Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events

Abstract

Introduction: More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events.

Materials and methods: We studied (1) 100 patients with acute ischemic stroke (n=50) or transient ischemic attack (TIA) (n=50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n=50) or TIA (n=50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI).

Results: The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p≤0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p<0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced.

Conclusion: Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors.

Conflict of interest statement

Conflict-of-interest Statement: The authors declare no competing financial interests.

Copyright © 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Thrombin generation curves for each group of patients with standard deviation bars at each time point. A=previous stroke; B=acute stroke; C=previous TIA; D=previous TIA.

Figure 2

(A) Thrombin generation curves for all acute patients, all previous patients and the mean physiologic control. The acute patients are represented by the curve + SD, and the previous patients are represented by the curve − SD. (B) Thrombin generation curves for all acute patients with levels of FII and AT set to 100%, all previous patients and the mean physiologic control. The acute patients are represented by the curve + SD, and the previous patients are represented by the curve − SD.

Figure 3

Effect of TFPI. (A and B) Thrombin generation curves for the mean physiologic control and the patients with levels of FII, AT and TFPI set to 100%. A=acute patients + SD; B=previous patients − SD. (C and D) Thrombin generation curves for the mean physiologic control and the patients with levels of TFPI set to 100%.