Is It Time To Reconfigure Lupus Anticoagulant Panels?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2648-2648
Author(s):  
Zella Rose Zeigler ◽  
Andrea L. Cortese Hassett

Abstract Traditional lupus anticoagulant (LAC) panels are designed to test the presence/absence of antiphospholipid antibodies (APA). These usually include testing for a LAC with clot based assays (dRVV, Hex PL, aPTT) or with the tissue thromboplastin inhibition assay (TTI) and ELISA assays for anticardiolipin antibodies (ACA). It is now recognized that antibodies to a phospholipid binding protein, beta-2-GPI are important in the autoimmune form of the antiphospholipid syndrome (aPls). Moreover, some patients (pts.) may only be positive in this latter testing and have what is termed sero-negative aPls. The present study is a retrospective medical record review methodology to analyze the results of APA tests in 258 consecutive pts. referred to the PI at the Hemostasis & Thrombosis Clinic at the Institute For Transfusion Medicine. Inclusion criteria were any pt. who had a lupus panel and anti-beta-2-GPI (IgG, IgM and IgA) testing performed. Exclusion criteria were any pts. who did not have this testing or pts. with positive results which were not repeated > 2 months later. The cohort consisted of 258 pts (69M:189F) with a median age of 48 (range=13–85). Of these pts., 35 (13%) were referred for risk assessment, 133 (52%) for arterial or venous thrombosis, 62 (24%) for neurologic reasons, and 27 (11%) for other reasons. Patients on no anticoagulation (OAC) were considered to be LAC+, if any of the clot based assays was repeatedly positive, did not correct on a mix, and shortened with the additon of phospholipid. OAC pts. with positive ELISA assays were considered to have a LAC if the dRVV was positive on a mixing study and/or if the Hex PL test was positive. OAC pts. with only evidence for a LAC, were taken off OAC and then studied. ELISA assays were considered to be positive if low titer positive or higher, e.g. ≥ 3 STD above the mean. Positive results were found in 59/258 (22.8%) of these pts. The antibody results are listed in the table below in the pts. referred for risk assessment and in the pts. referred with events. The results are listed in categories of APA positivity. Antiphospholipid Antibody Results In Pts With Risk Assessment and Pts With Clinical Events Pt. Group LAC+beta-2-GPI LAC Only Beta-2-GPI Only ACA Only Total NOTE: 36% of the positive pts. would be missed by the traditional LAC panel. Risk Assessment 0/35 (0%) 0/35 (0%) 1/35 (3%) 0/35 (0%) 1/35 (3%) Pts. With Events 26/233 (11%) 12/233 (5%) 20/233 (9%) 0/35 (0%) 58/233 (25%) Total Positive Results 26/59 (44%) 12/59 (20%) 21/59 (36%) 0 59 These results indicate that one-third of the pts. with phospholipid antibodies were sero-negative, e.g. negative in the presently constructed panels but positive for anti-beta-2-GPI antibodies. Skeptism exists about the meaning of isolated anti-beta-2GPI positivity. Of the pts. with only + beta-2-GPI antibodies, one male was asymptomatic (5%). The remaining pts. in this group were females. Ten/twenty-one (48%) of the pts. with isolated beta-2-GPI positivity were referred for neurologic reasons. These consisted of TIA’s in 6, complex migraines with TIA’s and acral cyanosis (1), recurrent fetal loss and TIA’s in 3. Eight pts. (38%) had recurrent venous thromboembolism and 2 (9%) had both arterial and venous thromboembolism. We suggest that it may be time to consider constructing LAC screening panels containing tests for both LAC and anti-beta-2-GPI antibodies (all three isotypes) as sero-negative APls appear to be fairly common in females referred for thrombophilic testing.

Lupus ◽  
2011 ◽  
Vol 20 (13) ◽  
pp. 1372-1377 ◽  
Author(s):  
TP Greco ◽  
AM Conti-Kelly ◽  
TP Greco

Background: Antiphospholipid antibody (aPL) positive patients and patients with purported chronic Lyme disease (‘CLD’) share many clinical features. After identifying significant aPL in sera of several index patients with ‘CLD’, we performed aPL tests on all patients referred inwhom ‘CLD’ was suspected, diagnosed or treated. Methods: All patients with suspected, diagnosed or treated ‘CLD’ and reportedly ‘positive’ Lyme assays were studied. aPL testing included anticardiolipin antibodies (aCL), anti-beta-2-glycoprotein-1 antibodies (anti-β2GP1) and lupus anticoagulant (LAC). Patients were classified into four newly described categories of CLD and data was analyzed. Results: One hundred and six patients were evaluated, of whom 82% had neurologic symptoms and 51% rheumatologic symptoms. Eighty-eight of 106 (83%) patients had positive Lyme serologies (enzyme-linked immunosorbent assay [ELISA] 62/106, 58.4%; western blot [WB] 64/106, 60%), while 18/106 (16.9%) were negative or equivocal. aPL was found in all ‘CLD’ categories. aCL and/or anti-β2GP1 were positive in 85/106 (80%), with aCL present in 69/106 (65%) and anti-β2GP1 present in 69/106 (65%). For all assays, IgM isotypes predominated: WB 55/64 (85%), aCL 63/69 (91%), anti-β2GP1 52/69 (75%), aCL and/or anti-β2GP1 74/85 (87%). Anti-β2GP1 assays occurred in higher titer than aCL: 36/69 (52%) versus 63/69 (91%), p<0.001. Seventeen patients had aPL-related events. Only 12/106 (11.3%) had true post-Lyme syndromes (PLS), category IV, or late Lyme disease (LLD). Most patients had been treated for Lyme: 82/106 (79%). Conclusion: aPL occurs frequently in patients with ‘CLD’. IgM anti-β2GP1, IgM aCL and IgM WB were frequently found. Documented PLS or LLD was uncommon. The role of aPL in patients with ‘CLD’ needs further investigation. Lupus (2011) 20, 1372–1377.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1208-1208
Author(s):  
Kanika Thapar ◽  
Nimesh Patel ◽  
Bolanle Gbadamosi ◽  
Daniel E Ezekwudo ◽  
Ishmael Jaiyesimi ◽  
...  

Abstract Introduction: The incidence of spontaneous miscarriages is 1%, and up to 50% of recurrent fetal losses (RFL) have unclear etiology. Antiphospholipid syndrome (APS) has been reported in 5-15% of women with RFL. Current clinical criteria for APS include venous thromboembolism (VTE) and /or fetal loss. In addition to the clinical criteria, laboratory confirmation must be obtained using tests for lupus anticoagulant (LA), anticardiolipin (ACL) and beta-2 glycoprotein I antibodies (β2GPI). These tests are often provided by many laboratories as panels; moreover, given the relatively large number of tests, judicious ordering of these panels is warranted to contain costs and to avoid mislabeling patients who have clinically insignificant positive results. Some existing literature suggests that patients with recurrent fetal loss and ACL antibodies are over-tested and/or over-diagnosed. We aim to determine the frequency and likelihood of positive antiphospholipid antibody (APA) among patients with fetal loss. Materials and Methods: A retrospective search was conducted for APA panels using data from our laboratory information system from Jan 2014 to Jan 2015. Recorded variables included age, ordering physician subspecialty and indication for testing. For patients with fetal loss, the number of losses and gestational age at the time of loss were recorded. Specimens were classified as positive, indeterminate or negative. For positive and indeterminate tests, the results of LA, ACL, and β2GPI antibody tests and titers were noted. Results: Our search identified 430 panels ordered for APA. The median age was 42 (range: 1-92). The three highest ordering physician subspecialties were Ob/Gyn (20.2%), Internal Medicine (17.7%) and Heme/Onc (17.2%). The three most common indications for ordering the APA panel were venous thromboembolism (26.5%), fetal loss (18.4%), and autoimmune disease (15.4%). The largest percentage of positive results came from panels ordered by Heme/Onc 45% (20/44) and for the indication of VTE 40.9% (18/44). Fetal loss (n=74) accounted for 4.5% (2/44) of positive results. Further investigation of the fetal loss cases showed that 82.4 % (61/74) met criteria for appropriate APA testing. There was no statistically significant difference for gestational age < 10 weeks (1 positive, 4 indeterminate, and 30 negative specimens) or > 10 weeks (1 positive, 1 indeterminate, and 37 negatives; p=0.334); ordering physician subspecialty and the APA testing result. Both fetal loss patients that tested positive for APS had increased titers of ACL IgM and β2GPI IgM. Conclusions: Despite being the second most common indication for APA testing, fetal loss only accounted for 4.5% of positive results. Compared to historical data that report an incidence of 5-15% APS in patients with recurrent fetal loss, we found an incidence of only 2.7%. The reason for this discrepancy is not clear. Confounding factors such as inappropriate work-ups or incomplete testing are unlikely as 82.7% of patients meet standard testing criteria and our APA panels included multiple tests for LA, ACL and β2GPI. Larger studies are needed to confirm our findings, as this may call for redefinition of APA testing guidelines to better target at risk obstetric patients. Disclosures No relevant conflicts of interest to declare.


1987 ◽  
Author(s):  
W Brien ◽  
G Denome ◽  
B O’Keefe

Patients with the Lupus Anticoagulant and/or anticardiolipin antibodies have been reported to be at increased risk of thrombosis and miscarriages. It has been proposed that the lupus anticoagulant is an antiphospholipid antibody.We evaluated 16 patients with the lupus anticoagulant for the presence of antiphospholipid antibodies. The lupus anticoagulant was documented by the presence of an abnormal APTT, abnormal mixing studies, positive tissue thromboplastin inhibition test and positive platelet neutralization test.Plasma from each patient was assessed for the presence of anticardiolipin, antiphosphatidylserine and antiphosphatidyl-glycerol antibodies by ELISAtechniques. As a control, a neutral phospholipid phosphatidylethanolamine was used. A positive result was established when a delta value of lipid minus control was greater than 3SD compared to a normal population (20 pt.).Using three different patient dilutions, positive results were obtained in 10/16 pt. for anticardiolipin, 11/16 pt. for antiphosphatidylserine and 5/16 pt. for antiphosphatidyl-glycerol antibodies. Three patients were negative for all lipids. If a neutral phospholipid was not used and a delta volume not obtained, 15/16 patients would have had positive results.Our results suggest 1) Not all patients with the Lupus Anticoagulant have antiphosphilipid antibodies by ELISA technique. In evaluating patients with thrombosis and/or miscarriages, both tests should be performed.2) Anticardiolipin antibodies are not present in all patients and with a panel of other negatively charged phospholipids more positive results are obtained. 3) A neutral lipid should be used as a control for non-specific binding of antibody and delta values obtained to see if the results obtained is truly against the negatively charged lipid.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4133-4133
Author(s):  
Zella Rose Zeigler ◽  
Andrea L. Cortese Hassett

Abstract Migraines are associated with an increased risk of stroke and are recognized as a non-stroke neurologic complicaton in the antiphospholipid syndrome (aPls). Traditional tests for antiphospholipid antibodies (APA) include PTT assays [aPTT, dRVV, and Hexagonal phospholipid (Hex PL)], a dilute PT assay (Tissue Thromboplastin Inhibition) for lupus anticoagulants (LAC), and ELISA assays for anticardiolipin antibodies (ACA). These assays have not correlated with migraines. It is now recognized that antibodies to a phospholipid binding protein called beta-2-GPI are important in autoimmune aPls. Some patients (pts) with aPls are sero-negative, eg. negative in the routine assays, but have + anti-beta-2-GPI antibodies. Animal studies have shown an association of the latter antibodies to neurologic dysfunction. This study is a clinical retrospective medical record methodology, examining the relationship between migraines and APA results in pts referred to the Hemostasis & Thrombosis Clinic at the Institute for Transfusion Medicine from 7/1/03-7/15/05. Inclusion criteria were any pt. referred to the PI, who had a LAC screening panel and anti-beta-2-GPI testing. Exclusion criteria were any pt who did not have this testing or were + without repeat testing &gt;2 mos later. Abstracted data included history of migraines (with or without aura), opthalmic migraines, referral reason, age, sex and APA results. Results were considered to be + (in non-anticoagulated pts), if any of the clotting assays were repeatedly +, did not correct on a mix, and shortened with phospholipid. Patients with only a + clotting assay, were taken off coumadin (OAC) and retested. Patients with + ELISA assays on OAC Rx, required an abnormal dRVV mix and/or a + Hex PL assay to be considered as + for a LAC. ELISA results were considered as +, if they were low titer or higher, e.g. ≥ mean ± 3 SD. The cohort consisted of 258 pts (69M: 189F) with a median age of 48 (range=13–85). Of these, 76 (29%) had migraines. Thirty-five/258 (13.6%) of the pts were referred for risk assessment and 10/35 (28.6%) had migraines. The remaining 223 pts were referred for clinical events: arterial or venous thrombosis [n= 133/233 (59.6%)], neurologic reasons [n=62/223 (28.2%)] and other [n=27/233 (12.1%)]. Of this group, migraines were present in 66 (29.6%). None of the 10 risk pts with migraines had + results. One of the 25 risk pts had a + anti-beta-2-GPI antibody (1/25=4.0%). Positive APA were detected in 58/233 (24.9%) pts with clinical events. Table 1 is a breakdown of the APA results vs migraines in pts with events vs those evaluated for risk issues. It appears that pts with thrombotic events with migraines have a higher incidence of +APA than those who do not have migraines. This data supports the suspected association between migraines and APA in the thrombphilic pt population. The same does not appear to be true in pts (without a thrombotic event) undergoing risk assessment. Incidence of Positive APA in Patients with regard to Migraine Status Group Total Pos Total Neg P OR CI APA = LAC/ACA and/or anti-beta-2-GPI Risk-no migraine 1/25 (4%) 24/25 (96%) Risk-migraines 0/10 (0%) 10/10 (100%) 1.00 0.810 0.03–21.5 Events-ALL pts 58/233 (25%) 175/233 (75%) 0.002 11.27 1.51 to 84.2 Events-no migraine 30/157 (19%) 127/157 (81%) 0.058 5.83 0.77 to 44.22 Events-migraines 28/66 (42%) 38/66 (58%) &lt;0.001 25.05 3.23 to 194.2


1998 ◽  
Vol 79 (02) ◽  
pp. 282-285 ◽  
Author(s):  
Josep Ordi-Ros ◽  
Francesc Monegal-Ferran ◽  
Nuria Martinez ◽  
Fina Cortes-Hernandez ◽  
Miquel Vilardell-Tarres ◽  
...  

SummaryObjective: To evaluate the usefulness of IgA antiphospholipid antibodies as markers of thrombosis and/or antiphospholipid antibody syndrome. Patients and Methods: A cross-sectional study design in a tertiary, university-based, autoimmune reference hospital. Seven-hundred ninety-five patients classified into five different groups – autoimmune diseases (255), deep vein thrombosis (153), transitory ischemic attacks (108), obstetric complications (196), infectious diseases (83) and controls (81) – were tested for IgA, IgG and IgM aPL, and lupus anticoagulant. Plasma and serum samples were drawn for detection of aPL using an internationally standardized ELISA method and LA was carried out using coagulometric assays. Results: True IgA aPL were found only in two patients with systemic lupus erythematosus; these patients were also positive to IgG aPL. Conclusion: The incidence of true positivity to IgA anticardiolipin antibodies is extremely low. Their determination was not helpful in diagnosing the antiphospholipid syndrome or in explaining thrombotic events or aPL related manifestations – fetal loss – in the groups studied.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 529-529 ◽  
Author(s):  
Koushi Paramsothy ◽  
Philip S. Wells

Abstract The presence of antiphospholipid antibodies (APLA), which include lupus anticoagulant (LA) and anticardiolipin antibodies (ACA), increases the risk of venous thromboembolism (VTE). Although, the association demonstrated between LA and VTE is strong, that between ACA and VTE is weak with the exception of high titers. This suggestion has been that this may be related to the induction of ACA by acute illness. This may be the explanation for the widely varying frequency of ACA positivity in patients with acute VTE in the current medical literature. The prevalence of LA in patients with acute VTE is more consistent but the value of testing for ACA and LA at presentation of acute VTE remains unknown. We routinely test all idiopathic VTE patients at presentation for LA and ACA. It had been our impression that most positive results revert to normal with subsequent testing. We sough to test this hypothesis. The objective was to determine the prevalence of abnormal LA and ACA results and the frequency of subsequent normalization in patients presenting with a first idiopathic venous thromboembolic event. A retrospective chart review was conducted at the Thrombosis Unit at the Ottawa Hospital. 278 charts of unrelated, consecutive patients with idiopathic VTE were reviewed. 232 patients with single idiopathic venous thromboembolic events with documented LA and ACA results were included. The patients were divided into two groups based on the time between the acute VTE and initial APLA test. The frequency of abnormal LA and ACA on initial and repeat tests was determined in each group. 170 and 177 patients were screened for LA and ACA within one month of the acute VTE. On initial tests, LA and ACA were detected in 14.1% and 7.9% of patients, respectively. However, LA and ACA were present in only 1.2% and 1.7% of patients, respectively, on subsequent tests. In patients screened more than one month after an acute VTE 3.8% of the 52 patients had evidence of LA on initial testing and all were positive on repeat tests. ACA were present in 8% of patients on initial tests and in 6% (75% of the initial positive results) of patients on subsequent tests. A high frequency of positive LA and ACA tests results is observed when these tests are performed at the time of presentation of acute VTE. Repeat testing beyond one month from presentation demonstrates most of the results return to normal suggesting false positive results are common at presentation. However, when the tests are performed one month or longer after the acute VTE, the frequency of positive APLA test is much lower and false positives are uncommon. Screening for APLA should not be performed until at least one month after the diagnosis of idiopathic.


1993 ◽  
Vol 70 (02) ◽  
pp. 342-345 ◽  
Author(s):  
Wei Shi ◽  
Beng H Chong ◽  
Philip J Hogg ◽  
Colin N Chesterman

SummaryAntiphospholipid antibodies, defined either by lupus anticoagulant (LA) activity or positive anticardiolipin immunoabsorbent assay (ACA) are associated with a predisposition to thromboses, recurrent fetal loss or thrombocytopenia. The mechanisms for these predispositions remain undefined. We have enriched immunoglobulin fractions from two patient plasmas to obtain antibodies with LA activity but no ACA, or conversely, with ACA positivity but no LA, in order to investigate in vitro characteristics which might explain a thrombotic propensity. β2-glycoprotein I (β2-GPI), the plasma cofactor required for ACA binding to negatively charged phospholipid, has previously been shown to inhibit prothrombinase generation in the presence of activated platelets (8). We now report that β2-GPI, at physiological concentrations, inhibits the generation of factor Xa in the presence of activated gel-filtered platelets. Further, ACA interferes with this inhibition, resulting in protracted, unopposed factor Xa generation. This interference with β2-GPI, a natural anticoagulant component of plasma, is potentially prothrombotic. LA immunoglobulins behave differently and inhibit factor Xa generation in a manner similar to β2-GPI. These findings provide the basis for a previously unsuspected mechanism for thrombosis in patients with aPL.


2012 ◽  
Vol 4 (02) ◽  
pp. 078-082
Author(s):  
Amel AA Al-Samarrai ◽  
Ferial A Hilmi ◽  
Nasir AS Al-Allawi ◽  
Amal F Murad

ABSTRACT Purpose: Antiphospholipid antibodies are often associated with recurrent pregnancy loss, and although many studies have addressed this association in Western countries, such studies are not so frequent from developing countries. The current study aims to determine the frequency of Antiphospholipid antibodies (Anticardiolipin antibodies and Lupus anticoagulant) among Iraqi women with recurrent mid-trimester abortions and to evaluate various tests used for their detection. Materials and Methods: Two hundred women with recurrent mid-trimester abortions were randomly enrolled from a main referral center in Baghdad-Iraq. The enrollees had their IgG and IgM anticardiolipin antibodies assayed by ELISA, and Lupus anticoagulant by a combination of the following screening tests: Activated Partial Thromboplastine Time (APTT), and Partial Thromboplastine Time-LA (PTT-LA), Kaolin Clotting Time (KCT) and confirmation was made by Hexagonal phospholipid neutralization test. Results: The women were aged between 19 and 45 years (median 30 years). Fifty three (26.5%) had one or both anticardiolipin antibodies present, while 27 (13.5%) were positive for lupus anticoagulant. The KCT and KCT index appeared to be the most sensitive tests, while the KCT index and APTT were the most specific for Lupus anticoagulant. Patients with antiphospholipid antibodies had higher rates of history of thrombosis, thrombocytopenia and family history of recurrent abortion (P = 0.0009, 0.0056 and 0.0003 respectively). Conclusions: Antiphospholipid antibodies constitute an important cause of recurrent mid-trimester abortion in Iraqi women, with frequencies intermediate between Western and Indian reports. While thrombocytopenia and thrombosis are well documented associations of antiphospholipid antibodies, the significant association with family history of recurrent fetal loss is intriguing and requires further scrutiny.


2014 ◽  
Vol 60 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Luci Maria Santana Dusse ◽  
Fernanda Dias e Silva ◽  
Letícia Gonçalves Freitas ◽  
Danyelle Romana Alves Rios ◽  
Sandra Cristina Armond ◽  
...  

Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia characterized by the presence of a heterogeneous family of antibodies that bind to plasma proteins with affinity for phospholipid surfaces. The two major protein targets of antiphospholipid antibodies are prothrombin and β2-glycoprotein I (β2GPI). APS leads to aprothrombotic state, and it is characterized by the occurrence of arterial, venous or microvascular thrombosis or recurrent fetal loss. The diagnosis of APS is based on a set of clinical criteria and the detection of lupus anticoagulant (LA), anticardiolipin antibodies (ACA) or anti-β2GPI in plasma. Although laboratory tests are essential for APS diagnosis, these tests have limitations associated with the robustness, reproducibility and standardization. The standardization of diagnostic tests for detection of APLAs has been a challenge and a variety of results have been obtained using different commercial kits and in-house techniques. An increased sensitivity of the ELISA kits for detection of ACA effectively has contributed to APS diagnosis. However, the lack of specificity associated with a high number of false-positive results is a clinical and laboratorial challenge, since such results may lead to mistaken clinical decisions, such as prescription of oral anticoagulant, leading to the risk of hemorrhaging. Furthermore, clinicians are often unfamiliar with these tests and have difficulty interpreting them, requiring interaction between clinical and laboratory professionals in order to ensure their correct interpretation.


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