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1.
Atherosclerosis ; 346: 124-132, 2022 04.
Article in English | MEDLINE | ID: mdl-35246318

ABSTRACT

BACKGROUND AND AIMS: Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation. METHODS: In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95-119). RESULTS: Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0-70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26-7.17, p < 0.001 and HR 6.21, 95% CI 3.40-11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately. CONCLUSIONS: To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents.


Subject(s)
Coronary Artery Disease , Factor IX/analysis , Myocardial Infarction , Stroke , Thromboembolism , Aged , Blood Coagulation Tests , Coronary Artery Disease/complications , Factor XIa/analysis , Female , Humans , Male , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/epidemiology , Risk Factors , Stroke/complications , Stroke/diagnosis , Stroke/epidemiology , Thromboplastin
2.
Vox Sang ; 116(6): 656-664, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33277936

ABSTRACT

BACKGROUND AND OBJECTIVES: In 2010, an intravenous immunoglobulin (IVIG) product was removed from the market due to an association with serious thromboembolic events. Investigations revealed that factor XIa (FXIa) was present as a process-related impurity. This study investigated the ability of two commercial FXIa assays to measure FXIa in immunoglobulin preparations and conducted a survey of FXIa activity in marketed immunoglobulin products. MATERIALS AND METHODS: Factor XIa assays were modified to include spiking of samples with FXIa before testing. An immunoglobulin product and its excipient were used to assess the ability of the assays to recover the spiked FXIa levels. RESULTS: The Biophen FXIa assay required a high pre-dilution of the sample to obtain statistically valid results and complete FXIa recovery. The ROX FXIa assay was more sensitive, giving statistically valid results at a lower sample pre-dilution and FXIa spike level. This modified ROX FXIa assay was used to assay 17 lots of immunoglobulin products for FXIa. Two product lots had measurable FXIa levels without the need for spiking. A further 3 lots produced detectable but not statistically valid FXIa results when left unspiked. Spiking produced statistically valid assays and recoveries above 100%, demonstrating inherent FXIa. CONCLUSION: This study shows marketed immunoglobulin products can contain detectable levels of FXIa. Spiking brings the FXIa levels into the quantifiable range of the assay, allowing measurement of inherent FXIa. Accurate measurement is important to inform on 'safe' levels of FXIa in these products and allow future safety guidelines to be set.


Subject(s)
Factor XIa , Immunoglobulins, Intravenous , Thromboembolism , Blood Coagulation Tests , Factor XIa/analysis , Humans
3.
J Thromb Thrombolysis ; 44(3): 362-370, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28879581

ABSTRACT

The impact of thrombolysis with recombinant tissue plasminogen activator (rtPA) on blood coagulation in acute ischemic stroke (AIS) patients is not completely understood. We studied the effect of thrombolysis on the thrombin generation (TG) profile as well as coagulant activity of activated factors IX (FIXa), XI (FXIa) and tissue factor (TF) in AIS patients. In a case-control study, TG parameters as well as FIXa, FXIa and TF levels were assessed in 95 AIS patients, including individuals receiving rtPA treatment within 4.5 h since AIS onset (n = 71, 74.7%) and those ineligible for thrombolysis (n = 24, 25.3%). Blood samples were collected at baseline and after 24 h since admission. The two groups were similar with regard to demographics and clinical factors. In thrombolysed patients, all TG parameters measured after 24 h were markedly decreased, with strongest impact on lag time (LT), when compared with the baseline values (81.3% longer LT, p < 0.0001), as well as when compared to the non-thrombolysed group (86% longer LT, p = 0.002). In non-thrombolysed AIS patients the TG remained unaltered. Logistic regression adjusted for potential confounders showed that high baseline ETP value (the top quartile) was solely predicted by the presence of circulating FIXa, whereas after 24 h FXIa predicted high ETP in the subgroup of thrombolysed and in all AIS patients. Thrombolysis in AIS patients markedly attenuates the TG. Elevated FXIa contributes to thrombin formation capacity after 24 h, highlighting a role of this factor in the regulation of blood coagulation in AIS.


Subject(s)
Blood Coagulation , Stroke/drug therapy , Thrombin/biosynthesis , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Aged , Aged, 80 and over , Brain Ischemia/blood , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Case-Control Studies , Factor IXa/analysis , Factor XIa/analysis , Female , Humans , Male , Stroke/blood , Stroke/metabolism , Thromboplastin
4.
J Trauma Acute Care Surg ; 82(6): 1073-1079, 2017 06.
Article in English | MEDLINE | ID: mdl-28328676

ABSTRACT

BACKGROUND: It has been observed that trauma patients often display elevated procoagulant activity that could be caused, in part, by tissue factor (TF). We previously observed that trauma patients with thermal, blunt, and penetrating injuries have active FIXa and FXIa in their plasma. In the current study, we evaluated the effect of injury severity, with or without accompanying shock, on the frequency and concentration of TF, FIXa, and FXIa in plasma from trauma patients. METHODS: Eighty trauma patients were enrolled and divided equally into four groups based on their Injury Severity Score and base deficit:Blood was collected at a 0 time-point (first blood draw upon arrival at hospital) and citrate plasma was prepared, frozen, and stored at -80 °C. FXIa, FIXa, and TF activity assays were based on a response of thrombin generation to corresponding monoclonal inhibitory antibodies. RESULTS: The frequency and median concentrations of TF were relatively low in non-severe injury groups (17.5% and 0 pM, respectively) but were higher in those with severe injury (65% and 0.5 pM, respectively). Although FXIa was observed in 91% of samples and was high across all four groups, median concentrations were highest (by approximately fourfold) in groups with shock. FIXa was observed in 80% of plasma samples and concentrations varied in a relatively narrow range between all four groups. No endogenous activity was observed in plasma from healthy individuals. CONCLUSIONS: (1) Frequency and concentration of TF is higher in patients with a higher trauma severity. (2) Concentration of FXIa is higher in patients with shock. (3) For the first time reported, the vast majority of plasma samples from trauma patients contain active FIXa and FXIa. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II.


Subject(s)
Factor IXa/analysis , Factor XIa/analysis , Thromboplastin/analysis , Wounds and Injuries/blood , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Injury Severity Score , Male , Middle Aged , Shock/blood , Young Adult
5.
J Proteomics ; 152: 312-320, 2017 01 30.
Article in English | MEDLINE | ID: mdl-27894965

ABSTRACT

Thromboembolic events (TEE) associated to trace amounts of plasmatic activated coagulation factor XI (FXIa) in administrated immunoglobulin (Ig) have recently raised concerns and hence there is a need for highly sensitive profiling of residual plasma source proteins. This study aims to consider LC-ESI-QTOF data-dependent acquisition in combination with sample fractionation for this purpose. Sample fractionation proved mandatory to enable identification of plasma residuals. Two approaches were compared: Ig depletion with protein G - protein A affinity chromatography and low-abundant protein enrichment with a combinatorial peptide ligand library (ProteoMiner™, Bio-Rad). The latter allowed a higher number of identifications. Highly sensitive detection of prothrombotic FXIa was assessed with confident identification of a 1ng/mg spike. Moreover, different residuals compositions were profiled for various commercial Ig products. Using a quantitative label free analysis, a TEE-positive Ig batch was distinguished from other regular Ig products, with increased levels of FXIa but also other unique proteins. This could have prevented the recently observed TEE problems with Ig. The method is a convenient tool to better characterize Ig products after any plasma pool or manufacture process change, gaining insights in the product quality profile without any prior information required. BIOLOGICAL SIGNIFICANCE: This study characterized residual plasma proteins in Ig products, using bottom-up LC-MS/MS with conventional data-dependent acquisition, preceded by sample fractionation. Without any prior information or target-specific development, >30 proteins were identified in a commercial Ig product. Quality control relevance was demonstrated with the identification of FXIa spiked at 1ng/mg in Ig, which is below the minimal thrombotic dose of 3ng/mg observed in an in vivo model. Relative label-free quantitation highlighted significant differences in normalized abundances of residual proteins between Ig products. A TEE-positive batch was distinguished by unique profile of residual proteins, including FXIa but also various blood stream-regulator proteins (fibrinogen, angiotensinogen, antithrombin-III, complement component C8, …). Those results emphasize that MS screening is a relevant first-line test to prevent any undesired concentration of plasma impurities after a plasma pool or manufacturing process change.


Subject(s)
Immunoglobulins/blood , Plasma/chemistry , Quality Control , Blood Proteins/analysis , Chromatography, Liquid , Factor XIa/analysis , Humans , Mass Spectrometry/methods , Plasma/metabolism , Tandem Mass Spectrometry
6.
PLoS One ; 11(7): e0158355, 2016.
Article in English | MEDLINE | ID: mdl-27419389

ABSTRACT

OBJECTIVE: In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS. METHODS: We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis. RESULTS: Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310-885) vs. 380(235-540) µg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2-20.9] and 4.5 [1.1-18.9]). CONCLUSION: ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events.


Subject(s)
Acute Coronary Syndrome/blood , Factor XIa/analysis , Thrombin/analysis , Acute Coronary Syndrome/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Blood Coagulation , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Recurrence
7.
J Thromb Haemost ; 13(11): 2041-52, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26340413

ABSTRACT

BACKGROUND: Conventional coagulation factor assays are associated with certain limitations, as they do not always reflect the clinical heterogeneity of bleeding in hemophilic patients or correctly reflect the individual patient response to treatment with bypassing agents or novel factor concentrates. The thrombin generation assay (TGA) is currently being assessed as a possible method for characterizing bleeding phenotypes in individuals with hemophilia. OBJECTIVES: This study assessed the robustness and sensitivity of the TGA for measuring the activity of recombinant factor VIII (rFVIII), recombinant factor IX (rFIX) and their glycoPEGylated derivatives, N8-GP and N9-GP, in vitro. METHODS: Factor-deficient plasma was spiked with 0.13-130 IU dL(-1) rFVIII or N8-GP (hemophilia A [HA] plasma), or rFIX or N9-GP (hemophilia B [HB] plasma). A calibrated automated thrombogram triggered with tissue factor (TF) or activated FXI (FXIa) was used to measure thrombin generation over time. Endogenous thrombin potential, peak thrombin, velocity index, lag time and time to peak thrombin were analyzed. RESULTS: FXIa-triggered assays were not affected by glycoPEGylation and were sufficiently sensitive to differentiate between spiked samples mimicking severe and moderate HB and HA; TF-triggered assays were not sufficiently sensitive for this distinction in HA. Both FXIa-triggered and TF-triggered assays had an acceptable level of variability (≤ 20%), although TF-triggered assays were associated with greater variability. CONCLUSIONS: FXIa-triggered TGA reactions produced more robust and sensitive results than TF-triggered TGA reactions, and have the potential for use in monitoring patients treated with glycoPEGylated or non-PEGylated coagulation factor concentrates. These promising results merit confirmation with clinical samples to correlate in vitro and in vivo data.


Subject(s)
Blood Coagulation Tests/methods , Factor IX/analysis , Factor VIII/analysis , Factor XIa/analysis , Hemophilia A/blood , Polyethylene Glycols/analysis , Thrombin/biosynthesis , Drug Monitoring/methods , Factor VIII/pharmacology , Factor XIa/pharmacology , Humans , Recombinant Proteins/analysis , Recombinant Proteins/blood , Recombinant Proteins/pharmacology , Sensitivity and Specificity , Thromboplastin/pharmacology
8.
J Thromb Haemost ; 13(9): 1568-75, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26178535

ABSTRACT

BACKGROUND: Myocardial infarction (MI) and ischemic stroke (IS) are acute forms of arterial thrombosis and share some, but not all, risk factors, indicating different pathophysiological mechanisms. OBJECTIVE: This study aims to determine if hypercoagulability has a differential effect on the risk of MI and IS. PATIENTS AND METHODS: We reviewed the results from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives study, a population-based case-control study involving young women (< 50 years) with MI, non-cardioembolic IS and healthy controls. From these data, relative odds ratios (ORIS /ORMI ) and their corresponding confidence intervals for all prothrombotic factors that were studied in both subgroups were calculated. RESULTS: Twenty-nine prothrombotic risk factors were identified as measures of hypercoagulability. Twenty-two of these risk factors (21/29, 72%) had a relative odds ratios > 1; for 12 (41%), it was > 2; and for 5 (17%), it was > 2.75. The five risk factors with the largest differences in associations were high levels of activated factor XI (FXI) and FXII, kallikrein, the presence of lupus anticoagulans, and a genetic variation in the FXIII gene. CONCLUSION: In young women, prothrombotic factors are associated more with the risk of IS than with MI risk, suggesting a different role of hypercoagulability in the mechanism leading to these two diseases.


Subject(s)
Brain Ischemia/epidemiology , Myocardial Infarction/epidemiology , Thrombophilia/epidemiology , Adult , Age Factors , Brain Ischemia/etiology , Case-Control Studies , Comorbidity , Confidence Intervals , Contraceptives, Oral/adverse effects , Diabetes Mellitus/epidemiology , Factor XIII/genetics , Factor XIIa/analysis , Factor XIa/analysis , Female , Hospital Mortality , Humans , Hypercholesterolemia/epidemiology , Hypertension/epidemiology , Kallikreins/analysis , Lupus Coagulation Inhibitor/blood , Middle Aged , Myocardial Infarction/etiology , Netherlands/epidemiology , Odds Ratio , Risk , Risk Factors , Sex Factors , Smoking/epidemiology , Thrombophilia/blood , Thrombophilia/chemically induced , Thrombophilia/complications , Young Adult
9.
Thromb Res ; 135(1): 198-204, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25467084

ABSTRACT

BACK GROUND: It has recently been reported that factor XIa can activate factor X directly and can bypass factors VIII-IX. We evaluated the consequences for factor analysis with the one-stage APTT. METHODS: APTT was performed with the Actin FS reagent with ellagic acid as the standard. Silica, high lipid (PTT-A) or low lipid (PTT-LA) were also tested. Factor depleted and deficient plasma's were obtained from commercial sources. RESULTS: The APTT clotting times in factor XII, XI, High Molecular Weight Kininogen, factor X and factor V deficient plasma's were all significantly longer (>100s) than the clotting times of factor VIII- and IX-depleted or deficient plasma's (<100s). That the shorter times for factor VIII and IX deficient plasmas were due to contact activation was supported by biphasic inhibition of the clotting times with addition of Corn Trypsin Inhibitor and Trasylol. The role of factor XI and the by-passing of factor VIII/IX was shown by the use of quenching antibodies towards factor XI and VIII. Enriching factor VIII or IX depleted plasma with purified factor XI and addition of factor XIa showed a strong dependence on factor XI level. Calibration curves for factor analysis were steeper for factors FXII, HMWK, FX and FV, compared to those of both factors VIII and IX. Curves for VIII/IX were found steeper by the use of APTT-A/silica-based, 50% diluted substrate plasma and low factor XI in the substrate plasma. CONCLUSIONS: In factors VIII and IX deficient plasmas, the APTT shows an activity which can be attributed to contact activation of factor X by factor XIa. This direct activity is lower with silica reagent compared to ellagic acid, dilution of plasma and low factor XI in substrate plasma.


Subject(s)
Ellagic Acid/chemistry , Factor IX/analysis , Factor XIII/analysis , Factor XIa/analysis , Factor X/analysis , Partial Thromboplastin Time , Blood Coagulation Tests , Calibration , Humans , Reproducibility of Results , Silicon Dioxide/chemistry
10.
Thromb Haemost ; 112(5): 960-71, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25103795

ABSTRACT

Human plasma-derived C1-esterase inhibitor (C1-INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1-INH at recommended or off-label, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1-INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1-INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1-INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1-INH at doses up to 800 IU/kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1-INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1-INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1-INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1-INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.


Subject(s)
Arterial Occlusive Diseases/chemically induced , Complement C1 Inhibitor Protein/toxicity , Venous Thrombosis/chemically induced , Animals , Blood Coagulation Tests , Complement C1 Inhibitor Protein/administration & dosage , Complement C1 Inhibitor Protein/pharmacokinetics , Complement C1 Inhibitor Protein/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Factor XIIa/analysis , Factor XIa/analysis , Femoral Artery , Fibrinolysis/drug effects , Humans , Infusions, Intravenous , Kallikrein-Kinin System/drug effects , Kallikrein-Kinin System/physiology , Platelet Aggregation/drug effects , Rabbits , Thrombelastography , Thrombin/biosynthesis
11.
Biologicals ; 41(6): 393-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24051302

ABSTRACT

BACKGROUND: Studies have demonstrated that traces of activated factor XI (FXIa) present in specific brands of intravenous immunoglobulin (IVIG) concentrates may pose a thrombogenic risk. AIM: To characterize procoagulant activity during fractionation and the elimination capacity of the Flebogamma(®) DIF (Grifols' IVIG) manufacturing process. METHODS: Flebogamma(®) DIF fractionation steps included cryoprecipitate supernatant (Cryo/S), Fraction (Fr) I supernatant, and Fr II + III suspension. Purification steps included ultrafiltrate I, acid treatment, and pasteurization. Samples were assessed for total protein, IgG, and procoagulant activation markers. RESULTS: Cryo/S showed no procoagulant activity for prekallikrein activator (PKA), kallikrein-like, and non-activated partial thromboplastin time (NaPTT) with normal (-PPP) or FXI-deficient (-FXI) platelet poor plasma. Thrombin generation test (TGT)-PPP and TGT-FXI were <83-148 and <53-197 nM thrombin, respectively. Shortened NaPTTs (100-296 s), high PKA (51-119 IU/mL), kallikrein-like activities (0.043-0.075 ΔAU/min), positive TGTs (98-298 nM), and FXIa (9.5-14.0 ng/mL) were detected in Fr II + III. After pasteurization, no residual evidence of any procoagulant activity marker was observed, including the final IVIG concentrate at 5% or 10% protein. Results were similar in Fr II + III from different IVIG manufacturing facilities. CONCLUSIONS: The Flebogamma(®) DIF production process is capable of eliminating procoagulant activity because of its purification steps.


Subject(s)
Coagulants/isolation & purification , Drug Contamination/prevention & control , Factor XIa/isolation & purification , Immunoglobulins, Intravenous/isolation & purification , Chemical Fractionation/methods , Coagulants/analysis , Factor XIa/analysis , Humans , Immunoglobulins, Intravenous/analysis , Immunoglobulins, Intravenous/standards , Quality Control , Reproducibility of Results
12.
Am J Hematol ; 88(12): 1035-40, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23907744

ABSTRACT

Thrombotic events (TEs) are rare serious complications following administration of hyperimmune globulin (HIG) products. Our retrospective claims-based study assessed occurrence of same-day TEs following administration of HIGs during 2008-2011 and examined potential risk factors using HealthCore's Integrated Research Database (HIRD(SM) ) and laboratory testing of products' procoagulant Factor XIa activity by U.S. Food and Drug Administration. Multivariable regression was used to estimate same-day TE risk for different products. Of 101,956 individuals exposed to 23 different HIG product groups, 86 (0.84 per 1,000 persons) had a TE diagnosis code (DC) recorded on the same day as HIG administration. Unadjusted same-day TE DC rates (per 1,000 persons) ranged from 0.4 to 148.9 for different products. GamaSTAN S/D IG >10 cc had statistically significantly higher same-day TE DC risk compared to Tetanus IG (OR = 57.57; 95% CI = 19.72-168.10). Increased TE risk was also observed with older age (≥45 years), prior thrombotic events, and hypercoagulable state(s). Laboratory investigation identified elevated Factor XIa activity for GamaSTAN S/D, HepaGam B, HyperHep B S/D, WinRho SDF, HyperRHO S/D full dose, and HyperTET S/D. Our study, for the first time, identified increase in the same-day TE DC risk with GamaSTAN S/D IG >10 cc and suggests potentially elevated TE risk with other HIGs.


Subject(s)
Databases, Factual/statistics & numerical data , Embolism/etiology , Immunoglobulins/adverse effects , Thrombosis/etiology , Adult , Age Factors , Blood Coagulation Tests , Blue Cross Blue Shield Insurance Plans/statistics & numerical data , Confounding Factors, Epidemiologic , Embolism/epidemiology , Factor XIa/analysis , Female , Humans , Immunoglobulins/chemistry , Immunoglobulins, Intravenous/adverse effects , Immunoglobulins, Intravenous/chemistry , Male , Recurrence , Retrospective Studies , Risk Factors , Thrombin/biosynthesis , Thrombophilia/complications , Thrombosis/epidemiology , Time Factors , United States/epidemiology
13.
Thromb Res ; 132(1): 138-42, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23746628

ABSTRACT

INTRODUCTION: The contribution of the contact system to arterial thrombosis is unclear, results of clinical studies are conflicting. Particularly, little is known about the involvement of the contact system in the progression of arterial thrombosis. Therefore, we investigated the activation of the contact system during an acute myocardial infarction (AMI) and 3 and 6 months following the acute event. METHODS: Plasma of patients with a first AMI was collected on admission and 3 and 6 months after the AMI. The levels of complexes of activated factor XI (FXIa), FXIIa and kallikrein with C1 esterase inhibitor (C1INH) and the levels of complexes of FXIa with α1-antitrypsin (AT) were measured in these plasmas. Recurrent cardiovascular events were recorded during a one year period after the AMI. RESULTS: We observed that the levels of FXIa-C1INH were elevated during the acute phase compared to the steady-phase 3 and 6 months after the AMI. The levels of FXIa-AT, FXIIa-C1INH and kallikrein-C1INH did not change over time. The levels of FXIa-C1INH, FXIa-AT, FXIIa-C1INH and kallikrein-C1INH were not predictive for a recurrent event. CONCLUSION: We observed that during an AMI, the activation of FXI was increased. The levels of FXIIa-C1INH were not elevated, suggesting that activation of FXI during the acute phase did not result from contact activation. The levels of the enzyme inhibitor complexes were not predictive for a recurrent event one year after the first AMI.


Subject(s)
Complement C1 Inhibitor Protein/analysis , Factor XIa/analysis , Kallikreins/blood , Myocardial Infarction/blood , alpha 1-Antitrypsin/blood , Acute Disease , Adult , Aged , Aged, 80 and over , Blood Coagulation , Complement C1 Inhibitor Protein/metabolism , Enzyme Activation , Factor XIa/metabolism , Female , Humans , Kallikreins/metabolism , Male , Middle Aged , Myocardial Infarction/metabolism , alpha 1-Antitrypsin/metabolism
14.
Blood Coagul Fibrinolysis ; 23(3): 189-94, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22343680

ABSTRACT

Circulating active tissue factor (TF) and activated factor XI (FXIa) have been detected in subgroups of acute coronary syndromes (ACSs) and stable angina patients. We sought to evaluate the determinants of active TF and FXIa in stable angina patients. We studied 124 consecutive stable angina patients. Recent ACS, atrial fibrillation, and anticoagulant therapy were the exclusion criteria. Plasma active TF and FXIa were determined by measuring the response to inhibitory antibodies. T helper 1 lymphocyte (Th1) and Th2 responses were assessed in plasma by interleukin (IL)-4, IL-6, IL-8, IL-10, IL-18, interferon-γ, and tumor necrosis factor-α, oxidative stress by 8-isoprostaglandin F(2α) (8-iso-PGF(2α)), and coagulation by prothrombin fragments F1+2 (F1+2) and free TF pathway inhibitor (f-TFPI). TF and FXIa activity were detected in 25 (20.2%) and 49 (39.5%) stable angina patients, respectively. Both factors were found in 23 (18.5%) patients. Patients with detectable TF or FXIa had higher F1+2, 8-iso-PGF(2α), IL-6, but not other cytokines, and lower f-TFPI (all P < 0.001) compared with the remainder. There were no intergroup differences with regard to cardiovascular risk factors or medication. Multivariate analysis showed that F1+2 and f-TFPI were the only independent predictors of the TF presence, whereas 8-iso-PGF(2α) and F1+2 predicted the presence of FXIa in stable angina patients. In stable angina patients, circulating active TF and FXIa are associated with enhanced thrombin formation, with a minor effect of inflammatory mediators. Moreover, FXIa is also related to oxidative stress, indicating additional links between coagulation and free radical generation in stable angina.


Subject(s)
Angina Pectoris/blood , Dinoprost/analogs & derivatives , Factor XIa/analysis , Lipoproteins/blood , Peptide Fragments/blood , Thromboplastin/analysis , Aged , Blood Coagulation , Cytokines/blood , Dinoprost/blood , Female , Humans , Immunoassay , Male , Middle Aged , Multivariate Analysis , Oxidative Stress , Prothrombin , Risk Factors , Th1-Th2 Balance , Thrombin/biosynthesis
15.
Vox Sang ; 102(1): 40-6, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21545600

ABSTRACT

BACKGROUND AND OBJECTIVES: The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events. MATERIAL AND METHODS: The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively. RESULTS: Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S-2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT. CONCLUSIONS: Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs.


Subject(s)
Factor XIa/analysis , Immunoglobulins, Intravenous/therapeutic use , Immunoglobulins/chemistry , Immunoglobulins/therapeutic use , Kallikreins/analysis , Blood Coagulation , Dose-Response Relationship, Drug , Drug Contamination , Drug-Related Side Effects and Adverse Reactions , Enzyme-Linked Immunosorbent Assay/methods , Factor XIIa/analysis , Fibrinolysin/analysis , Humans , Immunoglobulins, Intravenous/chemistry , Partial Thromboplastin Time , Prekallikrein/analysis , Thrombin/analysis , Thromboembolism/immunology
16.
Thromb Res ; 128(5): e62-6, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21820158

ABSTRACT

BACKGROUND: Elevated factor (F)XI is associated with an increased risk for ischemic stroke. Activated FXI (FXIa) and tissue factor (TF) have not been studied following stroke. The aim of the current study was to evaluate circulating FXIa and TF in patients with prior cerebrovascular events. PATIENTS/METHODS: We studied 241 patients, including 162 after ischemic stroke and 79 after transient ischemic attack (TIA), recruited 6 months to 4 years (median, 36 months) after the events. Plasma TF and FXIa activity following the index event were determined in clotting assays by measuring the response to inhibitory monoclonal antibodies. RESULTS: Active TF was detected in 25 (10.4%) of the patients, while FXIa activity (median, 37.5 [IQR 397] pM) was found in 64 (26.7%) of the patients (p<0.01). The prevalence of active TF and FXIa was higher in subjects with previous stroke compared with those with a history of TIA (13% vs 5.1%, p=0.05, and 34% vs 11.4%, p<0.0001, respectively). Patients with circulating FXIa were younger and had higher fibrinogen and interleukin-6 compared to the remainder. Patients with detectable TF or FXIa activity had higher NIHSS score, higher modified Rankin scale and lower Barthel Index than the remaining subjects (all p<0.05). CONCLUSION: Circulating active TF and FXIa can occur in patients with cerebrovascular ischemic events ≥6 months after the events. The presence of these factors is associated with worse functional outcomes, which highlights the role of persistent hypercoagulable state in cerebrovascular disease.


Subject(s)
Brain Ischemia/diagnosis , Factor XIa/analysis , Predictive Value of Tests , Thromboplastin/analysis , Adult , Age Factors , Blood Coagulation Tests , Brain Ischemia/blood , Female , Fibrinogen/metabolism , Humans , Interleukin-6/metabolism , Ischemic Attack, Transient , Male , Middle Aged , Prognosis , Stroke , Thrombophilia/blood , Young Adult
17.
J Trauma ; 67(2): 266-75; discussion 275-6, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19667878

ABSTRACT

OBJECTIVES: To investigate the hemostatic status of critically ill, nonbleeding trauma patients. We hypothesized that a hypercoagulable state exists in patients early after severe injury and that the pattern of clotting and fibrinolysis are similar between burned and nonburn trauma patients. MATERIALS: Patients admitted to the surgical or burn intensive care unit within 24 hours after injury were enrolled. Blood samples were drawn on days 0 through 7. Laboratory tests included prothrombin time (PT), activated partial thromboplastin time (aPTT), levels of activated factor XI, D-dimer, protein C percent activity, antithrombin III percent activity, and thromboelastography (TEG). RESULTS: Study subjects were enrolled from April 1, 2004, to May 31, 2005, and included nonburn trauma patients (n = 33), burned patients (n = 25), and healthy (control) subjects (n = 20). Despite aggressive thromboprophylaxis, three subjects (2 burned and 1 nonburn trauma patients [6%]) had pulmonary embolism during hospitalization. Compared with controls, all patients had prolonged PT and aPTT (p < 0.05). The rate of clot formation (alpha angle) and maximal clot strength were higher for patients compared with those of controls (p < 0.05), indicating a hypercoagulable state. Injured patients also had lower protein C and antithrombin III percent activities and higher fibrinogen levels (p < 0.05 for all). Activated factor XI was elevated in 38% of patients (control subjects had undetectable levels). DISCUSSION: Thromboelastography analysis of whole blood showed that patients were in a hypercoagulable state; this was not detected by plasma PT or aPTT. The high incidence of pulmonary embolism indicated that our current prophylaxis regimen could be improved.


Subject(s)
Thrombelastography , Thrombophilia/diagnosis , Thrombophilia/etiology , Wounds and Injuries/complications , Adult , Antithrombin III/analysis , Case-Control Studies , Factor XIa/analysis , Female , Humans , Intensive Care Units , Male , Middle Aged , Partial Thromboplastin Time , Protein C/analysis , Prothrombin Time , Pulmonary Embolism/diagnosis , Pulmonary Embolism/etiology , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology
18.
Platelets ; 17(5): 318-27, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16928604

ABSTRACT

The effect of the direct platelet P2Y12 receptor inhibitor, AR-C69931MX, on activation of blood induced by stents with and without heparin coating was investigated using a whole blood Chandler loop model in vitro. Stents were deployed in Chandler loops. Fresh human blood with heparin and AR-C69931MX was rotated for 1 h at 37 degrees C and used for measurements of platelets, microparticles, thrombin-antithrombin complex (TAT), fibrinogen binding to platelets, P-selectin expression by platelets, CD11b, Prothrombin Fragment F1+2, FXIa-AT, FXIIa-AT, C3a, sC5b-9 and stent score. In the first experiment there were four study groups with unmodified stents: 1a, no AR-C69931MX; 1b, 250 nmol/L; 1c, 750 nmol/L; 1d, 2250 nmol/L of AR-C69931MX. In the second experiment the concentration of AR-C69931MX was 500 nmol/L: 2a; tubings without stent; 2b; tubings with heparin-coated stent; 2c; tubings with unmodified stents. Heparin-coated stents were used in the third experiment: 3a; no AR-C69931MX; 3b; 500 nmol/L of AR-C69931MX. In the first experiment there were significant differences in all parameters analysed except for C3a, and stent score when the group with no AR-C69931MX was compared to all the groups with AR-C69931MX. In the second experiment there were significant differences in platelet count, TAT, FXIa-AT, FXIIa-AT and stent score when unmodified stents were compared to loops with no stents and partly to loops with heparin-coated stents. In the third experiment there was a significant reduction in generation of TAT, stent score and better preservation of platelet number by combining the platelet inhibitor and heparin-coated stents as compared to heparin-coated stents alone. The conclusion is that the direct P2Y12 receptor inhibitor AR-C69931MX reduced the different aspects of activation of blood induced by both unmodified and heparin-coated stents.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Blood Platelets/metabolism , CD11b Antigen/metabolism , Platelet Activation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Stents , Adenosine Monophosphate/pharmacology , Analysis of Variance , Anticoagulants/adverse effects , Anticoagulants/pharmacology , Antithrombin III/analysis , CD11b Antigen/drug effects , Complement Activation/drug effects , Drug Delivery Systems , Factor XIIa/analysis , Factor XIa/analysis , Flow Cytometry , Heparin/administration & dosage , Heparin/pharmacology , Humans , In Vitro Techniques , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/drug effects , Peptide Hydrolases/analysis , Platelet Activation/physiology , Purinergic P2 Receptor Antagonists , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2Y12
19.
Am J Hematol ; 65(1): 30-4, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10936860

ABSTRACT

A small number of thromboembolic events, including deep venous thrombosis and myocardial infarction, have been reported in patients receiving IVIG. These events have primarily occurred in patients receiving high-dose IVIG and have been attributed to an increase in blood viscosity. To test the hypothesis that a procoagulant might be present in IgG preparations, twenty-nine samples of intravenous immunoglobulin (IVIG) from eight different manufacturers were assayed for procoagulant activity. Twenty-six of these samples shortened the clotting time of factor XI-deficient plasma. Of these, fourteen samples had factor XI activities greater than 0.001 U/ml of normal pooled plasma. The remaining samples possessed less than 0. 001 U/ml of normal plasma activity. The procoagulant activity in these samples could be inhibited by an anti-factor XI polyclonal antibody, suggesting that the procoagulant activity was factor XI. The procoagulant activity increased in two samples after storage at 4 degrees C for 4 weeks, likely as a result of factor XIa autoactivation. Additionally, activity in some IVIG samples was able to directly activate factor IX, indicating that activated factor XI was present in these samples. Finally, the degree of factor XI(a) contamination in the samples was correlated with the manufacturer, suggesting that variations in the manufacturing process or source plasma affect the level of factor XI in the IVIG product. Because addition of small amounts of factor XIa to plasma can lead to production of significant amounts of thrombin, we suggest that factor XIa present in some IVIG preparations could contribute to the in vivo risk of thrombosis after IVIG therapy.


Subject(s)
Drug Contamination , Factor XI/analysis , Immunoglobulins, Intravenous/chemistry , Factor XI/adverse effects , Factor XIIa/pharmacology , Factor XIa/analysis , Factor XIa/metabolism , Humans , Immunoglobulins, Intravenous/adverse effects , Partial Thromboplastin Time , Venous Thrombosis/chemically induced
20.
Thromb Res ; 99(3): 285-93, 2000 Aug 01.
Article in English | MEDLINE | ID: mdl-10942795

ABSTRACT

The activation threshold for the intrinsic pathway of coagulation was experimentally determined in stirred recalcified plasma from the dependence of plasma clotting time after activation by celite. Concentration of factor XIa was used as a measure of activation. At free calcium concentrations below 0.45 mM, plasma clotting time depended nonlinearly on the factor XIa concentration: with decreasing concentration of factor XIa (or celite), the clotting time dramatically increased until no coagulation was observed at concentrations of factor XIa below the threshold. As the free calcium concentration increased, the threshold concentration of factor XIa sharply decreased, from 30 pM at 0.35 mM free calcium to less than 3 pM at 0.45 mM. In the range of free calcium concentrations from 0.45 mM to physiologic ones, plasma coagulated even in the absence of celite in plastic cuvettes. This fact and extremely low threshold concentrations of factor XI (on the order of 0.5 pM) preclude determining the factor XI threshold at physiologic free calcium. As factor XIa is localized to the activating surfaces, observing the local surface concentrations of factor XIa and the dynamics of fibrin formation in systems without stirring may solve the problem.


Subject(s)
Blood Coagulation Tests , Blood Coagulation/physiology , Adult , Blood Coagulation/drug effects , Calcium/blood , Diatomaceous Earth/pharmacology , Factor XIa/analysis , Humans , Hydrolysis , Motion , Plant Proteins/pharmacology , Plastics , Surface Properties , Trypsin Inhibitor, Kunitz Soybean/pharmacology
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