PF 4 Protein

The gene encoding human PF4 is located on chromosome 4. PF4 is a 70-amino acid protein that binds with high affinity to heparin. It is usually found in a complex with proteoglycan .

PF4’s primary physiological role is the neutralization of heparin-like molecules on the endothelial surface of blood vessels, thereby inhibiting local antithrombin activity and promoting coagulation. This function is essential for wound repair and inflammation . PF4 is also a strong chemoattractant for neutrophils, fibroblasts, and monocytes, and interacts with a splice variant of the chemokine receptor CXCR3, known as CXCR3-B .

PF4 is clinically significant in several contexts:

• Heparin-Induced Thrombocytopenia (HIT): The heparin:PF4 complex is the antigen in HIT, an autoimmune reaction to the administration of the anticoagulant heparin .
• Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Antibodies against PF4 have been implicated in cases of thrombosis and thrombocytopenia following vaccination with the Oxford–AstraZeneca or Janssen COVID-19 vaccines .
• Long COVID: Changes in PF4 expression have been associated with symptoms of long COVID .
• Systemic Sclerosis: PF4 levels are increased in patients with systemic sclerosis who also have interstitial lung disease .

PF4 has been found to kill malaria parasites within erythrocytes by selectively lysing the parasite’s digestive vacuole . It also has antiproliferative and antiangiogenic properties, interfering with FGF2 and VEGF heparin binding and thus inhibiting their signaling . However, it can also be proinflammatory and proatherogenic through multiple effects on monocytes, macrophages, and endothelial cells .

Despite being under intense investigation for over 30 years, the cellular functions, receptors, and signaling pathways of PF4 are still not fully understood and might be cell type-specific . Continued research is essential to fully elucidate the diverse roles of PF4 in health and disease.