Dosing and monitoring of low-molecular-weight heparin in high-risk pregnancy: Single-center experience

Study Objective. To evaluate dosing requirements and monitoring patterns of low-molecular-weight heparin (LMWH) when used in high-risk pregnancy. Design. Retrospective, observational, cohort study. Setting. University-affiliated medical center. Patients. Forty-nine women treated with LMWH between 2001 and 2005 for either prophylaxis or treatment of venous thromboembolism during pregnancy and monitored with antifactor Xa activity. Measurements and Main Results. Data were obtained on 53 pregnancies in the 49 women. The primary outcome was change in dosing requirements of LMWH throughout pregnancy as determined by the corresponding antifactor Xa activity peak levels. Mean starting doses of twice-daily enoxaparin and doses most proximate to delivery were 39.2 mg (range 30– 60 mg) and 55.0 mg (range 30–100 mg, p=0.06), respectively, for the prophylaxis group and 83.0 mg (range 30–180 mg) and 85.7 mg (range 30–160 mg, p=0.41), respectively, for the therapeutic group. Weight-based mean starting doses and doses most proximate to delivery were 0.46 and 0.62 mg/kg (p=0.03), respectively, for the prophylaxis group and 0.90 and 0.87 mg/kg (p=0.29), respectively, for the therapeutic group. Dose changes were required in 9 (69%) of 13 pregnancies and 21 (55%) of 38 pregnancies (data from two of the 40 pregnancies were excluded—one in a patient receiving dalteparin, and one in a patient with mitral valve replacement who had higher antifactor Xa goals) in the prophylaxis and therapeutic groups, respectively, to achieve target antifactor Xa activity. The weight-based prophylactic dose was consistently 0.6 mg/kg in all three trimesters, achieving a mean ± SD target antifactor Xa activity of 0.39 ± 0.18 units/ml, whereas the therapeutic dose was 0.9 mg/kg to maintain antifactor Xa activity of 0.71 ± 0.22 units/ml. Conclusion. Dose changes for LMWH throughout pregnancy as guided by antifactor Xa activity were common. A significant increase in the LMWH dose requirements in the prophylactic group suggests that more frequent monitoring of antifactor Xa activity may be appropriate in pregnant patients to maintain target anticoagulant levels

Decreased Warfarin Clearance with the CYP2C9 R150H (*8) Polymorphism

The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We examined whether the CYP2C9*8 allele impacts warfarin clearance through a pharmacokinetic study in warfarin-treated African American patients and an in vitro kinetic study of S-warfarin 7-hydroxylation using cDNA-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and 25% lower R- to S-warfarin plasma concentration in patients with the CYP2C9*8 allele (n=12) compared to CYP2C9*1 homozygotes (n=26). Consistent with these findings, the in-vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein compared to the wild-type protein. These data show that the R150H variant of the CYP2C9*8 allele reduces S-warfarin clearance, thus providing clinical and experimental evidence to explain lower warfarin dose requirements with the CYP2C9*8 allele

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans

Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements >7.5 mg/day in an African American population. Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes tested for their association with dose requirements >7.5 mg/day alone and in the context of other variables known to influence dose variability. Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring >7.5mg/day versus those who required lower doses (12% vs 3%, p=0.003; odds ratio 4.0, 95% CI, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat allele frequency of only 0.27% (p=0.008 compared to African Americans). Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared to Caucasians