Prothrombotic factors enhance heparin-induced thrombocytopenia and thrombosis in vivo in a mouse model.
BACKGROUND
Heparin-induced thrombocytopenia/thrombosis (HIT/T) is a common cause of life- and limb-threatening thrombosis. The development of antibodies that react with complexes of heparin and platelet factor 4 (PF4) is fundamental to the development of the disease. However, anti-PF4/heparin antibodies are far more common than is HIT/T and there is less understanding of the factors that contribute to thrombosis in only a subset of patients.


OBJECTIVE
Both qualitative and quantitative differences in multiple factors (e.g. antibodies, heparin and platelets) may influence the clinical course of patients who develop anti-PF4/heparin antibodies. We examined the hypothesis that host-specific factors, such as comorbid prothrombotic conditions, would exacerbate the pathologic effects of anti-PF4/heparin antibodies.


RESULTS
A mouse model transgenic for human Fcgamma RIIa and PF4 and null for mouse PF4 was used to study the influence of prothrombotic conditions on the effects of anti-PF4/heparin antibodies in vivo. To simulate a prothrombotic milieu, mice were fed a hypercholesterolemic diet (HD). HD-fed mice had elevated plasma cholesterol, increased platelet reactivity and increased endothelial activation relative to mice fed a standard diet (SD). Age- and sex-matched mice from each diet group were treated with an anti-PF4/heparin antibody and heparin. HD-fed mice developed more severe thrombocytopenia than similarly treated SD-fed mice. Mice with moderate to severe thrombocytopenia had elevated plasma levels of thrombin-antithrombin complexes, indicative of increased thrombin generation in vivo. Platelet-fibrin thrombi were observed in multiple organs of HD-fed mice that developed severe thrombocytopenia.


CONCLUSIONS
Host-specific factors, such as prothrombotic changes in platelet reactivity and/or endothelial activation, may influence the development of thrombosis in a subset of patients who develop anti-PF4/heparin antibodies.
Reilly
M P
MP
Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA 19107, USA. michael.reilly@jefferson.edu
Taylor
S M
SM
Franklin
C
C
Sachais
B S
BS
Cines
D B
DB
Williams
K J
KJ
McKenzie
S E
SE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000925:Anticoagulants / Q000009:adverse effects / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000990:Antithrombin III; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D006493:Heparin / Q000009:adverse effects / Q000276:immunology*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010447:Peptide Hydrolases / Q000097:blood; D015539:Platelet Activation; D010974:Platelet Aggregation; D010976:Platelet Count; D010978:Platelet Factor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood* / Q000209:etiology / Q000276:immunology / Q000473:pathology; D013927:Thrombosis / Q000097:blood* / Q000209:etiology / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D015703:Antigens, CD; D002791:Cholesterol, Dietary; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; C046193:antithrombin III-protease complex; D010978:Platelet Factor 4; D000990:Antithrombin III; D006493:Heparin; D010447:Peptide Hydrolases