Clinical manifestations associated with antiphospholipid antibodies

The antiphospholipid antibodies are immunoglobulins able to join negative charge phospholipids. The have been related to a great variety of conditions, specially among connective tissue illness although the idiopathic form seems to be the most frequent. Their presence must be ruled out in cases of young patients with stroke, deep veins thrombosis, acute heart attack and woman suffer multiple abortions and foetal death. These antibodies appear to be related to different clinical entities like Sneddon syndrome. Evans syndrome, "chorea gestationis", migraine. The laboratory determinations are based in direct methods (ELISA, RIA, ...) as well as in indirect ones (activated partial thromboplastin time, reptilase time, ...). The appropriate management and treatment may be based upon clinical expression, in case of arterial thrombosis (type II APS), or deep vein thrombosis (Type II) long term anticoagulation is indicated; Association with pentoxifylline in the case of retinal thrombosis (type IIIa), Stroke (type IIIb) cases may require long term anticoagulation as well as aspirin. Type IV cases are better managed with an individualised treatment.     

Intracardiac thrombi associated with antiphospholipid antibodies

Two cases of intracardiac thrombi associated with antiphospholipid antibodies are presented, one in the right atrium and the other in the left ventricle, the latter occurring in the presence of normal left ventricular function. In each, the diagnosis was made by transthoracic echocardiography. Both patients had contraindications to thrombolytic therapy and underwent successful surgical thrombectomy. We suggest that serial transthoracic echocardiography may be warranted in the follow-up of patients with primary hypercoagulable states.     

Partial seizures associated with antiphospholipid antibodies in childhood

We report antiphospholipid antibody positivity in three of a consecutive series of 23 children presenting partial epileptic seizures. There was no clinical or serological evidence of systemic lupus erythematosus or other connective-tissue disease. Neither computed tomography nor magnetic resonance imaging revealed ischemic alteration. The presence of antiphospholipid antibodies in 3/23 children may indicate that immune-mediated neuronal damage could be a pathogenetic mechanism for partial epilepsy.     

An elderly patient with Takayasu's arteritis associated with antiphospholipid antibodies

We report a patient with Takayasu's arteritis associated with antiphospholipid antibodies. An 84-year-old woman gradually developed gait and visual disturbances, dementia, myocardial infarction, and gangrene in all four limbs during a period of 8 years. Persistent inflammatory signs also continued for at least 8 years. Positive reaction for lupus anticoagulant by the diluted Russel viper venous time and positive reactions for cardiolipin antibodies were confirmed. However, she did not develop SLE. MR angiography revealed multiple and extensive occlusive changes in large vessels such as the aorta and its major branches. We believe antiphospholipid antibodies may have been related to severe occlusive vasculopathy in this patient.     

Activation of cultured vascular endothelial cells by antiphospholipid antibodies

Circulating antiphospholipid antibodies (aPL) are associated with a syndrome of thrombosis, recurrent fetal loss, and thrombocytopenia. We have demonstrated the activation of cultured human umbilical vein endothelial cells (HUVEC) by IgG from patients with anticardiolipin antibodies (aCL). Incubation of HUVEC for 4 h with purified IgG (100 micrograms/ml) from patients with high-titer aCL induced a 2.3-fold increase in monocyte adhesion over that seen in HUVEC incubated with IgG's from normal subjects. The effect of aCL was not attributable to LPS contamination, Fc receptors, or immune complexes. Monocyte adhesion was not induced when the aCL were added in serum-free media but was restored by the addition of purified beta 2GP1, previously described as a necessary cofactor for aCL reactivity. Purified rabbit polyclonal IgG raised against beta 2GP1 also induced monocyte adhesion when incubated with HUVEC. Preadsorption of patient serum with cardiolipin reduced monocyte adhesion by 60%. Immunofluorescent microscopy demonstrated that endothelial cells incubated with patient IgG expressed cell adhesion molecules, including E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1. These data support the hypothesis that aPL activate vascular endothelial cells, thereby leading to a pro-thrombotic state.     

Neurological dysfunction and hyperactive behavior associated with antiphospholipid antibodies. A mouse model

BACKGROUND: Currently, there exists no effective monitor that can predict the probability of a patient being conscious during general anesthesia. The electroencephalogram-derived bispectral index (BIS) is a promising new method to assess anesthetic adequacy. This study used the BIS to predict the probability of recovery of consciousness after a single bolus induction dose of propofol or thiopental. METHODS: Twenty unpremedicated surgical patients were anesthetized with 4 mg/kg thiopental and 20 patients with 2 mg/kg propofol. The BIS was monitored throughout the study. After induction, before administration of neuromuscular blocking agent, a tourniquet was applied to one arm and inflated above the systolic blood pressure. This allowed preservation of the ability to move the hand after neuromuscular blocking agent onset. Patients were then prompted to squeeze the investigator's hand every 30 s, until they responded to the request. At the time of response, anesthesia was reinduced and the study terminated. RESULTS: The BIS at loss of consciousness and recovery of a response was not statistically different between propofol and thiopental. No patient with a BIS less than 58 was conscious. In both groups, a BIS of less than 65 signified a less than 5% probability of return of consciousness within 50 s. CONCLUSION: The BIS can be used to predict probability of recovery of consciousness after a single injection of either thiopental or propofol.     

Thromboembolic disease developing during oral contraceptive therapy in young females with antiphospholipid antibodies

The role of oral contraceptives as a triggering factor for thrombosis in patients with lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA) has not yet been established. We describe the cases of three women aged 19, 29 and 48 years who developed venous thrombosis after 16 +/- 3.4 (mean +/- SD) cycles of oral contraceptives. They were all asymptomatic before taking the pill. Two patients subsequently developed venous and/or arterial recurrence of thrombosis. Laboratory studies performed after the diagnosis of thrombosis, showed the presence of LA and elevated levels of ACA (IgG and IgM) in all three patients. None of these patients had autoimmune diseases and therefore appeared to have a primary antiphospholipid antibody syndrome. The three patients belonged to a group of 45 young females who experienced their first thrombotic event while taking the pill. This group had a similar prevalence (8%) for antithrombin deficiency and antiphospholipid antibodies. We surmise that some of the women who developed venous thrombosis while taking the pill might have an undetected primary antiphospholipid syndrome.     

Ocular symptoms in association with antiphospholipid antibodies

OBJECTIVE: To describe the clinical and serologic findings of 50 antiphospholipid antibody (APA)-positive patients within a retrospective study. METHODS: Measurement of visual acuity, slit-lamp biomicroscopy, tonometry, fundus examination and perimetry. Laboratory tests were performed for detection of APA against thromboplastin and cardiolipin. Antinuclear antibodies (ANA), antibodies to dsDNA, antithyroidal and antiparietal antibodies were also tested. RESULTS: A combination of both transient and permanent visual disturbances was noticed in more than half of the patients. Transient visual disturbances included transient blurred vision, partial defects of the visual fields and amaurosis fugax. The most frequent permanent abnormalities were optic atrophy in 20 patients, due to AION in 9 cases, and disturbances of the choroidal circulation in 17 patients. Fourty-six patients had positive levels of thromboplastin APA; cardiolipin APA were found to be increased in 36 patients. CONCLUSIONS: We did not find a clear correlation between APA activity or the immunoglobulin classes in the individual and the severity of the ocular disease. The benefit from a therapy with the antiplatelet agent acetylsalicylic acid was evident in a reduction of the patients' transient visual disturbances and, in most cases, no further progression of permanent visual field defects was observed.     

Obstetric complications of antiphospholipid antibodies

Upper-eyelid retraction is a common sign of thyroid-associated eye disease (TAED), and these patients are highly bothered by the appearance of their eyes. In this study, botulinum toxin A (BTA) was injected into the levator palpebrae superioris muscle in 8 eyes of 4 patients in an attempt to control the abnormal elevation of the upper eyelid. BTA provided control of the upper-eyelid retraction, and the cosmetically acceptable effect lasted for 3-4 months. It was concluded that BTA is an effective method of treatment in this condition. Since it has a temporary effect, it can safely be used to provide relief of symptoms related to upper-eyelid retraction during unstabilized periods of TAED, which may last as long as several years in some patients.     

Prevalence of antiphospholipid antibodies in patients with ankylosing spondylitis

OBJECTIVE: To establish the prevalence of antiphospholipid antibodies (aPL) in a group of patients with ankylosing spondylitis (AS). The relation of the antibodies with different clinical and analytical features was studied. METHODS: Eighty-four patients with AS (71 men) and 40 age and sex matched controls were studied. aPL determinations included: anticardiolipin antibodies (aCL) of the IgM, IgG, and IgA classes, the presence of lupus anticoagulant (LAC), and a false positive serologic test for syphilis. Comparisons between variables were done by Student t test, Mann-Whitney test and Chi squared test. Correlations between aPL and clinical variables were performed by Pearson coefficients. RESULTS: Twenty-four patients with AS (29%) has positive IgG aCL, compared with only 2 cases in the control group (5%) (p < 0.002). There were no differences in other aPL determinations between patients and controls. There was no correlation between the presence of aCL (IgG, IgM, or IgA) and LAC and the different aspects of the disease. Two patients fulfilled the criteria for antiphospholipid syndrome. CONCLUSION: Our results indicate the presence of IgG aCL in patients with AS higher than in the normal population but their relation with thrombosis and other systemic manifestations seems weak.     

Lupus anticoagulants and antiphospholipid antibodies

In recent years, clinical syndromes involving lupus anticoagulants and antiphospholipid antibodies have come into increasing clinical prominence. Since the discovery that most antiphospholipid antibodies require the presence of anionic phospholipid-binding proteins such as B2-glycoprotein I and prothrombin, a large number of studies have attempted to delineate the specificity of these antibodies. Several mechanisms have been proposed to explain the hypercoagulable state associated with these antibodies. This review attempts to summarize these data and the challenges that confront efforts to delineate the pathogenesis of the prothrombotic state associated with the presence of these antibodies.     

Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies

Lupus anticoagulant (LA) antibodies are acquired inhibitors of coagulation belonging-together with anticardiolipid (aCL) antibodies-to the family of antiphospholipid antibodies. Since LA antibodies affect coagulation reactions via recognition of the complex of lipid-bound prothrombin, they may be better named anti-prothrombin antibodies. We studied their immunological properties in the plasma of 59 patients with antiphospholipid antibodies by means of specific ELISA systems that allowed the characterization of the interaction of these antibodies with human prothrombin and anionic phospholipids. The mode of presentation of prothrombin was found to greatly influence the reactivity of anti-prothrombin antibodies. In fact, when plain polystyrene plates were used to immobilize prothrombin, virtually no binding was observed. Conversely, when prothrombin was coated on high-activated PVC ELISA plates, 34 samples (58%) contained antibodies that recognize human prothrombin in solid phase. In particular, IgG antibodies were found in 21 plasmas and IgM in 22; both IgG and IgM isotypes were present in 9 of these cases. A higher prevalence was observed in the ELISA for the detection of the antibodies directed at the calcium-mediated complex of phosphatidylserine (PS)-bound prothrombin: 53 samples (90%), preadsorbed with cardiolipin liposomes to remove aCL antibodies, showed the presence of IgG and/or IgM anti-prothrombin antibodies. When the results were analyzed according to the immunoglobulin isotypes, 44 (75%) and 39 (66%) samples were found to contain IgG and IgM anti-prothrombin antibodies, respectively. Both IgG and IgM were present in the plasma of 30 patients. Only half of these samples reacted also with PVC-bound prothrombin. Apparently, the higher rate of positivity of the ELISA for the detection of antibodies to the complex of PS-bound prothrombin was not due to differences in the amount of antigen available in the 2 systems, as judged by binding experiments performed with a rabbit polyclonal anti-human prothrombin antiserum. Finally, the anticoagulant properties of 14 total IgG preparations (12 of them contained anti-prothrombin antibodies positive in both ELISA systems, whereas the other 2 cases reacted either with PVC-bound prothrombin only or with PS-bound prothrombin only) were evaluated by diluted Russell's Viper Venom Time and by diluted activated Partial Thromboplastin Time. To rule out the beta 2-glycoprotein I (beta 2-GPI)-dependent anticoagulant effect of the aCL antibodies contained in the preparations, the coagulation tests were performed in beta 2-GPI deficient plasma. Six preparations failed to show anticoagulant activity in both assay systems, suggesting that 2 types of IgG anti-prothrombin antibodies exist, that differ with respect to their anticoagulant properties. These findings suggest that anti-prothrombin antibodies resemble aCL antibodies with respect to the behaviour in "in vitro" coagulation reactions and underline the wide heterogeneity of antiphospholipid antibodies.     

Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)

OBJECTIVE: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). DESIGN: Randomised controlled trial. SETTING: Specialist clinic for recurrent miscarriages. SUBJECTS: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. INTERVENTION: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation. MAIN OUTCOME MEASURES: Rate of live births with the two treatments. RESULTS: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). CONCLUSION: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.     

The clinical syndrome associated with antiphospholipid antibodies. A diagnosis to be confirmed after a long follow-up

A clinical case of syndrome of antiphospholipid antibodies is reported. The patient is a 10-year-old girl with thrombophlebitis of the right leg associated with the presence of lupus-like anticoagulant antibodies. No secondary pathologies were found. It is not possible, anyway, to make a definitive differential diagnosis between primary and secondary forms of syndrome of antiphospholipid antibodies because of intermediate situations where antiphospholipid antibodies are associated with 2 or 3 ARA criteria for the diagnosis of lupus (lupus-like syndrome). A long term follow-up is therefore necessary.     

The syndrome of thrombosis, thrombocytopenia, and recurrent spontaneous abortions associated with antiphospholipid antibodies: Hughes syndrome

aPL-associated thrombosis (Hughes syndrome) is widely recognized as a major cause of organ damage in autoimmune diseases. Beginning with the first symposium in 1984, international aPL symposia have facilitated research on aPL antibodies, and the clinical standardization of aPL tests. It is hoped that the present symposium will continue this tradition, because much remains to be learnt about the origin and pathogenicity of aPL antibodies. In addition, new insights are needed for more effective therapies to be developed.