Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: potential mechanisms for heightened prothrombotic potential.
OBJECTIVE
The purpose of this study was to determine the mechanistic basis for thrombin generation and increased prothrombotic potential after the abrupt cessation of intravenous (i.v.) unfractionated heparin among patients with acute coronary syndromes.


BACKGROUND
A "rebound" increase in prothrombotic potential has been observed biochemically and clinically after the abrupt cessation of unfractionated heparin (UFH) among patients with acute coronary syndromes. Although the mechanism is unknown, tissue factor and the extrinsic coagulation cascade, both operative in atherosclerotic vascular disease and arterial thrombosis, are thought to be centrally involved.


METHODS
In a single-center, pilot study, 30 patients with either unstable angina or non-ST segment elevation myocardial infarction who had received a continuous i.v. infusion of UFH for 48 h were randomly assigned to: 1) abrupt cessation, 2) i.v. weaning over 12 h or 3) subcutaneous weaning over 12 h.


RESULTS
Thrombin generation (prothrombin fragment 1.2) was evident within 1 h of UFH cessation, increased progressively (by nearly two-fold) at 24 h (p = 0.002) and correlated inversely with tissue factor pathway inhibitor concentration (r = -0.61). Thrombin generation was greatest among patients randomized to abrupt cessation (1.6-fold increase at 24 h) and least in those with i.v. weaning.


CONCLUSIONS
Thrombin generation after the abrupt cessation of UFH may represent a drug-induced impairment of physiologic vascular thromboresistance in response to locally generated tissue factor. A dosing strategy of abbreviated i.v. weaning attenuates but does not prevent heparin rebound among patients with acute coronary syndromes.
Becker
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RC
Cardiovascular Thrombosis Research Center, Laboratory for Vascular Biology Research, University of Massachusetts Medical School, Worcester 01655, USA. richard.becker@banyan.ummed.edu
Spencer
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Li
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Ball
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Hurley
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Hebert
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D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000097:blood / Q000188:drug therapy; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D001779:Blood Coagulation Factors / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy*; D010314:Partial Thromboplastin Time; D010865:Pilot Projects; D013375:Substance Withdrawal Syndrome / Q000097:blood*; D013917:Thrombin / Q000378:metabolism*
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D013917:Thrombin