This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.OBJECTIVESTo determine, through pharmacokinetic parameters, the ideal dosing protocol for dalteparin (a low molecular weight heparin) and unfractionated heparin (UFH) for women desiring pregnancy who have evidence of an acquired (specifically, antiphospholipid syndrome) or inherited thrombophilia.BACKGROUND The most common cause of maternal death in pregnancy is thromboembolic disease (i.e. blocking of vessels by blood clot). The risk of venous thromboembolism is five times greater in pregnant vs. age-matched non-pregnant women. In addition, women with a previous history of a thromboembolic event have a significantly increased risk of another thromboembolic complication during pregnancy. Dr. Stephenson (Principal Investigator) and Dr. Ensom (Sub-Investigator) conducted a previous randomized trial, in which women with APS desiring pregnancy received either dalteparin or unfractionated heparin. Based on the results of this pilot pharmacokinetic study, dosing protocols have been revised, which now need to be verified. METHODOLOGYIndividual study subjects will participate in the study prior to and throughout their pregnancy, as well as postpartum. The study population will consist of 10 subjects prescribed dalteparin and 10 subjects prescribed UFH (20,000 units/mL). Research Protocol: Study procedures will consist of serial blood sampling (over a 12h and 24h period for UFH and LMWH, respectively) under steady-state conditions during the pre-pregnant state and the 1st (9-11 weeks), 2nd (22-24 weeks), and 3rd (34-36 weeks) trimesters and postpartum, to characterize heparin pharmacokinetics and pharmacodynamics. Pharmacokinetic and pharmacodynamic modeling: Pharmacokinetic parameters [area under the concentration time curve (AUC), maximal (Cmax), minimal (Cmin), and mean concentrations, and elimination half-life (t1/2)] will be calculated by traditional noncompartmental (PHARM/PCS, MicroComputer Specialists, Philadelphia, PA), compartmental (PKAnalyst, MicroMath Scientific Software, Salt Lake City, UT) and Bayesian (Abbottbase Pharmacokinetics Program, Abbott Laboratories, Diagnostic Div., Irving, TX) analyses. The best dosing strategy (i.e. best model selected) will be the one exhibiting the best balance between a modified Akaike information criterion value, residual sum of squares, and coefficient of determination.Statistical analysis: Two-factor repeated measures analysis of variance will be used to determine within group (UFH and LMWH, respectively) and between group (UFH vs. LMWH) differences over time (pre-pregnancy, each trimester and post-pregnancy). Linear regression analysis will be used to assess relationships between continuous variables (e.g. dose vs. APTT, etc.).
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