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

Publication ,  Journal Article
Dai, J; Madeeva, D; Hayes, V; Ahn, HS; Tutwiler, V; Arepally, GM; Cines, DB; Poncz, M; Rauova, L
Published in: Blood
August 16, 2018

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.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

August 16, 2018

Volume

132

Issue

7

Start / End Page

727 / 734

Location

United States

Related Subject Headings

  • Thrombocytopenia
  • Platelet Factor 4
  • Monocytes
  • Mice
  • Immunology
  • Humans
  • Human Umbilical Vein Endothelial Cells
  • Heparin
  • Gene Expression Regulation
  • Blood Platelets
 

Citation

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Dai, J., Madeeva, D., Hayes, V., Ahn, H. S., Tutwiler, V., Arepally, G. M., … Rauova, L. (2018). Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia. Blood, 132(7), 727–734. https://doi.org/10.1182/blood-2018-02-830737
Dai, Jing, Daria Madeeva, Vincent Hayes, Hyun Sook Ahn, Valerie Tutwiler, Gowthami M. Arepally, Douglas B. Cines, Mortimer Poncz, and Lubica Rauova. “Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia.Blood 132, no. 7 (August 16, 2018): 727–34. https://doi.org/10.1182/blood-2018-02-830737.
Dai J, Madeeva D, Hayes V, Ahn HS, Tutwiler V, Arepally GM, et al. Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia. Blood. 2018 Aug 16;132(7):727–34.
Dai, Jing, et al. “Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia.Blood, vol. 132, no. 7, Aug. 2018, pp. 727–34. Pubmed, doi:10.1182/blood-2018-02-830737.
Dai J, Madeeva D, Hayes V, Ahn HS, Tutwiler V, Arepally GM, Cines DB, Poncz M, Rauova L. Dynamic intercellular redistribution of HIT antigen modulates heparin-induced thrombocytopenia. Blood. 2018 Aug 16;132(7):727–734.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

August 16, 2018

Volume

132

Issue

7

Start / End Page

727 / 734

Location

United States

Related Subject Headings

  • Thrombocytopenia
  • Platelet Factor 4
  • Monocytes
  • Mice
  • Immunology
  • Humans
  • Human Umbilical Vein Endothelial Cells
  • Heparin
  • Gene Expression Regulation
  • Blood Platelets