Recurrent deep vein thrombosis, ovarian carcinoma and antibodies to mitochondria M5 in a patient with asymptomatic primary "plus" antiphospholipid syndrome: an unusual combination.

An asymptomatic thirty-eight-year-old female developed recurrent DVT at the latter end of her first pregnancy and in the puerperium. Blood tests revealed a moderately elevated ANF (1:640) with a speckled pattern, hyperglobulinemia, and antibodies to thyroid tissues. Two months postpartum, following neurological disturbances she was found to have a patent foramen ovale and had developed paradoxical emboli to the brain causing multiple arterial occlusions. However, she also had cerebral venous occlusions as well as deep venous thromboses and pulmonary emboli, indicating a generalised prothrombotic state. Abdominal ultrasound examination revealed the presence of tumour which, on surgical removal, proved to be an ovarian carcinoma. The only antiphospholipid antibodies detectable were antibodies to mitochondria Type M5 in moderately elevated titres.

High titres of IgM-antiphospholipid antibodies are unrelated to pathogenicity in patients with non-Hodgkin's lymphoma.

Heterogeneity in the mechanisms of coagulation may contribute to an increased thrombotic risk for patients with malignancies. The coincidence of malignancies and antiphospholipid antibodies (aPL) have been described in several important epidemiological studies. The pathological significance of aPL in patients with malignancies is, however, still unclear. In this study, we investigated the clinical manifestations of four patients with elevated IgM-aPL titres lying outside the region signifying 95% of normal cases and with a history of non-Hodgkin's lymphoma. The patients had elevated IgG- and IgM-anticardiolipin antibodies (aCL) and also tested positive for lupus anticoagulants. Other aPL were measured, and we found high positive results for all tested antibodies in three patients. The production of aPL, however, occurred in the absence of thrombotic complications. No thromboembolic manifestations occurred during the follow-up period either. It could also be demonstrated that the degree to which the aCL titre was elevated resembles the elevation of the non-classical antiphospholipid antibodies, but not that of beta2-GP-1 or anti-annexin antibodies. Therefore, it can be postulated that these extremely high levels of IgM-aCL antibodies do not enhance the risk of thrombosis and may be completely different from aCL antibodies in an antiphospholipid syndrome patient population without malignancies. In particular, haematological and lymphoproliferative malignancies may indeed be associated with the generation of aPL, but do not necessarily enhance the thrombophilic risk in these patients.

"Primary" antiphospholipid syndrome evolving into Waldenstrom's macroglobulinaemia: a case report.

A 57-year-old woman with a history of transient ischaemic attacks and six recurrent foetal losses accompanied by elevations of antiphospholipid antibodies was diagnosed as having a "primary" antiphospholipid syndrome. She was followed up for 5 years, and she developed anaemia, leucopenia and splenomegaly. A bone marrow trephine was diagnostic of Waldenstrom's macroglobulinaemia. A false positive serological test for syphilis was demonstrated and apparently had been noted in her second pregnancy more than 20 years prior to her presentation with an antiphospholipid syndrome. There had previously been no indication to perform serum electrophoretic studies. This case illustrates the importance of this investigation in any middle-aged patient presenting with an antiphospholipid syndrome and a monoclonal gammopathy This finding might presage the development of a more serious condition, even years later (as in our patient).

Efficacy of intravenous immunoglobulin treatment in lupus erythematosus chorea.

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.

The role of malignancies in patients with catastrophic anti-phospholipid (Asherson's) syndrome.

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.

Severe limb necrosis: primary thrombotic microangiopathy or "seronegative" catastrophic antiphospholipid syndrome? A diagnostic dilemma.

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.

Catastrophic antiphospholipid (Asherson's) syndrome and genetic thrombophilic disorders in obstetrics.

Catastrophic antiphospholipid syndrome (CAPS) (Asherson's Syndrome), is a life-threatening condition characterized by a rapidly progressive thromboses resulting in a multiorgan dysfunction syndrome (MODS), evidence of systemic inflammatory response syndrome (SIRS) in the presence of antiphospholipid antibodies. CAPS differs from the classic APS by predominantly affecting small vessels, involvement of unusual organs, rapid onset of MODS, and the development of acute respiratory distress syndrome (ARDS) in 25% of patients, which is a feature of SIRS. Obstetric-related multiorgan failure may be a feature of a subset of CAPS more frequently than was previously thought. Patients with obstetric complications should be tested for antiphospholipid antibodies and genetic thrombophilia in order to institute early prophylaxis. Low-molecular-weight heparin is the drug of choice for preventing obstetric complications and CAPS due to its anticoagulant and anti-inflammatory properties.

The catastrophic antiphospholipid (Asherson's) syndrome and malignancies.

The catastrophic antiphospholipid syndrome is characterised by the rapid chronological development of fulminant thrombotic complications that predominantly affect small vessels. It has been reported as frequently occurring in patients with underlying malignancies. We analysed the web site-based international registry of patients with catastrophic APS. The clinical characteristics of patients with CAPS and an underlying malignancy were evaluated. Of the 262 patients included in the CAPS registry, information on associated malignancies was available in 23 (9%) cases. Haematological malignancies were present in 6 (26%) patients. Four of the patients suffered from lung carcinoma (17%), and two patients (9%) from colon carcinoma. In most of the patients (61%), malignancy was the precipitating factor for CAPS. In 4 patients (17%), however, surgical procedures related to the carcinoma were noted as precipitating factors. In one patient CAPS occurred during allogenic stem cell transplantation after diagnosis of acute lymphoblastic leukemia (ALL). Cerebral manifestations were most common and consisted mainly of cerebral infarcts and encephalopathy. Recovery occurred in 9/23 (39%) patients. Malignancy may be an important risk factor for CAPS. 9% of patients with CAPS presented with an underlying malignancy. In most of these patients, the malignancy and/or surgical procedures were the precipitating factors for CAPS.

The antiphospholipid antibody syndrome: diagnosis, skin manifestations and current therapy.

Antiphospholipid antibody syndrome is characterized by venous and/or arterial thrombosis and/or pregnancy morbidity associated with antiphospholipid antibodies (aPL), such as anticardiolipin antibodies, anti beta 2 glycoprotein I antibodies and positive lupus anticoagulant test. This syndrome may potentially affects any organ system including the skin. Livedo reticularis is the most frequently observed cutaneous lesion; other lesions, by order of frequency, are ulcerations, digital gangrene, subungueal splinter hemorrhages, superficial venous thrombosis, thrombocytopenic purpura, pseudovasculitic manifestations, extensive cutaneous necrosis and primary anetoderma. Skin lesions are more frequently observed in the catastrophic antiphospholipid syndrome, characterized by widespread microvascular occlusions involving multiple organs simultaneously. Patients with antiphospholipid associated thrombosis should receive long-term oral anticoagulants. The intensity of anticoagulation should be guided according to the nature of the thrombotic event (venous vs. arterial thrombosis). Patients with aPL-associated pregnancy morbidity should be treated with aspirin plus heparin and closely monitored during pregnancy. The treatment of the catastrophic antiphospholipid syndrome remains unsatisfactory. High dose intravenous steroids and parenteral anticoagulation should be supplemented by intravenous gammaglobulin and repeated plasma exchanges using fresh frozen plasma early on in the course of the syndrome.

Thrombosis, recurrent fetal loss, and thrombocytopenia. Predictive value of the anticardiolipin antibody test.

To determine the predictive value of the IgG anticardiolipin antibody (ACA) test for thrombosis, recurrent fetal loss, and thrombocytopenia, the clinical features of 121 patients with varying antibody levels were studied. When patients were grouped into high-positive, low-positive, and normal groups according to their ACA levels, there were strong statistical correlations with arterial thrombosis, venous thrombosis, fetal loss, thrombocytopenia, and a positive Coombs' test. At levels of 7 SD and above, the test was highly specific (greater than 80%) and predictive (greater than 70%) for thrombosis, thrombocytopenia, and recurrent fetal loss. This study suggests that the IgG ACA test may be a useful predictor for thrombosis, recurrent fetal loss, and thrombocytopenia in patients with autoimmune disorders.

Antiphospholipid syndrome.

The antiphospholipid antibodies (aPL), namely, the lupus anticoagulant and the anticardiolipin antibodies, are a family of autoantibodies directed predominantly against negatively charged phospholipids. Many studies have confirmed that patients with these antibodies are prone to repeated episodes of thrombosis, fetal losses, and thrombocytopenia. The association of aPL with these clinical events has been termed the antiphospholipid syndrome. Several skin lesions have been found in patients with this syndrome, including livedo reticularis, livedoid vasculitis, thrombophlebitis, cutaneous infarctions and gangrene of digits, ulcerations, lesions resembling vasculitis (nodules, macules), cutaneous necrosis/infarctions, subungual splinter hemorrhages, and, less commonly, discoid lupus and Degos' disease (malignant atrophic papulosis). In this article, we review the main immunologic and clinical aspects of this syndrome with special emphasis on the dermatologic features.

Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.

We analyzed the clinical, radiologic, and immunologic characteristics of 50 patients with chorea and the antiphospholipid syndrome (APS) (6 from our clinics and 44 from a MEDLINE computer-assisted review of the literature from 1985 through 1995). Forty-eight (96%) patients were female and 2 (4%) were male. Twenty-nine (58%) patients had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 15 (30%) patients had "primary" APS. Mean age of patients in this series was 23 +/- 12 years (range, 6-77 yr); mean age at presentation of chorea was 21 +/- 12 years (range, 6-77 yr). In 11 (22%) patients, the onset of chorea was in childhood (6-14 yr), and in 2 (4%) patients it presented at 60 years or more. Six (12%) patients developed chorea soon after they started taking estrogen-containing oral contraceptives, 3 (6%) developed chorea gravidarum, and 1 (2%) patient developed chorea shortly after delivery. Most patients (66%) presented only 1 episode of chorea. Chorea was bilateral in 55% of patients. Computed tomography and magnetic resonance imaging scans reported cerebral infarcts in 35% of patients. The following antibodies were detected: lupus anticoagulant (92%), anticardiolipin antibodies (91%), antinuclear antibodies (82%), anti-DNA (59%), anti-Ro (10%), anti-RNP (8%), anti-La (2%), and anti-Sm (2%). The chorea in these patients responded to a variety of medications, for example, steroids, haloperidol, antiaggregants, anticoagulants, or a combination of therapy, usually prescribed in the presence of other manifestations of APS or SLE. However, many patients responded well to haloperidol and to the discontinuation of oral contraceptives if this was the precipitating factor.

The "primary" antiphospholipid syndrome: major clinical and serological features.

The antiphospholipid syndrome--the association of venous and/or arterial thromboses, often accompanied by thrombocytopenia in the presence of the antiphospholipid antibodies ("lupus anticoagulant" antibodies to cardiolipin)--is seen mainly in patients with systemic lupus erythematosus (SLE) and the closely related "lupus-like" disease, i.e., lupus patients not conforming to the 1982 revised American Rheumatism Association classification for SLE. It is also seen in a group of patients who do not manifest any of the major clinical or serologic features of SLE, the majority of whom do not appear to progress to classical lupus. A multicenter study of 70 of these patients is documented and their major clinical and serologic characteristics examined: They have been characterized as suffering from a "primary" antiphospholipid syndrome and present typically with a history of deep vein thromboses, often accompanied by pulmonary thromboembolism, which in a few is complicated by thromboembolic pulmonary hypertension, arterial occlusions (most commonly strokes), or fetal loss. The events are often recurrent and may be accompanied by hemocytopenias (thrombocytopenia and less frequently Coombs positivity and/or hemolytic anemia). They are often antinuclear antibody-negative and are always negative for antibodies to dsDNA and to ENA, typical serologic features of SLE. There may be a family history of SLE or a familial clotting tendency in a minority. The group of patients presented appears to be closely related, but distinctly separate from SLE.

Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients.

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.

Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome.

PURPOSE AND PATIENTS AND METHODS: Antiphospholipid antibodies, lupus anticoagulant antibodies to cardiolipin, and a false-positive result on testing for syphilis have been linked to thrombotic vascular occlusions, particularly in patients with systemic lupus erythematosus (SLE) or lupus-like disease, i.e., patients not fulfilling four American Rheumatism Association criteria for the classification of SLE. The clinical and serologic features of 35 patients with cerebrovascular disease (strokes/transient ischemic attacks) who demonstrated antibodies to phospholipids are presented. Complete histories were obtained from all 35 patients, and all underwent routine physical examinations, radiography, electrocardiography, computed tomographic brain scanning, and immunologic studies. Psychometric tests were performed in nine patients. RESULTS: The strokes were often multiple and were followed by multi-infarct dementia in nine patients. Of particular interest were 10 patients in whom the presence of antiphospholipid antibodies was the major and often the sole immunologic disturbance present. Several of these patients were antinuclear antibody-negative, and the antinuclear antibodies, when present, were usually of a low titer (1:40 to 1:160). These patients conform to a group classified as having a primary antiphospholipid syndrome. CONCLUSION: Antiphospholipid antibodies are strongly associated with cerebrovascular occlusions in patients with SLE as well as in those with lupus-like disease and the primary antiphospholipid syndrome. All patients with any of these conditions who present with vascular events should be screened for these antibodies, as their occurrence may have a bearing on future therapy.

Clinicopathologic correlations of the antiphospholipid syndrome.

Since the original description and definition of the antiphospholipid syndrome (APS), a number of distinct clinical manifestations related to it have appeared in the literature. These include vascular obstruction of both veins and arteries, thrombus formation on the endocardium and its consequences, as well as a group of other conditions where vascular obstructive mechanisms are either incompletely understood or unproven, eg, chorea, avascular necrosis, and pulmonary hypertension. Single vessel (large/medium) involvement or multiple vascular occlusions may cause 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. Rapid chronological occlusive events occurring over days to weeks have been termed the "catastrophic" APS. Most of these complications may be ascribed to the hypercoagulable state of which antiphospholipid antibodies appear either to be "markers" or intimately connected with the highly complex coagulation mechanisms resulting in thrombotic occlusions.

Urticarial vasculitis in a connective tissue disease clinic: patterns, presentations, and treatment.

Findings in 27 patients with typical skin lesions of urticarial vasculitis (UV) who were seen at a connective tissue disease clinic over a 5-year period (1986 to 1990) are reviewed. The majority suffered from systemic lupus erythematosus (SLE) or from "lupus-like" disease (18 patients), 1 from "mixed" connective tissue disease (MCTD), and 5 from primary UV. All of the latter patients had normal serum complement levels (normocomplementemic urticarial vasculitic syndrome; NUVS). No patients with hypocomplementemic UV were encountered. Two patients suffered from necrotizing vasculitis (polyarteritis nodosa, Wegener's granulomatosis); one had a C1-esterase inhibitor deficiency and also demonstrated an immunoglobulin G paraproteinemia. Angioedema occurred in many patients and could not be used as a differential diagnostic feature. The course of the illness was chronic in most patients, lasting for up to 23 years, and the response to therapy was unpredictable, erratic, and unsustained. The use of intravenous "pulse" methylprednisolone, cyclophosphamide, or high-dose oral steroids helped selected patients. Colchicine was dramatically effective in one patient with NUVS of 15 years duration. Azathioprine was not beneficial. None of the five patients with NUVS suffered from severe systemic involvement or renal disease, confirming observations by others that this form of UV represents a milder example of the condition.

Adult-onset polymyositis-dermatomyositis: description of 25 patients with emphasis on treatment.

A retrospective study of 25 patients with polymyositis-dermatomyositis (PM-DM) is analyzed with special attention to the effects of therapy and follow-up. All patients (100%) complained of muscle weakness and 68% of these demonstrated typical skin changes of DM. All patients, except 2, received corticosteroids at the onset of the disease, 23 were treated with azathioprine, 7 received cyclophosphamide, 4 methotrexate, and 1 had total body irradiation. Among the patients adequately treated with azathioprine, 75% had a good response, but 5 patients did not improve. Cyclophosphamide was used subsequently in 2, with a satisfactory response in 1. Another patient had a striking response to oral methotrexate, and total body irradiation helped to improve another patient. Although high dose corticosteroids were the preferred starting medication for the treatment of PM-DM, it is important to detect those patients who do not respond adequately and/or develop side effects. In these circumstances, the prompt use of immunosuppressive agents appears justified.

Catastrophic antiphospholipid syndrome: remission following leg amputation in 2 cases.

OBJECTIVE: The antiphospholipid syndrome is characterized by venous and arterial thrombotic events that are often recurrent, thrombocytopenia, recurrent fetal loss, and elevated titers of antiphospholipid antibodies. A subtype of patients with a particularly overwhelming clinical picture has been termed catastrophic antiphospholipid syndrome (CAPS). In this report, we present 2 patients who exhibited a similar multisystem disorder associated with gangrenous changes in the lower extremities. METHODS: Two patients with CAPS are presented, highlighting the impact of this disorder on the patients and the response to various therapeutic modalities. RESULTS: Both patients had pulmonary, cardiac, cutaneous, and neurologic findings consistent with CAPS. In addition, they had large purulent leg ulcers associated with livedo reticularis. Amputation of the legs in each case induced remission of the systemic illness. CONCLUSIONS: We believe that infection plays a significant role in the pathogenesis and amplification of the antiphospholipid syndrome. In certain patients, this association probably is mediated via immune mechanisms, which also enhance the genesis of atherosclerosis. After the foci of infection (suppurative leg ulcers) were removed, the underlying illness improved. These case studies provide an opportunity to study the interrelationship between several confounding factors that converge and lead to the development of this autoimmune condition.

Chorea in systemic lupus erythematosus and "lupus-like" disease: association with antiphospholipid antibodies.

Twelve patients with chorea from a population of 500 patients with SLE and "lupus-like" disease were reviewed. Clinical histories, including time relationships of chorea to the systemic illness and other neurologic manifestations, are reported. Chorea appeared early in the course of disease in most patients, but the development of cerebral infarctions or TIAs occurred subsequently in seven of nine patients demonstrating antiphospholipid antibodies. The relationship of chorea to the presence of these antibodies in nine of 12 patients and the therapeutic outcome are briefly discussed.