New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

Abstract

Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4–VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4–VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.

The role of CXCL family members in different diseases

“…CXCL4, called as platelet factor 4, is a small protein released from activated platelets. It exerts many functions like hemostasis and stimulation of immune cells at site of tumor [ 9 ]. CXCL5, known as epithelial activating neutrophil protein, plays a role in immune system and inflammation.…”

Dynamic molecular choreography induced by acute heat exposure in human males: a longitudinal multi-omics profiling study

“…VWF binds the glycoprotein Iba on platelets causing platelet adhesion, activation and aggregation, which is crucial for hemostasis and thrombosis ( 44 , 45 ). PF4, also known as chemokine (C-X-C motif) ligand 4, has the ability to bind with negatively charged polyanions such as VWF, resulting in the formation of immune complexes that can contribute to the development of thrombosis ( 46 ). THBS1, which is produced by platelets when stimulated by thrombin, plays a role in platelet aggregation ( 47 ).…”

Molecular choreography to acute heat exposure in a simulated extreme high temperature environment

“…VWF binds the glycoprotein Iba on platelets causing platelet adhesion, activation and aggregation, which is crucial for hemostasis and thrombosis (40). PF4, also known as chemokine (C-X-C motif) ligand 4, has the ability to bind with negatively charged polyanions such as VWF, resulting in the formation of immune complexes that can contribute to the development of thrombosis (41). THBS1, which is produced by platelets when stimulated by thrombin, plays a role in platelet aggregation (42).…”