Thrombophilic Patients with Migraines Have a High Incidence of Antiphospholipid Antibodies.

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 >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%) <0.001 25.05 3.23 to 194.2

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.


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 ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2730-2741 ◽  
Author(s):  
KR McCrae ◽  
AM DeMichele ◽  
P Pandhi ◽  
MJ Balsai ◽  
P Samuels ◽  
...  

Abstract Women with anticardiolipin antibodies (ACLA) are at increased risk for fetal loss. One potential explanation for this outcome is that sera from these individuals contain antibodies reactive with trophoblast cells, which are involved in the establishment of the uteroplacental vasculature and maintenance of placental blood fluidity. To examine this hypothesis, we compared the incidence of trophoblast-reactive antibodies in 27 patients with ACLA and a history of fetal loss with that in 29 normal pregnant women. Sera from 20 patients, but only one control, contained trophoblast-reactive antibodies (P < .001). These antibodies were not directed against major histocompatibility class I antigens, and reacted with both term and first-trimester trophoblast cells. In most cases, sera from which ACLA were adsorbed by cardiolipin- containing liposomes maintained reactivity against cells. In addition, patient Ig fractions immunoprecipitated an approximately 62-kD protein from the trophoblast cell surface, stimulated the release of arachidonic acid and thromboxane A2 by trophoblasts, and inhibited the binding of prourokinase to trophoblast urokinase receptors. These observations show that sera from women with ACLA and a history of fetal loss contain antitrophoblast antibodies. These antibodies may be serologically distinct from ACLA, and may contribute to the pathogenesis of fetal demise.


1998 ◽  
Vol 79 (01) ◽  
pp. 46-49 ◽  
Author(s):  
Catello Tommasino ◽  
Giovanna D’Andrea ◽  
Luigi Iannaccone ◽  
Vincenzo Brancaccio ◽  
Maurizio Margaglione ◽  
...  

SummaryTo evaluate the significance of common thrombophilic genotypes in subjects with idiopathic antiphospholipid antibodies (aPL) we determined the methylenetetrahydrofolate reductase C677→ (MTHFR) and factor V A506→ G (FV Leiden) polymorphisms in 49 subjects with idiopathic aPL (57% of whom suffered spontaneous vein thrombosis), in 70 subjects with a history of spontaneous vein thrombosis and in 193 healthy subjects. The prevalence of MTHFR C677→+/+ (homozygotes) was 25%, 18% and 17% respectively amongst aPL thrombotics, non aPL thrombotics and controls and that of MTHFR C677→+/– (heterozygotes) was 53%, 59% and 53% respectively in the same groups. The prevalence of FV Leiden was higher in aPL thrombotics (14%) and in non aPL thrombotics (18%) than in controls (4%) (p ≤ = 0.05). APL thrombotics with MTHFR C677→+/+ had a lower mean age at first thrombotic event (22 ± 6 years) than aPL thrombotics with MTHFR C677→+/– and non mutated considered together (38 ± 14 years, p = 0.0004) and than non aPL thrombotics with MTHFR C677→+/+ (38 ± 14 years, p = 0.003). FV Leiden may con tribute to the hypercoagulability of a small, albeit significant proportion of thrombotic aPL subjects, whereas the association between MTHFR C677→+/+ and aPL may have an impact on age at first occlusive event and suggests a possible pathogenetic interaction.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3833-3833
Author(s):  
Jennifer L Curnow ◽  
Marie-Christine Morel-Kopp ◽  
Ninfa Rojas ◽  
Margaret Aboud ◽  
Christopher Ward

Abstract We have previously demonstrated hypercoagulability utilizing a global haemostatic assay, the Overall Haemostatic Potential (OHP) in a heterogenous population of patients with a demonstrable lupus anticoagulant. Our aim in this study was to determine whether the OHP assay demonstrated a persistent hypercoagulable state in a well-defined prospective population with APLS and whether global assays were able to predict the occurrence of thrombotic complications. Informed consent was obtained and blood was collected on three occasions, three months apart from 54 patients with APLS, recruited from Haematology clinics at Royal North Shore Hospital, Sydney, Australia between May 2005 and November 2007. Clinical data was collected including history of prior and subsequent thrombotic events. Two control groups consisted of 200 healthy blood donors and 20 patients with autoimmune disorders, but no history of thrombosis. Assays performed were PT, INR, APTT, FVIIIc, lupus anticoagulant assay (LAC), anticardiolipin antibodies (ACLA), b2-glycoprotein1 antibodies (B2GP1), a thrombin generation assay (Calibrated Automated Thrombogram, CAT) and the OHP assay which utilizes thrombin (0.03 IU/ml) and rt-PA (350 ng/ml) to trigger fibrin generation and fibrinolysis, respectively, in platelet poor plasma. Change in optical density in microtitre wells is measured over 60 minutes. Statistical analysis involved calculation of means, SD, T-tests and paired T-tests utilizing SPSS v16.0. Fifty percent of APLS patients were male, compared with 10% of the autoimmune control group. APLS had been diagnosed on the basis of persistent antiphospholipid antibodies and at least one thrombotic event: VTE (n=46), ATE (n=6) or recurrent late miscarriage (n=2). Number of thrombotic events prior to study entry ranged form 1 to 6 per patient, with 49/66 events unprovoked. Samples from APLS patients on anticoagulation (OAC, n=35) were analysed separately from those not anticoagulated (n=19). Global assay results for samples collected at different time points were stable, with no significant differences on paired T-test. APLS patients had significantly shorter PT, higher fibrinogen, increased fibrin generation and reduced fibrinolysis parameters (p<0.001), compared with healthy donors. The autoimmune control group also showed hypercoagulable OHP parameters compared with healthy donors (p<0.001), with assay results comparable to those in APLS patients, not on OAC. The only thrombin generation assay parameter significantly increased in APLS patients, not on OAC, compared with controls was peak thrombin (266 vs 298 nM, p=0.016). However thrombin generation was significantly suppressed in those on OAC (p<0.001). Only one patient had recurrent DVT during the study. The OHP assay identifies a hypercoagulable state in APLS patients with reduced fibrinolysis and increased fibrin generation, even when anticoagulated. The calibrated automated thrombogram (CAT) showed increased peak thrombin generation in APLS patients not on OAC but endogenous thrombin potential (ETP) was not significantly elevated. Thrombin generation was suppressed by OAC therapy. These global assays show differential results in patients with APLS. More prolonged follow up will be necessary to determine whether the assays predict recurrent thrombotic events and are useful in risk stratification of APLS patients.


2005 ◽  
Vol 17 (2) ◽  
pp. 155-164 ◽  
Author(s):  
Osvaldo P. Almeida ◽  
Leon Flicker

The results of in vitro and animal studies provide a strong rationale for the use of hormone replacement therapy (HRT) to prevent dementia and Alzheimer's disease (AD). In humans, the results of 16 observational studies are consistent with the hypothesis that estrogen use reduces the risk of AD by 10 to 60%. However, women who are prescribed HRT are less likely to have hypertension, diabetes and history of stroke than nonusers. As all of these factors have been associated with increased risk of dementia (including AD), this “prescription bias” may have a significant impact on the results of observational studies. Randomized trials are designed with the aim of avoiding many of the potential biases and confounding (measured or unmeasured) of observational studies. The results of the Women's Health Initiative Memory Study (WHIMS) indicate that HRT (estrogen plus progestin or estrogen alone) increases the risk of dementia (hazard ratio, HR=1.8, 95% CI=1.2–2.6). Taking into account the results of the WHIMS and the adverse health events associated with the use of estrogen plus progestin or estrogen alone, we conclude that HRT cannot be recommended as a safe and effective strategy to prevent dementia.


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.


1999 ◽  
Vol 81 (05) ◽  
pp. 695-700 ◽  
Author(s):  
Guido Finazzi ◽  
Francesca Norbis ◽  
Stefana Marziali ◽  
Roberto Marchioli ◽  
Tiziano Barbui ◽  
...  

SummaryLupus anticoagulants belong to the family of antiphospholipid antibodies. They include two phospholipid-dependent inhibitors of coagulation that may be distinguished on the basis of specific coagulation profiles generated from the comparison of the ratios of the Kaolin Clotting Time (KCT) and the dilute Russell’s Viper Venom Time (dRVVT): when the ratio of the KCT exceeds that of the dRVVT, the plasma is allocated to the “KCT” coagulation profile, when the opposite occurs, the plasma is defined to belong to the “dRVVT” coagulation profile group. We prospectively followed-up a historical cohort of 100 consecutive patients with lupus anticoagulants referred to our Institution between January 1988 and October 1997 to investigate the relationship between their coagulation profile at diagnosis and the development of thrombosis during a median follow-up time of 37.5 months (range 1-115 months). Fifty-six patients were allocated to the “dRVVT” coagulation profile, whereas the other 44 displayed the “KCT” profile. Lupus anticoagulants were transient in 17 patients, without differences between the two groups. None of these patients developed clinical events before disappearance of the phospholipid-dependent inhibitors of coagulation. The 83 cases with persistent lupus anticoagulants consistently displayed the same coagulation profile they had been allocated to at entry. Fourteen patients developed 18 thromboembolic events during the follow-up, with an overall rate of thrombosis of 4.2% patients-year. Twelve of them belonged to the “dRVVT” coagulation profile, whereas the other 2 to the “KCT” profile (p = 0.03). The “dRVVT” coagulation profile gave an odds ratio of thrombosis of 5.25 (95% confidence interval [C.I.]: 1.17-23.50). Ten of the 14 patients who developed thrombosis during follow-up had already experienced thrombosis: a previous thrombotic event caused an odds ratio of recurrency of 2.72 (95% C.I.: 0.85-8.73) (p = 0.09). By multivariate analysis, the “dRVVT” coagulation profile was still associated with a trend to a higher risk of thrombosis, but the difference did not reach statistical significance. Increased levels of anticardiolipin antibodies (> 40 GPL and/or MPL units) were found in all the 14 patients (p = 0.0064). The “KCT” coagulation profile was significantly associated (p = 0.005) with moderate thrombocytopenia (platelets 50-150 × 109/l). Neither profile was found to represent a risk factor for the development of recurrent miscarriages, neoplastic diseases and death. In conclusion, the “dRVVT” profile appears to have predictive value with respect to the thrombotic complications suffered by patients with antiphospholipid antibodies.


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.


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