Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia.

Abstract

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder initiated by antibodies to platelet factor 4 (PF4)/heparin complexes. PF4 released from platelets binds to surface glycosaminoglycans on hematopoietic and vascular cells that are heterogenous in composition and differ in affinity for PF4. PF4 binds to monocytes with higher affinity than to platelets, and depletion of monocytes exacerbates thrombocytopenia in a murine HIT model. Here we show that the expression of PF4 on platelets and development of thrombocytopenia are modulated by the (re)distribution of PF4 among hematopoietic and endothelial cell surfaces. Binding of PF4 to platelets in whole blood in vitro varies inversely with the white cell count, likely because of the greater affinity of monocytes for PF4. In mice, monocyte depletion increased binding of PF4 to platelets by two- to three-fold. Induction of HIT in mice caused a transient >80-fold increase in binding of HIT antibody to monocytes vs 3.5-fold increase to platelets and rapid transient monocytopenia. Normalization of monocyte counts preceded the return in platelet counts. Exposure of blood to endothelial cells also depletes PF4 from platelet surfaces. These studies demonstrate a dynamic interchange of surface-bound PF4 among hematopoetic and vascular cells that may limit thrombocytopenia at the expense of promoting prothrombotic processes in HIT.

• Authors: Jing Dai, Daria Madeeva, Vincent Hayes, Hyun Sook Ahn, Valerie Tutwiler, Gowthami M Arepally, Douglas B Cines, Mortimer Poncz, Lubica Rauova
• Journal: Blood (Blood) Vol. 132 Issue 7 Pg. 727-734 (08 16 2018) ISSN: 1528-0020 [Electronic] United States
• PMID: 29914979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Antigens
• Platelet Factor 4
• Heparin

Topics

• Animals
• Antigens (biosynthesis)
• Blood Platelets (metabolism, pathology)
• Gene Expression Regulation
• Heparin (adverse effects, therapeutic use)
• Human Umbilical Vein Endothelial Cells (metabolism, pathology)
• Humans
• Mice
• Monocytes (metabolism, pathology)
• Platelet Factor 4 (biosynthesis)
• Thrombocytopenia (chemically induced, metabolism, pathology)