Recent Advances in Anticoagulant Treatment of Immune Thrombosis: A Focus on Direct Oral Anticoagulants in Heparin-Induced Thrombocytopenia and Anti-Phospholipid Syndrome

Abstract

For more than 10 years, direct oral anticoagulants (DOACs) have been increasingly prescribed for the prevention and treatment of thrombotic events. However, their use in immunothrombotic disorders, namely heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS), is still under investigation. The prothrombotic state resulting from the autoimmune mechanism, multicellular activation, and platelet count decrease, constitutes similarities between HIT and APS. Moreover, they both share the complexity of the biological diagnosis. Current treatment of HIT firstly relies on parenteral non-heparin therapies, but DOACs have been included in American and French guidelines for a few years, providing the advantage of limiting the need for treatment monitoring. In APS, vitamin K antagonists are conversely the main treatment (+/- anti-platelet agents), and the use of DOACs is either subject to precautionary recommendations or is not recommended in severe APS. While some randomized controlled trials have been conducted regarding the use of DOACs in APS, only retrospective studies have examined HIT. In addition, vaccine-induced immune thrombotic thrombocytopenia (VITT) is now a part of immunothrombotic disorders, and guidelines have been created concerning an anticoagulant strategy in this case. This literature review aims to summarize available data on HIT, APS, and VITT treatments and define the use of DOACs in therapeutic strategies.

Keywords: antiphospholipid syndrome; direct oral anticoagulants; heparin-induced thrombocytopenia; immune thrombosis; vaccine-induced immune thrombotic thrombocytopenia.

Figure 1

Mechanism of action of anti-β2GPI antibodies in APS. Adapted from Masliah-Planchon J. et al., Rev. Med. Int., 2012 [14]. Anti-β2GPI antibodies bind to negative phospholipids of endothelial cells, monocytes, and, to a lesser extent, platelets. By interacting with membrane receptors (GPIbα, ApoER2, TLR, and annexin A2), they trigger the activation of many intracellular kinases, thereby modulating the expression of procoagulant and anticoagulant molecules. In addition, this binding to membrane phospholipids induces acquired APCR by preventing the formation of coagulation factor complexes on the cell surface which reduces inhibition of factor Va and VIIIa by protein C/protein S complex. These antibodies are also involved in complement activation. APCR: activated protein C resistance; ApoER2: apolipoprotein E receptor 2; GP: glycoprotein; ICAM1: intracellular adhesion molecule; MAPK: mitogen-activated protein kinases; miRNA: microRNA; PC: protein C; PS: protein S; PLA2: phospholipase A2; TLR: toll-like receptor; TM: thrombomodulin; TXA2: thromboxane A2; VCAM: vascular cell adhesion molecule.

Figure 2

HIT pathophysiology. Antibodies directed against PF4/H complexes induce a multicellular activation, leading to the production of procoagulant microparticles from platelets and monocytes, the tissue factor expression by endothelial cells and monocytes, and the production of NETs by neutrophils. NETs: Neutrophil extracellular traps; PF4: platelet factor 4; PF4/H: PF4/heparin.