Homocysteine and antiphospholipid antibodies in rheumatoid arthritis patients: relationships with thrombotic events

OBJECTIVE: To investigate the possible relationships between plasma homocysteine levels and thrombotic events in a select population of rheumatoid arthritis (RA) patients with or without antiphospholipid (aPL) antibody positivity. METHODS: 168 female RA patients attending the Extra-articular Involvement RA Clinic of University of Genova and 72 female subjects matched for age and vascular diseases as controls were included in the study. 30 of the RA patients showed aPL antibody positivity and 138 aPL antibody negativity on the basis of the concomitant presence or absence of high concentrations of anticardiolipin (aCL) antibodies or the presence of lupus anticoagulant (LA). All subjects were evaluated for plasma homocysteine concentrations and for the occurrence of thrombotic events. RESULTS: Twenty-five RA patients and 5 controls reported a history of thrombotic events. Eleven and 5 of RA patients were found to have been previously affected by venous or arterial thrombosis, respectively. Plasma levels of homocysteine in aPL antibody positive patients with thrombosis were found to be significantly higher than in aPL antibody positive RA patients without thrombosis (p < 0.001). When RA patients with thromboses were analyzed, a significant increase of plasma homocysteine levels was found in aPL antibody-positive RA patients versus aPL antibody-negative RA patients (p < 0.04) and versus related controls (p < 0.003). CONCLUSIONS: The association observed between aPL antibody positivity and high levels of plasma homocysteine in RA patients may represent a possible risk factor for thrombotic events. Therefore, it is suggested that hyperhomocysteinemia might be involved in the vascular-related mortality observed in RA patients with a history of thrombosis.     

Cerebral infarction in systemic lupus: association with anticardiolipin antibodies

We report fifteen patients, thirteen with systemic lupus and two patients with a "lupus-like" illness who developed cerebral infarction. All fifteen patients were shown to have elevated anticardiolipin antibody levels using a newly devised solid phase radioimmunoassay. The lupus anticoagulant was detected in all eleven patients tested. It is proposed that anticardiolipin antibodies and the lupus anticoagulant make up a population of antiphospholipid antibodies capable of causing cerebral vascular injury and thrombosis resulting in cerebral infarction. These antibodies may also play a pathogenic role in autoimmune disorders other than lupus where cerebral thrombotic disease is a prominent feature.     

Prothrombin gene mutation G20210A, homocysteine, antiphospholipid antibodies and other hypercoagulable states in ocular thrombosis.

The purpose of the present study was to determine whether using an extended panel of laboratory tests increases the detection of a hypercoagulable state in patients with ocular thromboses. Twenty consecutive patients with ocular thromboses (vein, artery, or choriocapillaris occlusions) underwent testing for activated protein C resistance/factor V Leiden, prothrombin G20210A, lupus anticoagulant, anticardiolipin antibodies, hyperhomocysteinemia, and deficiencies of protein C, protein S, and antithrombin. For each patient, we selected two age-matched and gender-matched individuals without ocular thromboses as controls. Sixteen of the 20 patients (80%) had one or more laboratory tests that supported a hypercoagulable condition. Prothrombin G20210A (P < 0.02) and hyperhomocysteinemia (P < 0.0006) were significantly more frequent in ocular thrombosis patients compared with controls. The most common condition was antiphospholipid antibody syndrome, present in 40% of patients (confirmed by repeat testing at least 6 weeks later), but this did not reach statistical significance compared with the controls. No patients with ocular thromboses had hereditary abnormalities of protein S, protein C, or antithrombin. In conclusion, an extended panel of laboratory tests improved the detection of a hypercoagulable state in ocular thromboses. Testing for homocysteine, antiphospholipid antibodies, and the prothrombin G20210A mutation should be considered in patients with ocular thromboses.     

中青年缺血性脑血管病与血浆高同型半胱氨酸血症的关系研究

目的：探讨中青年缺血性脑血管病与血浆高同型半胱氨酸血症之间的关系。方法：纳入我院2014年1月至2015年12月确诊为脑梗死的中青年患者100例,短暂性脑缺血组100例,健康对照组100例,分别于确诊后检查各组的血浆高同型半胱氨酸水平及高同型半胱氨酸血症的发生率,分析高同型半胱氨酸血症与中青年缺血性脑血管病之间的关系。结果：脑梗死组和短暂性脑缺血组中青年患者的同型半胱氨酸明显高于对照组,差异具有统计学意义（P＜0.05＝;脑梗死组（90.00%）和短暂性脑缺血组（84.00%）中青年患者的高同型半胱氨酸血症的发病率明显高于对照组（10.00%）,差异具有统计学意义（P＜0.05＝;高同型半胱氨酸血症中青年患者中缺血性脑血管病的发生率(94.57%)明显高于无高同型半胱氨酸血症者（P＜0.05＝。结论：高同型半胱氨酸血症与中青年缺血性脑血管病的发生存在一定关联,同型半胱氨酸值可能可以成为一个预测缺血性脑血管发生及预后的指标,但仍需要进一步研究。     

Antiphosphatidylethanolamine antibody as the sole antiphospholipid antibody in systemic lupus erythematosus with thrombosis.

A previously healthy 34-year-old woman, was diagnosed as having systemic lupus erythematosus (SLE), with membranous glomerulopathy which improved rapidly. Neither lupus anticoagulant nor anticardiolipin antibodies were detected in her plasma. After three months of total remission, she developed a severe pulmonary thromboembolism for which no specific biological cause was found. Her plasma was analysed for different antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies were again negative. Using an ELISA prepared with either five different anionic phospholipids or zwitterionic phosphatidylethanolamine, solely an anti-phosphatidylethanolamine IgG was discovered in her plasma. In lupus patients, the presence of antiphospholipid antibodies is now well recognized as a high risk factor for repeated thrombosis and/or recurrent abortions. This case suggests that the presence of antiphosphatidylethanolamine antibody should be investigated in cases of unexplained thrombosis in SLE, where the usual clinical and biological investigations have failed to shed light.     

Severe thrombophilia with antiphospholipid syndrome and hyperhomocysteinemia in a patient with Schnitzler's syndrome

Schnitzler's syndrome is a rare condition with chronic urticaria, intermittent fever, bone pain, and a monoclonal IgM gammopathy. Most patients have a chronic and indolent course, but a small number ultimately progress to a lymphoplasmacytic malignancy. We describe a patient with Schnitzler's syndrome who entered an accelerated phase of clinical deterioration with repeated thromboses of the cerebral and coronary arteries that ultimately led to a fatal outcome. We found that the he fulfilled the Sapporo criteria for definite antiphospholipid syndrome and had elevated blood levels of homocysteine during the active clotting phase of the disease. We suggest that the association with immune-mediated or metabolic disorders, such as the antiphospholipid syndrome and hyperhomocysteinemia, may unfavorably affect the otherwise chronic and stable course of patients with Schnitzler's syndrome. The systemic clotting disorder, the association with the antiphospholipid syndrome and hyperhomocysteinemia, and the biclonal rather than monoclonal IgM gammopathy were striking features of this atypical case of Schnitzler's syndrome.     

Occlusive vasculopathy in systemic lupus erythematosus. Association with anticardiolipin antibody

Patients with systemic lupus erythematosus and with antiphospholipid antibody are subject to sudden occlusion of multiple blood vessels. We describe two patients with systemic lupus erythematosus with acute, catastrophic, widespread non-inflammatory visceral vascular occlusions associated with high-titer antiphospholipid antibody. The histopathologic features clearly distinguished these patients from classic systemic lupus erythematosus vasculitis. We further suggest that, based on a probable pathogenesis related to the presence of antiphospholipid antibody, and based on the non-inflammatory vascular occlusion, steroids and other immunosuppressive medications are of limited value. Plasmapheresis along with anticoagulant therapy should be considered.     

Antinuclear antibody, lupus anticoagulant, and anticardiolipin antibody in women with idiopathic habitual abortion. A controlled, prospective study of forty-four women

In a controlled, prospective study of 44 consecutive women with idiopathic habitual abortion, only 5% had symptoms of rheumatic disease. Patients did not differ from control subjects in the frequency of positive results on tests for antinuclear antibody or anti-double-stranded DNA. Levels of C3 and C4 were higher in the habitual aborters. No patients had anti-Ro. The antiphospholipid antibody results were analyzed using 2 methods: the frequency of antiphospholipid antibodies was 9% by lupus anticoagulant using the Russell viper venom time (95% confidence interval 22-2.5) and 11% by anticardiolipin antibody assay (95% confidence interval 25-3.7), which was not significantly different from that in control subjects. However, the mean levels in the aborters (although within the normal range) were significantly higher than those in control subjects for anti-double-stranded DNA (P = 0.004), lupus anticoagulant (by Russell viper venom time; P = 0.05), and anticardiolipin antibody (P = 0.0007), when examined by multiple linear regression analysis corrected for age and concurrent pregnancy. Of the 3 patients with antiphospholipid antibodies and subsequent successful pregnancies, only 1 was treated with prednisone and aspirin. We conclude that, in the majority of women, subclinical lupus, anti-Ro, the lupus anticoagulant, and anticardiolipin antibodies are not associated with idiopathic habitual abortion.     

Cerebral ischemic events associated with endocarditis, retinal vascular disease, and lupus anticoagulant

PURPOSE: A group of young patients presenting with cerebral ischemic events, endocardial lesions, and lupus anticoagulant is described in order to highlight the common clinical laboratory features. PATIENTS AND METHODS: Fourteen consecutive patients (10 females, age range 17 to 53 years [mean 38 years]) at onset of symptoms of cerebral ischemia who had evidence of the lupus anticoagulant syndrome and were being followed prospectively are reviewed. All patients had abnormal phospholipid-dependent coagulation test results, and most had anticardiolipin antibody at the time of presentation. Three of 14 had four or more American Rheumatism Association criteria for definite systemic lupus erythematosus and the remaining patients were considered to have primary lupus anticoagulant syndrome. RESULTS: The common features among these patients included at least one cerebral ischemic event at presentation (stroke or transient ischemic attack), or recurrent episodes suggesting cerebral ischemia (amaurosis fugax, recurrent severe migraine headaches), livedo reticularis, endocardial valvular lesions noted on echocardiography (11 mitral, two aortic valve) that were often associated with discrete vegetations, retinal vascular lesions, and computed tomographic/magnetic resonance imaging scanning or angiographic evidence of multiple cerebral infarction. Venous thromboembolic events were uncommon (three of 14). Common laboratory studies included thrombocytopenia (10 of 14), positive direct Coombs' test result (11 of 14), and hypocomplementemia (11 of 14). Follow-up after initial treatment with either salicylates or anticoagulant therapy (warfarin) for up to 10 years indicated that while many patients had recurrent symptoms suggesting cerebral ischemia, major stroke syndromes did not recur nor new episodes emerge. CONCLUSION: The combination of multiple cerebral ischemic lesions and endocardial lesions, including valvular vegetations, suggests that these cerebral ischemic events represent cerebral emboli, and that these cerebral embolic events originate from vegetative lesions on the mitral or, less commonly, aortic valve, in association with lupus anticoagulant.     

Antiphospholipid antibodies: a disease marker in 25 patients with antinuclear antibody negative systemic lupus erythematosus (SLE). Comparison with a group of 91 patients with antinuclear antibody positive SLE

Twenty-five antinuclear antibody (ANA) negative patients with systemic lupus erythematosus (SLE) or lupus-like disease were compared to 91 ANA positive patients with SLE for clinical and biological symptoms. Cutaneous symptoms were infrequent in ANA negative patients (p less than 0.03). Thrombocytopenia (p less than 0.001), venous or arterial thrombosis (p less than 0.02) as well as cerebral infarction (p less than 0.001) were more frequent. Three types of antiphospholipid antibodies were determined by different methods; the VDRL, the lupus anticoagulant and an ELISA for IgG anticardiolipin antibody (aCL). The frequency of a positive VDRL test was significantly higher in the ANA negative group (p less than 0.05). Correlation studies suggest that the 3 methods are not redundant and detect overlapping but not identical antibodies. Of the 3 antiphospholipid antibody assays, only the IgG aCL test was significantly associated with thrombosis in the ANA negative group (p less than 0.02).     

Definition of thrombophilia

Thrombophilia is characterized by clinical tendency to thrombosis or molecular abnomalities of hemostasis that predisposes to thromboembolic disease. Hereditary thrombophilia may be due to antithrombin deficiency, or protein C or protein S deficiency. More recently, other molecular abnormalities have been described: activated protein C resistance due to factor V Leiden, G 20210 A polymorphism on the prothrombin gene, increased factor VIII plasma levels or hyperhomocysteinemia. Acquired thrombophilia is frequently associated with the antiphospholipid syndrome characterized by thrombosis and presence of lupus anticoagulant or phospholipid-binding antibodies. In some cases, no molecular abnormality is found despite recurrent thrombosis observed in patient and his/her family. This situation can be considered as clinical thrombophilia.     

Valvular heart disease as a cause of cerebrovascular disease in patients with systemic lupus erythematosus

Thirty-seven patients with systemic lupus erythematosus underwent complete clinical and laboratory evaluations, including antiphospholipid antibodies and lupus anticoagulant, magnetic resonance imaging of the brain, and transesophageal echocardiography. Cerebrovascular disease manifested as stroke, transient ischemic attack, or cerebral infarcts in patients with nonfocal neurologic deficits was detected in 19 patients (51%), and significant left-sided valvular heart disease in 25 (68%). Valve vegetations, valve thickening, valve regurgitation, and lupus anticoagulant antibody occurred 2 to 3 times more often in patients with than without cerebrovascular disease (all p < or =0.04) and were the only independent predictors of cerebrovascular disease (odd ratios 5.3 to 10.6, all p < or =0.03). Thus, valvular heart disease probably exacerbated by hypercoagulability appears to be a source of embolic ischemic brain injury and cerebrovascular disease.     

Antiphospholipid antibody syndrome: immunologic and clinical aspects

Antiphospholipid antibody is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss, and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. A positive antiphospholipid antibody test is defined by enzyme-linked immunosorbent assay (ELISA) (antiphospholipid antibody itself) or by coagulation assay (lupus anticoagulant). These are similar but not identical antibodies. The test for syphilis is less closely related to the preceding two and is less regularly associated with clinical complications. The mechanism of action of either antiphospholipid antibody or lupus anticoagulant is as yet unknown. SLE-induced but not infection-induced antiphospholipid antibody has immunoglobulin G2 (IgG2) and IgG4 predominance. It recognizes all negatively charged phospholipids, but various physical characteristics of the phospholipids alter the recognition patterns. Treatment for the antiphospholipid antibody syndrome has not been clearly defined. Anticoagulation with aspirin, heparin, or warfarin is currently favored. A role for corticosteroid remains to be demonstrated.     

An IgG antiprothrombin antibody enhances prothrombin binding to damaged endothelial cells and shortens plasma coagulation times.

OBJECTIVE: To test the hypothesis that some lupus anticoagulants are antiprothrombin antibodies, and that such antibodies enhance prothrombin binding to endothelial cells (EC) and thus promote clotting on the cell surface. METHODS: We generated a monoclonal antiprothrombin antibody (designated IS6) from a patient with primary antiphospholipid syndrome (APS). The antibody was analyzed for its binding properties, lupus anticoagulant activity, and pathophysiologic activity, using an EC-based plasma coagulation assay. RESULTS: IS6 is the first patient-derived monoclonal IgG antiprothrombin antibody. It bound to prothrombin with low affinity, reacted with 3 phospholipids (cardiolipin, phosphatidylethanolamine, and phosphatidylserine), and showed lupus anticoagulant activity. Moreover, IS6 enhanced the binding of prothrombin to damaged EC and shortened the EC-based plasma coagulation times. CONCLUSION: These findings suggest that IS6 may promote coagulation in areas of damaged EC in the host, and thus contribute to thrombosis in patients with APS.     

Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance

PURPOSE: To determine the prevalence of lupus anticoagulant and anticardiolipin in systemic lupus erythematosus (SLE) and in non-SLE disorders, and to evaluate the clinical significance of these autoantibodies as they relate to thromboembolic events, neuropsychiatric disorders, thrombocytopenia, and fetal loss. DATA IDENTIFICATION: A computer-assisted search of the literature (MEDLINE, 1966 to 1989) and review of the bibliographies of all identified articles. STUDY SELECTION: Series of ten or more subjects were included if the assays used for detecting lupus anticoagulant or anticardiolipin met the specified minimal criteria for validity. DATA EXTRACTION: Series were categorized according to antibody type and underlying disease. A systematic appraisal of patient selection methods, study design, and assay methods was done. RESULTS OF DATA ANALYSIS: An analysis of 29 published series (comprising over 1000 patients with SLE) yielded an average frequency of 34% for the lupus anticoagulant and 44% for anticardiolipin. Antiphospholipid antibodies are also prevalent in patients with various non-SLE disorders. In patients with SLE, a statistically significant association exists between the presence of either antibody and a history of thrombosis, neurologic disorders, or thrombocytopenia. The available data suggest, but do not firmly support, an association between antiphospholipid antibodies and history of fetal loss in women with SLE. Contrary to prevailing opinion, none of these associations have been shown conclusively in patients with non-SLE disorders. CONCLUSIONS: The results of predominantly retrospective series suggest that for certain persons (patients with SLE or closely related disorders) antiphospholipid antibodies may be important risk factors for thrombosis, neurologic disease, thrombocytopenia, and fetal loss. Standardized tests for lupus anticoagulant and anticardiolipin, as well as long-term, prospective clinical studies, are needed to determine the prognostic value of antiphospholipid antibodies.     

Homocysteine activates platelets in vitro.

The mechanism of thrombogenicity in hyperhomocysteinemia remains controversial. The authors investigated the association between elevated plasma homocysteine levels, platelet function, and blood coagulation. Blood was collected from healthy subjects and patients with critical limb ischemia. Basal platelet counts and platelet aggregation as well as flow cytometry were performed to assess spontaneous- and agonist-induced platelet aggregation as well as P-selectin and Glycoprotein IIb/IIIa expression at different homocysteine concentrations. Thromboelastography was performed, and platelet shape change was assessed, using a channelyzer, by measuring median platelet volume. Lactate dehydrogenase was measured, to indirectly assess red blood cell membrane integrity, after homocysteine exposure. The study results suggest that platelet activation and hypercoagulability occur after exposure to homocysteine, especially in patients with critical limb ischemia. Homocysteine concentrations of approximately 50 micromol/L appear to be the level at which these changes occur in vitro, and this effect on platelets appears to be indirect.     

Lupus anticoagulants in children

Lupus anticoagulant and ACAs are made up of heterogeneous IgG and IgM antibodies that prolong in vitro clotting times and are associated with increased risks of venous and arterial thrombosis, recurrent fetal loss, and autoimmune thrombocytopenia and anemia. These clinical findings with the appropriate laboratory results make up the antiphospholipid antibody syndrome. The antiphospholipid antibodies found in this syndrome are directed against a variety of phospholipid binding proteins of which beta2-glycoprotein and prothrombin are considered to be common antigens. Children who present with thrombosis and are positive for lupus anticoagulant and ACAs have similar clinical presentations and prognoses as adults. Isolated lupus anticoagulant and ACAs in children who are asymptomatic likely do not lead to clinical complications and are transient.     

Diagnose des Antiphospholipid-Syndrom beim antikoagulierten Patient: Was gibt es zu beachten?

The antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.     

Prolonged half-life of argatroban in patients with renal dysfunction and antiphospholipid antibody syndrome being treated for heparin-induced thrombocytopenia

Argatroban is a direct thrombin inhibitor approved for the treatment of heparin-induced thrombocytopenia (HIT) type II. Argatroban is predominantly metabolized in the liver. It is widely believed that no dosage adjustment is required in patients with renal insufficiency, making it a preferred agent in patients on renal replacement therapy (Reddy and Grossman, Ann Pharm 2005;39:1601-1605). The elimination half-life of argatroban is approximately 50 min. Lupus anticoagulants can cause baseline elevation of the PTT and hence it is difficult to monitor the effects of anticoagulants such as heparin, lepirudin, or argatroban in patients with antiphospholipid antibody syndrome. Heparin levels may be used as an alternative for heparin monitoring but plasma levels of argatroban are not commercially available. A chromogenic antifactor IIa assay could be useful for monitoring argatroban in the presence of a lupus anticoagulant, but it is not widely available at present. We report a patient with end-stage renal disease, maintained on peritoneal dialysis with HIT, who demonstrated a markedly prolonged half-life when treated with argatroban despite the discontinuation of therapy. This case also demonstrates the lack of guidelines for the monitoring of argatroban therapy in the presence of an underlying lupus anticoagulant.     

Primary, secondary, and catastrophic antiphospholipid syndrome: what's in a name?

The association of the lupus anticoagulant with thrombosis and recurrent pregnancy loss was first recognized over a 20-year period between the early 1960s and early 1980s. The introduction of the anticardiolipin test in 1983 and the recognition of its association with clinical features similar to the lupus anticoagulant led to an exponential growth of interest in this disorder. The belief that anticardiolipin antibodies and lupus anticoagulant belonged to the family of antiphospholipid antibodies led to the disorder being named the antiphospholipid syndrome (APS). Efforts by individual investigators to introduce criteria for classification of APS and to standardize anticardiolipin antibody and lupus anticoagulant tests were started in the mid-1980s to ensure more reliable recognition and treatment of affected patients. Another layer of complexity was introduced with recognition that many anticardiolipin antibody-positive sera also bound the antigen beta (2) glycoprotein I. With increasingly sophisticated epidemiologic and prospective studies in the 1990s, more structured and better-documented criteria for APS were introduced in 1999 and modified in 2006. These criteria have been widely adopted. Whereas data supporting subclassification of APS into primary and secondary subgroups remain tenuous, a small percentage of patients do appear subject to clinical features termed the catastrophic antiphospholipid syndrome. Introduction of classification criteria for APS has enabled more reliable prospective studies, the promise of better management, and more valid tests for recognition of the disorder.