Combined thrombogenic effects of vessel injury, pregnancy and procoagulant immune globulin administration in mice

Yanqun Xu,Yideng Liang,Evi B Struble,Dorothy Scott,Daryl Despres,Leonid Parunov,Michael Eckhaus,Mikhail Ovanesov

doi:10.1186/s12959-020-00245-8

Abstract

BackgroundPregnant women are at increased risk of thrombotic adverse events. Plasma derived immune globulin (IG) products, which are used in pregnancy for various indications, may contain procoagulant impurity activated coagulation factor XI (FXIa). Procoagulant IG products have been associated with increased thrombogenicity but their effect in pregnancy is unknown.MethodsLate pregnant (gestation days 17–20) or early lactation (days 1–3) and control female mice were treated with IGs supplemented with human FXIa then subjected to ferric chloride (FeCl3) vessel injury. Occlusion of blood vessel was assessed by recording blood velocity in the femoral vein for 20 min using doppler ultrasound laser imaging. FXIa dose was selected by the ability to increase thrombin generation in mouse plasma in vitro.ResultsFXIa produced robust thrombin generation in mouse plasma ex vivo. Following FeCl3 injury, pregnant and non-pregnant mice receiving IG + FXIa exhibited faster reduction of blood velocity in femoral vein compared to IG alone or untreated controls. In vitro, thrombin generation in plasma samples collected after thrombosis in FXIa-treated animals was elevated and could be reduced by anti-FXI antibody.ConclusionsOur results suggest that intravenously-administered FXIa may contribute to thrombosis at the site of vascular injury in both pregnant and non-pregnant animals.

Highlights

Normal pregnancy is a hypercoagulable condition that mitigates the risk of bleeding during delivery
We studied pregnant and control mice to compare the thrombogenic risks of infusions of non-procoagulant immune globulin (IG) with or without added Coagulation factor XIa (FXIa)
We unexpectedly found that FXIa activity persists in circulation, despite presence of proteins known to inactivate it

Summary

Introduction

Normal pregnancy is a hypercoagulable condition that mitigates the risk of bleeding during delivery. These changes to the hemostatic system put pregnant women at risk of thrombotic events (TEs) including deep venous thrombosis (DVT), pulmonary embolism, cerebral vein thrombosis [1, 2], myocardial infarction and stroke [3, 4]. Immune globulin (IG) products are used in moderate to high doses in pregnancy to prevent recurrent pregnancy loss, complications of anti-phospholipid syndrome, neonatal alloimmune thrombocytopenia, post-partum relapses in relapsing-remitting multiple sclerosis, and as treatment for primary immunodeficiency and various autoimmune. Pregnant women are at increased risk of thrombotic adverse events. Procoagulant IG products have been associated with increased thrombogenicity but their effect in pregnancy is unknown

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Conclusion