Crit Care Clin 18 (2002) 805 817

Catastrophic antiphospholipid syndrome in the intensive care unit

Gloria E. Westney, MDa,*, E. Nigel Harris, MDb
a

Pulmonary/Critical Care Section, Department of Medicine, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA b Dean and Senior Vice President for Academic Affairs, Department of Medicine, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA

Antiphospholipid syndrome (APS), a condition resulting from derangements of the coagulation system and causing systemic episodes of thrombosis, has been described in the literature over the past 40 years. In 1963, the first description of thrombosis occurring in patients with circulating anticoagulants was soon followed by a report of similar manifestations in patients diagnosed with systemic lupus erythematosus (SLE) [1,2]. Introduction of the anticardiolipin test led to identification of increased numbers of patients, many of whom did not have SLE but who manifested systemic thrombosis or recurrent pregnancy losses [3]. The term antiphospholipid syndrome was introduced to define this group of patients who exhibited episodes of thrombosis, thrombocytopenia, or recurrent fetal loss, with increased antiphospholipid antibodies (aPL) in the circulation manifest by positive anticardiolipin antibodies (aCL) or lupus anticoagulation (LA) tests [4 7]. In the late 1980s, reports described a subset of patients with APS who exhibited a fulminant clinical course with widespread vascular occlusions, often leading to rapid demise [8 16]. In 1992, Asherson categorized the presentation of this clinical entity and introduced the term catastrophic antiphospholipid syndrome (CAPS) to describe these patients [17]. Catastrophic antiphospholipid syndrome was defined as a vaso-occlusive process, involving at least three organs, in association with elevated levels of circulating aCL or a positive LA finding. Thrombocytopenia and microangiopathic hemolytic anemia (often Coombspositive) were often present. The syndrome can occur in patients with primary or secondary (with concomitant SLE) APS, and less frequently in patients with other rheumatologic diseases or without a previous history of thrombosis [18,19]. The mortality of CAPS was reported to be as high as 50% in one series of patients, with cardiopulmonary failure being the most frequent cause of death [20]. Besides
* Corresponding author. E-mail address: westneg@msm.edu (G.E. Westney). 0749-0704/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 7 0 4 ( 0 2 ) 0 0 0 2 6 - X

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the initial description of 10 cases in 1992 [17], additional case series reporting 50 [20] and now 80 [21] patients with CAPS have provided information regarding its pathogenesis, clinical characteristics, and manifestations.

Pathology and pathophysiology The predominant pathology in CAPS is a noninflammatory, thrombotic microangiopathy of small vessels resulting in multiorgan failure [18]. The pathophysiology of CAPS seems to involve derangements in the coagulation process causing continued and widespread thrombosis within the microvascular circulation. Antiphospholipid antibodies present in the serum of these patients represent a group of immunoglobulins that bind plasma proteins (such as b2-glycoprotein I [b2-GPI]), prothrombin, annexin, high and low molecular weight kininogens) [22 25], or phospholipid microparticles in the circulation [26]. Antibody binding to proteins on the cell surfaces of platelets, monocytes, tumor cells, or endothelial cells can result in activation of these cells leading to a procoagulant state. For example, endothelial cells, when activated, increase the expression of adhesion molecules, promoting leukocyte adhesion to endothelial surfaces and thus promoting thrombosis [27 29]. Antiphospholipid antibodies have also been implicated in promoting thrombosis by inhibiting the decreased expression of activated factors V and VIII, causing increased thrombin production [18,30,31]. Also, during the process of coagulation, the presence of fresh clots can potentiate coagulation activation products in the plasma [32,33], resulting in depletion of antithrombin III, protein C, or protein S. The term thrombotic storm has been used to describe this process in an underlying hypercoagulable state [34]. The widespread, microvascular thrombosis seen in CAPS causes tissue ischemia and necrosis, leading to a clinical picture similar to the systemic inflammatory response syndrome (SIRS) seen in clinical settings such as trauma, septic shock, and so forth [18]. SIRS is characterized by activation of cells (ie, monocytes and macrophages, endothelial cells, neutrophils) with release of inflammatory mediators that affect hemostasis through the extrinsic pathway, inducing plasminogen activator inhibitor type-1, resulting in altered hemostasis, increased coagulation, and microvascular fibrin deposition [35]. Possibly, by its action on endothelial cells, aPL, alone or as a component of antibody-antigen complexes, can induce a picture akin to SIRS.

Clinical presentation of CAPS Patient history Early recognition of CAPS is important for effective intervention and patient survival. Knowledge of the patients history may be helpful. A previous diagnosis of APS with prior thrombotic episodes may be present. Previous symptoms

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and signs of APS are reported to be present in 49% to 66% of patients presenting with CAPS [20,21]. Most frequently, deep vein thrombosis (DVT), recurrent fetal loss, and thrombocytopenia are reported in the history. Evidence of previous major venous or arterial occlusive episodes should be sought. Such episodes may include pulmonary embolism (PE), superior or inferior vena caval thrombosis, myocardial infarction, cerebrovascular accidents, adrenal and renal infarction, and mesenteric and splenic artery thrombosis [20]. Other manifestations are retinal artery occlusions, digital ischemic episodes, renal artery occlusion, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, livedo reticularis, nonhealing leg ulcers, nasal septal perforation, heart valve lesions, hemolytic anemia, and chorea [20,21]. Precipitating factors Up to 22% of the patients may have identifiable precipitating factors [20]. Infections have been identified as dominant triggers in up to one third of patients. Organisms include Escherichia coli, Shigella, Salmonella, Streptococcus, and Staphylococcus, with sites originating from the upper respiratory, urinary, and gastrointestinal tracts, the skin, and central venous line sites [18]. Evidence suggests that some infectious agents can induce antibodies to phospholipids and b2-GPI [36,37], and production of these antibodies may in turn trigger CAPS [20,21]. Trauma [38], surgical procedures such as biopsy [39], endoscopic retrograde cholangiopancreatography (ERCP) [40], arterial manipulation [41], pregnancy, and postfetal demise [42,43] have all been cited as precipitating CAPS. Induction of autoimmune disease processes secondary to stress [44] and increased production of tissue factors following invasive procedures [45] are possible explanations for this association. The association of malignancies with CAPS emerged from the most recent case series and was implicated as a precipitating factor in 8% of patients [21]. Some solid tumors have been associated with aPL positivity [46], contributing to a procoagulant state that may be involved in CAPS development. Clinical settings that cause formation of fresh clots (gangrenous limbs with major vessel occlusions) in an underlying hypercoagulable state may incite the aforementioned thrombotic storm [18,34]. Withdrawal of anticoagulation therapy or a decrease in the international normalized ratio (INR) may lead to recurrent thrombosis and development of CAPS [18]. The cessation of anticoagulation therapy in preparation for surgical or dental procedures, administration of drugs affecting the metabolism of warfarin (barbiturates, carbamazepine, rifampin, phenytoin), or gastrointestinal problems that result in poor absorption of anticoagulant medication are clinical scenarios that may be implicated. Additional situations cited as precipitating factors include SLE flares and use of oral contraceptives and the drugs thiazide and captopril [20,21]. In approximately 35% of patients, a causative factor was not identified [21].

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Presentation Progression to CAPS can occur within days to weeks [20]. The presentation is one of simultaneous or rapidly progressing multiorgan failure. Although thrombosis of large cerebral and peripheral vessels (DVT causing PE) can occur, this condition is present only in 15% to 20% of patients. Widespread thrombotic microangiopathy seems to be the basic pathologic condition in whatever organ is examined [18]. The patient progressing to CAPS should be evaluated for a wide range of systemic signs and symptoms occurring simultaneously. In the series of 50 patients summarized by Asherson, renal involvement was present in 78%, followed by lung (66%), central nervous system (CNS) (56%), skin and heart (50%), gastrointestinal (38%), and adrenal gland (26%) involvement [20]. Involvement of the pancreas, spleen, thyroid gland, muscles, and peripheral nerves has also been cited [47]. In the most recent series of patients with CAPS, manifestations on initial presentation were cardiopulmonary (25%), CNS abnormalities (22%), abdominal pain (22%), and renal abnormalities (14%) [21]. It is progressive cardiopulmonary failure, however, that brings patients to the ICU needing acute life-saving intervention.

Organ involvement in CAPS Pulmonary features and manifestation Pulmonary complications described in patients with primary or secondary APS include PE with or without infarction, pulmonary hypertension (PHT), pulmonary arterial thrombosis, pulmonary in situ microthrombosis, alveolar hemorrhage, and a case of fibrosing alveolitis [48]. These entities may be present when CAPS develops, but the dominant feature in CAPS is the clinical picture of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) [18,20,21]. ALI and ARDS represent a spectrum of injury to the lung capillary endothelial and epithelial surfaces resulting in pulmonary edema and hypoxemia. Criteria are bilateral infiltrates seen on chest radiograph, absence of left atrial hypertension (pulmonary artery wedge pressure  18 mm Hg) and a partial pressure of arterial, oxygen to fraction of inspired oxygen (PaO2/FIO2) ratio of 300 mm Hg or less (in ALI) or of 200 mm Hg or less (in ARDS) [49]. In the series of 50 patients with CAPS, 66% had some pulmonary symptoms or abnormality. In reported case series [20,21], 34% to 41% of patients developed ARDS. Seven case reports provide some details regarding the features of ARDS [14,50 53]. The typical scenario is worsening dyspnea and hypoxemia resulting in the need for intubation and mechanical ventilation. Pulmonary examination reveals localized or diffuse crackles, and chest radiographs show bilateral infiltrates suggestive of pulmonary edema. Computed tomographic (CT) scan-

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ning of the thorax may show evidence of PE, pleural effusions, basilar atelectasis, and diffuse ground-glass opacities [53]. The development of ARDS may reflect an acute increase in hydrostatic pressure from occluding pulmonary emboli or result from microvascular emboli causing vascular endothelial damage with neutrophil influx and release of cytokines. Alveolar hemorrhage is also reported but occurs less frequently. Diagnosis has been by bronchoscopy, with hemosiderin-laden alveolar macrophages and erythrocytes seen in bronchoalveolar lavage (BAL) fluid [53] or at autopsy [51]. Pulmonary artery catheter (PAC) measurements obtained in four cases supported the presence of PHT and showed normal cardiac output and pulmonary capillary wedge pressures [50,52,53]. In one novel case [52], BAL fluid was obtained after the development of CAPS in a patient with primary APS and was compared with fluid from a control group. The percentages of BAL neutrophils, total protein, and albumin were increased over those in controls. There were also high levels of antiphosphatidylserine and antiphosphatidic acid IgG antibodies and a quantitative and qualitative deficiency of surfactant phospholipids in the BAL fluid [52]. Autopsy reports have described interstitial and alveolar hemorrhage without evidence of vasculitis [51], diffuse alveolar damage with signs of chronic interstitial inflammation [53], extensive infarction with thrombi in alveolar capillary lumen, and interstitial fibrosis [54]. Cardiac features and manifestation Cardiac involvement has been described in APS. Abnormalities include valvular vegetations indistinguishable from Libman-Sacks endocarditis, other valvular abnormalities that may be associated with hemodynamic abnormalities, coronary artery occlusions resulting in myocardial infarction, and thrombus formation within the cardiac chambers [55,56]. When CAPS develops, a range of abnormalities can be seen. Case reports describe a presentation of acute and progressive dyspnea and radiographic evidence of cardiomegaly and pulmonary infiltrates with or without pleural effusions, consistent with decompensated congestive heart failure (CHF). Microvascular thrombi involving the myocardium have been reported as the prominent feature causing cardiac failure and circulatory collapse [20]. Left ventricle dilatation with global hypokinesis has been shown by transthoracic echocardiography (TTE) [57,58]. As more cases have been reviewed, a better picture of cardiac involvement in CAPS has been obtained. In the series of 50 CAPS patients, 36% had myocardial involvement, and 32% had valve abnormalities with mitral, aortic, and tricuspid valvular incompetence being noted [20]. In the later series of 80 patients, there were episodes of valvular lesions in 31%, diagnosis of myocardial infarction in 20%, and diagnosis of heart failure in 16% of patients presenting with CAPS. Pericardial effusions and atrial thrombi were described in 2 cases each, at CAPS presentation [21]. These lesions may be seen together. The simultaneous occur-

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rence of acute myocardial infarction, valvular marantic vegetations, and pericarditis was reported in one case [59]. Transesophageal echocardiography (TEE) in this case revealed vegetations consistent with Libman-Sacks endocarditis that was missed on TTE. There is interest in obtaining more information regarding the presence of aCL and its effects on cardiac function. Some evidence suggests that aCL may be associated with decreased left ventricular systolic and diastolic function [60], and left ventricular diastolic dysfunction has been documented in CAPS [59]. A study of TTE patients with primary or secondary APS found more severe right ventricular diastolic dysfunction, independent of valvular disease and systolic dysfunction, in patients with primary APS. PHT (shown to be present by PAC measurements during CAPS presentation) and primary APS were strong independent predictors of more severe right ventricular diastolic impairment [61]. PHT and myocardial ischemia are associated with a poor prognosis in patients with APS [62]. The pre-existence of these clinical entities may influence the manifestations of cardiac abnormalities in the patient presenting with CAPS. Information gained from diagnostic procedures, such as echocardiography, may become helpful in management. Renal features and manifestation There seems to be a strong association between intrarenal thrombosis and APS with or without accompanying autoimmune disease (such as SLE). In patients with SLE, up to 32% of renal biopsies show thrombi [63], and in a series of patients with primary APS, 31% of biopsies had thrombotic microangiopathy with fibrin thrombi in arterioles and glomeruli [47,64]. In CAPS, renal abnormalities are reported as the initial presentation in 14% of patients. Renal abnormalities during CAPS are quite common, however, and represent 72% of thrombotic manifestations [21]. Laboratory abnormalities that can be encountered on initial presentation include elevated blood urea nitrogen and creatinine levels, with the urinalysis showing hematuria, proteinuria, hyaline, or granular casts in the urine sediment. Renal failure may initially be nonoliguric but can rapidly progress to oliguria with development of edema and the need for urgent dialysis [11,20,21,47]. The usual histopathologic picture is renal thrombotic microangiopathy of the glomerular capillaries and small renal arteries [18,47]. Changes of proliferative [11,20] and crescentic glomerulonephritis [47] have been reported in autopsies, suggesting that aCL may be involved in causing glomerular wall damage [47,65]. Systemic hypertension is also a prominent feature in APS, being present in 93% of patients [64]. With the development of CAPS, there is often the presentation of malignant hypertension that requires management, along with further worsening of renal function [21]. If CAPS presentation is dominated by myocardial failure or by infection with sepsis, however, hemodynamic support with vasopressor and inotropic agents is required.

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CNS features and manifestations A range of CNS findings have been reported in CAPS. Altered mental status causing stupor and coma, or seizures (with status epilepticus, uncommonly) can compromise respiratory function, resulting in the need for intubation and mechanical ventilation [20]. The predominant pathology is microthombi or microinfarctions in the brain, reported in 26% of patients in one series, with large vessel infarctions seen less frequently (in 13%) [20]. Other reported manifestations include retinal artery thrombosis [58], mononeuritis multiplex, and pituitary gland necrosis [20]. Intra-abdominal features and manifestation Abdominal pain (with or without nausea and vomiting) is a common presenting symptom. Diffuse abdominal tenderness may be elicited on examination [18,20,21]. Hepatic involvement is reported in 34% to 37%, splenic involvement in 17% to 20%, and pancreatic involvement in 12% of CAPS manifestations. Liver and pancreatic enzyme levels may be elevated. [20,21]. Vascular occlusions (of hepatic, splenic, bowel, or pancreatic vessels) seem to be common, and arterial occlusions may result in bowel gangrene or splenic infarctions [20]. Esophageal perforation with mediastinitis, ischemic colitis, and acalculous ischemic necrosis of the gallbladder have also been reported [20]. Adrenal gland involvement is reported in APS [66], but complications in CAPS seem to be higher than anticipated. In the 2001 series of 80 CAPS patients, 10% of thrombotic episodes involved the adrenal glands [21], and 26% of patients from the 1998 series had adrenal involvement [20]. Autopsy findings have reported multiple adrenal thrombi, bilateral hemorrhagic necrosis, and adrenal infarction [20]. Adrenal gland involvement seems to be frequently missed in the ICU CAPS patient. Sudden collapse in a patient receiving heparin therapy for PE may be mistakenly attributed to recurrent embolism [21]. Patients presenting with CAPS may often already be taking steroids as part of their management, and adrenal insufficiency may be unmasked only as steroid use is being discontinued [20]. Abdominal and flank pain, hypotension poorly responsive to vasopressor agents, and laboratory findings of hyponatremia with or without hyperkalemia suggest adrenal hypofunction. Evaluating the cortisol level, performing an adrenocorticotropic stimulation test, and CT imaging of the abdomen can provide a timely diagnosis [20,21,50]. Skin and extremity features and manifestation Skin involvement is common in CAPS and has been reported in 50% to 52% of patients [20,21]. Manifestations include livedo reticularis, digital ischemia, splinter hemorrhages, ulcerations, and superficial gangrene in the lower limbs, cheeks, and ears [20]. Evidence of previous large vessel thrombosis (gangrene, or amputation) may be apparent on presentation. Isolated or multiple new lesions reflecting ongoing microvascular thrombosis may become evident as CAPS

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progresses. Gangrene of the extremities is associated with a worse prognosis in patients with APS [62]. Recognizing these lesions when CAPS develops may aid significantly in making the diagnosis. In the 2001 patient series, the occurrence of bone marrow necrosis in 7% of the patients was greater than expected [21]. More frequently associated with neoplasms, sickle-cell disease, and severe bacterial infections, bone marrow necrosis has been described in patients with APS, most of whom suffered from CAPS. The reasons for bone marrow necrosis in these patients are not fully known [21]. Laboratory findings Consistent serologic findings in CAPS are elevated titers of aCL (usually of the IgG type) or positive LA [20,21]. Both tests were positive in 94% of CAPS patients in the 1998 series [20], whereas LA was detected in 68% of patients and aCL titers were positive in 98% of patients tested in the 2001 series [21]. Serologic studies for antinuclear antibodies (ANAs) were positive (usually in low titers) in 58% to 63% of patients and were positive for anti-double-stranded DNA antibodies in 53% to 87% of patients with concomitant SLE [20,21]. The presence of anti-Ro, anti-RNP, and anti-La was uncommon [20]. Recent reports have focused on the presence of increased b2-GPI antibody levels in patients presenting with CAPS [67 69]. Thrombocytopenia, reported in 60% to 68% of patients, a Coombs-positive hemolytic anemia in 26% to 39%, features of disseminated intravascular coagulation (DIC) in 19% to 28%, and schistocytes detected on peripheral blood smear in 9% to 14% of patients are other hematologic findings observed in CAPS [20,21]. Differential diagnosis The presence of thrombocytopenia, hemolytic anemia, schistocytes, and features of DIC may cloud the diagnosis of CAPS. Entities to be considered in the differential diagnosis of CAPS include thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT), disseminated intravascular coagulation (DIC), and hereditary thrombophilia (HT) [25]. The overlap of clinical and laboratory features found in TTP and CAPS can pose a particularly difficult diagnostic challenge. In patients with TTP, there have been reports of IgG autoantibodies to a proteolytic enzyme involved in the metabolism of von Willebrands factor [25,70]. The presence of schistocytes and prominent platelet consumption is specific for TTP [25]. In HIT, platelet aggregation studies and identification of the platelet factor 4-heparin complex can be diagnostic [25]. In DIC, the finding of fibrin degradation products rules out CAPS, and in considering HT, testing for factor VLeiden is diagnostically useful [25]. Treatment and recovery The treatment of CAPS requires two processes: (1) supporting failing organ systems, and (2) suppressing the widespread microvascular thrombotic process

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causing organ dysfunction. Intubation and mechanical ventilation to improve hypoxemia in respiratory failure, inotropic support to improve cardiac failure, hemodynamic monitoring for guidance in fluid and inotropic administration, and dialysis, are supportive measures that may be required simultaneously or at various intervals in the ICU treatment of CAPS. Given the evidence that infections are a significant precipitating factor in CAPS, the use of antibiotics can be guided by cultures or given empirically based on the clinical setting. Appropriate management of ongoing sources of infection (ie, gangrenous extremities, central intravenous lines) requires close attention. Several treatment modalities that have been applied or considered in CAPS include anticoagulation therapy (in the form of heparin, then switching to warfarin), fibrinolytic agents, high-dose steroids, plasmapheresis, cyclophosphamide, intravenous gamma globulin, prostacylin, danazol, cyclosporine, azathioprine, and defibrotide (a metallic salt of DNA with antithrombotic and fibrinolytic properties) [20,21]. In the series of 50 CAPS patients described in 1998 [20], multiple combinations of these modalities were used. In patients receiving a combination of anticoagulation therapy, steroids, plasmapheresis, or intravenous gamma globulins, the recovery rate was 70% [20]. Interest in plasmapheresis as a treatment for CAPS arose from reports of its successful use in episodes of APS [71 74], and CAPS [14,75,76]. Explanations for the benefit of plasmapheresis center around its success in the treatment of TTP, a thrombotic disorder with some similarity to CAPS [77]. Also, because of evidence that elevated levels of b2-GPI antibodies are involved in thrombosis [78 80], it was hypothesized that plasmapheresis may achieve beneficial results by reduction of b2-GPI antibody levels and removal of cytokines and mediators that promote the thrombotic process in CAPS [81]. At the same time, however, other reports emphasized anticoagulation therapy as the mainstay of treatment, with the addition of plasmapheresis in more refractory cases [75,82]. The combination of plasmapheresis with immunosuppressive therapy has been suggested as a promising approach [77]. In eight case reports of ARDS in CAPS, pulmonary improvement was noted in seven cases, with the addition of steroids (in four) [50 52], and with the combined use of steroids and plasmapheresis (in three) [14,53]. There is some suggestion, however, that the response to plasmapheresis may differ in patients with the IgG and those with the IgA b2-GPI antibody type [67,69]. Also, a coexisting hypercoagulable state may affect response [69]. With more case reports available in the literature, retrospective analysis suggests some treatment approaches that are associated with improved survival. From combined analysis of the 50 and 80 CAPS patient series by Asherson, the mortality rate was reduced to 38% in those treated with anticoagulation therapy, versus 75% in those not receiving anticoagulation therapy [21]. Concomitant use of steroids, plasmapheresis, or immunoglobulins did not significantly improve mortality rates. Anticoagulation therapy is needed for lysis of existing clots and suppression of ongoing clotting, and higher than usual doses of heparin are suggested, given the extreme hypercoagulability of these patients [18]. The timely

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and aggressive use of anticoagulation therapy is also supported by Kitchens in his description of patients with thrombotic storm [34]. With anticoagulation as the first-line therapy, the addition of steroids is still recommended to reduce the cytokine effects in CAPS or to treat a possible vasculitis mimicking CAPS in patients with SLE [21]. Whether plasmapheresis or fibrinolytic agents will have a positive effect on survival in selected patients remains to be seen. More information regarding the pathophysiology of CAPS may provide more specific guidance in the selection of treatment modalities in this disorder.

Summary CAPS is characterized by development of widespread microvascular thrombosis. Patients at risk are those with positive aCL or LA factor. Precipitating events, such as infection, trauma, surgical procedures, or reduction in anticoagulation therapy, may contribute to the development of CAPS. Presentation to the ICU can be dramatic, with progressive multiorgan failure and need for rapid institution of life-supporting measures. Cardiopulmonary failure has been the major contributor to mortality. A variety of therapeutic modalities have been used in an attempt to offset the widespread thrombosis and organ damage from high aCL levels. Anticoagulation therapy and high dosages of steroids seem to have a positive effect on survival.

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