Is the ideal anticoagulant a myth?

Figures & data

Figure 1. The coagulation network.

Here the initiation of clot formation is shown via tissue-bound tissue factor and clot formation occurs when the cumulative production of fibrin reaches a threshold value. The coagulation network is described by a computer model that allows for in vivo interactions and application of in vitro clotting time tests.

APC: Activated protein C; AT-III: Antithrombin III; CA: Contact activator; F: Fibrin; PC: Protein C; PS: Protein S; TF: Tissue factor; Tmod: Thrombomodulin; VKO: Vitamin K epoxide; XF: Cross-linked fibrin.

Adapted with permission from [6].

Figure 2. A pharmacological utility curve estimated for warfarin in the treatment of chronic atrial fibrillation.

Here an E_max model is fitted to the thrombotic rates (expressed as thrombotic rate saved) and a power model to the intracranial hemorrhage rates. Positive values of this utility function describe net benefits of treatments; negative values describe net losses. The dashed lines are either thrombosis rates saved (positive utility) or intracranial hemorrhage caused (negative utility). The solid line is the difference of those rates under the simple assumption that a positive benefit is equally as good as a negative loss is bad.

INR: International normalized ratio.

Data taken from [8].

Figure 3. The coagulation network, highlighting potential or existing targets.

Current targets include the VKORIs (e.g., warfarin), DTIs (e.g., dabigatran), aXa (e.g., rivaroxaban) and an investigational target depicting activity at TF:VIIa.

APC: Activated protein C; AT-III: Antithrombin III; aXa: Factor Xa antagonist; CA: Contact activator; DTI: Direct thrombin inhibitor; F: Fibrin; PC: Protein C; PS: Protein S; TF: Tissue factor; Tmod: Thrombomodulin; VKO: Vitamin K epoxide; VKORI: Vitamin K oxide reductase inhibitor; XF: Cross-linked fibrin.

Adapted with permission from [6].

Table 1. Between-subject variability in clearance for oral anticoagulants.

Anticoagulant	Target	BSV CL (%CV)	Ref.
Rivaroxaban	Factor Xa	30–59	[12,13]
Warfarin^†	VKOR	25–49	[14–16]
Dabigatran	Factor IIa	50	[17]
Argatroban	Factor Xa	37	[18]
Melagatran	Factor IIa	27 (BSV) + 23 (BOV)^‡	[19]

^†Values exclude studies enrolling healthy volunteers.

^‡The variability within an individual from day to day. If BSV is not considered, then the apparent BSV is the sum of 27 and 23%.

BOV: Between-occasion variability; BSV: Between-subject variability; CL: Clearance; CV: Coefficient of variation; VKOR: Vitamin K oxide reductase.

Table 2. Unpredictable variability in clotting factors.

Factor	Reported normal variability
Fibrinogen	2–4 g/l
Factor II	50–165 mg/l
Factor VII	70–125%
Factor VIII	500–2000 U/l
Factor XI	65–140%
AT-III	75–128%
Factor V	54–155%
Factor XII	65–140%

AT-III: Antithrombin III.

Data taken from [20].

Table 3. Ranges of international normalized ratio values for various drug targets.

Drug target	Therapeutic description	INR range for clotting factor activity range
		75–150%^†,‡	50–200%^†,§
Factor IIa	Direct thrombin inhibitor	1.6–3.9	1.3–5.5
Factor Xa	Factor Xa inhibitor	1.6–3.6	1.3–5.2
TF:Factor VIIa	TF:Factor VIIa inhibitor	1.5–3.4	1.3–4.8
Vitamin K cycle	Vitamin K oxide reductase inhibitor	1.5–4.5	1.2–5.9

^†Percent value of the baseline concentrations of fibrinogen, and Factors II, V, VII, VIII, XI and XII.

^‡Conservative variability in the coagulation factors.

^§Nonconservative variability in the coagulation factors.

INR: International normalized ratio; TF: Tissue factor.

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