Table 1.
Plasma composition within either healthy controls or individuals with a known DVT.
Figure 1.
Schematic of the computational model of the tissue factor pathway.
The multicomponent processes encompassed in the computational model are illustrated as either: enzymes (open circle), inhibitors (hatched circle), zymogens (open boxes) or complexes (open ovals). Upon injury to the vessel wall, tissue factor, the cofactor for the extrinsic tenase complex, is exposed to circulating factor VIIa and forms the vitamin K dependent complex the extrinsic tenase. Factor IX and factor X are converted to their serine proteases factor IXa (FIXa) and factor Xa (FXa) which then form the intrinsic tenase and the prothrombinase complexes, respectively. The combined actions of the intrinsic and extrinsic tenase and the prothrombinase complexes lead to an explosive burst of the enzyme thrombin (IIa). The procoagulant response is down regulated by the stoichiometric inhibitors tissue factor pathway inhibitor (TFPI) and antithrombin (AT). TFPI serves to attenuate the activity of the extrinsic tenase trigger of coagulation. AT directly inhibits thrombin, FIXa and factor Xa. The proteins in which the concentrations from individual subjects are used are shown in red. Tissue factor in blue is arbitrarily set to 5 pM. Circulating FVIIa is set at 1% of the concentration of FVII from each individual.
Figure 2.
Factor Xa profiles of case and control individuals.
Plasma compositions from 473 healthy individuals and 426 individuals with a known DVT were used to generate time courses of total active fXa upon a Tf stimulus of 5 pM. The mean total active fXa level at each second is shown with the standard deviation in grey.
Table 2.
Factor Xa generation outputs for healthy controls (no known DVT).
Table 3.
Factor Xa generation outputs for individuals with a known DVT.
Table 4.
Comparison of fXa generation in individuals with a known DVT versus controls.
Figure 3.
Factor Xa generation segregated by potential risk factors.
Individuals within the healthy control population were separated into categories to evaluate the response of fXa generation between groups. The groups were: Panel A) Body Mass Index (BMI); ≤26 kg/m2 (n = 264) and >26 kg/m2 (n = 193); Panel B) Sex; men (n = 201) and women (n = 272); Panel C) Age; ≤45 yrs (n = 223) and >45 yrs (n = 250). All fXa profiles are shown as the mean and the 95% CI.
Figure 4.
Premenopausal women aged 15 to 49 were segregated into categories of: Panel A: control women +OC use (n = 47) and –OC use (n = 90) and Panel B: women with a known DVT +OC use (n = 30) and –OC use (n = 40). FXa generation was evaluated for these groups. The grey shaded area represents 1 SD.
Figure 5.
Comparing factor Xa and thrombin generation.
Thrombin generation profiles from the same population, previously determined using the same methodology [15], are compared to their fXa profiles. Three pairs of overlapping individual thrombin generation profiles are shown on the left. The dashed line indicates the mean time to the maximum level of thrombin generation within the healthy population (432 s). The corresponding fXa generation profiles in the same individuals are shown on the right.
Figure 6.
Factor Xa and thrombin generation curves for oral contraceptive users and non-users.
Panel A: Factor Xa curves for oral contraceptive users, non-users, users with fIX and TFPI adjusted to the mean value of the non-users and users with fIX, TFPI and AT adjusted to the mean value of the non-users. Panel B: Thrombin curves for oral contraceptive users, non-users, users with fIX and TFPI adjusted to the mean value of the non-users, users with fIX, TFPI and AT adjusted to the mean value of the non-users and users with fIX, TFPI, AT and fII adjusted to the mean value of the non-users.