Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

M Margaret Prechel,Jeanine M Walenga

doi:10.1186/1477-9560-11-7

Abstract

Heparin Induced Thrombocytopenia (HIT) is caused by antibodies that recognize platelet factor 4 (PF4) associated with polyanionic glycosaminoglycan drugs or displayed on vascular cell membranes. These antibodies are elicited by multimolecular complexes that can occur when heparin is administered in clinical settings associated with abundant PF4. Heparin binding alters native PF4 and elicits immune recognition and response. While the presence of heparin is integral to immunogenesis, the HIT antibody binding site is within PF4. Thus HIT antibodies develop and function to cause thrombocytopenia and/or thrombosis only in the presence of PF4. Future emphasis on understanding the biology, turnover and regulation of PF4 may lead to insights into the prevention and treatment of HIT.

Highlights

With the introduction of heparin into clinical practice in the 1940s, surgeons were able to perform complex operations using this anticoagulant to prevent and/or treat obstructive clots
In the absence of an effective alternative therapy, HIT thrombosis (HITT) can progress to thromboembolic complications including deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke [6]
A determining factor in the risk that Heparin Induced Thrombocytopenia (HIT) antibodies will be elicited as a result of heparin anticoagulant therapy is the presence of platelet factor 4 (PF4)

Summary

Introduction

With the introduction of heparin into clinical practice in the 1940s, surgeons were able to perform complex operations using this anticoagulant to prevent and/or treat obstructive clots. A direct test of the concept that endogenous PF4-bound target antigens resemble the antigen generated by heparin during anticoagulant therapy used a mouse model of polymicrobial bacteria sepsis, and demonstrated that bacterial exposure resulted in development of PF4/ heparin-reactive antibodies with a time course of a typical primary immune response [120] These studies support the concept that HIT antibodies may resemble naturally occurring antibodies elicited by PF4 functioning as an antimicrobial agent [120,137]. This provides a context to understand how anticoagulant therapy may provoke antibody formation, as the presence of PF4 in complexes with heparin or expressed on the surface of vascular cells may mimic the presentation of PF4 bound to a pathogen, triggering a protective, innate immune response. It is a particular advantage that ODSH has already undergone trials demonstrating that it can be safely administered to humans [160]

Conclusions

Chong BH

33. Cines DB

Findings

36. Slungaard A