A less-intensive anticoagulation protocol of therapeutic unfractionated heparin administration for pregnant patients.

Heparin anticoagulant therapy for thromboembolic disorders during pregnancy is problematic due to unexpected adverse bleeding. To avoid bleeding, we have used a less-intensive anticoagulation protocol of unfractionated heparin (UFH). The protocol had a therapeutic activated partial thromboplastin time (APTT) ratio of 1.5-2.0 with the control value, a UFH dose of ≤ 30,000 U/day, and an antithrombin (AT) activity target of ≥ 70%. In the present study, we evaluated this protocol using an anti-Xa assay. We collected UFH-treated plasma samples from ten consecutive pregnant Japanese patients with current or previous thromboembolic disorders. Seven patients remained in the therapeutic APTT ratio range (heparin-sensitive [HS] group). The other three patients had difficulty remaining within the therapeutic range (heparin-resistant [HR] group). In the HR group, two had AT deficiency and one had congenital absence of the inferior vena cava. Of the HS and HR samples, 73% and 31%, respectively, were within the therapeutic anti-Xa activity range 0.3-0.7 U/mL, indicating difficulty for the HR group to remain within the therapeutic range. Neither major bleeding nor symptomatic thromboembolic episodes occurred in either group. These findings suggest that the less-intensive anticoagulation protocol is permissive and may be beneficial in the HS group.

Effects of factor VIII levels on the APTT and anti-Xa activity under a therapeutic dose of heparin.

In pregnant women, activated partial thromboplastin time (APTT) does not precisely reflect the anticoagulant effect of a therapeutic dose of heparin. However, the measurement of anti-Xa activity can be used to monitor the anticoagulant effect of heparin, since the plasma concentrations of coagulation factors increase in pregnant women. We evaluated the in vitro effects of increased concentrations of fibrinogen and other coagulation factors (FVII, FVIII, and FIX) on the results of assays of APTT and anti-Xa activity in plasma samples with various therapeutic concentrations of unfractionated heparin (UFH). In the presence of UFH, APTT was shortened by increased concentrations of fibrinogen, FVII, or FVIII, and this effect was much stronger when the FVIII concentration was increased. In the plasma samples containing 0.5 or 0.7 U/mL of UFH, the APTT was shortened by approximately half or one-third, respectively, when 6 U FVIII/mL was added to the sample. The anti-Xa activity was not influenced by increased concentrations of the coagulation factors. In the present study, we also evaluated the sensitivities to UHF of four APTT reagents, and found a 1.65-fold difference in the sensitivity to UFH among APTT reagents. Our results demonstrate that increased FVIII concentration shortens APTT under therapeutic doses of UFH, and that APTT thus underestimates the anticoagulant effect of UFH in pregnant women, mainly due to the increased FVIII concentration.

Association of platelet aggregation with lipid levels in the Japanese population: the Suita study.

AIM: Platelets play a pivotal role in atherothrombotic diseases. Platelet aggregability induced by agonists has great interindividual variability; however, the factors influencing platelet aggregability variation have not been characterized in Asia. METHODS: To examine the confounding factors influencing platelet counts and responsiveness to agonists, we measured the platelet counts and platelet aggregability induced by 1.7 µM adenosine diphosphate (ADP) or 1.7 µg/mL collagen using a light transmittance aggregometer in the Japanese general population without medication or cardiovascular disease (387 men and 550 women) in the Suita Study. RESULTS: Platelet counts were negatively correlated with age in both men and women (Spearman's rank correlation coefficient: r(s)=-0.230 and -0.227; p< 0.01, respectively). In women, platelet counts were correlated negatively with the high-density lipoprotein (HDL) cholesterol level and positively with the low-density lipoprotein (LDL) cholesterol/HDL cholesterol (L/H) ratio (r(s)=-0.135 and 0.119; p< 0.01, respectively). In women, platelet aggregabilities by ADP and collagen were correlated with age (r(s)=0.118 and 0.143; p< 0.01, respectively), and collagen-induced platelet aggregability was correlated with the LDL cholesterol level, the L/H ratio, and the non-HDL cholesterol level (r(s)=0.167, 0.172, and 0.185; p< 0.01, respectively). Even after adjustment for age, systolic blood pressure, body mass index, and current smoking and drinking, the association of platelet counts with the L/H ratio in women and associations of collagen-induced platelet aggregability with the L/H ratio and the non-HDL cholesterol level remained. CONCLUSION: Examination of platelet counts and platelet aggregability induced by ADP and collagen revealed gender, age and lipid levels as factors influencing inter-individual variability.

Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism.

Inherited antithrombin deficiency, an established risk factor for venous thromboembolism (VTE), can be classified into type I (quantitative deficiency) or type II (qualitative deficiency). In the present study, we assessed the VTE risk associated with the phenotypes of antithrombin deficiency in patients admitted to our hospital. We found that patients with type I deficiency (n = 21) had more VTE events and earlier onset of VTE than those with type II deficiency (n = 10). The VTE-free survival analysis showed that the risk for VTE in patients with type I deficiency was sevenfold greater than that in patients with type II deficiency (hazard ratio: 7.3; 95% confidence interval: 1.9-12.2; P = 0.0009). The prevalence of type I deficiency in the VTE group (5.6%, 6/108) was higher than that in the general population (0.04%, 2/4,517) (odds ratio: 132.8; 95% confidence interval: 26.5-666.1; P < 0.0001). However, the prevalence of type II deficiency was not different between the VTE group and the general population. Our study indicated that the risk for VTE in patients with type I deficiency was much higher than that in patients with type II deficiency. Thus, simple phenotypic classification of antithrombin deficiency is useful for assessment of VTE risk in Japanese.