this case, a switch from clopidogrel to heparin is needed during pregnancy [18].

4. Low-Molecular-Weight Heparins

Usually, low-molecular-weight heparins (LMWHs) are used to start anticoagulant treatment in case of venous thromboembolism, while long-term treatment is usually performed with oral drugs as warfarin or direct oral anticoagulants (DOACS). Clinical experience for long-term treatment of venous thromboembolism (VTE) with LMWHs is available only for cancer patients because LMWHs were first choice for several years [21]. Therefore, clinical experience in long-term treatment of VTE in non-oncological patients is not supported by randomized clinical trials or specific guidelines.

However, sometimes long-term anticoagulant treatment with warfarin or anti-vitamin k drugs may be difficult because some laboratory interference or because some reduced absorption or abnormal liver metabolism as in severe CAPS [11]. For this reason, long-term treatment with LMWHs has been suggested in small cohorts of patients with APS or case series [22,23]. In these reports, therapeutic doses or over-therapeutic doses of LMWHs seem to be safe but recurrent VTE occurs in an insignificant number of cases.

For these reports, LMWHs are considered together with warfarin to be the most useful antithrombotic drugs for APS [24,25].

Reported data seem to be positive because of the low incidence of recurrent thrombotic events, in particular venous thrombosis, but no improvements in quality of life have been reported [23,24].

Long-term treatment with LMWHs during pregnancy has been reported as safe and effective with an increase in live births [26]. Furthermore, prophylaxis of thrombosis after delivery with LMWHs is suggested for 6 weeks. These clinical data support the in vitro reports that provided an important mechanism by which LMWHs are able to prevent the aPL-mediated placental damage in OAPS [27].

5. Fondaparinux

Limited evidence exists to guide the therapeutic anticoagulation in patients with thrombotic antiphospholipid syndrome (APS) with fondaparinux.

Case reports or rare case series are available in the literature.

Holtan et al. described a case in which in acute phase recurrent VTE in a patient with APS, therapeutic doses of fondaparinux are safe and effective [28].

Sayar et al. reported a small series in which therapeutic doses of fondaparinux in patients with recurrent thrombosis for APS did not show effectiveness because of the occurrence of recurrent VTE during long-term treatment. On the other hand, in the same series bleedings were not reported, therefore therapeutic doses of fondaparinux were safe in this clinical setting [29].

Yet, Tanguay et al. reported safe and effectiveness of therapeutic doses of fondaparinux for long-term treatment of several patients with APS and recurrent VTE [30].

Due to these non-concordant clinical reports, therapeutic doses of fondaparinux are considered by expert physicians only in patients with APS and recurrent VTE [31].

6. Unfractioned Heparin (UFH)

UFHs were used in a large part of patients with VTE before the great impact in clinical practice of LMWHs. Yet during the management of patients with VTE and APS. UFH at therapeutic doses usually prolong activated partial thromboplastin time (aPTT) and because of both antiphospholipid antibodies and lupus anticoagulant may prolong phospholipid-dependent coagulation tests such as the activated partial thromboplastin time (aPTT), the hemorrhagic risk of these patients was very difficult to treat in daily clinical practice [32]. For this reason, actually UFHs are not considered for acute phase treatment or long-term treatment of patients with APS and thrombotic complication.

7. Direct Oral Anticoagulants

In this setting of patients, the use of VKAs (vitamin K antagonists) is difficult to assess. This was due not only to the numerous food–drug interactions and the frequent monitoring but also to the direct effect of LA (lupus anticoagulant) on the INR (international normalized ratio) [33]. For this, as seen theoretically, direct oral anticoagulants (DOACs) are an attractive alternative. A high rate of thrombotic stroke was observed in six patients randomly assigned to apixaban (318 events per 1000 person–years) and in no patients assigned to warfarin, according to a prospective randomized controlled pilot study on the rates of thrombosis and bleeding events among APS patients receiving either apixaban or warfarin, which was conducted over a 12-month follow-up period [32]. These results are consistent with other reports from prospective randomized clinical studies that compared VKA and rivaroxaban in patients with APS. Pengo et al. carried out a randomized study enrolling 536 triple-positive APS patients. In this study, 7 out of 59 patients randomly assigned to rivaroxaban developed arterial thrombosis compared to none on warfarin [33,34,35]. A non-inferiority randomized control trial comparing rivaroxaban 20 mg daily with warfarin (target INR 2.5 or 3.5 among those with a history of recurrent thrombosis) in APS patients was reported by Ordi-Ros et al. In a follow-up period of 36 months, patients in the rivaroxaban group experienced a thrombosis rate of 3.9%, while the VKA group experienced a rate of 2.1% (risk ratio 1.83 [95% CI, 0.71–4.76]). This did not reach the predetermined non-inferiority margin of 1.4. Nine patients who were randomly assigned to rivaroxaban experienced a stroke, while none of the participants assigned to VKA died [23]. The labeling of all DOACs was modified by US and European regulatory bodies in May 2019 to discourage usage in patients with APS, particularly those who are triple-positive, in light of these findings [16]. Acceptable safety profiles for DOACs with minimal rates of recurrent thrombosis were described by three case series involving 69 patients with thrombotic APS [36,37,38,39,40]. However, there are serious doubts regarding the effectiveness of DOACs because previous trials have shown a high prevalence of recurrent thrombosis, including arterial events, in patients with thrombotic VTE who switched to them. However, DOACs are not always advised for these patients; instead, they should only be used for those who are intolerant or refractory to low-molecular-weight heparin or VKA. Patients who have a clear contraindication to VKA (allergy or intolerance) or who are unable to reach a target INR even with adequate VKA adherence may be candidates for DOACs in the interim. Particularly when considering arterial thrombosis and triple-positive aPL patients, the current international guidelines do not support the recommendation of DOACs for the secondary prevention of thrombotic APS. The use of DOACs in the other clinical situations (VTE) or aPL profiles (e.g., single or double positive) is hotly contested, and further research is required to elucidate their effectiveness [36,41].

8. Warfarin

Considering the high incidence of recurrent thrombosis in individuals with APS, the standard of therapy for patients who develop thrombosis is long-term anticoagulation with a vitamin K antagonist (VKA) [42]. Patients with persistent APLA had a 40% higher rate of recurrent thrombosis after stopping anticoagulation than patients with venous thromboembolism (VTE) unrelated to APLA [unadjusted relative risk 1.4 (95% CI 0.99–2.36)], according to a systematic review of eight prospective studies of patients with a first APS-related thrombotic event [43]. However, when receiving therapeutic anticoagulation with any kind of medication, a considerable percentage of individuals with APS experience recurrent thrombosis [44,45]. A special mention should be given to patients who have only tested positive for LA. In the Vienna APS project, a prospective observational cohort of patients with or without thrombosis who tested positive for LA had a greater 10-year death rate (cumulative relative survival of 87%) than a reference sample that was matched for inclusion year, sex, and age [46]. However, the international normalized ratio (INR) in patients on lupus anticoagulant (LA) may be highly dependent on the thromboplastin utilized in the test because of the subtle effects of LA on the INR [47]. According to one study, in which therapeutic ranges were directly evaluated using a chromogenic factor X assay, almost 10% of patients with LA treated with VKA might have an erroneously increased INR [48].

9. Biologic Therapy

Recent data highlight the potential effectiveness of biologics that can fight the autoimmune response linked to the production of APLA, including anti-CD38 monoclonal antibody (Daratumumab), BAFF/Blys inhibitor (Belimumab), BTK inhibitor (Zanubrutinib), and anti-tumor necrosis factor monoclonal antibody (adalimumab, certolizumab) [49]. Although anticoagulation is still the primary treatment for APS, studies examining comparable clinical outcomes on long-term treatment with biologics, with or without associated anticoagulants, are scarce in the literature. However, the specificity of biologics makes them promising options for the development of more appropriate tailored therapies.

10. Management of Obstetric Antiphospholipid Syndrome

Optimizing maternal and fetal pregnancy outcomes is the primary goal of surveillance and therapy for pregnant women with APS, who are considered to be in a “high-risk pregnancy”. Obstetrical APS management is still debatable. For women who fulfill the clinical and serologic criteria for obstetric APS, the most common treatment, supported by the American College of Chest Physicians guidelines, is the combination of low-dose aspirin (75–100 mg) daily and heparin (unfractionated or low molecular weight; prophylactic or intermediate dose). Seventy-one percent of pregnancies treated with aspirin in combination with either heparin or low-molecular-weight heparin (LMWH) had live births, according to prospective observational research [50]. Despite using varying amounts of heparin, two randomized studies comparing aspirin with unfractionated heparin showed a higher incidence of live births when compared to aspirin alone [51,52]. Aspirin and LMWH at the therapeutic dose should be used in women with APS and a history of thrombosis. Since warfarin has been connected to fetal abnormalities, women taking VKA as an anticoagulant should be switched to LMWH.

11. Discussion

The optimal antithrombotic secondary prevention of thrombosis in patients with APS is still a challenge. Differences should be performed for primitive APS or secondary APS but the most of pharmacological treatment is based on antithrombotic drugs with a particular attention for anticoagulants [11,12].

In last years, improvements about safety of available anticoagulant drugs as warfarin and low-molecular-weight heparins have been reported in several reports and suggested by expert panels and guidelines. Yet a considerable number of recurrences and bleedings complications are still reported despite thorough clinical surveillance.

Similar evidence in a number of cases is available for long-term anticoagulation with fondaparinux in patients with APS.

On the other hand, the use of DOACs in this clinical setting showed a failure in the treatment and prevention of atherosclerotic complications, such as myocardial infarction and stroke with acceptable effectiveness in prevention of recurrent VTE.

Regarding the prevention of abortion during OAPS, the combined use of low doses of aspirin plus prophylactic doses of LMWH seem to be associated with an increase in live births with a significant reduction in recurrent abortion.

However, supplementary future studies are needed on this topic. One of the most important points of interest is the role of DOACs in this setting of patients for their lower risk of bleeding. However, at time, we have a large clinical trial planned especially in patients treated with DOACs and in minimal part on the use of LMWHs, fondaparinux and warfarin.

Furthermore, data regarding main clinical outcomes when anticoagulants are associated with other drugs as low doses or full doses of steroids, hydroxychloroquine, low doses of immunomodulants or biological treatments are lacking on large cohorts.

Table 1. Therapeutic approach to APS.

Aspirin, low dose (100 mg/die)	Low doses of aspirin are usually the first choice for secondary prevention of thrombosis in patients with SLE and associated APS Low doses of aspirin are the first choice of treatment for APS in patients with clinical history of obstetric complications (OAPS).
Low-molecular-weight heparin (LMWH)	Used to start anticoagulant treatment in case of venous thromboembolism Long-term treatment with LMWHs during pregnancy has been reported as safe and effective with increase in live births.
Fondaparinux	therapeutic doses of fondaparinux are considered by expert physicians only in patients with APS and recurrent VTE.
Unfractioned heparin (UFH)	UFHs are not considered for acute phase treatment or long-term treatment of patients with APS and thrombotic complication.
Direct oral anticoagulants	The current international guidelines are not in favor of recommending DOACs for secondary prevention of thrombotic APS.
Warfarin	Vitamin K antagonist (VKA) is the standard of care.
Biologic therapy	New evidence underlines the potential efficacy of biologics such as anti-CD38 monoclonal antibody (Daratumumab), BAFF/Blys inhibitor (Belimumab), BTK inhibitor (Zanubrutinib), Anti-TNF-a monoclonal antibody (adalimumab, certolizumab).

summarizes the main therapeutic approach.

12. Conclusions

In conclusion, autoantibodies that identify phospholipids and phospholipid-binding proteins on the cell surface induce antiphospholipid syndrome, a thrombo-inflammatory autoimmune illness. This raises the risk of thrombotic events, pregnancy problems, and other inflammatory or autoimmune diseases. According to the available evidence, vitamin K antagonists continue to be the best course of treatment for the majority of individuals with thrombotic antiphospholipid syndrome and seem to be more effective than direct oral anticoagulants. Recent studies have identified the complement system and NETs as new possible therapeutic targets within the innate immune system, in addition to anticoagulants and antiplatelets.