In 1992, the “catastrophic” antiphospholipid syndrome (APS) was first defined as a potential life threatening variant of the APS which is characterised by multiple small vessel thrombosis that can lead to multiorgan failure.¹ Fortunately, this is an unusual form of presentation that represents fewer than 1% of the APS cases.² The recurrence rate is low with a stable clinical course if these patients are treated with adequate anticoagulation.³ Owing to the rarity of its presentation, an international registry of patients (the CAPS registry) was created in 2000 supported by the European Forum on Antiphospholipid Antibodies (aPL).

The heterogeneity of the different clinical forms of presentation led to the need to develop consensus criteria for the classification of this condition. In 2002, a precongress workshop at the Tenth International Congress on aPL held in Taormina, Italy, allowed the establishment of the preliminary criteria for the classification of catastrophic APS that were published recently.⁴ The objectives of the present study were to describe the characteristics of the patients with catastrophic APS included in the CAPS registry and to analyse the value of the preliminary criteria for their classification using the data from this registry.

METHODS

We reviewed the 220 patients who were included in the website based international registry of patients with catastrophic APS (CAPS registry) at 1 October 2003, and tested the recently proposed preliminary criteria for the classification of catastrophic APS⁴ in those patients whose clinical data were sufficient for application of the criteria. The CAPS registry compiles all the published reports as well as newly diagnosed cases of catastrophic APS from all over the world. The diagnoses and data have been submitted by a wide variety of interested clinicians, but efforts were made in most cases to contact these clinicians and verify the accuracy of the data sent in. The basis for submitting patient data was clinical judgement, as no classification criteria were published until 2003. The different variables of the database are detailed at http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM.

Additionally, we analysed 175 unselected patients from our clinics as controls: 100 with systemic lupus erythematosus (SLE), classified according to the American College of Rheumatology (ACR) revised criteria⁵—all with positive aPL and 65 with associated APS—and 75 with primary APS, fulfilling the preliminary criteria for the classification of definite APS.⁶

RESULTS

DISCUSSION

Over the last 10 years, various different case reports and small series have described patients with catastrophic APS. Two major paper summarised the different characteristics of a total of 130 patients and provided information on the pathogenesis, clinical features, treatment, and outcome.^8,9 The website based CAPS registry has also compiled a large amount of information but the present study indicates that additional efforts should be made in the future because the registry often receives insufficient data or information on patients who do not have “definite” or “probable” catastrophic APS from physicians all over the world.

Recognition of catastrophic APS has increased over the past years, and it is now clear that it is not only associated with SLE or primary APS, but also with other autoimmune conditions such as rheumatoid arthritis, systemic sclerosis, intestinal inflammatory diseases, and Behçet’s disease, among others. Despite earlier recognition and better knowledge of the pathophysiology, the mortality rate is still unacceptably high (48%), specially in SLE patients and in patients with cardiac, pulmonary, renal, splenic, and adrenal involvement.

Recently, Erkan et al³ evaluated the clinical outcome of 58 survivors of a catastrophic APS event. Thirty eight patients (66%) did not develop further APS related events, 15 (26%) developed a new thrombotic episode (in 13 cases during anticoagulation therapy), but none of them developed further catastrophic APS episodes.

The clinical approach to the treatment of catastrophic APS will depend on the site and extension of the vascular occlusions and the degree of systemic inflammatory response. The cornerstone of the treatment includes readiness to suspect the condition and the treatment of any precipitating factor, especially adequate antibiotic therapy for related infections based on the clinical setting, appropriate anticoagulant management, and the use of immunosuppressive drugs (especially steroids), plus third line therapy (plasma exchange or intravenous immunoglubulins) for the treatment of the thrombotic and cytokine “storm”.⁴ Finally, a series of life support measures are needed, such as mechanical ventilation, inotropic drugs, and continuous haemodialysis.¹⁰

The differential diagnosis in some circumstances is very difficult, specially with other microangiopathic syndromes that are capable of producing multiorgan thrombotic events. These conditions include thrombotic thrombocytopenic purpura, haemolytic-uraemic syndrome, heparin induced thrombocytopenia, and the HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome.¹¹ In these critically ill patients there is a high chance that their blood samples may show false positive results in lupus anticoagulant assays (for example, coagulation factor deficiencies or heparin use), or that treatment decisions have to be made before the results of laboratory tests are available. However, the presence of persistent positive levels of aPL in a patient with these conditions will lead to the diagnosis of concomitant catastrophic APS. In fact, several patients in the CAPS registry fulfilled criteria for thrombocytopenic purpura or HELLP as well. Thus we only analysed patients with aPL as controls—including both SLE and primary APS patients—and for this reason we did not include controls with multiorgan thrombotic events (for example, thrombotic thrombocytopenic purpura, haemolytic-uraemic syndrome, or HELLP) but without aPL.

Though microthrombosis is one of the typical markers of a catastrophic APS event, it may be difficult to confirm, and many patients could only be labelled as “probable” catastrophic APS based on large vessel multiorgan thrombotic involvement over a short period of time in the presence of aPL. Because of these difficulties in the confirmation of a definite catastrophic APS event, we included both “definite” and “probable” catastrophic APS in the evaluation of the classification criteria. According to our results, the International Consensus Statement on Preliminary Classification Criteria for the catastrophic APS is a useful tool for epidemiological studies and it is hoped that these criteria will be tested in future prospective multicentre studies, and that modifications or additions to the criteria will be made at subsequent workshops. It should be emphasised that these criteria are mostly empirical and have been accepted for classification purposes only. They are not intended to be used as strict diagnostic criteria in a given patient.

APPENDIX

THE CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME REGISTRY PROJECT GROUP

The members of the Catastrophic APS Registry Project Group who contributed with clinical data to this study are as follows: Mary-Carmen Amigo, Rheumatology Department, Instituto Nacional de Cardiología, Ignacio Chavez, Mexico City, Mexico; Leonor Barile-Fabris, Rheumatology Department, Hospital de Especialidades, Centro Medico la Raza IMSS, Mexico City, Mexico; Jean-Jacques Boffa, Department of Nephrology, Hôpital Tenon, Paris, France; Joab Chapman, Neuroimmunology Service, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel; Christopher Davidson, Department of Cardiology, Royal Sussex Hospital, Brighton, UK; Alex E Denes, Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA; Ronald H W M Derksen, Department of Rheumatology and Clinical Immunology, University Medical Centre, Utrecht, Netherlands; J F Diaz Coto, Caja Costarricense del Seguro Social, San Jose, Costa Rica; Patrick Disdier, Service de Medecine Interne, Centre Hospitalier Universitaire Timone, Marseille, France; Rita M Egan, Department of Medicine, University of Kentucky Medical Center, Lexington, Kentucky, USA; M Ehrenfeld, Chaim Sheba Medical Centre and Tel-Aviv University, Tel-Hashomer, Israel; R Enriquez, Nephrology Section, Hospital General de Elche, Spain; Doruk Erkan, Hospital for Special Surgery, New York, USA; Fernanfa Falcini, Department of Paediatrics, University of Florence, Italy; Leslie S Fang, Renal Associates, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Mario García-Carrasco, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico; John T Grandone, Neenah, Wisconsin, USA; Anagha Gurjal, Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA; Gilles Hayem, Department of Rheumatology, CHU Bichat-Claude-Bernard, Paris, France; Graham R V Hughes, Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, UK; Sohail Inam, Riyadh Armed Forces Hospital Riyadh, Saudi Arabia; K Shashi Kant, Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio, USA; Munther A Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, UK; Craig S Kitchens, Department of Medicine, University of Florida, Gainesville, Florida, USA; Michael J Kupferminc, Department of Obstetrics and Gynaecology, Lis Maternity Hospital, Tel Aviv University, Tel Aviv, Israel; Gabriela de Larrañaga, Hospital Muñiz, Buenos Aires, Argentina; Roger A Levy, Department of Rheumatology, Faculdade de Ciencias Medicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; Daryl Tan, Singapore General Hospital, Singapore; Siu Fai Lui, Department of Medicine, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong; Peter J Maddison, Gwynedd Rheumatology Service, Ysbyty Gwynedd, Bangor, UK; Yoseph A Mekori, Department of Medicine, Meir Hospital, Kfar Saba, Israel; Takako Miyamae, Department of Paediatrics, Yokohama City University School of Medicine, Yokohama, Japan; John Moore, Department of Haematology, St Vincents Hospital, Sydney, Australia; Haralampos M Moutsopoulos, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; Francisco J Munoz-Rodriguez, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain; Jacek Musial, Jagiellonian University School of Medicine, Krakow, Poland; Ayako Nakajima, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan; Michael C Neuwelt, Medical Service, VA Palo Alto Health Care System, California, USA; Ann Parke, Department of Internal Medicine, Division of Rheumatic Diseases, University of Connecticut Health Center, Connecticut, USA; Sonja Praprotnik, University Clinical Centre, Department of Rheumatology, Ljubljana, Slovenia; Bernardino Roca, Department of Internal Medicine, Hospital General de Castelló, Castelló, Spain; Jorge Rojas-Rodriguez, Department of Rheumatology, Specialties Hospital, Manuel Avila Camacho National Medical Centre, Puebla, Mexico; R Roldan, Rheumatology Department, Hospital Reina Sofia, Cordoba, Spain; Allen D Sawitzke, Division of Rheumatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA; Cees G Schaar, Department of Haematology, Leiden University Medical Centre, The Netherlands; Alenka Šipek-Dolnicar, Department of Rheumatology, University Medical Centre, Ljubljana, Slovenia; Alex C Spyropoulos, Clinical Thrombosis Center, Albuquerque, New Mexico, USA; Renato Sinico, Nephrology and Dialysis Unit and Centre of Clinical Immunology and Rheumatology, San Carlo Borromeo Hospital, Milan, Italy; Ljudmila Stojanovich, Clinical-Hospital Centre “Bezhanijska Kosa”, Belgrade, Yugoslavia; Marcos Oaulo Veloso, Hospital Universitario Clementino Fraga Filho, Rio de Janeiro, Brazil; Maria Tektonidou, Department of Pathophysiology, Medical School, National University of Athens, Athens, Greece; Carlos Vasconcelos, Hospital General de San Antonio, Porto, Portugal; Marcos Paulo Veloso, Hospital Universitario Clementino Fraga Filho, Rio de Janeiro, Brazil; Margaret Wislowska, Outpatients Department of Rheumatology, Central Clinical Hospital, Warsaw, Poland.