Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants

Abstract Acquired activated protein C resistance (APCR) has been hypothesized as a possible mechanism by which antiphospholipid antibodies (APLAs) cause thrombotic events (TEs). However, available evidence for an association of acquired APCR with APLAs is limited. More importantly, an association of acquired APCR with TEs has not been demonstrated. The objective of the study was to determine, in pediatric patients with systemic lupus erythematosus (SLE), whether (1) acquired APCR is associated with the presence of APLAs, (2) APCR is associated with TEs, and (3) there is an interaction between APCR and APLAs in association with TEs. A cross-sectional cohort study of 59 consecutive, nonselected children with SLE was conducted. Primary clinical outcomes were symptomatic TEs, confirmed by objective radiographic tests. Laboratory testing included lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), APC ratio, protein S, protein C, and factor V Leiden. The results revealed that TEs occurred in 10 (17%) of 59 patients. Acquired APCR was present in 18 (31%) of 58 patients. Acquired APCR was significantly associated with the presence of LAs but not ACLAs. Acquired APCR was also significantly associated with TEs. There was significant interaction between APCR and LAs in the association with TEs. Presence of both APCR and LAs was associated with the highest risk of a TE. Protein S and protein C concentrations were not associated with the presence of APLAs, APCR, or TEs. Presence of acquired APCR is a marker identifying LA-positive patients at high risk of TEs. Acquired APCR may reflect interference of LAs with the protein C pathway that may represent a mechanism of LA-associated TEs.

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Activated protein C resistance associated with lupus anticoagulants is a high risk in acute mesenteric venous thrombosis

Journal of Vascular Surgery Venous and Lymphatic Disorders ◽

10.1016/j.jvsv.2013.10.055 ◽

2014 ◽

Vol 2 (2) ◽

pp. 155-159

Author(s):

Jun Li ◽

Xinhua Hu ◽

Qiang Zhang ◽

Hui Cao ◽

Chengwei Liu ◽

...

Keyword(s):

High Risk ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Mesenteric Venous Thrombosis ◽

Activated Protein C Resistance ◽

Lupus Anticoagulants

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Increased Thrombophilic Tendency in Pediatric Cystic Fibrosis Patients

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029609334627 ◽

2009 ◽

Vol 16 (1) ◽

pp. 71-76 ◽

Cited By ~ 12

Author(s):

Vaughan Williams ◽

Adrian B. M. Griffiths ◽

Zen L. Yap ◽

James Martin ◽

Gregory Smith ◽

...

Keyword(s):

Cystic Fibrosis ◽

General Population ◽

Protein C ◽

Activated Protein C ◽

Protein S ◽

Activated Protein C Resistance ◽

Antithrombin Deficiency ◽

Indwelling Catheters ◽

C Protein ◽

Lupus Anticoagulants

Thrombophilia has recently been reported to be increased in patients with cystic fibrosis (CF). We wanted to determine whether this was applicable to our population with CF and how our patients compared to the previously reported groups. Seventy one pediatric CF patients were assessed for a thrombophilic tendency, using a lupus anticoagulant screen, protein C, protein S, antithrombin assay, and activated protein C resistance (APCR) screen. The incidence of activate protein C resistance (4.2%) was within expected limits for the general population as was the incidence of antithrombin deficiency. However there was a marked increase in the incidence of lupus anticoagulants (18%) and 14% and 19.7% of the patients showed a reduced protein C and protein S, respectively, far in excess of the general population. This increased incidence of thrombophilia was not related to any specific CF phenotype and while perturbed liver function cannot be entirely ruled out, it appeared unlikely to be responsible for all the abnormal coagulation findings. Despite the apparent thrombophilic tendency, no clinically evident thrombotic episodes were noted during the study period. Thrombophilia is of concern because of the increasingly frequent placement of indwelling catheters in CF patients. The precise cause for the thrombophilic tendency in CF patients is unknown at this stage.

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Acquired Activated Protein C-Resistance in Patients with Lupus Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649818 ◽

1995 ◽

Vol 74 (02) ◽

pp. 797-798 ◽

Cited By ~ 35

Author(s):

S Ehrenforth ◽

K P Radtke ◽

I Scharrer

Keyword(s):

Protein C ◽

Activated Protein C ◽

Activated Protein C Resistance ◽

Lupus Anticoagulants

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Hypercoagulability Evaluation in Antiphospholipid Syndrome without Anticoagulation Treatment with Thrombin Generation Assay: A Preliminary Study

Journal of Clinical Medicine ◽

10.3390/jcm10122728 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2728

Author(s):

Paul Billoir ◽

Sébastien Miranda ◽

Herve Levesque ◽

Ygal Benhamou ◽

Véronique Le Cam Duchez

Keyword(s):

Antiphospholipid Syndrome ◽

Protein C ◽

Thrombin Generation ◽

Activated Protein C ◽

Control Group ◽

Activated Protein C Resistance ◽

Thrombin Generation Assay ◽

Clinical Events ◽

Biological Criteria ◽

Preliminary Study

Antiphospholipid syndrome (APS) is associated with thrombotic events (tAPS) and/or obstetrical morbidity (oAPS), with persisting antiphospholipid antibodies (aPL). Despite an update of aPL in 2006, several patients had typical clinical events without the classical biological criteria. The aim of our study was to evaluate the hypercoagulability state with both thrombin generation (TG) profiles and activated protein C resistance (aPCR) in different types of APS. Methods: We retrospectively included 41 patients with Sydney criteria classification (tAPS, oAPS) and no clinical manifestation of APS with persistent aPL (biological APS). A thrombin generation assay was performed with a Fluoroskan Ascent fluorometer in platelet-poor plasma (PPP). Activated protein C resistance was measured as a ratio: ETP+aPC/ETP-aPC × 100. Results: Thrombotic APS and oAPS had an increase of global thrombin generation (ETPcontrol = 808 nM.min (756–853) vs. 1265 nM.min (956–1741) and 1863 nM.min (1434–2080), respectively) (Peakcontrol = 78 nM (74–86) vs. 153 nM (109–215) and 254 nM.min (232–289), respectively). Biological APS had only a lag time increase (Tcontrol = 4.89 ± 1.65 min vs. 13.6 ± 3.9 min). An increased aPCR was observed in tAPS (52.7 ± 16.4%), oAPS (64.1 ± 14.6%) as compared to the control group (27.2 ± 13.8%). Conclusion: Our data suggest an increase of thrombin generation in thrombotic and obstetrical APS and no hypercoagulable states in patients with biological APS. The study of a prospective and a larger controlled cohort could determine the TGA useful for APS monitoring and could confirm an aPCR evaluation in PPP.

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Comparison of Acquired Activated Protein C Resistance, Using the CAT and ST-Genesia® Analysers and Three Thrombin Generation Methods, in APS and SLE Patients

Journal of Clinical Medicine ◽

10.3390/jcm11010069 ◽

2021 ◽

Vol 11 (1) ◽

pp. 69

Author(s):

Maria Efthymiou ◽

Philip J. Lane ◽

David Isenberg ◽

Hannah Cohen ◽

Ian J. Mackie

Keyword(s):

Lupus Erythematosus ◽

Protein C ◽

Thrombin Generation ◽

Activated Protein C ◽

Kappa Coefficient ◽

Antiphospholipid Antibody ◽

Data Handling ◽

Activated Protein C Resistance ◽

Systemic Lupus ◽

Pregnancy Morbidity

Background: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Objective: To assess agreement between the ST-Genesia® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods. Methods: APCr was assessed with the ST-Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohen's kappa coefficient. Results: APCr values were consistently lower with the ST-Genesia® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac®, but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients (p < 0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients (p < 0.05). Notably, the ST-Genesia®, unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9–49.0%) compared to thrombotic (45.7%, 39.6–55.5%) APS patients (p = 0.03). Conclusion: Despite the broadly similar methodology used by CAT and ST-Genesia®, agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling.

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