Search

SECTION I: PHOSPHOLIPIDS AND CLOTTING. Structures and Properties of Self-Assembled Phospholipids in Excess Water (Ching-Hsien Huang). Phospholipids and the Clotting Process (Robert F.A. Zwaall, Edouard M. Bevers, Jan Rosing). SECTION II: THE IMMUNOLOGY OF PHOSPHOLIPID BINDING AUTOANTIBODIES. Autoantibodies: Their Nature and Significance (Keith B. Elkon). Antibodies to Lipids and Lipid Membranes: Reactions with Phosphatidyl-Choline, Cholesterol, Liposomes, and Bromolin-Treated Erythromytes (Carl R. Alving). Phospholipid Binding Antibodies in Natural and Experimental Syphilis (Konrad Wicher, Victoria Wicher). Role of Monoclonal Antibodies in Understanding the Interactions Between Anti-Phospholipid Antibodies and Phospholipids (Joyce Rauch, Andrew S. Janoff). The Immunology of Phospholipid Binding Antibodies in the Anti-Phospholipid Syndrome and Related Disorders (E. Nigel Harris, Genesio Balestrieri, Angela Tincani, Azzudin E. Gharavi). SECTION III: MEASUREMENT OF PHOSPHOLIPID BINDING ANTIBODIES. Lupus Anticoagulants: Characteristics, Methods of Laboratory Detection and Some Clinical Associations (Thomas Exner, Douglas Triplett). Acquired Circulating Anticoagulants Other Than Lupus Anticoagulants (Thomas Exner, David Green). The Anti-Cardiolipin Assay (E. Nigel Harris, Azzudin E. Gharavi, Graham R.V. Hughes). SECTION IV: PHOSPHOLIPID BINDING ANTIBODIES AND THROMBOSIS. Arterial Thrombosis: Diagnosis and Management (H. Patrick McNeil, Steven A. Krilis, Colin Chesterman). Spontaneous (Unexplained) Thrombosis: The Inherited Basis for the Thrombohemorrhagic Balance (Helge Stormorken). The Pathogenic Role of Anti-Phospholipid Antibodies in Thrombosis (Ronald H. Derksen, Paula Hasselaar, Ph.G. DeGroot). Anti-Phospholipid Antibodies and Impairment of Prostacyclin Synthesis by Endothelium (Luis O. Carreras, Jos Vermylen). Anti-Phospholipid Autoantibodies in Thrombosis: Cause and/or Consequence of the Rupture of the Protein C-Dependent Hemostatic Balance (Jean-Marie Freyssinet, Catherine Ravanat, Lelia Grunebaum, Marie Louise Wiesel, Jean Pierre Cazenave). SECTION V: PHOSPHOLIPID BINDING ANTIBODIES AND PREGNANCY LOSS. Habitual Abortion (Dwight D. Pridham, Christine L. Cook). Pregnancy in SLE (Michael D. Lockshin). Treatment of Anti-Phospholipid Antibody Mediated Fetal Loss: The Case for Corticosteroid Therapy (Neil S. Pattison, Wilhelm F. Lubbe). Clinical Implication of Anti-Phospholipid Antibodies: The Utah Experience (Ware D. Branch, James R. Scott). Alternative Approaches to Treatment of Women with Anti-Phospholipid Antibodies and Fetal Loss (Susan F. Cowchock). Anti-Phospholipid Antibodies and Fetal Loss-Proposed Mechanism (Neil A. MacLachland, Murdo G. Elder). SECTION VI: THE ANTI-PHOSPHOLIPID SYNDROME. The "Anti-Phospholipid Syndrome" - An Introduction (E.Nigel Harris). The "PRIMARY" Anti-Phospholipid Syndrome (Ronald A. Asherson). Anti-Phospholipid Antibodies: Clinical Complications Reported in the Literature (Ronald A. Asherson). Hematological Immune Cytopenias and Anti-Phospholipid Antibodies (Munther A. Khamashta, Samuel J. Machin). Anti-Phospholipid Syndrome in Murine Lupus (Azzudin E. Gharavi). Anti-Phospholipid Antibodies: A Personal History (Graham R.V. Hughes).

The term “lupus” anticoagulant was first used by Feinstein and Rapaport in 1972,1 to describe the in vitro anticoagulant phenomenon observed mainly in patients with systemic lupus erythematosus. It has since been shown that this anticoagulant effect was due to the presence of antibodies directed against phospholipids and could not be corrected by the addition of normal plasma.2-3 This “anticoagulant” was paradoxically associated with thrombotic events. In 1984 a strong correlation was found between the lupus anticoagulant, antibodies to cardiolipin and the occurrence of these thrombotic events, which affected both the venous and arterial circulations, and the term anti-phospholipid syndrome was proposed by Harris et al. Spinal syndromes including Transverse Myelitis and the Guillain-Barre have been infrequently documented in association with anti-phospholipid antibodies. A familial clotting disorder or the presence of anti-phospholipid antibodies in family members may also be demonstrable.

Apart from occlusions involving a large variety of venous and arterial vessels, antiphospholipid antibodies (aPL) have been associated less frequently with a number of other clinical manifestations. Some of these complications are more often associated with aPL antibodies (e.g., chorea, livedo reticularis) while others occur less frequently. Clearly, thrombotic occlusions may be the underlying pathogenetic mechanism operating in some, but other factors, as yet unidentified, may be responsible in conditions such as chorea or pulmonary hypertension. Skin lesions occurring in association with aPL antibodies may comprise a variety of cutaneous and subcutaneous manifestations similar to vascular occlusions seen in vessels to other organs. Livedo reticularis, a cyanotic, geographically distributed “network” pattern of dilated superficial veins, often precipitated or aggravated by cold, may occur in normal children and adults.

Background The catastrophic variant of the antiphospholipid syndrome (CAPS), also now known as Asherson's syndrome, is defined as a potential life-threatening variant of the antiphospholipid syndrome, which is characterized by multiple small-vessel thrombosis that can lead to multiorgan failure. Relapses in patients with the CAPS are very uncommon. Objective To describe the clinical and laboratory features of patients with relapsing episodes of CAPS. Methods Three patients with relapsing CAPS are presented with their clinical and laboratory features. Results Seven episodes of CAPS that occurred in the 3 patients reported were analyzed. The median time between the episodes of CAPS was 12.5 months (range, 2.5-48). Precipitating factors were identified in 2 episodes only ( Legionella respiratory tract infection and periodontal infection). The most significant manifestations of the episodes were renal involvement (5 episodes), central nervous system and cardiac involvement (4 episodes), and pulmonary and hepatic involvement (3 episodes each). Interestingly, laboratory features of definite microangiopathic hemolytic anemia (MHA) were present in 5 of 7 episodes of relapsing CAPS. The remaining episodes presented with thrombocytopenia, schistocytes, and anemia but data concerning hemolysis and Coombs tests were not reported. Rituximab was used in 2 episodes. Conclusions Relapses occur very infrequently in patients with the CAPS. The presence of MHA is common in these patients, suggesting that an association between MHA and relapses of CAPS could be present and that a "continuum" between various MHAs might exist, as recently suggested.

This article provides a review of the various types of antiphospholipid (aPL) antibodies and antiphospholipid syndromes, their prevalence, presumed origin, relationship to autoimmunity in general, and their role in the body's defenses and apoptosis. New hypotheses such as the role of antibodies to beta2 glycoprotein I (beta2GPI) and the signaling of toll-like receptors are also discussed, as is the spectrum of clinical manifestations associated with the demonstration of these antibodies, now assumed to be "pathogenic." A distinction is made between antibodies present in sera of patients with a variety of microangiopathic syndromes (MAPS; e.g., HELLP syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathic syndromes). In these conditions, the antibodies might not be "pathogenic" but, alternatively, generated by small vessel endothelial damage. These conditions are differentially referred to as microangiopathic antiphospholipid-associated syndromes, and they should be differentiated from the microvascular occlusions that are seen in the antiphospholipid syndrome. Current treatments of the antiphospholipid syndrome are briefly reviewed.

Small vessel occlusions may occur as part of the vascular manifestations of the Antiphospholipid Syndrome (APS) and may affect glomerular, skin, retinal, bowel, hepatic or pulmonary vessels. These thrombotic lesions are proven (usually by biopsy, surgical procedures, at autopsy or by specialized techniques e.g. in the case of retinal vascular occlusions). Another group of small vessel occlusions remain unproven and include osteonecrosis, hearing loss and a variety of brain syndromes. All these constitute the microvascular manifestations of the APS. Another separate group exists viz. thrombotic microangiopathic antiphospholipid-associated syndromes including Thrombotic Thrombocytopenic Purpura (TTP), HELLP syndrome and the thrombotic microangiopathies (primary or secondary e.g. to SLE itself or lupus-like disease). There is an accompanying haemolytic anaemia, often thrombocytopenia and presence of schistocytes. There are no large vessel occlusions and the antiphospholipid antibodies (aPL) may be generated by endothelial damage. It is possible that some of these "non-pathogenic" aPL may be rendered pathogenic by factor(s) unknown at this time causing a disturbance of the haemostatic equilibrium with resultant large vessel occlusions. This may be occurring in patients with the catastrophic antiphospholipid syndrome (CAPS/Asherson's syndrome). The term "MAPS" is suggested for these two groups of conditions.

A recent publication in this journal has drawn attention to the association of HELLP syndrome with antiphospholipid antibodies (aPL) accompanied by a 20210A mutation of the prothrombin gene, resulting in bilateral deep vein thromboses after termination of the pregnancy [1]. The association of hemolysis-elevated liver enzymes and thrombocytopenia, known as the HELLP syndrome, is a thrombotic microangiopathic state with thrombocytopenia complicating pregnancy [2]. It usually occurs before the 32nd week of gestation but may manifest in the postpartum period in 25% of cases [3]. Although usually resolving with delivery of the fetus without any complications, sequelae have been reported in 30% of patients [4]. The diagnosis of HELLP syndrome is based on the presence of hemolysis (anemia with characteristic blood smear), elevated levels of lactic dehydrogenase, total bilirubin of >1.2 mg/dl, and elevated alanine aminotransferase more than twofold. “Complete” HELLP syndrome is defined by the presence of all four criteria and partial or “incomplete” HELLP syndrome by the presence of two criteria [5]. The association of HELLP syndrome with aPL extends as far as back to 1994. Two cases of HELLP syndrome with demonstrable aPL were first reported by Ornstein and Rand in 1994 [6]. Their cases were refractory to delivery of the fetus, corticosteroids as well as anticoagulation, the first indication in the literature that this combination of events presaged a rather different clinical entity to the simple HELLP syndrome. Plasmapheresis resulted in resolution of the condition. The authors hypothesized whether an association between this “refractory” microangiopathic condition and the presence of the aPL existed. In 1995, Ibery et al. [7] then reported a single patient with positive lupus anticoagulant and HELLP complicated by hepatic, dermal, adrenal infarctions as well as placental abruption, the first true “overlap” of antiphospholipid syndrome (APS) and HELLP, although it seems that this case might have been an example of the catastrophic variant of the APS. Alsulyman et al. [8], Nagayama et al. [9], McMahon and Smith [10], and Amant et al. [11] all documented cases with demonstrable aPL; some of whom had developed hepatic infarctions, necrosis, or hemorrhage. Severe liver complications such as hemorrhage/rupture were only seen in 1% of HELLP patients in a large series of patients [12]. Roberts et al. [13] in 2003 documented a systemic lupus erythematosus patient with both HELLP and APS with acute renal failure who responded well to plasma exchanges. Hepatic infarcts occurring in two patients with HELLP syndrome were reported by Zissin et al. in 1999 [14]. No mention, however, is made of aPL in this article. Central retinal vein occlusion was reported in one patient [15], while thrombosis of the inferior vena cava was reported by Clin Rheumatol (2008) 27:1–4 DOI 10.1007/s10067-007-0742-7

Although less than 1% of patients with the antiphospholipid syndrome (APS) develop the catastrophic variant, its potentially lethal outcome emphasizes its importance in clinical medicine today. However, the rarity of this variant makes it extraordinarily difficult to study in any systematic way. In order to put together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS ("CAPS Registry") was created in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory, and therapeutic data of more than 300 patients whose data have been fully registered. This registry can be freely consulted at the Internet (www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) and it is expected that the periodical analysis of these data will allow us to increase our knowledge of this condition.

The catastrophic anti-phospholipid syndrome (CAPS) differs from the anti-phospholipid syndrome in its accelerated systemic involvement leading to multi-organic failure. In this study, the occurrence of malignancies in patients with CAPS was evaluated and the clinical findings of CAPS patients with and without malignancies were compared. We investigated the web site-based international registry of patients with CAPS for all cases in which both CAPS and underlying malignancies were present. The clinical characteristics of these cases were subsequently evaluated to establish common characteristics. The CAPS registry included information on a total of 262 cases. Twenty-three (9%) patients suffered from malignancies. In 78% of these patients, the malignancy itself or the treatment modalities instituted for the carcinoma was the precipitating factor of CAPS. Only 39% of CAPS patients with malignancies recovered in comparison to 58% of patients without malignancies (p = 0.07). Treatment modalities, however, did not differ significantly between these patients. Infections were not evident as precipitating factors for any of the malignancy patients. The mean age of patients with malignancies was 9 years older than the average age of other patients with CAPS and the prevalence of SLE was significantly less common than in patients without malignancy. Malignancy may play a pathogenic role in patients with CAPS, whereas infections are more important as triggering factors in patients without malignancies. CAPS patients with malignancies are generally older than CAPS patients without malignancies; they generally have the worst prognosis of the entire CAPS cohort.

The catastrophic antiphospholipid syndrome is a potentially life-threatening condition with a high mortality rate, the diagnosis of which requires a high degree of clinical awareness on the part of attending physicians. Patients with this syndrome have various symptoms in common: clinical evidence of multiple organ involvement developed over a very short time period, histopathological evidence of multiple small-vessel occlusions and laboratory confirmation of the presence of antiphospholipid antibodies, usually in high titers. The combination of high doses of intravenous heparin, steroids, gamma-globulins and/or repeated plasma exchanges are the basic treatment of choice for all patients with this severe condition.

Objective To analyze the clinical and laboratory characteristics of 97 patients with intestinal involvement secondary to the antiphospholipid syndrome (APS) (37 patients with classic APS and 60 with catastrophic APS). Methods A computer-assisted (PubMed) search of the literature was performed to identify all cases of intestinal involvement associated with the APS from 1983 to December 2005. In addition, we analyzed the web-site-based international registry of patients with catastrophic APS ("CAPS Registry"). Results There were no differences in distribution by gender, mean age, and previous clinical manifestations of APS between the 2 groups. The prevalence of abdominal pain as the presenting manifestation of intestinal ischemia was higher in patients with classic APS (76% versus 37%; P P P Conclusions Intestinal involvement, although infrequent, is an important complication in patients with APS, especially in those with catastrophic APS. This would support the need for systematic screening for aPL in all cases of mesenteric thrombosis or ischemic colitis without clear underlying predisposing factors, and for systematic screening procedures in all classic APS patients complaining of abdominal pain.

Although less than 1% of patients with the antiphospholipid syndrome (APS) develop the catastrophic variant, its potentially lethal outcome emphasizes its importance in clinical medicine today. However, the rarity of this variant makes it extraordinarily difficult to study in any systematic way. In order to put together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS (“CAPS Registry”) was created in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory and therapeutic data of more than 300 patients whose data has been fully registered. This registry can be freely consulted at the Internet (www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) and it is expected that the periodical analysis of these data will allow us to increase our knowledge of this condition.

An episode of gastroenteritis triggered severe necrosis of all extremities in a previously asymptomatic male. Hepatic and renal involvement were also manifest, while the hematological picture was one of thrombotic microangiopathic hemolytic anemia. Antiphospholipid antibodies were negative. He responded well to a combination of plasma exchange, anticoagulation (heparin), parenteral steroids, and antibiotics, as well as vasodilators (prostacycline) and hyperbaric oxygen, but died because of a cerebral hemorrhage. The differential diagnosis included thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, or seronegative catastrophic antiphospholipid (Asherson's) syndrome. The dangers of administering such a combination of therapies with anticoagulation, as well as vasodilatation (prostacycline) and hyperbaric oxygen, are highlighted by the case report and emphasized.

The cases reported by Sneddon and referrred to as "Sneddon's syndrome" (1) had only cerebrovascular disease and livedo reticularis accompanied by benign hypertension in some. Sneddon linked the livedo and cerebrovascular pathology, suggesting that endarteritis obliterans similar to that occurring in the Takayasu arteriopathy might be the etiology histo­ pathologically. This has indeed been subsequently verified by several investigators (2-4). Rebollo et al. (2) showed multiple occlusions of medium-sized arteries in the brain and digital vessels by cerebro­ renal arteriography, and digital biopsy confirmed the presence of an arteriopathy. These histological fea­ tures were also identified by Quimbyand Perry (3) as well as by Pinol Aigvade et al. (4). Antiphospholipid antibodies were first documented in patients with cerebrovascular disease and livedo reticularis in a patient documented by Asherson et al. in 1985 who had originally presented with an aortic arch syn­ drome (5). The patient identified by Rumpl et al. (6) had a positive VORl, and Jonas et al. (7) then pub­ lished a case of Sneddon's syndrome with a compli­ cating retinal occlusion in the presence of antiphos­ pholipid antibodies. In other words, as early as 1985, we were already seeingliterature to the effect that the original concept of Sneddon's syndrome was slowly being extended to involve arterial occlusions in other organs. In our first report of a study on livedo reti­ cularis in 1987 (8), and subsequently followed by a full communication in 1989 (9), we pointed out that some patients with livedo reticularis with antiphos­ pholipid antibodies and cerebrovascular accidents

Enzyme-linked immunoabsorbent assay (ELISA) techniques for the detection of antibodies to the Venereal Disease Research Laboratories (VDRL) antigen as well as for the estimation of antibodies to cardiolipin (aCL) in cerebrospinal fluid (CSF) were performed in several groups of patients, including those with definite paretic neurosyphilis (DPNS, 10 patients), probable paretic neurosyphilis (PPNS, 19 patients), systemic lupus erythematosus (SLE, 71 patients), and miscellaneous neurologic disorders (30 patients), and normal subjects (11 patients). In the DPNS group, all demonstrated positive VDRL by ELISA, and 7 also had positive aCL tests, whereas only 7 of the 10 had positive CSF fluorescent treponemal antibody absorption (FTA-ABS) and Treponema pallidum hemagglutination assay (TPH A) tests. Three had positive VDRL tests by flocculation. In the PPNS group, no patients had positive FTA-ABS, TPH A, or VDRL flocculation tests in CSF. However, 18 of the 19 had positive CSF VDRL by ELISA; two of these also had positive aCL tests. Four SLE patients had positive CSF aCL tests (three with positive ELISA VDRL). Only one patient in the miscellaneous group had positive CSF aCL (Guillain-Barre syndrome), and one had positive IgM VDRL tests (bacterial meningitis). The value of VDRL ELISA in the diagnosis of neurosyphilis in the face of other negative conventional tests is established by our study and had important therapeutic consequences in patients with possible/probable neurosyphilis. The aCL test often may be positive in patients with DPNS but is less useful in the PPNS group.

The catastrophic antiphospholipid syndrome (CAPS, Asherson's syndrome) develops rapidly following an identifiable triggering factor (eg infection, trauma, inadequate coagulation neoplasia, obstetric) in antiphospholipid antibody positive patients. It is most frequently encountered in patients with a primary antiphospholipid syndrome or systemic lupus erythematosus (SLE) or "lupus-like" disease (LLD). It manifests mainly with small vessel thromboses affecting organs (gastrointestinal tract, brain, heart), large vessel occlusions in one-third, manifestations of the systemic inflammatory response syndrome (SIRS), particularly the acute respiratory distress syndrome (ARDS). The mortality is high, although with early and effective therapies, including full parenteral anticoagulation, corticosteroids, plasma exchanges and IV globulins, an improvement in this high death rate has been noted recently.

Revealing the evolution of the term APS and its commonalities with other microangiopathic disorders The occurrence of small-vessel occlusions (thrombotic microangiopathy) in association with anti-phospholipid antibodies (aPL) affecting, for example, the retinal vessels,1 the nail fold,2,3 the skin,4 or major intrabdominal organs such as the kidney, the liver or the bowel,5 although uncommon, is well documented. These occlusions have been described in the simple or classic antiphospholipid syndrome (APS), whether or not associated with systemic lupus erythematosus (SLE), or in the primary APS,6 but they do not in any way dominate the clinical picture in these conditions. However, with the description and definition of the catastrophic APS (also known as Asherson’s syndrome) in 19927,8 (a new subset of the APS, often fatal, with many distinguishing characteristics separating it from the simple APS),9–11 there has been renewed interest in the thrombotic microangiopathies and their association with aPL. Although large-vessel occlusions do occur in catastrophic APS, they do not dominate the clinical picture, and their frequency is completely different from that encountered in the classic APS itself. Additionally, the catastrophic APS is frequently accompanied by a systemic inflammatory response syndrome (SIRS). The term thrombotic microangiopathic haemolytic anaemia (TMHA) was originally introduced by Symmers12 in 1952 to describe a clinical state with localised or diffuse microvascular thrombosis in association with haemolytic anaemia and fragmented red cells referred to as schistocytes. Indeed, the great haematologist John Dacie and his colleagues13 published a seminal paper on TMHA and related the condition to vascular damage some 10 years later. TMHA encompasses a spectrum of disorders including thrombotic thrombocytopenic purpura (TTP), haemolytic–uraemic syndrome (HUS), malignant hypertension, postpartum renal failure, pre-eclampsia and catastrophic APS. Recent articles still refer to the difficulty in distinguishing among these conditions …

Catastrophic APS is a potentially life-threatening condition with a high mortality, which requires high clinical awareness. New mechanisms for its production can only be explored if samples are obtained, stored, and dis-patched to investigation sites in Europe (Barcelona), the United States (Atlanta), and Japan (Sapporo). Details will be posted and made available on the International Registry Web Site in 2006. It is essential that the condition be diagnosed early and treated aggressively. The combination of high doses of iv heparin, iv steroids plus repeated doses of iv gammaglobulins or plasma exchange is the treatment of choice in patients with this severe condition. Additionally, preventive measures in patients with APS may be effective if the development of the catastrophic APS is to be avoided.

SUMMARY We document a study of 65 patients presenting to our clinics, over a 2-year period, with livedo reticularis. All patients were screened for the presence of anti-cardiolipin antibodies and assessed for the presence of central nervous system disease and features of the ‘antiphospholipid’ syndrome, including venous and arterial thromboses and foetal loss. Patients were also assessed for other clinical features such as Raynaud's phenomenon and valvular lesions. Twenty-eight anti-cardiolipin positive patients were compared with 37 anti-cardiolipin negative patients. There was a statistically significant difference in the incidence of cerebrovascular disease (including strokes and transient ischaemic attacks) thrombocytopenia, valvular heart lesions and foetal loss in the anti-cardiolipin positive patients as compared with the anti-cardiolipin negative groups.

The original description and definition of the antiphospholipid syndrome (APS) included predominantly thromboses of large veins and large arteries (deep vein thromboses [DVT] and strokes), fetal losses and thrombocytopenia (mild to moderate). The thromboses and fetal losses were often recurrent. Small vessel occlusions did occur (affecting renal and retinal skin vessels, etc.) but these did not dominate the clinical picture. The systemic nature of the syndrome was recognized in 1992 and is referred to as Hughes’ Syndrome. In 1992, a new subset consisting predominantly of small vessel microangiopathy, with considerably less large vessel occlusive disease, was defined as the catastrophic antiphospholipid syndrome (CAPS) and the eponym Asherson’s Syndrome has been attached. Severe thrombocytopenia and features of the systemic inflammatory response syndrome appear to accompany this very often fatal condition. Recurrences were very rare. A new subset is highlighted and reviewed in this paper and is termed the ...

Catastrophic antiphospholipid syndrome is a rapidly progressive life-threatening disease that causes multiple organ thromboses and dysfunction in the presence of antiphospholipid antibodies. A high index of clinical suspicion and careful investigation are required to make an early diagnosis so that treatment with anticoagulation and corticosteroids can be initiated; plasma exchange and/or intravenous immunoglobulins can be added if the life-threatening condition persists. Despite aggressive treatment and intensive care unit management, patients with catastrophic antiphospholipid syndrome have a 48% mortality rate, primarily attributable to cardiopulmonary failure. This article reviews the current information on the etiopathogenesis, clinical manifestations, diagnosis, management, and prognosis of catastrophic antiphospholipid syndrome.

Objective To describe the different types of malignancies associated with antiphospholipid antibodies (aPL). Methods We performed a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature from 1966 to 2003 to identify all cases of malignancies having aPL. Results One hundred twenty patients were found. The mean age was 56 ± 17 years (range 5 to 88). Sixty-two (52%) patients were men and 58 (48%) were women. A heterogeneous group of malignancies were found. Regarding hematological malignancies, 10 (8%) patients suffered from B-cell lymphoma, 8 (7%) from spleen lymphoma, 7 (6%) from chronic myeloid leukemia, and 6 (5%) from non-Hodgkin’s lymphoma (NHL). Regarding solid tumors, renal cell carcinoma was diagnosed in 7 (6%) patients, primary tumor with unknown origin in 7 (6%), lung adenocarcinoma in 6 (5%), breast carcinoma in 6 (5%), and melanoma in 6 (5%). The main aPL-related manifestations were thrombocytopenia (25%), cerebrovascular accidents (24%), deep vein thrombosis (19%), pulmonary embolism (15%), and heart valve lesions (9%). In 17 cases, catastrophic antiphospholipid syndrome was considered to be triggered by the malignancy. Seventy-one (63%) of 113 patients recovered or are still alive after cancer treatment. Twenty-three (35%) of 65 patients achieved aPL remission after proper treatment of the malignancy. Conclusions It is important to bear in mind, especially in elderly patients, that thrombotic events associated with aPL can be the first manifestation of malignancy. At the same time, the presence of aPL in patients with malignancies has important implications in their treatment and prognosis.

Catastrophic antiphospholipid syndrome, a severe form of antiphospholipid syndrome, is associated with a high mortality rate; approximately 50% of patients die from thrombotic diathesis. As discussed in this Review, efforts to facilitate early diagnosis, institute effective treatments in a timely manner, and to better understand the causes of this extreme condition are needed to improve patient outcome. Antiphospholipid syndrome (APS) is a thrombotic disorder associated with autoantibodies that target membrane phospholipids and phospholipid-binding proteins, which regulate coagulation. APS is usually characterized by major arterial or venous occlusions, pregnancy complications, or both. In 1992, Asherson described an unusual variant of APS termed the catastrophic antiphospholipid syndrome (also known as Asherson's syndrome), the hallmark of which is rapid multiorgan failure caused by widespread small-vessel thrombi. Empiric treatments have improved the prognosis of patients, but half still die from thrombotic diathesis, even though those who survive the acute stages frequently remain well. Given the persistently high mortality rate, efforts have been underway to facilitate early diagnosis, institute effective treatments in a timely manner and to better understand the cause (or causes) of this extreme condition in order to improve outcomes.

Objective. To assess the main causes of death and the prognostic factors that influence mortality in patients with the catastrophic antiphospholipid syndrome (CAPS). Methods. We analyzed the case reports of 250 patients included in the CAPS Registry up to February 2005. To identify prognostic factors for CAPS, we compared the main clinical and immunologic features and the types of treatment in the patients who died with those features in the patients who survived. Results. Recovery occurred in 56% of the episodes of CAPS and death occurred in 44%. Cerebral involvement, consisting mainly of stroke, cerebral hemorrhage, and encephalopathy, was considered the main cause of death, being present in 27.2% of patients, followed by cardiac involvement (19.8%) and infection (19.8%). The only factor we identified that was prognostic of a higher mortality rate was the presence of systemic lupus erythematosus (SLE). A higher recovery rate was associated with combined treatment with anticoagulants (ACs) plus corticosteroids (CS) plus plasma exchange (PE) (77.8%), followed by ACs plus CS plus PE and/or intravenous immunoglobulins (69%). In contrast, concomitant treatment with cyclophosphamide did not demonstrate additional benefit. Conclusion. Cerebral involvement (mainly consisting of stroke), cardiac involvement, and infections were considered the main causes of death in patients with CAPS. The presence of SLE was related to a higher mortality rate. According to the results of the present study, ACs plus CS plus PE should be the first line of therapy in patients with CAPS.

To determine the prevalence and clinical correlates of anti-phospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), lupus anti-coagulant (LA), anti-beta2-glycoprotein 1 (abeta2GP1), and anti-prothrombin (aPT) antibodies, in Black South African patients with systemic lupus erythematosus (SLE).A cross-sectional study of 100 SLE patients in whom clinical characteristics, including features of the anti-phospholipid syndrome (APS), disease activity, and damage were documented, and sera tested for aCL, abeta2GP, and aPT of all isotypes, and LA.Positive aCL, abeta2GPI, aPT, and LA were found in 53, 84, 20, and 2 patients, respectively. Immunoglobulin (Ig)A aCL and IgG abeta2GPI were the commonest aCL (49.1%) and abeta2GPI (47%) isotypes, respectively. IgA abeta2GPI were associated with both a history of thrombosis alone (p0.05) and a history of any clinical feature, thrombosis, and/or spontaneous abortion of the APS (p0.05); IgA aCL were associated with a history of any clinical APS event (p0.05); and abeta2GPI of any isotype were associated with a history of arthritis (p0.001).Our findings provide further evidence that screening for abeta2GPI and IgA aCL isotypes may improve the risk assessment for APS in SLE patients of African extraction. Further prospective studies are warranted to determine the clinical utility of these tests and to elucidate the genetic basis for the increased IgA aPL response in SLE patients of African extraction.

O quadro clínico de trombose generalizada de múltiplos órgãos acompanhada de insuficiência ou falência dos mesmos, em associação com anticorpos antifosfolípides, é chamado de "síndrome antifosfolípide catastrófica" (síndrome de Asherson). Esta é uma variante da síndrome antifosfolípide, que pode ocorrer em pacientes sem este diagnóstico ou mesmo durante o curso da síndrome primária e/ou secundária, mesmo com terapêutica anticoagulante. Os pacientes apresentam, principalmente, oclusões de pequenos vasos e as manifestações clínicas dependem dos órgãos acometidos. Fatores desencadeantes podem ser observados em metade dos casos e, apesar dos tratamentos, a sua mortalidade ainda é alta. Esta revisão apresentará a evolução de nossos conhecimentos sobre esta condição e como nós a compreendemos na atualidade.

Objective: To describe the characteristics of patients with catastrophic antiphospholipid syndrome (APS) included in the International Registry of patients with this condition (CAPS registry) and to analyse the value of the recently proposed preliminary criteria for the classification of catastrophic APS. Methods: A review of the first 220 patients included in the website based CAPS registry was undertaken and the preliminary criteria for their classification were tested; 175 unselected patients with systemic lupus erythematosus or APS, or both, acted as controls. Results: The mean age of the patients was 38 (14) years (range 7 to 74), with a female preponderance (F/M, 153/67). The main clinical manifestations included renal involvement in 154 (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%); 114 patients (52%) recovered after the catastrophic APS event (mortality 48%). Patients who received the combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins had the best survival rate (63%, p = 0.09). Sufficient data could be analysed for application of the classification criteria in 176 patients. According to the preliminary criteria, 89 patients (51%) could be classified as having “definite” and 70 (40%) as having “probable” catastrophic APS, thus given a sensitivity of 90.3% with a specificity of 99.4%. Positive and negative predictive values were 99.4% and 91.1%, respectively. Conclusions: The preliminary criteria for the classification of catastrophic APS and the CAPS registry are useful tools for epidemiological studies.

An unusual variant of the antiphospholipid syndrome (APS) termed the Catastrophic Antiphospholipid Syndrome (CAPS) in 1992 by Asherson is described. The condition may arise “de-novo” in a patient previously not suspected of having an APS or during the course of a “Primary” APS or Secondary APS (most commonly SLE). The patient may already be on therapy. “Trigger” factors (infections most commonly) have been identified in 45% of patients but in the majority, they remain unidentified. Clinically, the patients present with small vessel occlusions involving organs (e.g. bowel, brain, heart, kidney) but large vessels occlusions do occur. Unusual organs are involved and the clinical features depend on which organs are affected. Because of tissue necrosis, the Systemic Inflammatory Response ensues (“SIRS”) and many patients develop ARDS. Despite seemingly adequate therapy (parenteral heparin, steroids, antibiotics), the mortality remains high (approximately 50%).

The term ‘catastrophic’ antiphospholipid syndrome (CAPS) is defined as an accelerated form of antiphospholipid syndrome (APS) usually resulting in multiorgan failure. These patients have in common: (i) clinical evidence of multiple organ involvement developing in a very short time period; (ii) histopathological evidence of multiple small vessel occlusions (a minority also have large vessel thrombosis); and (iii) laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titres. Although less than 1% of patients with the APS develop this complication, its potentially lethal outcome emphasizes its importance in clinical medicine.

Objective: To describe and analyse the clinical characteristics of 100 patients with antiphospholipid syndrome (APS) associated with infections. Methods: Patients were identified by a computer assisted search (Medline) of published reports to locate all cases of APS published in English, Spanish, and French from 1983 to 2003. The bilateral Fisher exact test was used for statistics. Results: 59 female and 41 male patients were identified (mean (SD) age, 32 (18) years (range 1 to 78)): 68 had primary APS, 27 had systemic lupus erythematosus, two had “lupus-like” syndrome, two had inflammatory bowel disease, and one had rheumatoid arthritis. APS presented as a catastrophic syndrome in 40% of cases. The main clinical manifestations of APS included: pulmonary involvement (39%), skin involvement (36%), and renal involvement (35%; nine with renal thrombotic microangiopathy, RTMA). The main associated infections and agents included skin infection (18%), HIV (17%), pneumonia (14%), hepatitis C (13%), and urinary tract infection (10%). Anticoagulation was used in 74%, steroids in 53%, intravenous immunoglobulins in 20%, cyclophosphamide in 12%, plasma exchange in 12%, and dialysis in 9.6%. Twenty three patients died following infections and thrombotic episodes (16 with catastrophic APS). Patients given steroids had a better prognosis (p = 0.024). The presence of RTMA and requirement for dialysis carried a worse prognosis (p = 0.001 and p = 0.035, respectively). Conclusions: Various different infections can be associated with thrombotic events in patients with APS, including the potentially lethal subset termed catastrophic APS. Aggressive treatment with anticoagulation, steroids, and appropriate antibiotic cover is necessary to improve the prognosis.

We report on a 32-year old female patient with primary antiphospholipid syndrome (PAPS) and several thromboembolic events despite stable doses of oral anticoagulation, good patient compliance and maintained INR values of3. Over the preceding 3 years the patient had presented a wide spectrum of manifestations of APS, including recurrent venous and arterial thromboses, cardiac, gynecological (HELLP syndrome), neurological involvements, livedo reticularis, a mild thrombocytopenia and the most feared manifestation of the catastrophic antiphospholipid syndrome (CAPS). Life-threatening bilateral subdural bleeding occurred while she was anticoagulated. The clinical features appeared to be refractory to oral anticoagulation with phenprocoumon. They were life threatening on each occasion and she developed repetitive episodes of organ damage with cardiac insufficiency (NYHA III), pulmonary hypertension and other residual defects. Even during heparinization recurrent thromboembolism supervened as well as livedo reticularis of the extremities. Lupus anticoagulants (LAC), anticardiolipin (aCL) antibodies and anti-beta(2)-glycoprotein-1 (beta(2)GPI) titers were all markedly elevated. This case report shows that recurrent episodes of thrombosis can occur despite seemingly adequate anticoagulation in patients with CAPS.

The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to define an accelerated form of APS resulting in multiorgan failure. Although catastrophicAPS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the pre-symposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classification criteria. On the other hand, the optimal management of catastrophicAPS must have three clear aims: to treat any precipitating factors (prompt use of antibioticsif infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients.

The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous and arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or antibodies to the protein “cofactor” b2 glycoprotein I. Single vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Any combination of vascular occlusive events may occur in the same individual and the time interval between them also varies considerably from weeks to months or even years. Deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation in this syndrome. Cerebrovascular accidents—either stroke or transient ischemic attacks—are the most common arterial thrombotic manifestations. Early and late fetal losses, premature births and pre-eclampsia are the most frequent fetal and obstetric manifestations. Additionally, several other clinical features are relatively common in these patients, i.e., thrombocytopenia, livedo reticularis, heart valve lesions, hemolytic anemia, epilepsy, myocardial infarction, leg ulcers, and amaurosis fugax. However, a large variety of other clinical manifestations have been less frequently described in patients with the APS, with prevalences lower than 5%. These include, among others, large peripheral or aortic artery occlusions, Sneddon's syndrome, chorea, transverse myelopathy, intracardiac thrombus, adult respiratory distress syndrome, renal thrombotic microangiopathy, Addison's syndrome, Budd-Chiari syndrome, nodular regenerative hyperplasia of the liver, avascular necrosis of the bone, cutaneous necrosis or subungual splinter hemorrhages. In this article, some of these “unusual” manifestations are reviewed.

A 24-y-old male who developed necrotic lesions on the lower extremities together with testicular thrombosis necessitating orchiectomy, demonstrated high level IgG anticardiolipin (aCL) associated with acute HIV infection. This is one of the first cases describing a close relationship between viral infection and the classic antiphospholipid syndrome (APS). It is well documented that HIV patients may produce antiphospholipid antibodies (aPL), but the full-blown picture of the APS is distinctly uncommon with HIV or any other viral infection, possibly due to the overproduction of the IgM isotype rather than IgG aCL as in this case. The induction of thrombosis following infections has been well described in patients with catastrophic antiphospholipid syndrome (CAPS) but not in patients with the ‘classic or simple’ APS.

Antiphospholipid antibodies (APA) are a common cause of acquired thrombophilia. APA recognize plasma phospholipid-binding proteins (e.g., β2-glycoprotein I, prothrombin, annexin V, etc.). Catastrophic antiphospholipid syndrome (CAPS) is an uncommon variant of the antiphospholipid syndrome. CAPS patients often present with multiorgan failure. Precipitating factors include surgical procedures, drugs, and discontinuation of anticoagulant therapy. Increasingly, infections are recognized as a major precipitating condition. The majority of patients present with renal involvement as well as evidence of acute respiratory distress syndrome (ARDS). This review discusses the clinical and pathophysiologic aspects of CAPS as well as the differenital diagnosis. Am. J. Hematol. 65:154–159, 2000. © 2000 Wiley-Liss, Inc.

Chorea is a rare complication of systemic lupus erythematosus (SLE) and is strongly related to the presence of antiphospholipid antibodies. Various infections may also be triggering factors in the development of choreiform movements. Additionally, Salmonella infection is the most common opportunistic bacterial infection in SLE patients. We report a case of a 33-year-old woman with SLE who developed lupus erythematosus-associated chorea with multiple involuntary movements and cognitive disturbances. Because the methylprednisolone therapy administered appeared to lead to Salmonella enteritidis infection, intravenous immunoglobulin (IVIg) in a total dose 100 g was administered after which a remarkable improvement of the abnormal movements and cognitive function was noted. Within 7 days, the patient had returned to normal. We therefore conclude that IVIg therapy may be an effective therapeutic approach for the treatment of the acute cerebral complications of SLE, especially in cases in whom other therapeutic strategies are ineffective or harmful.

We analyzed the clinical and laboratory characteristics of 50 patients with catastrophic antiphospholipid syndrome (APS) (5 from our clinics and 45 from a MEDLINE computer-assisted review of the literature from 1992 through 1996). Thirty-three (66%) patients were female and 17 (34%) were male. Twenty-eight (56%) patients had primary APS, 15 (30%) had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 1 (2%) had rheumatoid arthritis. Mean age of patients in this series was 38 +/- 14 years (range, 11-74 yr). Three (6%) patients developed the clinical picture of catastrophic APS under the age of 15 years, and 11 (22%) were 50 years old or more. In 11 (22%) patients, precipitating factors contributed to the development of catastrophic APS (infections in 3, drugs in 3, minor surgical procedures in 3, anticoagulation withdrawal in 2, and hysterectomy in 1). The presentation of the acute multi-organ failure was usually complex, involving multiple organs simultaneously or in a very short period of time. The majority of patients manifested microangiopathy--that is, occlusive vascular disease affecting predominantly small vessels of organs, particularly kidney, lungs, brain, heart, and liver--with a minority of patients experiencing only large vessel occlusions. Thrombocytopenia was reported in 34 (68%) patients, hemolytic anemia in 13 (26%), disseminated intravascular coagulation in 14 (28%), and schistocytes in 7 (14%). The following antibodies were detected: lupus anticoagulant (94%), anticardiolipin antibodies (94%), anti-dsDNA (87% of patients with SLE), antinuclear antibodies (58%), anti-Ro/SS-A (8%), anti-RNP (8%), and anti-La/SS-B (2%). Anticoagulation was used in 70% of the patients, steroids in 70%, plasmapheresis in 40%, cyclophosphamide in 34%, intravenous gammaglobulins in 16%, and splenectomy in 4%. Most patients, however, received a combination of nonsurgical therapies. Death occurred in 25 of the 50 (50%) patients. In most, cardiac problems seemed to be the major cause of death. In several of these, respiratory failure was also present, usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Among the 20 patients who received the combination of anticoagulation, steroids, and plasmapheresis or intravenous gammaglobulins, recovery occurred in 14 (70%) patients. The use of ancrod and defibrotide appeared to be effective in the 2 respective patients in whom they were used.

A 61-year-old female with a history of previous digital ischemia and stroke, developed bilateral brachial artery thromboses thought originally to be due to fibromuscular hyperplasia. Histology from one artery revealed bland thrombi only with no evidence of vasculitis. Minimal elevations of anti-B2GP1 were demonstrated with levels of other isotypes measurable at just below cut off levels for normality. Three months later, she developed carcinoma of the breast, which required surgical treatment followed by chemotherapy. Three years later, all aPl determinations were negative with levels well below the cutoff levels for all isotypes. The minimal anti-B2GP1 elevation may have been triggered by the vascular damage caused by the thromboses or may perhaps have been pathogenic in the causation of these thromboses. An alternative explanation is that the antibodies may have presaged the development of the malignancy. To favour any one of these explanations remains highly speculative.