Table 6. Selected studies describing... | American Society of Hematology

Table 6.

Selected studies describing complement activation in the pathogenesis of aPL-induced pregnancy morbidity or thrombosis

First author/reference	Experimental/clinical setting	Important findings	Comment
Davis¹⁶⁰	Analysis of complement activation levels in stroke patients with and without aPL-abs	C5b-9 levels were higher in sera of patients with aPL and stroke when compared with stroke in absence of aPL-abs	TP activation seems to be implicated in the pathophysiology of aPL-ab–associated stroke
Holers¹⁶¹	• Murine model of aPL-ab induced fetal loss • Pregnant mice injected with human IgG containing aPL-abs	C3 activation is required for aPL-ab induced intrauterine growth restriction and/or fetal loss in mice	C3 KO mice or mice treated with complement inhibitor Crry are protected from fetal loss
Girardi¹⁶²	• Murine model of APS induced fetal loss • Pregnant mice injected with human IgG containing aPL-abs	Protected from fetal loss by • blocking C5 function (ie, C5 KO mice or applying anti-C5 mAb) • blocking C5a receptor signaling (C5aR KO)	• Indicates TP to be necessary for pathophysiology since proximal complement activation occurs unhindered in C5 KO mice • Suggests that C5a drives fetal loss via C5a mediated chemotaxis of neutrophils
Girardi¹⁶³	Murine model of aPL-ab induced fetal loss treated with anticoagulants	Heparin but not other anticoagulants (like fonda-parinux or hirudin) prevents aPL-ab–induced fetal loss	unfractionated or low-molecular-weight heparin prevented complement activation in vitro and in vivo while other anticoagulants failed to do so
Fischetti¹⁶⁴	• Rat model of APS induced thrombosis (including C6 KO rats) • Administration of human anti–β2-glycoprotein I with or without inflammatory priming with LPS	Thrombus formation induced by antibodies to β2-glycoprotein I requires complement TP activation and a priming factor	• C3 and C9 colocalize with aPL IgG on the thrombotic lesions • Indicates MAC (and not C5a) in the pathophysiology since C6 KO protects similarly well than anti-C5 blocking mAb
Carrera-Marín¹⁶⁵	• Rat model of APS induced thrombosis • Administration of human aPL-abs in mice (including C6 KO mice)	C6 knock-out mice are protected from thrombophilia mediated by aPL-abs	Indicates MAC (and not C5a) as a main driver of pathophysiology in addition to direct cell activating effects of aPL-abs
Agostinis¹⁶⁶	• Rat model of APS induced thrombosis (including C6 KO rats) • CH2-domain lacking anti–β2-glycoprotein I antibodies used as therapeutic approach	An engineered antibody that efficiently binds PL but cannot activate complement fails to induce vascular thrombosis and fetal loss (even after LPS priming)	• Antibody lacking the “comp lement activating” CH2 domain can prevent blood clot formation and fetal loss induced by aPL • aPL binding to its epitope alone has no/minor pathophysiological relevance
Meroni¹⁶⁷	Patient with recurrent thrombotic complications (despite anticoagulation) was treated with Ecu to prevent rethrombosis after vascular surgery	First report demonstrating colocalization of aPL-ab and complement (C1q; C4, C3 and C5b-9 or MAC) in the arterial wall of an APS patient	Suggests activation of complement classical pathway and involvement of MAC in pathophysiology
Arachchillage¹⁶⁸	Complement activation markers were compared in APS patients treated with anticoagulants	Complement activation markers were elevated in warfarin anticoagulated thrombotic APS patients, but decreased when switching to rivaroxaban	sC5b-9 plasma levels decreased when warfarin was substituted with rivaroxaban indicating that FXa may activate complement proteins fueling the cross-activation of inflammatory and prothrombotic pathways
Rand¹⁶⁹	Novel 2-stage assay that detects the complement activation potential in patients with aPL-abs	Highly sensitive assay system using patient plasma to distinguish APS from other inflammatory and thrombotic disorders that are not associated with aPL-abs	• APS-associated aPL-abs activate CP/LP and AP on anionic phospholipid surfaces leading to C5 activation • This test can be useful for detecting patients with aPL-abs who have a high risk for thrombotic complications
Kim¹⁷⁰	Complement activation markers were determined in pregnant patients with SLE and/or antiphospholipid antibodies	Complement activation levels predict adverse pregnancy outcome	sC5b-9 plasma levels detectable early in pregnancy are strongly predictive of adverse pregnancy outcomes
Tinit¹¹⁴^, Skoczynska¹¹⁵ Nauseel¹⁷¹	Each: a case report of CAPS and optional systematic review of the literature for other case reports	TP inhibition by Ecu can be a salvage therapy for CAPS refractory to conventional therapy	• Clinical evidence for a contribution of C5 activation in CAPS pathophysiology • Yelnik et al¹¹⁶ discover that not all refractory CAPS cases respond to Ecu treatment; responders have lower platelet counts and microangiopathic hemolytic anemia when compared with nonresponders
Chaturvedi¹⁷²	Sera and genetic information were investigated for the propensity to activate complement in patients suffering from APS, CAPS, and SLE	• A modified Ham assay detects complement activation propensity in APS and CAPS patients which associates with thromboembolism • Patients with CAPS harbor rare germline mutations in complement regulator genes	Anti–β2-GP-I antibodies trigger • complement activation mainly via CP • induced MAC (ie, C5b-9) deposition on test cells in modified Ham assay

First author/reference	Experimental/clinical setting	Important findings	Comment
Davis¹⁶⁰	Analysis of complement activation levels in stroke patients with and without aPL-abs	C5b-9 levels were higher in sera of patients with aPL and stroke when compared with stroke in absence of aPL-abs	TP activation seems to be implicated in the pathophysiology of aPL-ab–associated stroke
Holers¹⁶¹	• Murine model of aPL-ab induced fetal loss • Pregnant mice injected with human IgG containing aPL-abs	C3 activation is required for aPL-ab induced intrauterine growth restriction and/or fetal loss in mice	C3 KO mice or mice treated with complement inhibitor Crry are protected from fetal loss
Girardi¹⁶²	• Murine model of APS induced fetal loss • Pregnant mice injected with human IgG containing aPL-abs	Protected from fetal loss by • blocking C5 function (ie, C5 KO mice or applying anti-C5 mAb) • blocking C5a receptor signaling (C5aR KO)	• Indicates TP to be necessary for pathophysiology since proximal complement activation occurs unhindered in C5 KO mice • Suggests that C5a drives fetal loss via C5a mediated chemotaxis of neutrophils
Girardi¹⁶³	Murine model of aPL-ab induced fetal loss treated with anticoagulants	Heparin but not other anticoagulants (like fonda-parinux or hirudin) prevents aPL-ab–induced fetal loss	unfractionated or low-molecular-weight heparin prevented complement activation in vitro and in vivo while other anticoagulants failed to do so
Fischetti¹⁶⁴	• Rat model of APS induced thrombosis (including C6 KO rats) • Administration of human anti–β2-glycoprotein I with or without inflammatory priming with LPS	Thrombus formation induced by antibodies to β2-glycoprotein I requires complement TP activation and a priming factor	• C3 and C9 colocalize with aPL IgG on the thrombotic lesions • Indicates MAC (and not C5a) in the pathophysiology since C6 KO protects similarly well than anti-C5 blocking mAb
Carrera-Marín¹⁶⁵	• Rat model of APS induced thrombosis • Administration of human aPL-abs in mice (including C6 KO mice)	C6 knock-out mice are protected from thrombophilia mediated by aPL-abs	Indicates MAC (and not C5a) as a main driver of pathophysiology in addition to direct cell activating effects of aPL-abs
Agostinis¹⁶⁶	• Rat model of APS induced thrombosis (including C6 KO rats) • CH2-domain lacking anti–β2-glycoprotein I antibodies used as therapeutic approach	An engineered antibody that efficiently binds PL but cannot activate complement fails to induce vascular thrombosis and fetal loss (even after LPS priming)	• Antibody lacking the “comp lement activating” CH2 domain can prevent blood clot formation and fetal loss induced by aPL • aPL binding to its epitope alone has no/minor pathophysiological relevance
Meroni¹⁶⁷	Patient with recurrent thrombotic complications (despite anticoagulation) was treated with Ecu to prevent rethrombosis after vascular surgery	First report demonstrating colocalization of aPL-ab and complement (C1q; C4, C3 and C5b-9 or MAC) in the arterial wall of an APS patient	Suggests activation of complement classical pathway and involvement of MAC in pathophysiology
Arachchillage¹⁶⁸	Complement activation markers were compared in APS patients treated with anticoagulants	Complement activation markers were elevated in warfarin anticoagulated thrombotic APS patients, but decreased when switching to rivaroxaban	sC5b-9 plasma levels decreased when warfarin was substituted with rivaroxaban indicating that FXa may activate complement proteins fueling the cross-activation of inflammatory and prothrombotic pathways
Rand¹⁶⁹	Novel 2-stage assay that detects the complement activation potential in patients with aPL-abs	Highly sensitive assay system using patient plasma to distinguish APS from other inflammatory and thrombotic disorders that are not associated with aPL-abs	• APS-associated aPL-abs activate CP/LP and AP on anionic phospholipid surfaces leading to C5 activation • This test can be useful for detecting patients with aPL-abs who have a high risk for thrombotic complications
Kim¹⁷⁰	Complement activation markers were determined in pregnant patients with SLE and/or antiphospholipid antibodies	Complement activation levels predict adverse pregnancy outcome	sC5b-9 plasma levels detectable early in pregnancy are strongly predictive of adverse pregnancy outcomes
Tinit¹¹⁴^, Skoczynska¹¹⁵ Nauseel¹⁷¹	Each: a case report of CAPS and optional systematic review of the literature for other case reports	TP inhibition by Ecu can be a salvage therapy for CAPS refractory to conventional therapy	• Clinical evidence for a contribution of C5 activation in CAPS pathophysiology • Yelnik et al¹¹⁶ discover that not all refractory CAPS cases respond to Ecu treatment; responders have lower platelet counts and microangiopathic hemolytic anemia when compared with nonresponders
Chaturvedi¹⁷²	Sera and genetic information were investigated for the propensity to activate complement in patients suffering from APS, CAPS, and SLE	• A modified Ham assay detects complement activation propensity in APS and CAPS patients which associates with thromboembolism • Patients with CAPS harbor rare germline mutations in complement regulator genes	Anti–β2-GP-I antibodies trigger • complement activation mainly via CP • induced MAC (ie, C5b-9) deposition on test cells in modified Ham assay

Disease: APS/CAPS (prevalence APS: 500 per 1 million¹⁷³; CAPS about 1% of APS).

Ecu, eculizumab.