Page 56 - Haematologica March 2020

P. Pignatelli et al.
atrial fibrillation (AF). Thus, APS patients had a shorter time within the therapeutic range than those with AF (53.5% vs. 68%; P=0.001) and needed a higher mean weekly dose of warfarin to reach the therapeutic range.10
In the case of low-quality therapy with warfarin or recur- rent thrombosis, two possible therapeutic approaches could be considered. The first is to adopt a higher intensity war- farin therapy with target INR 3-4, which is, however, not current practice given its association with a reduced risk of thrombosis in the majority of patients.6,72,75 A second approach is represented by the addition of LDA to antico- agulation, which should, however, be reserved for high- risk patients, particularly after an arterial thrombotic event.6,76
More recently, non-vitamin K antagonist oral anticoagu- lants (NOAC) have been investigated in patients with APS with divergent results.77 Following the results from the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS),78 which included triple positive thrombotic APS, rivaroxaban is contraindicated in APS patients with triple aPL positivi- ty.72 An analysis from the RE-COVER/RE-COVER II and RE-MEDY trials showed similar safety and efficacy of dabi- gatran in patients with thrombophilia and previous venous thromboembolic events, in whom APS represented the sec- ond most common inherited disorders, accounting for 20% of all patients.79 These results need to be confirmed in real- world studies. A randomized trial investigating the efficacy and safety of apixaban in APS patients is currently ongo- ing;80 this study will include patients with both venous and arterial thrombosis. Laboratory testing of NOAC may be useful in patients with APS as no pre-clinical data in this patient population are available.
Recently, new drugs have been administered in APS patients with thrombotic events. A first example is repre- sented by mTOR inhibitors; these were found to reduce the onset of new vascular lesions after transplantation in patients with APS nephropathy.81 Monoclonal antibodies such as rituximab82 (anti-CD20 agent) and eculizumab23 (anti-C5 agent) are currently administrated to manage non- criteria symptoms refractory to standard therapy and to add-on in catastrophic APS and kidney transplantation in APS patients, respectively. Despite these findings, the use of these drugs should be avoided due to lack of strong evidence in APS patients; their use could be considered in patients with refractory C-APS, as suggested by EULAR guidelines.72
Obstetric antiphospholipid syndrome
Women who are diagnosed with confirmed APS should
be treated with antepartum administration of prophylac- tic or intermediate dose of unfractionated heparin or pro- phylactic LMWH combined with LDA (75-100 mg/day), according to the 2012 American College of Cardiology (ACC) guidelines.74
Recent 2019 EULAR recommendations suggest that women: 1) with a history of obstetric APS, such as a his- tory of ≥3 recurrent spontaneous miscarriages <10th week of gestation and in those with a history of fetal loss (≥10th week of gestation); and 2) with a history of delivery <34 weeks of gestation due to eclampsia/severe pre-eclampsia or due to placental insufficiency, should be started on a combined therapy including LDA and prophylactic heparin during pregnancy.72
Heparin at prophylactic dose should be maintained for six weeks after delivery to avoid maternal thrombosis. Finally, heparin should be increased to therapeutic doses, in addition to LDA, in women with a history of throm- botic APS.
Conclusions
The diagnosis of SN-APS should be formulated only after the exclusion of other causes of inherited and acquired thrombophilic conditions. Although several dif- ferent antibodies to a number of antigens are involved in SN-APS, the routine testing of these non-criteria antibod- ies is not recommended, but may be considered in patients with a high clinical suspicion of APS, such as those presenting with recurrent unexplained thrombosis, thrombosis at unusual sites, or women with recurrent pregnancy-related complications. The assessment and interpretation of these non-conventional antibodies should be performed by specialized centers of hemostasis and thrombosis to reduce laboratory variability.
The detection of non-criteria aPL may help guide antithrombotic strategies in SN-APS patients with arterial or venous thrombosis. As an example, patients treated with NOAC for recurrent VTE events, who become posi- tive for non-criteria aPL, may be switched to VKA or LMWH, especially in cases of a recurrent thrombotic events. Moreover, in case of an unprovoked DVT, and among patients who could be withdrawn from anticoagu- lation, the positivity for a non-criteria aPL may help decide whether or not to continue long-term anticoagulation.
In conclusion, there is growing evidence to suggest a role for non-criteria aPL in those patients defined as “seronegative”.
References
1. Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7(6):330-339.
2. Andreoli L, Chighizola CB, Banzato A, et al. Estimated frequency of antiphospholipid antibodies in patients with pregnancy mor- bidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken). 2013;65(11):1869-1873.
3. Hughes GR. Thrombosis, abortion, cerebral
disease, and the lupus anticoagulant. Br Med
J (Clin Res Ed). 1983;287(6399):1088-1089. 4. Duarte-Garcia A, Pham MM, Crowson CS, et al. The Epidemiology of Antiphospholipid Syndrome. A Population- Based Study. Arthritis Rheumatol. 2019;71
(9):1545-1552.
5. Hughes GR, Khamashta MA. Seronegative
antiphospholipid syndrome. Ann Rheum
Dis. 2003;62(12):1127.
6. Garcia D, Erkan D. Diagnosis and
Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;378(21): 2010-2021.
7. Limper M, de Leeuw K, Lely AT, et al.
Diagnosing and treating antiphospholipid syndrome: a consensus paper. Neth J Med. 2019;77(3):98-108.
8. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for defi- nite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306.
9. Lopez-Pedrera C, Barbarroja N, Jimenez- Gomez Y, et al. Oxidative stress in the pathogenesis of atherothrombosis associat- ed with anti-phospholipid syndrome and systemic lupus erythematosus: new thera- peutic approaches. Rheumatology (Oxford). 2016;55(12):2096-2108.
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