Senior Scholars Program

Title

Comparative effects of unfractionated heparin and low molecular weight heparin on vascular endothelial cell tissue factor pathway inhibitor release: a model for assessing intrinsic thromboresistance

UMMS Affiliation

Cardiovascular Thrombosis Research Center, Laboratory for Vascular Biology Research; School of Medicine

Date

10-1-2002

Document Type

Article

Medical Subject Headings

Cells, Cultured; Endothelial Cells; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Lipoproteins; Thrombosis; Vascular Resistance

Disciplines

Cardiology | Cardiovascular Diseases | Cell Biology

Abstract

OBJECTIVES: The purpose of our study was to characterize tissue factor pathway inhibitor (TFPI) release from human vascular endothelial cells following daily exposure to varying concentrations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

BACKGROUND: A "rebound" increase in ischemic/thrombotic events, including myocardial infarction and cardiovascular death, has been observed after the abrupt cessation of UFH. In a single center pilot study of patients with acute coronary syndromes (ACS) we reported that thrombin generation was evident within one (1) hour of UFH cessation, increased progressively over the subsequent 24 hours, correlated directly with factor VII activity and inversely with TFPI (concentration and activity). METHODS: Human umbilical vein endothelial cells were grown to confluence and incubated with varying concentrations of UFH or dalteparin, a low molecular weight haparin, for up to 144 hours. Daily samples of the cells supernatant were obtained and assayed for TFPI. Cellular reserve and responsiveness to recombinant endothelial cell growth factor (rEGF) stimulation were determined at 168 hours.

RESULTS: In low concentrations (0.5 U/mL) UFH caused a progressive rise in TFPI concentration with a peak level of 6.36 +/- 0.5 ng/10(5) cells at 24 hours. By 72 hours of daily exposure, the levels declined to below control values and TFPI release following rEGF stimulation was reduced by approximately 60% compared to control (1.93 +/- 0.42 vs 4.3 +/- 0.78 ng/10(5) cells; p = 0.001). Initial endothelial cell release and rate of decline were more robust with high concentrations of UFH (5.0 U/ml). TFPI levels were above control values at each sampling time point up to 120 hours and cellular responsiveness to stimulation was preserved with dalteparin (compared to UFH) (p < 0.001).

CONCLUSIONS: Thrombin generation and clinical events that occur during treatment with UFH and following its abrupt cessation may represent an acquired state of transiently impaired thromboresistance to the tissue factor-VIIa complex. The differing effects of UFH and LMWH on vascular endothelial cell TFPI synthesis, release and reserve with prolonged administration require further investigation.

Rights and Permissions

Citation: J Thromb Thrombolysis. 2002 Oct;14(2):123-9. Doi: 10.1023/A:1023280811804 Link to article on publisher's site

Related Resources

Link to Article in PubMed

Comments

Medical student Miguel Rodriguez participated in this study as part of the Senior Scholars research program at the University of Massachusetts Medical School.

The author's last name is misspelled in the journal article and in PubMed.

PubMed ID

12714831