Lupus-like Anticoagulant Research Articles

Inhibition of Binding of β2-Glycoprotein 1 to Phosphatidylserine by Polymyxin B, a Lupus-Like Anticoagulant

Polymyxin B is a cationic peptide that inhibits phospholipid-dependent coagulation tests including activated partial thromboplastin time and to a lesser degree prothrombin time. Thrombin clotting time is insensitive to polymyxin B. β2-glycoprotein 1 (β2GP1) is a cofactor of antiphospholipid antibodies. Antiphospholipid autoantibodies also poses lupus anticoagulant activity through interactions with β2GP1. Using affinity chromatography, polymyxin B can effectively decrease the binding of β2GP1 to immobilize phosphatidylserine. Since then, anticoagulant effect of polymyxin B is most likely due to the binding to negatively charged phospholipids, preventing formation of coagulation complexes.

To Mix or Not to Mix in Lupus Anticoagulant Testing? That is the Question

Mixing patient and normal plasma has been used for many years to assist with making decisions on which direction to proceed for further investigation of abnormally prolonged coagulation tests, namely, either individual coagulation factor measurement or the search for circulating anticoagulants. Mixing tests, however, gained wide acceptance only after the so-called lupus-like anticoagulant (LA) phenomenon was described and were, therefore, included in the guidelines for LA detection issued by the working group of the International Society on Thrombosis and Haemostasis. Important though they may be considered, the dispute between those who advocate the use of mixing tests and those who deny their superiority (or their need) for LA detection is difficult to resolve. This article aims to provide a balanced view on this dispute. Based on the limited information provided by the literature one may conclude that the disadvantages of performing mixing studies are the fact that (1) they are time-consuming; (2) they require a suitable source of normal pool plasma; and (3) weak LA may be lost at diagnosis due to the dilution of index plasma into normal pooled plasma. On the contrary, performing mixing tests makes the occurrence of false-negative LA in patients who present with the so-called "lupus cofactor phenomenon" relatively unlikely and, therefore, justifies their performance even though the frequency of the occurrence of this phenomenon in LA-positive patients is still unknown.

Anticardiolipin and anti-β2glycoprotein I antibodies and lupus-like anticoagulant: prevalence and significance in systemic sclerosis

It has been suggested that both anticardiolipin (aCL) and anti-beta(2) glycoprotein I (abeta(2)GPI) antibodies may play a critical role in the pathogenesis of systemic sclerosis (SSc)-related vascular impairment. To evaluate the prevalence of aCL and abeta(2)GPI antibodies and lupus-like anticoagulant (LAC) in patients with SSc and healthy controls. We also investigated a possible relationship between clinical and biological variables of patients with SSc and the presence of aCL/abeta(2)GPI antibodies and/or LAC. Measurements of aCL and abeta(2)GPI antibodies, and LAC were performed in 69 consecutive patients with SSc and 69 age- and sex-matched controls. Clinical and biological findings were compared between patients with and without antiphospholipid antibodies. aCL and abeta(2)GPI antibodies and/or LAC were detected in 13 (19%) of 69 consecutive patients with SSc; in the healthy control group, aCL antibody was found in only one (2%) subject (P = 0.0007). None of the healthy controls had abeta(2)GPI antibody and/or LAC. Moreover, pitting scars, pulmonary arterial hypertension, macrovascular involvement as well as severity of capillary impairment (using nailfold videocapillaroscopy) were more frequent in SSc patients with aCL/abeta(2)GPI antibodies and/or LAC compared with those without. Our findings suggest that antiphospholipid antibodies may have a role in the genesis of vascular involvement related to SSc. Finally, the assessment of antiphospholipid antibodies (aCL and abeta(2)GPI antibodies, as well as LAC) may contribute to a better recognition of clinical features in patients with SSc; in essence, the patients with aCL/abeta(2)GPI antibodies and/or LAC may require close monitoring of vascular changes, including in particular pulmonary arterial hypertension and digital infarcts.

Prevalence and Clinical Significance of Elevated Antiphospholipid Antibodies in Adults with Immune Thrombocytopenic Purpura.

Background: The clinical and pathogenic significances of the presence of antiphospholipid antibodies (APA) [anticardiolipin antibodies (aCL) and lupus-like anticoagulant (LA)] in patients with immune thrombocytopenic purpura (ITP) remain controversial.Objective: To determine the prevalence and clinical significance of positive APA in a large monocentric cohort of adults with newly diagnosed ITP.Methods: aCL (IgG and IgM) and LA were searched at time of diagnosis in 260 adults with ITP and a platelet count < 50×109/L over a 15 years period. Thirty-five patients with definite systemic lupus, 5 with primary antiphospholipid syndrome and 4 with HIV infection were excluded and the analysis was performed on 216 patients.Results: APA (aCL and LA) were detected at ITP diagnosis in 55 patients (25%) including: IgG-aCL in 43 patients (20%) with a level between 15-39 UI/L in 31 and ≥40UI/l in 12; IgM-aCL in 11 patients (5%); and LA in 16 patients (7%). LA was associated with IgG-aCL in 14 patients, IgM-aCL in 1 patient, and was isolated in 1 patient. Positive test for LA was correlated with the presence of highly positive IgG-aCL (≥40UI/L) (p=0.001). Age, gender, initial platelet count, acute or chronic outcome of ITP were not associated with the presence of APA (aCL and LA), aCL and LA status except for age which was lower in LA positive group (mean age 22 years vs 42 years in LA negative group, p=0.002). After a median follow-up of 31 months (range: 1 to 185 months), 15/216 (7%) patients experienced a thrombosis (arterial = 3, deep venous thrombosis and/or pulmonary embolism = 12); 5 of whom (33%) had positive aCL (with a level ≥ 40 UI/L in 4). In 4 of these 5 patients, aCL were associated with positive LA. In multivariate analysis, thrombosis events were associated with age [Hazard ratio = 1.5 (IC95% : 1.1–2.0], presence of LA [Hazard ratio = 6.5 (IC95% : 1.7–25.5] or presence of IgG-aCL at high level (≥40UI/L) [Hazard ratio = 6.1 (IC95% : 1.6–23.7]. In contrast, there was no association of thrombosis events with sex, platelet count at diagnosis, acute or chronic evolution (≥ 6 months), antinuclear antibodies or treatments used.Conclusions: Prevalence of APA (25%) in adults with newly diagnosed ITP is lower in our cohort than previously observed in other studies. Though the incidence of thrombosis is significantly increased in patients with LA and/or highly positive aCL, this risk seems too low to recommend a systematic testing in patients with ITP and no previous history of thrombosis.

Acquired von Willebrand’s Disease Associated with Multiple Myeloma and Lupus-Like Anticoagulant

Acquired von Willebrand’s Disease Associated with Multiple Myeloma and Lupus-Like Anticoagulant

Acquired von Willebrand's Disease Associated with Multiple Myeloma and Lupus-Like Anticoagulant

Acquired von Willebrand's Disease Associated with Multiple Myeloma and Lupus-Like Anticoagulant

Prevalence and Clinical Significance of Elevated Antiphospholipid Antibodies in Patients With Idiopathic Thrombocytopenic Purpura

Antibodies against phospholipid antigens (APA) have been demonstrated in idiopathic thrombocytopenic purpura (ITP), but their clinical and pathogenetic significance has remained elusive. In this study we analyzed the prevalence and clinical features of ITP patients with elevated APA. In addition, we prospectively evaluated APA levels after treatment with corticosteroids and compared them with platelet-associated immunoglobulin (PAIgG) titers. We studied 149 patients with newly diagnosed ITP. Of these, 78 had a platelet count less than 50 x 10(9)/L and received an initial treatment with oral prednisone (PDN). In 71 asymptomatic cases with platelet counts between 50 x 10(9)/L and 120 x 10(9)/L, no therapy was scheduled. However, in five of them, the platelet count fell below 50 x 10(9)/L after more than 12 months; these patients were treated with PDN. Tests for APA included the measurement of anticardiolipin antibodies (ACA) with a solid-phase immunoassay and the detection of the lupus-like anticoagulant (LA) activity with coagulation tests that included kaolin-clotting time, dilute Russel's Viper venom time, activated partial thromboplastin time (aPTT), and dilute aPTT. Controls consisted of 174 apparently healthy subjects. Either LA or elevated ACA was seen in 69 patients (46.3%) at diagnosis. LA and ACA were both elevated in 24 cases (16.1% of the overall patient population and 34.8% of patients with high APA concentrations). No correlation was found between LA ratio values and ACA-IgG or -IgM titers, or between ACA-IgG and ACA-IgM levels. The presence of these antibodies was not associated with sex, age, platelet count, or the severity of hemorrhages. PAIgG was detected in 106 of 127 cases (83%). Again, no relationship was observed with clinical parameters or with APA levels. However, all cases with elevated APA also had increased PAIgG. With regard to the clinical course, we were not able to detect any significant difference between patients with normal and elevated APA. An initial complete response to prednisone treatment was observed in 43 of 83 cases (51.8%), with 13 (15.7%) achieving a prolonged complete remission. APA levels were not significantly modified after PDN therapy and on relapse. We conclude that APA positivity is a common finding in patients with ITP and does not select a category with different clinical features. APA levels are not influenced by immunosuppressive therapy with steroids and are not related to the activity of the disease. Therefore, we do not support a role for APA in the pathogenesis of ITP.

Antiphospholipid Antibodies: Prevalence, Clinical Significance and Correlation to Cytokine Levels in Acute Myeloid Leukemia and Non-Hodgkin’s Lymphoma

This study was designed to explore the prevalence and clinical significance of elevated antiphospholipid antibodies (APA) titres in patients affected by acute myeloid leukemia (AML) and high-grade non-Hodgkin's lymphoma (NHL). We also analyzed possible correlations with circulating levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and the soluble form of the receptor for interleukin-2 (sIL-2r). Nineteen patients with de novo AML and 14 patients with newly-diagnosed NHL were investigated. Tests for APA included the measurement of anticardiolipin antibodies (ACA) with a solid-phase immunoassay, and the detection of the lupus-like anticoagulant (LA) activity. Five patients with AML (26.3%) and 5 patients with NHL (35.7%) presented elevated APA at diagnosis, as compared to 3 of 174 persons of the control group (p < 0.0001). APA titres became normal in all patients responding to treatment, whereas non-responders retained elevated levels. In addition, 6 patients (4 with AML and 2 with NHL), who had normal APA at diagnosis and were either refractory to treatment or in relapse, subsequently developed LA and/or ACA positivity. At presentation, the mean levels of IgG- and IgM-ACA in patients were not significantly different from controls, and concordance between ACA and LA results reached just 30%. With regard to the clinical course, we were not able to detect any statistically significant difference between patients with normal and elevated APA. Pretreatment concentrations of IL-6 and TNF-alpha in AML, and sIL-2r in NHL were found significantly elevated compared to controls (p = 0.003, p = 0.009 and p = 0.024 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Anticardiolipin antibodies (ACA) are most often not associated with lupus‐like anticoagulant (LLAC) in human immunodeficiency virus (HIV) infection

Anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LLAC) have been studied in a group of 142 non-hospitalized and a group of 72 hospitalized HIV infected patients. We observed a variable frequency of ACA positivity ranging from 7.7% to 30.3% according to the groups of patients and the isotype of immunoglobulin fraction containing ACA activity. None of the patients investigated presented a prolongation of the activated partial thromboplastin time (APTT) compatible with the presence of a LLAC. Some patients presented a weak anticoagulant activity only detected by the tissue thromboplastin inhibition (TTI) test. No positive correlation was found between this latter test and ACA. We conclude that, like in syphilitic patients, ACA present in HIV infected patients are most often not associated with LLAC.

T-PA, PAI, and Protein C Before and After Vascular Occlusion of the Upper Limb in Patients with Raynaud's Phenomenon

Tissue plasminogen activator (t-PA) and its inhibitor (PAI) were assessed in venous blood drawn before and after venous occlusion (bvo, avo) for 33 patients with Raynaud's phenomenon (RP), 14 with primary RP (PRP), 9 with suspected secondary RP (SSRP), and 10 with definite collagen disease and secondary RP (SRP). There were significant differences in PAI values avo between PRP (and controls), SSRP, and SRP. PAI activity decreased significantly avo only in controls and in PRP, and there was significant t-PA antigen elevation avo in the same groups. In addition, since PAI is neutralized by activated protein C (PC), both PC antigen and PC activity were assessed avo and bvo. PC Ag remained unchanged in all groups, with PC activity significantly lower than controls in SRP and SSRP. Finally the authors looked for interference of anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LAC) with the PC system in collagen disease-associated RP. Specific IgG ACA were found in only 1 patient with SRP. In conclusion, there is an endothelial derangement, involving t-PA release and PAI, in SSRP and SRP patients. The reduced PC activity in these latter groups appears to be due to increased PAI influence rather than to ACA/LAC.

Study of three patients with monoclonal gammopathies and ‘lupus‐like’ anticoagulants

In three patients with monoclonal gammopathies: a case of multiple myeloma, a case of monoclonal gammopathy of uncertain significance (MGUS) and a case of monoclonal gammopathy associated with lymphocytic lymphoma, we found the presence of a circulating lupus-like anticoagulant. Coagulative studies showed that the paraproteins: an IgG3k, an IgG1k and an IgMlambda, were responsible for the anticoagulant activity by interacting with the thromboplastin phospholipids. Using isoelectrofocusing we demonstrated that the three monoclonal immunoglobulins had a strong basic charge which may have contributed to determining their interaction with the acidic thromboplastin phospholipids. The binding of various phospholipids to the monoclonal proteins was assessed by the fluorescence quenching method which showed heterogeneous specificity. In order to establish whether the electrical charge is also relevant in cases with polyclonal lupus anticoagulant, the polyclonal immunoglobulins were fractionated according to their charge. The strongest inhibitor activity was found in the most basic immunoglobulins. Monoclonal lupus-like anticoagulants represent useful tools for investigating the heterogeneous world of polyclonal lupus-like anticoagulants.

Biological and Clinical Heterogeneity of Lupus and Lupus-Like Anticoagulant in Fifty-Seven Patients

A lupus or lupus-like inhibitor was detected in 57 patients: 24 systemic lupus erythematosus, 9 autoimmune diseases, 10 lymphoproliferative disease, 11 miscellaneous diseases and 3 asymptomatic patients. No hemorrhagic diathesis was observed in spite of major surgery. Thromboembolism occurred in 19 patients. Among them, 5 patients had recurrent abortions. An extensive study of coagulation profile compared different assays to investigate lupus-like inhibitor: the most sensitive assay was the partial thromboplastin time performed without activator. When performed with kaolin, it was the only assay detecting the lupus cofactor. Prothrombin time was prolonged in only 53% of the patients. Factors VIII, IX, XI and XII were in the normal range in 40% of the patients. When decreased, apparent deficiencies were usually not detectable on further dilutions of the test samples. In 7 patients factor XII antigen and activity were both decreased, suggesting an apparent factor XII deficiency. No relationship was observed between thromboembolic events, underlying disease or biological pattern.

Transient Acquired-Inhibitors to Factor IX and Lupus-Like Anticoagulant in a 4-Year-Old Boy

Transient Acquired-Inhibitors to Factor IX and Lupus-Like Anticoagulant in a 4-Year-Old Boy

Case report: Oncogenous osteomalacia: A new case secondary to a malignant tumor

A case of oncogenous osteomalacia secondary to a fibrous malignant histiocytoma in a 31-year-old male is described. The patient also demonstrated a lupuslike anticoagulant. Clinical signs of osteomalacia preceded by 9 years those of the tumor, a feature occurring in only 8% of these malignancies. Surgical resection of the tumor and surrounding tissues was followed by a clinical improvement and a return to normal of serum phosphorus and tubular reabsorption of phosphate, though the lupuslike anticoagulant persisted. This first description of a fibrous malignant histiocytoma with associated osteomalacia and lupuslike anticoagulant makes compulsory the inclusion of these syndromes among those already described that may appear with this tumor.

The lupus anticoagulant.

Lupus-like anticoagulant (LLAC) is the term used to identify an acquired inhibitor (1) of blood coagulation, first described by Conley and Hartmann in patients with systemic lupus erythematosus (SLE) (2). A circulating “lupus-like” anticoagulant has been detected in 5-10% of all SLE patients. A lupus anticoagulant is also found in other diseases including immunologic, oncologic, gynecologic, and neurologic disorders (3-12). In autoimmune diseases a lupus anticoagulant may occur in families, suggesting a genetic predisposition (13-15). Methods now available can distinguish between lupus anticoagulant and other inhibitors of coagulation (i.e., agonist factor VIII, IX, X, XI, and XII) occurring in SLE (16-19) and, more generally, in autoimmune diseases. In fact, in mixtures of LLAC plasma and normal plasma an immediate inhibition can be observed which is not increased by prolonging the incubation period, in contrast to the gradual time-dependent inhibition that occurs in patients with other types of coagulat...

Anticoagulant antibodies in the synovial membranes of patients suffering from haemophilia, rheumatoid arthritis and other rheumatic disorders.

This study has identified IgG and IgM anticoagulant antibodies in the synovial membranes of patients suffering from haemophilia and rheumatoid arthritis (RA) but not in synovial tissues from normal subjects or in patients with other arthritides. In the majority of cases the antibody appeared to have the specificity of the lupus-like anticoagulant (LLA) seen in patients with systemic lupus erythematosus (SLE). The importance of these findings with regard to the treatment of certain cases of haemophilia and RA and the possible relation between the presence of these antibodies and viral infections is discussed.

796 TRANSIENT LUPUS-LIKE ANTICOAGULANT IN 3 FAMILY MEMBERS SHARING THE A11BW35 HAPLOTYPE

The lupus-like anticoagulant is being seen more frequently in the pediatric population, particularly as a transient occurrence after a presumed viral URI. We herewith report the transient occurrence of lupus-like anticoagulant in a patient, his sister and his mother, all of whom shared the same HLA haplotype. The patient is a 6-year-old white male diagnosed as having AML in 9/80 who went into remission with CCSG-251 (combination adria-mycin + ARA-C). The patient was randomized to the transplant arm of CCSG-251 and upon routine screening a PTT of 75 was discovered. Work-up revealed a circulating anticoagulant of the lupus-type (Rapaport, AIM 2/80) with decreased factors IX, and XII and a clear cut prolongation of the mixed PTT. The thrombin time, PT, and fibrinogen were normal. The patient's entire family was evaluated. The mother and the HLA-identical sister (donor) had the same abnormalities as the patient; while the two other siblings and the father did not. Follow-up studies within two months on the 3 affected family members reverted entirely to normal. The family has no history of autoimmune disease, bleeding, or thromboembolic problems. Family testing for VDRL, C2 or C4 deficiency, immune complexes and ANA was negative. In summary we report 3 members of a family sharing the A11Bw35 haplotype all of whom had the transient simultaneous occurrence of a weak lupus-like anticoagulant.

The varied sensitivity of partial thromboplastin and prothrombin time reagents in the demonstration of the lupus-like anticoagulant.

An acquired inhibitor of blood coagulation, similar to that described in patients with Systemic Lupus Erythematosus (SLE), was detected during routine coagulation screening in 10 patients who did not meet the criteria for a diagnosis of SLE. The lupus-like anticoagulant (LLAC) was diagnosed on the basis of prolonged activated partial thromboplastin time (APTT) and/or prothrombin time (PT) which failed to correct when patient plasma was added to normal plasma; an additional criterion was an abnormal tissue thromboplastin inhibition test. No patient had a specific inhibitor directed against factors VIII and IX. Demonstration of LLAC was highly dependent upon the type of reagents adopted in the APTT and PT: the abnormality was detected consistently by one reagent only. One-stage assays of factors VIII and IX were characteristic of the presence of an inhibitor, showing non-parellel dose-response curves or decreased activity at low dilutions which were partially corrected at higher dilutions. Although 7 patients were free of abnormal bleeding, unequivocal signs of haemorrhagic tendency after a surgery were present in the remaining 3 patients. The findings suggest that LLAC is a non-exceptional cause of prolonged coagulation screening tests, and that it may sometimes be associated with impaired haemostasis.