Local Preconditioning by Thermal Stress Accelerates Microvascular Thrombus Formation

Abstract

Heme oxygenase 1 (HO-1) has been shown to suppress microvascular thrombus formation. Because stress conditioning induces HO-1 and, in addition, the anticoagulant thrombomodulin and thrombospondin 1, we studied the effect of hyperthermic and hypothermic local stress conditioning on microvascular thrombus formation. For local stress conditioning, the hindlimb of Sprague-Dawley rats was subjected to local heating (42.5 degrees C) or cooling (4 degrees C) for 30 min at 24 h before induction of thrombosis. Sham-exposed hindlimbs served as controls. Thrombosis was induced photochemically in arterioles and venules of the preconditioned tissue (muscle, subcutis, and periosteum) by continuous light exposure after injection of a fluorescent dye. Immunohistochemistry revealed that stress conditioning distinctly induced HO-1, thrombomodulin, and thrombospondin 1 but also von Willebrand factor in endothelial cells. Of interest, intravital fluorescence microscopic analysis of the kinetics of thrombus formation could not confirm an antithrombotic effect of stress conditioning but showed, in contrast, a significant acceleration of thrombosis (P < 0.05) in both arterioles and venules of either of the tissues studied. Although hypothermic and hyperthermic stress conditioning induces antithrombotic HO-1, thrombomodulin, and thrombospondin 1, it enhances endogenous thrombogenicity, most probably due to upregulation of the prothrombotic von Willebrand factor. Thus, preconditioning with local stress cannot be considered as a strategy to prevent thrombus formation.

Repetitive progressive thermal preconditioning hinders thrombosis by reinforcing phosphatidylinositol 3-kinase/Akt-dependent heat-shock protein/endothelial nitric oxide synthase signaling

“…30 An acceleration of thrombosis in arterioles and venules subjected to local stress heating (42.5°C) for 30 minutes was probably due to upregulation of the prothrombotic von Willebrand factor, despite antithrombotic heme oxygenase-1, thrombomodulin, and thrombospondin-1 induction. 31 The present data, consistent with our previous report, 13 indicate PTP attenuates enhanced hemodynamic parameters via decreased activation of ␣-adrenergic and ␤-adrenergic neurotransmission. The less enhanced levels of ER stress and blood ROS were also noted during PTP compared with TP.…”

Victims of lethal hypothermia have decreased levels of thrombomodulin in myocardium and urine

“…The observed low myocardial TM protein level might be related to a compensatory increase in the release of soluble TM into circulation. An increased level of TM protein expression has been seen in rats 4 [9] and 24 h [12] after cold exposure, but this could not be confirmed in the present study, as there was no recovery phase.…”

Transient ischemia elicits a sustained enhancement of thrombus development in the cerebral microvasculature: Effects of anti-thrombotic therapy

“…Studies of microvascular thrombogenesis after preconditioning have been more limited. However, one report (Rucker et al 2009) describes a significant acceleration of thrombus formation in microvessels (both arterioles and venules) of muscle and subcutis of rat hindlimb preconditioned by thermal stress (either hypothermia or hyperthermia). The latter study, when considered with the findings in our study of the cerebral microvasculature and published data from large arteries, suggest that, unlike large arteries, arterioles respond to preconditioning stimuli by exhibiting an exaggerated thrombogenic response.…”