Rothschild B (2020) Antiphospholipid Antibody-Related Problems, the Orphan Child of Medicine. J Rheum Dis Treat 6:085.

Commentary | OPEN ACCESS DOI: 10.23937/2469-5726/1510085

Antiphospholipid Antibody-Related Problems, the Orphan Child of Medicine

Bruce Rothschild*

Department of Medicine, IU Health, USA


Thromboembolic disease, Antiphospholipid antibodies, COVID-19, Anticoagulation

Failure to routinely recognize and/or treat immunologic sources of thromboembolic disease has undermined our ability to improve the quality of life of the patients we serve and even compromised their survival. It's time to bring it into the mainstream. Explanation for persistence of related oversights and potential resolution is presented.

Thromboembolic disease is so common that it is typically treated without workup for underlying processes (other than hyperlipidemia, diabetes, and sometimes for elevated homocysteine levels). Thromboembolic disease complicates surgical procedures, in which it often seems resistant to conventional prophylactic and therapeutic interventions. There is a litany of metabolic derangements that can stimulate thromboembolic activity. These includes, but are not limited to abnormal or deficient Protein C, Protein S, prothrombin, homocysteine, Factor V Leiden, antithrombin III, disseminated intravascular coagulation. These seem relatively rare and their presence could not be invoked to explain the high population prevalence of thromboembolic disease. There is another cause, which actually is commonly present, immunologic, related to antiphospholipid antibodies [1,2].

One of the challenges created by identification of a disorder new to medical diagnosis is that its initial recognition is generally based on extreme manifestations. Catastrophic antiphospholipid syndrome was one such entity. It was/is the tip of the iceberg related to antiphospholipid-related disease. As the most flagrant manifestations of disease are most "newsworthy," lesser manifestations receive less attention and the spectrum of disease effects may not receive deserved attention. It is perhaps not surprising that antiphospholipid antibodies have been associated with increased thromboembolic events immunologic disorders such as systemic lupus erythematosus [1,3], dermatomyositis [4], scleroderma [5], rheumatoid and psoriatic arthritis [5] and vasculitis [5]. However, they are also commonly present in individuals with thromboembolic disease, including strokes and myocardial infarctions [1,2]. Perhaps not as widely known is their association with certain infections (syphilis, malaria, Lyme disease and viral infections, including hepatitis C and human immunodeficiency virus (HIV) [6-10]. Such antibody induction has been documented as a post-surgical phenomenon [11].

While presence of antiphospholipid antibodies has been recognized in the above-mentioned disorders, there are other circumstances in which their presence would explain therapeutic failures (Table 1). COVID-19 could be added to this list, given associated thromboembolic disease and anticoagulation failures. Verification of their presence would offer an opportunity for more effectively intervention.

Table 1: Publications decrying the resistance of thromboembolic disease to medical intervention. View Table 1

Could antiphospholipid antibodies (which are not rare [1]) be responsible for the above-delineated failures, as prophylaxis with the very convenient low molecular weight heparins and factor Xa antagonists have not proven effective [19] in the presence of antiphospholipid antibodies? Thrombotic event prevention in their presence requires utilization of either unfractionated heparin [20], high doses warfarin (producing prothrombin time INR of 3.0-3.5 [21] (with lesser doses generally ineffective) or antiplatelet-based strategies which reduce their function as inducers of thrombosis. The efficacy of the latter intervention suggests, at least in the post-transcatheter aortic-valve replacement study [13], that antiphospholipid antibodies were present.

When disorders are associated with significant thromboembolic phenomena, it seems reasonable to prospectively identify their antiphospholipid antibody status. Given the implications for choice of medication and dosage, identifying their presence would be expected to have a major impact on medical intervention decisions. So, what should be measured? Perhaps the most reasonable approach is to assess for presence of IgG, IgM and IgA antibodies to anticardiolipin and to beta-2-glycoprotein I (BGPI I) and antibodies to anti-phosphatidylserine/prothrombin and for the lupus anticoagulant [2]. Studies to detect IgA anti-beta-2-GPI I, AnxA5 R and IgG aDI are of particular interest because they have shown potential in the pathogenesis of antiphospholipid syndrome. However, more studies, especially prospective ones, are needed to confirm these findings [22]. Caution must be considered if vitamin K antagonists are in use as they alter assessment for the lupus anticoagulant.

Antiphospholipid antibody related problems are quite insidious, far outside standard diagnostic algorithms and therefore routinely evade consideration. Algorithms are the basis and the bane of medical practice. Habits are cultivated/developed for assessing information and for its application. Most physicians have a personal litany of standardized questions related to specific patient concerns, symptoms or signs. Our review of systems is also standardized, whether for generic assessment or limited to specific diagnostic considerations. The physical examination we perform follows a personal template, whether incorporating a full examination or targeting select systems. Sometimes referred to as a search image, our technique for examination of laboratory and radiologic studies similarly follows a template, whether conscious or unconscious. It must be noted that this is medical practice by habit, even rote. That is good medicine and assures that distractions don't compromise our evaluations.

One aspect of medical care relates to recommending/stimulating patient's development of new habits or modifying those which are ingrained. We have learned how difficult it is to modify or induce new behaviours, whether related to diet, tobacco or other drug usage. We are no different than the patients we serve in facing the challenge of altering algorithms/search images to accommodate new diagnostic or therapeutic issues and implications.


Perhaps it is time to initiate a new paradigm, time, to adopt and take responsibility for orphan diseases? It's time to bring antiphospholipid antibodies into the mainstream. They are an often overlooked source of some of the most common clinical events. Our clinical algorithm could be enhanced by assuming that everyone with thromboembolic disease has antiphospholipid antibodies and assuring that our evaluation algorithm is revised to require proactive disproval of their presence. It is obvious that not all individuals with thromboembolic disease have antiphospholipid antibodies, but the prevalence is not insignificant (15-33%). However, their role will be missed if the possibility is not routinely considered and tested.

As the goal is prevention as well as treatment of thromboembolic events, historical recurrence is an indication for long-term treatment. Treatment for the first episode (attributable to antiphospholipid antibodies) should probably continue for the duration of antibody persistence, an approach which requires further study.

Conflict of Interest

There are no financial associations or other possible conflicts.


  1. Garcia D, Erkan D (2018) Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 378: 2010-2021.
  2. Sciascia S, Sanna G, Khamashta MA, Cuadrado MJ, Erkan D, et al. (2015) The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: A systematic review. Ann Rheum Dis 74: 2028-2033.
  3. Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris AE, et al. (2015) Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: A newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol 67: 2990-3003.
  4. Moshtaghi-Svensson J, Lundberg IE, von Euler M, Arkema EV, Holmqvist M (2019) The risk of ischemic and hemorrhagic stroke in patients with idiopathic inflammatory myopathies: A Swedish population-based cohort study. Arthritis Care & Res 71: 970-976.
  5. Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM (2010) Diagnosis and management of the antiphospholipid syndrome. BMJ 340: 2541.
  6. García Moncó JC, Wheeler CM, Benach JL, Furie RA, Lukehart SA, et al. (1993) Reactivity of neuroborreliosis patients (Lyme disease) to cardiolipin and gangliosides. J Neurol Sci 117: 206-214.
  7. Leroy V, Arvieux J, Jacob MC, Maynard-Muet M, Baud M, et al. (1998) Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol 101: 468-474.
  8. Prieto J, Yuste JR, Beloqui O, Civeira MP, Riezu JI, et al. (1996) Anticardiolipin antibodies in chronic hepatitis C: implication of hepatitis C virus as the cause of the antiphospholipid syndrome. Hepatology 23: 199-204.
  9. Ünlü O, Zuily S, Erkan D (2016) The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus. Eur J Rheumatol 3: 75-84.
  10. Uthman IW, Gharavi AE (2002) Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 31: 256-263.
  11. Su Z, Izum T, Thames EH, Lawson H, Ortel TL (2002) Antiphospholipid antibodies after surgical exposure to topical bovine thrombin. J Lab Clin Med 139: 349-356.
  12. Matharu GS, Kuinutsor SK, Judge A, Blom AW, Whitehouse MR (2020) Clinical effectiveness and safety of aspirin for venous thromboembolism prophylaxis after total hip replacement. A systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med 180: 376-384.
  13. Dangas GD, Tijsen JG, Wöhrle J, Søndergaard L, Gilard M, et al. (2020) A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 382: 120-129.
  14. Smith SR, Katz JN, Losina E (2019) Cost-effectiveness of alternative anticoagulation strategies for postoperative management of total knee arthroplasty patients. Arthritis Care Res 71: 1621-1629.
  15. Aledort LM (2019) Deaths associated with emicizumab in patients with hemophilia A. N Eng J Med 381: 1878-1879.
  16. Auñón-Chancellor SM, Pattarini JM, Moll, Sargsyan A (2020) Venous thrombosis during spaceflight. N Engl J Med 382: 89-90.
  17. Arnaud L, Mathian A, Ruffatti A, Erkan D, Tektonidou M, et al. (2014) Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: An international and collaborative meta-analysis. Autoimmun Rev 13: 281-291.
  18. Tan TL, Foltz C, Huang R, Chen AF, Higuera C, et al. (2019) Potent anticoagulation does not reduce venous thromboembolism in high risk patients. J Bone Joint Surg Am 101: 589-599.
  19. Pengo V, Denas G, Zoppellaro G, Padayattil Jose S, Hoxha A, et al. (2018) Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 132: 1365-1371.
  20. Ziakas PD, Pavlou M, Voulgarelis M (2010) Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: A systematic review and meta-analysis. Obstet Gynecol 115: 1256-1262.
  21. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, et al. (1995) The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 332: 993-997.
  22. Lopez-Pedrera C, Aguirre-Zamorano MÁ, Pérez-Sánchez C (2017) Mecanismos de aterosclerosis y enfermedad cardiovascular en el síndrome antifosfolípido y el lupus eritematoso sistémico. Alternativas terapéuticas. Medicina Clínica 149: 160-169.


Rothschild B (2020) Antiphospholipid Antibody-Related Problems, the Orphan Child of Medicine. J Rheum Dis Treat 6:085.