The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

Abstract

The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-β-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.

Keywords: antiphospholipid syndrome; autoantibodies; autoimmunity; miscarriage; thrombosis.

Figure 1.

Physiological roles of β2GPI. β2GPI has several functions. It may act as an opsonin leading the clearance of anionic phospholipid composed vesicles as well as a scavenger of LPS. These two effects reduce the inflammatory response. On the other hand, β2GPI is a modulator of the complement system, angiogenesis, and hemostasis.

Figure 2.

Pathophysiology of obstetric APS. aPLs may directly activate the placenta through the interaction of anti-β2GPI with β2GPI and/or annexin A2, leading to the production of pro-inflammatory cytokines and chemokines (primarily IL-8) which may recruit neutrophils. In turn, these cells are activated by aPLs which may induce the generation of NETs and the consequent activation of the placenta by the coupling to TLR2/4. Finally, activation and lipid peroxidation of the placenta may trigger myometrial and uterine contraction, cervical ripening, membrane rupture, and labor induction.

Figure 3.

Histones can activate cells through the engagement of TLR2/4. aPLs may trigger the release of NETs composed mainly of histones, neutrophil elastase, and myeloperoxidase. These biochemical compounds are recognized by TLR2/4 and, when complexed, they may trigger the activation of the placenta, endothelium, and platelets, among other cells. Furthermore, these constituents may prolong the activated thromboplastin time test through the direct inhibition of the contact phase activation. In addition, they can enhance the thrombin rate generation and the endogenous thrombin potential.

Figure 4.

Physiopathology of APS. aPls may activate different cells. In monocytes, aPLs binds to β2GPI triggering the production of TF, cytokines, and proinflammatory chemokines. In endothelial cells, aPLs induce the production of chemokines, proinflammatory cytokines, TF, ROS, and ET-1 and the consumption of NO. On the other hand, aPLs increase the platelet sensitivity to its agonists while increasing the production of TxA2. The effects of aPLs on hemostasis and fibrinolysis range from inhibition of tPA activity and inhibition of FXII-mediated fibrinolysis to inhibition of FXI inactivation by antithrombin as well as increased FXIII synthesis. Indirectly, aPLs also activate cells involved in APS through the activation of neutrophils and the release of NETs. In NETs, DNA and elastases are recognized by TLR2/4, leading to activation of the placenta, endothelium, and platelets.