Should Direct Oral Anticoagulants (DOAC) be Used in Individuals with Antiphospholipid Syndrome (aPS) vs Long Term Warfarin Treatment?

Posted on: April 14, 2023

David L. McGlasson, MS, MLS(ASCP)

At the recent HTRS 2023 Scientific Symposium, a lively discussion in a Plenary Session was presented titled, “Do We Dare to DOAC?”

The HTRS session was moderated by Ayesha N. Zia MD, MSCS and Bethany T. Samuelson, MD, and included three presenters:

Introduction to Science: Stephan Moll, MD, University of North Carolina School of Medicine
The argument against using DOACs was given by Dr. Mark Crowther, MD, MSc FRCPC FRSC, McMaster University
The argument in favor of using DOACs for treatment of the presence of aPS was delivered by ThomasDeLoughery, M.D., M.A.C.P., FAWM. Oregon Health & Science University, and Sleater Kinney video fame

I have been performing special coagulation work for over 6 decades, yet each year I find myself more confused about the “correct” approach to working up evidence of the presence of Lupus Anticoagulant (LA) / antiphospholipid Syndrome (aPS). Further, the guidelines for how to treat a patient with this condition change frequently and even vary from clinician to clinician so I was particularly drawn to this session. In fact, one of the presenters, Mark Crowther, MD, stated that he knows less about aPS in 2023 than he did in 1993 and I found this statement truly relatable.

These statements and work with LAs reminded me of a statement by one of the greatest minds in blood coagulation history, Doug Triplett, MD, PhD. The late Dr. Triplett paraphrased Winston Churchill in describing a lupus anticoagulant/antiphospholipid antibody as: “a riddle, wrapped in a mystery, inside an enigma.” In other words, a difficult problem to identify and analyze as you will see in the following communication.

With that in mind, it seems that at every meeting I attend, we argue about new issues in LA/aPS testing and treatments, but that we always end up in the same place, or at least the same ballpark. Continue reading for a brief history of LA/aPS and how it is being diagnosed and treated.

Thrombotic aPS are inhibitors that were originally described as lupus anticoagulants (LA) and are now recognized to be part of a more diverse group of inhibitors collectively referred to as antiphospholipid antibodies (APA). They are immunoglobulins of the IgG, IgM, or IgA class against anticardiolipin (aCL) and anti-β2GPI glycoprotein I (aβ2GPI) that are directed against the protein component of protein-phospholipid complexes. In vivo, APAs may be associated with a thrombotic tendency. In vitro, they prolong phospholipid-dependent clotting assays. Thrombotic aPS is an autoimmune disorder with clinical conditions that can include venous, arterial or placental thrombosis issues, with laboratory testing positive occurring at least 12 weeks apart.

The diagnosis of antiphospholipid antibody syndrome (aPS) requires the demonstration of (1) an abnormality of phospholipid-dependent coagulation reactions (LAs), (2) an abnormality that results from the presence of an inhibitor rather than a factor deficiency, and (3) the phospholipid-dependence of the inhibitor. True aPS subjects should also be evaluated 12 weeks later to see if the laboratory findings are persistent,not transient . These LA and solid phase tests are used to evaluate (1) patients with history of recurrent pregnancy loss, venous or arterial thrombosis, (2) as part of the evaluation of autoimmune disorders, and (3) potential cause for elevated APTT (with or without elevated PT).

LA/aPS subjects can be classified as single, double, or triple antibody positive by laboratory testing.

Triple positive: High risk profile consists of the continued presence at 3 months intervals of LA -positive testing. This data displays prolonged phospholipid testing such as the aPTT, DRVVT, presence of an inhibitor that is not factor specific with mixing studies, and overcoming the inhibitor with testing that has excess phospholipid.

Persistent high titers of ACL antibodies (IgG, IgM), β2GPI antibodies (IgG, IgM) is also evidence of a high-risk presence of a triple positive APS.

Double positive: Medium-high risk profile consists of the presence of ACL IgG/IgM in titers >40 GPL or MPL units >99^th percentile or aβ2GPI isotype presence >99^th percentile, both measured by a standard ELISA assay.

Single positive: This profile consists of an isolated ACL test or aβ2GPI isotype at low or medium titers, which may be transiently positive.

NOTE* If LA positive coagulation testing are not transient and still are present after 3 months this can be considered a high-risk marker for the presence of a thrombotic event.

Some recent work has focused on potential therapeutic targets within the immune system that include harnessing the complement system and neutrophil extracellular traps (NETs). Neutrophils play a role in several autoimmune‐associated disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), multiple sclerosis (MS), and Crohn’s disease (CD). In fact, neutrophils play a bidirectional regulatory role in autoimmune‐associated disorders and may serve as a predictor of disease progression. Further, increased knowledge of neutrophils’ features can lead to the development of novel therapeutics.

To date, Vitamin K antagonists (VKAs) such as warfarin remain the preferred drug of choice despite the issues of drug, diet interference, and required monitoring of the prothrombin time/International normalized ratio (PT/INR) and patient compliance issues. Therefore, we are constantly searching for better thromboprophylaxis treatments to replace the current standards of treatments.

In today’s world of coagulation treatments, DOACs are used for long term anticoagulation over Vitamin K antagonists such as warfarin. DOACs are now preferred against for venous thromboembolism (VTE) due to their fixed dosing, safety, and lack of need to monitor with laboratory testing except in special situations, unlike warfarin, which requires testing on a regular basis to stay in the therapeutic range. The suggested therapeutic INR range is between 2.0-3.5, depending on the existing condition. Warfarin still has a failure rate in aPS patients. This could be for many reasons, such as patient compliance. Another issue is that INR tests can be influenced by many different reagent/instrument combinations with different sensitivities of thromboplastins. There is also a difference between mechanical and photo-optic instrumentation measurements, particularly in cases of elevated INRs (>4.0). A solution to this issue may be the chromogenic Factor X assay, which directly measures the level of FX. One can then compare INR to FX level. This has been employed in targeted patient cases.

DOACs are being tested in many random controlled trials to determine if they can provide alternatives to the VKAs, particularly in patients who are at elevated risk with triple-positive aPS.

DOACs have shown a failure rate with individuals who have a mechanical heart valve, atrial fibrillation with mitral stenosis, and aPS. Warfarin remains the drug of choice in these subjects. The DOACs can be used with great success in nonvalvular atrial fibrillation, DVT, and pulmonary embolism (PE), and cancer related DVT/PE patients.

One reason postulated regarding the effectiveness of VKAs over DOACs in certain subjects is that the DOACs are factor-specific targets, either for FIIa (thrombin) or FXa. The VKAs affect FII, FVII, FIX, FX, Protein C, and Protein S. This multi-target approach may be key.

Since 2014, there have been many meta-analysis studies investigating the use of DOACs as the safer, more convenient treatment instead of VKAs such as Warfarin. An excellent paper on this subject looked at studies from 2017 through 2022 using PubMed with special attention to words such aPS, APA, aCL, LA, and aβ2GPI. Some publications deemed relevant outside the timeline parameters were picked based on the relevance of their reference sources. More recent studies were perused more closely based on their randomized controlled trials (RCT) and meta-analyses, mechanistic accuracy, or relevance with well-defined reagent/instrument combinations. The paper on this subject by Khairani et al: Direct Oral Anticoagulants vs Vitamin K antagonists in patients with Antiphospholipid Syndromes JACC 2023. 81(1) 16-30 is recommended reading.

Dr. Crowther and Dr. DeLoughery each brought forth many pros and cons for and against DOACs vs. warfarin. One question we might ask in response to the belief that warfarin was not a great choice in aPS patients due to the failure rate is, how was the dosing for each drug measured.? Triple positive patients had a higher failure rate with DOACs than with warfarin. One might ask, what patients were enrolled? Were certain groups excluded? Were there strict guidelines on the interpretation of results from the LA/APA testing using ISTH or European Congress of Rheumatology guidelines in a standardized manner? Were arterial events excluded in clinical trials?

Dr. DeLoughery argues that DOACs are a viable option for aPS treatment. However, aPS is tricky and can be misdiagnosed. Titers in the ELISA testing may be low positive or the LA tests may not be positive in all assays and repeat studies may not be re-tested. It was noted that “More people think they have aPS than those who have aPS.” There are many risk factors using warfarin such as monitoring, medication interference, availability of testing at a good anticoagulation clinic, erratic INRs especially those that have INRs >4.0.

Therefore Dr. DeLoughery stated the position that DOACs may be used for low titer double and single positive APA subjects with a history of thrombosis. Further, there are many publications that state that if a patient can’t tolerate warfarin, DOACs can be considered.

The question also arose whether the new FXI inhibitors currently in clinical trials could help patients with triple-positive aPS. For a review of these potential anticoagulants, see our previous Clot Club post.

Dr. Crowther presented a case that DOACs may not be the best choice for low-risk patients with aPS (e.g. low double-positive and single positive subjects).

He also stated he thought laboratory testing is lacking, which received applause. To some extent he is right. There is very little standardization of the testing for LA/aPS in the phospholipid dependent testing. The speakers noted, however, that that a new algorithm and app would be appearing that will make a diagnosis more definite.

Other opinions he made I think are valid and thought-provoking. Has anyone ever isolated the antibody (or antibodies) for LA/APA that cause the laboratory testing to be measured? He stated, there is no convincing evidence that antibodies quantitated really cause this disease state. He maintains the aβ2GPI really is not helpful in the diagnosis of this disorder. He stated that clinical evidence is lacking. Due to the lack of standardization of the testing with warfarin, you can’t rely on who is at high risk for using this anticoagulant. Additionally, we have seen in other publications that any INR value >4.0 may be suspect.

Other questions arose, such as, despite the statements in many review studies by meta-analysis and in house protocols, do DOACs really have a high arterial failure rate? Should patients be put on statins to control inflammation? Dr. Crowther said he places patients on hydroxychloroquine. This has been used in many settings to control inflammatory issues. Should we question if meta- analysis may not be accurate? What if aPS was really several multiple diseases? Excellent questions, which require open minds and more research.

Anticoagulation in cases of catastrophic antiphospholipid syndrome (CAPS) was discussed. CAPS has a rapid incidence for thrombosis that can lead to multiorgan shutdown caused by micro-thromboses. This may include at least 3 organ systems with a highly elevated risk of demise (36%). CAPS can mimic other thrombotic inflammatory conditions and must be distinguished from disorders such as thrombotic thrombocytopenia (TTP), heparin induced thrombocytopenia (HIT), and hemolytic-uremic syndromes (HUS). CAPS can be induced by several factors. Some of them are under-anticoagulation, rapid onset of infections, complement regulatory genes, neoplasm, and high-risk vascular surgery incidents. It has been discovered in retrospective that subjects may develop CAPS because they were under-anticoagulated. Their INR values many times were <2.0. This brings up the question about monitoring a patient with the presence of a strong LA inhibitor? How many laboratories test their PT reagent/instrument combination against an LA positive commercial control plasma? I have found no evidence in any laboratory that this verification is performed. The procedure is not on any College of American Pathology check lists. What test can be used to measure the Warfarin effect to get the patient in the therapeutic range of anticoagulation? The chromogenic FX assay can be used here to measure % FX. A discussion on comparing those ranges vs. INR can be found on a previous Clot Club post.

In summary, after writing this blog post, I also am wondering if LA/aPS patients are always getting the best anticoagulation treatments.

SUGGESTED READING:

Arora S, Nair, S, Prabhu R, Avanthika C et al: Role of Direct Oral Anticoagulation Agents as Thrombopholaxis in antiphospholipid Syndrome. 2021.Cureus 13(10): 1-14.

Balaban M, Stannc V, Rincic G Ledinsky M et al: Recurrent venous thrombosis despite ‘optiman anticoagulation therapy’ for antiphospholipid syndrome—could new oral anticoagulants solve the problem? 2010. Acta Clin Croat;49(4):469-77.

Cerda P, Becattini C, Inarte, A, Cortes Hernandez J et al: Direct oral anticoagulants versus vitamin K antagonists in antiphospholipid syndrome: A meta-analysis. Eur J Intern Med. 2020;79:43-5-

Chantarangkul V, Peyvandi F, Tripodi A, Investigating Group. Effect of different methods for outlier detection and rejection when calculating cut off values for diagnosis of lupus anticoagulants. Thromb Res 2020. 190:20-25.

Cohen H, Efthymiou, M Devreese KMJ. 2020. Monitoring of anticoagulation in thrombotic antiphospholipid syndrome. J of Thromb and Haemostasis. 2021.:892-908

Cohen H, Dore CJ, Clawson S, Hunt BJ et al: Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban bersus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE. Lupus 2015; 24:1087-1094.

Cohen H, Efthymiou M, Isenberf DA. Use of direct oral anticoagulants in antiphospholipid syndrome. J of Thromb and Haemostasis 2018. 16:1028-1039.

Crowther MA, Jones AE Witt DM. Warfarin Is the Preferred Therapy for Patients With Thrombotic APS. Editorial Comment. JACC. 2023. 81(1)31-33.

Crowther MA, Ginsberg JS, Julian J, Math M et al: A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. NEJM 2003.;349:1133-1138.

Dufrost V, Risse J, Reshetnyak T, Satybaldyeva M et al: Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev 2018;17(10):1011-1021.

Dufrost V, Wahl D, Zuily S. Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials. Autoimmun Rev 2021;20(1):102711.

Elesbaie MT, Van Es N, Langston A, Bullert et al: Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta-analysis. J of Thrombosis and Haemostasis. 2019.;17:645-656.

Francke B, Luxembourg B, Heidinger K, Kemkes-Matthes B. Direct oral anticoagulants in patients with antiphospholipid syndrome: a retrospective study in a rea-life patient cohort. Blood Coagul Fibrinolysis. 2022;33(3)184-187.

Giarretta I, Ageno W, Dentali F. Letter to the Editor. Lack of efficacy of direct oral anticoagulants compared to warfarin in antiphospholipid antibody syndrome. Haematologica 2022; 107:2737-2341.

Gullapalli K, Prasad RM, Al-abcha A, Hussaid Z et al: Efficacy and Safety of Direct Oral Anticoagulants in Patients with Antiphospholipid Syndrome: A systematic Review and Meta-Analysis. Cureus. 2022; DOI:10.7759cureus.29449.

Khairani CD. Bejjani AB, Piazza G, Jimenez D. Direct Oral Anticoagulants vs Vitamin K antagonists in Patients With Antiphospholipid Syndromes. Meta-Analysis of Randomized Trials. J Am Coll Cardiol. 2023;81(1):16-30.

Knight JS, Branch DW, Ortel TL. Antiphospholipid syndrome: advances in diagnosis pathogenesis, and management. BMJ. 2023;380: e069717.

Koval N, Alves M, Placido R, Almeida AG et al: Direct oral anticoagulants versus vitamin K antagonists in patients with antiphospholipid syndrome: systematic review and meta-analysis. RMD open 2021;7: e001678

Kreuziger-Baumann LM, Datta YH, Johnson AD. Monitoring Anticoagulation in Patients with an Unreliable PT/INR: Factor II vs Chromogenic Factor X Testing. Blood Coagul Fibrinolysis 2014;25(3):232-236.

Liu A, Karishma VR, Naymagon L. Direct oral anticoagulants versus warfarin in patients with single antibody-positive anti-phospholipid syndrome. Eur J Haematol 2022:109(1):69-74.

McGlasson DL, Hickman JR, More LE, Best HA, Jacobs LO, Brickey DA, Doe RH. Discrepancies in International Normalized Ratios (INR) in Swine and Humans. Clin Lab Sci,1(3) 1998, pg. 156-160.

McGlasson, DL, Brickey DA, Doe RH. Oral anticoagulant Therapy and International Normalized Ratios in Swine. Lab Animal Sci, 48(4), Aug, 1998. Pg. 371-373.

McGlasson DL. Laboratory Variables That May Affect Test Results in Prothrombin Times (PT)/International Normalized Ratios (INR). Lab Med Feb 2003(2)34:124-129.

McGlasson DL, Romick BG, Rubal BL. Comparison of a chromogenic factor X assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagulation and Fibrinolysis 2008. 19(6):513-517.

https://diapharma.com/news-and-events/chromogenic-factor-x-assays-vs-the-pt-inr-to-monitor-subjects-on-coumadin-therapy-when-an-individual-approach-is-necessary/ McGlasson DL 2022

https://diapharma.com/news-and-events/the-chromogenic-factor-x-assay-cfx/ McGlasson DL 2019

Memon MM, Siddiqui AA, Amin E, Shaikh FN et al: Novel oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation after transcatheter aortic valve replacement: A systematic review and meta-analysis. Catheter Cardiovasc Interv 2022:1-10.

Ordii-Ros J, Saez-Comet L, Perez-Corona M, Vidal X et al: Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A randomized Noninferiority Trial. Ann Intern Med. 2019;171(10):685-694.

Pastor D, Menichelli D, Cammisotto V, Pignatelli P. Use of Direct Oral Anticoagulants in Patients With Antiphospholipid Syndrome: A Systematic Review and Comparison of the International Guidelines. Frontiers in Cardiovascular Medicine 2021;8;715878.

Resseguier AS, Pereira B, Rieu V, Guenno G Le. Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome? Lupus 2017.26(12):1297-1303.

Sanchez-Redondo J, Espinosa G, Delgado DV, Cervera R. Recurrent Thrombosis With Direct Oral anticoagulants in Antiphospholipid Syndrome: A Systematic Literature Review and Meta-analysis. Clin Ther 2019;41(9)a:1839-1862.

Stammler R, Nguyen Y Yelnik C, LeGuern V et al: Precipitating factors of catastrophic antiphospholipid syndrome: the role of anticoagulant treatment in a series of 112 patients. J Thromb Haemost 2023;1-8.

Tektonidou MG Andreoli, Limper M, Amoura Z et al: EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78:1296-1304.

Wu X, Cao S, Yu B, H Tao. Comparing the efficacy and safety of direct oral anticoagulants versus Vitamin K antagonists in patients with antiphospholipid syndrome: a systematic review and meta-analysis. Blood Coagulation and Fibrinolysis 2022.;33:389-401.

Clot Club, ML-01035Rev01