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American Journal of Clinical Pathology Oct 2019Anti-β2 glycoprotein I domain I (anti-domain I) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are present in patients with antiphospholipid syndrome...
OBJECTIVES
Anti-β2 glycoprotein I domain I (anti-domain I) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are present in patients with antiphospholipid syndrome (APS); however, their use in evaluation remains unclear.
METHODS
Diagnostic attributes of lupus anticoagulant (LAC), anti-domain I IgG, anti-cardiolipin, anti-β2 glycoprotein I (anti-β2GPI), and aPS/PT IgG and IgM antibodies were assessed in 216 patients evaluated for APS.
RESULTS
LAC had the best odds ratio (OR, 14.2) while that for anti-domain 1 IgG was comparable to anti-β2GPI IgG (OR, 8.3 vs 9.4) but higher than all others. Significant correlations were observed for thrombosis (P = .03) and pregnancy-related morbidity (P = .001) with anti-domain IgG and for any thrombosis with aPS/PT IgG (P = .006). Use of noncriteria antiphospholipid with or without criteria markers did not significantly increase the probability to diagnose APS.
CONCLUSIONS
Noncriteria tests can contribute to diagnosis and stratification of APS but do not improve diagnostic yield. Optimal strategies for implementation require prospective investigation.
Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; Cardiolipins; Female; Humans; Immunoglobulin G; Immunoglobulin M; Lupus Coagulation Inhibitor; Male; Middle Aged; Odds Ratio; Phosphatidylserines; Pregnancy; Pregnancy Complications; Prothrombin; Retrospective Studies; beta 2-Glycoprotein I
PubMed: 31305881
DOI: 10.1093/ajcp/aqz085 -
Journal of Hepatology May 2023In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of...
BACKGROUND & AIMS
In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of treatment, and long-term outcomes. We report our experience on these issues.
METHODS
From 1973 to 2002, 117 children with type 1 (n = 65) or type 2 (n = 52) hepatitis, excluding fulminant hepatitis, were treated, primarily with prednisone and azathioprine. Median follow-up was 20 years in survivors.
RESULTS
Normalisation of aminotransferases and prothrombin ratio were observed in 93% and 84% of children, respectively; sustained remission after treatment withdrawal was recorded in 24% of the entire population, with a median follow-up of 7 years. Sustained treatment-free remission was obtained in 11 of 24 children with follow-ups of 4-22 years based on durable normalisation of aminotransferases (without histological assessment). Gastrointestinal bleeding from varices and the emergence of extrahepatic autoimmune disorders occurred in 10 and 22 patients, respectively. Liver transplantation was performed in 23 patients at a median age of 21 years. The 30-year probabilities of overall and native liver survival were 81% and 61%, respectively. No differences were observed between type 1 and 2 hepatitis for any of the component parts of outcome. In the multivariate analysis, a persistent abnormal prothrombin ratio was associated with worse probabilities of overall and native liver survival.
CONCLUSIONS
In terms of liver outcome, type 2 hepatitis is not different from type 1. Withdrawal of treatment is possible without prior liver histology. A persistent abnormal prothrombin ratio identifies patients who will require liver transplantation in adolescence or early adulthood.
IMPACT AND IMPLICATIONS
In children with autoimmune hepatitis, there are conflicting reports on the differences in outcome between type 1 and type 2 hepatitis, and on the possibility of treatment withdrawal, before which liver histology is required; data concerning >10-year overall and native liver survival rates are limited. In this study, we found no differences in outcomes between type 1 and 2 hepatitis; a durable treatment-free state was achieved in 19% of all patients throughout childhood and early adulthood, and in 45% of children for whom treatment withdrawal was attempted without prior liver histology; prothrombin was found to be predictive of 30-year overall and native liver survival. The results allow for a less-strict approach to treatment withdrawal in children, avoiding the risks of a liver biopsy, and they provide a tool to help anticipate the need for liver transplantation before complications occur.
Topics: Child; Adolescent; Humans; Adult; Young Adult; Immunosuppressive Agents; Hepatitis, Autoimmune; Prothrombin; Azathioprine; Transaminases
PubMed: 36708813
DOI: 10.1016/j.jhep.2023.01.013 -
Clinical Immunology (Orlando, Fla.) Dec 2023COVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid...
BACKGROUND AND OBJECTIVES
COVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid syndrome (APS), a prototype antibody-mediated autoimmune disease. Several groups have reported elevated levels of criteria and non-criteria antiphospholipid antibodies (aPL), assumed to cause APS, during acute or post-acute COVID-19. However, disease heterogeneity of COVID-19 is accompanied by heterogeneity in molecular signatures, including aberrant cytokine profiles and an increased occurrence of autoantibodies. Moreover, little is known about the association between autoantibodies and the clinical events. Here, we first aim to characterise the antiphospholipid antibody, anti-SARS-CoV-2 antibody, and the cytokine profiles in a diverse collective of COVID-19 patients (disease severity: asymptomatic to intensive care), using vaccinated individuals and influenza patients as comparisons. We then aim to assess whether the presence of aPL in COVID-19 is associated with an increased incidence of thrombotic events in COVID-19.
METHODS AND RESULTS
We conducted anti-SARS-CoV-2 IgG and IgA microELISA and IgG, IgA, and IgM antiphospholipid line immunoassay (LIA) against 10 criteria and non-criteria antigens in 155 plasma samples of 124 individuals, and we measured 16 cytokines and chemokines in 112 plasma samples. We additionally employed clinical and demographic parameters to conduct multivariable regression analyses within multiple paradigms. In line with recent results, we find that IgM autoantibodies against annexin V (AnV), β2-glycoprotein I (β2GPI), and prothrombin (PT) are enriched upon infection with SARS-CoV-2. There was no evidence for seroconversion from IgM to IgG or IgA. PT, β2GPI, and AnV IgM as well as cardiolipin (CL) IgG antiphospholipid levels were significantly elevated in the COVID-19 but not in the influenza or control groups. They were associated predominantly with the strength of the anti-SARS-CoV-2 antibody titres and the major correlate for thromboses was SARS-CoV-2 disease severity.
CONCLUSION
While we have recapitulated previous findings, we conclude that the presence of the aPL, most notably PT, β2GPI, AnV IgM, and CL IgG in COVID-19 are not associated with a higher incidence of thrombotic events.
Topics: Humans; Antibodies, Antiphospholipid; Influenza, Human; COVID-19; SARS-CoV-2; Antiphospholipid Syndrome; Antibodies, Anticardiolipin; Thrombosis; beta 2-Glycoprotein I; Immunoglobulin G; Prothrombin; Immunoglobulin A; Immunoglobulin M; Cytokines
PubMed: 37995947
DOI: 10.1016/j.clim.2023.109845 -
Journal of Thrombosis and Haemostasis :... Jul 2023The added value of antiphosphatidylserine/prothrombin antibodies (aPS/PT) in the diagnostic workup of antiphospholipid syndrome (APS) is unclear. Currently, diagnosis of...
Added value of antiphosphatidylserine/prothrombin antibodies in the workup of obstetric antiphospholipid syndrome: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies.
BACKGROUND
The added value of antiphosphatidylserine/prothrombin antibodies (aPS/PT) in the diagnostic workup of antiphospholipid syndrome (APS) is unclear. Currently, diagnosis of thrombotic APS (TAPS) and obstetric APS (OAPS) requires persistent presence of lupus anticoagulant (LAC), anticardiolipin (aCL) immunoglobulin (Ig) G/IgM, or anti-β2-glycoprotein I (aβ2GPI) IgG/IgM antibodies.
OBJECTIVES
To evaluate the role of aPS/PT IgG and IgM in OAPS.
METHODS
aPS/PT IgG/IgM, aCL IgG/IgM, aβ2GPI IgG/IgM, and LAC were determined in 653 patients (OAPS, TAPS, and controls). In-house aPS/PT cut-off values were calculated, titers and prevalence were compared between OAPS, TAPS, and controls and type of pregnancy morbidity. Sensitivity, specificity, likelihood ratios, and odds ratios (OR) with 95% CI were calculated.
RESULTS
In OAPS, aPS/PT IgG and IgM showed an OR of 4.32 (95% CI, 2.54-7.36) and 3.37 (95% CI, 1.93-5.89), respectively, but the association was not independent of LAC. Prevalence and titers of aPS/PT IgG and IgM were lower in OAPS than in patients with TAPS. aPS/PT were more prevalent and showed higher titers in patients with late pregnancy loss than in patients with early pregnancy loss with a positivity of 86.4% and 39.3%, respectively. Higher aPS/PT titers did not increase the likelihood of having OAPS.
CONCLUSION
The added value of aPS/PT testing in the current diagnostic workup of OAPS seems limited compared with LAC, aCL, and aβ2GPI. aPS/PT might be useful in specific subsets of patients with OAPS. However, future multicentric studies are needed to elucidate the risk of less frequent and most severe obstetrical manifestations.
Topics: Female; Humans; Pregnancy; Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Immunoglobulin G; Immunoglobulin M; Lupus Coagulation Inhibitor; Phosphatidylserines; Prothrombin
PubMed: 37061133
DOI: 10.1016/j.jtha.2023.04.001 -
Lupus Dec 2023Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-β2 glycoprotein I (anti-β2GPI)...
Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-β2 glycoprotein I (anti-β2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of β2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of β2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16 International Congress on aPL, Manchester, UK, September 2019.
Topics: Humans; Antiphospholipid Syndrome; Prothrombin; Lupus Erythematosus, Systemic; Antibodies, Antiphospholipid; Lupus Coagulation Inhibitor; Antibodies, Anticardiolipin; beta 2-Glycoprotein I
PubMed: 37933818
DOI: 10.1177/09612033231211820 -
International Journal of Molecular... Nov 2023Hepatocellular carcinoma (HCC) accounts for more than 75% of primary liver cancers, which are the second leading cause of cancer-related deaths. The GALAD (gender, age,...
BACKGROUND
Hepatocellular carcinoma (HCC) accounts for more than 75% of primary liver cancers, which are the second leading cause of cancer-related deaths. The GALAD (gender, age, AFP-L3, AFP, and des-carboxy-prothrombin) score is a diagnostic tool developed based on gender, age, alpha-fetoprotein, alpha-fetoprotein L3, and des-gamma-carboxy prothrombin, originally designed as a diagnostic tool for HCC in high-risk patients.
METHODS
We analyzed 212 patients with and without cirrhosis. The population study was divided into patients with liver cirrhosis without evidence of HCC at the time of serum sample collection for GALAD score determination and patients with liver cirrhosis and a confirmed diagnosis of HCC at the time of serum sample collection for GALAD score determination. Patients were followed up until death or liver transplantation. The association between variables and HCC mortality risk was performed, and the results were presented as hazard ratio (HR). The receiver operating characteristic (ROC) curve was used to assess the performance of the GALAD HCC diagnosis. The survival probability was explored using the non-parametric test, and the equality of survival amongst categories was assessed with the log-rank test.
RESULTS
Biomarkers were higher in the HCC group compared to cirrhosis. Kaplan-Meier survival probability analysis for individual GALAD categories revealed that a high GALAD level was associated with decreased survival during follow-up, and the difference between the curves was statistically significant ( = 0.01).
CONCLUSIONS
Our findings suggest that the GALAD score has promise as a prognostic tool, with implications for improving patient management and treatment strategies for HCC.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Biomarkers, Tumor; Prognosis; Biomarkers; ROC Curve; Liver Cirrhosis; Prothrombin
PubMed: 38003675
DOI: 10.3390/ijms242216485 -
Clinical Immunology (Orlando, Fla.) Nov 2023Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy...
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy complications. Within the diverse range of aPLs, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have gained significance in clinical practice. The detection of aPS/PT has proven valuable in identifying APS patients and stratifying their risk, especially when combined with other aPL tests like lupus anticoagulant (LA) and anti-β-glycoprotein I (aβGPI). Multivariate analyses have confirmed aPS/PT as an independent risk factor for vascular thrombosis and obstetric complications, with its inclusion in the aPL score and the Global Anti-Phospholipid Syndrome Score (GAPSS) aiding in risk evaluation. However, challenges remain in the laboratory testing of aPS/PT, including the need for assay standardization and its lower sensitivity in certain patient populations. Further research is necessary to validate the clinical utility of aPS/PT antibodies in APS diagnosis, risk stratification, and management.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Prothrombin; Phosphatidylserines; Antibodies, Antiphospholipid; beta 2-Glycoprotein I; Thrombosis
PubMed: 37838215
DOI: 10.1016/j.clim.2023.109804 -
Journal of Thrombosis and Haemostasis :... May 2024Thrombin generation (TG) in the presence of thrombomodulin (TG-TM) in the plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low...
BACKGROUND
Thrombin generation (TG) in the presence of thrombomodulin (TG-TM) in the plasma of patients with cirrhosis (PWC) is tilted toward a hypercoagulable phenotype. Low protein C and elevated factor VIII levels play a role, but other determinants, such as the prothrombin/antithrombin pair, must also be studied.
OBJECTIVES
The objectives were (i) to quantitatively assess the subprocesses (prothrombin conversion and thrombin decay) and (ii) to understand the underlying mechanism by studying TG dynamics after prothrombin and antithrombin plasma level correction in PWC.
METHODS
We studied TG-TM in plasma samples of 36 healthy controls (HCs) and 41 PWC with prothrombin and antithrombin levels of <70% and after their correction. We initiated coagulation with an intermediate picomolar concentration of tissue factor. We determined the overall thrombin potential, prothrombin conversion, and thrombin decay.
RESULTS
TG-TM was increased in PWC compared with HC due to impaired thrombin inhibition. Indeed, thrombin decay capacity (min) decreased from 0.37 (0.35-0.40) in HC to 0.33 (0.30-0.37) in the Child-Turcotte-Pugh A (CTP-A; P = .09), 0.27 (0.26-0.30) in the CTP-B (P < .001), and 0.20 (0.19-0.20) in the CTP-C (P < .001) group. Concomitant correction of prothrombin and antithrombin increased endogenous thrombin potential with prothrombin conversion surpassing thrombin decay. By contrast, when we corrected only antithrombin, TG-TM was normalized and even consistent with a hypocoagulable phenotype in the CTP-C group.
CONCLUSION
Our results highlight that in PWC, hypercoagulability (evidenced in the presence of TM) is due to impaired thrombin decay, whereas low prothrombin levels do not translate into decreased prothrombin conversion, likely due to altered TM-activated protein C negative feedback.
Topics: Humans; Prothrombin; Thrombin; Male; Female; Middle Aged; Case-Control Studies; Blood Coagulation; Liver Cirrhosis; Aged; Thrombomodulin; Adult; Antithrombins; Blood Coagulation Tests; Phenotype; Thromboplastin
PubMed: 38309434
DOI: 10.1016/j.jtha.2024.01.016 -
Journal of Pharmacy Practice Dec 2022Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages. (Review)
Review
STUDY OBJECTIVE
Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages.
METHODS
A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*.
RESULTS
Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent.
CONCLUSION
Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.
Topics: Humans; Rivaroxaban; Prothrombin; Blood Coagulation Factors; Factor Xa Inhibitors; Intracranial Hemorrhages; Thromboembolism; Hemostatics; Anticoagulants; Retrospective Studies
PubMed: 34036837
DOI: 10.1177/08971900211015059 -
Eye (London, England) Oct 2022To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and...
BACKGROUND
To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and laboratory testing.
METHODS
Patients with confirmed diagnosis of CCF treated between 2003 and 2019 were included and administered a questionnaire screening for HS risk factors and undergone laboratory investigations which included complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody titres), Factor V Leiden, prothrombin, protein C, protein S, antithrombin III, homocysteine, prothrombin G20210, CALR and JAK2 mutation screening. Participants with abnormal laboratory testing and/or past history of ischemic stroke, atrial fibrillation, cancer or hypercoagulability-associated hereditary disorders were deemed to have HS.
RESULTS
Twenty-two patients were enrolled. Seventeen were women and the mean age at diagnosis was 60. Fourteen (64%) had evidence of HS: six on medical history, three with laboratory evidence and five with both. Eight (36%) had current abnormal hypercoagulability markers. One had a diagnosis of Klippel-Trenaunay Syndrome, but no others had evidence of hereditary thrombophilia. Nine were on anti-coagulation initiated after diagnosis of stroke or atrial fibrillation discovered on average 5.5 years after the diagnosis of CCF.
CONCLUSION
A total of 64% percent of patients with previous indirect CCF had evidence of underlying HS indicating that hypercoagulability might play a role in the pathogenesis of CCF. The results support need for comprehensive testing for underlying HS in patients with indirect CCFs to better identify, manage, and prevent further thromboembolic events.
Topics: Antibodies, Anticardiolipin; Antithrombin III; Atrial Fibrillation; Female; Fibrinogen; Fistula; Homocysteine; Humans; Lupus Coagulation Inhibitor; Male; Protein C; Prothrombin; Thrombophilia
PubMed: 34635794
DOI: 10.1038/s41433-021-01801-w