Remote ischemic preconditioning reduces thrombus formation in the rat

Abstract

13 Huang Q, Neuenschwander PF, Rezaie AR, Morrissey JH. Substrate recognition by tissue factor-factor VIIa. Evidence for interaction of residues Lys165 and Lys166 of tissue factor with the 4-carboxyglutamate-rich domain of factor X. J Biol Chem 1996; 271: 21752-7.14 Boettcher JM, Davis-Harrison RL, Clay MC, Nieuwkoop AJ, Ohkubo YZ, Tajkhorshid E, Morrissey JH, Rienstra CM. Atomic view of calcium-induced clustering of phosphatidylserine in mixed lipid bilayers. Biochemistry 2011; 50: 2264-73.Remote ischemic preconditioning reduces thrombus formation in the rat Ischemic preconditioning (IPC) is known to protect tissue from ischemia and has an effect both locally [1] and systemically [2]. Remote IPC (RIPC) induced by limb ischemia provides systemic protection against prolonged ischemia in the target organ. RIPC has been reported to reduce infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary angioplasty [3] and is currently being evaluated in patients with ischemic stroke undergoing thrombolysis (NCT00975962). We hypothesized that the reduction in ischemic damage with RIPC could rely on a direct effect on arterial thrombus formation and embolization, and investigated this in a dynamic in vivo rat model of experimental thrombosis [4].Animals were treated according to Danish law on animal experiments. RIPC was induced using a protocol described previously [5]. At the time of surgery, a tourniquet was placed for 10 minutes on the left hind limb. Photographs demonstrating blue coloring of the left paw documented ischemia.Ten millimeters of the femoral artery on the right hind leg were dissected distal to the inguinal ligament. The artery was fixed in a clamp and an arteriotomy was performed comprising one-third of the vessel circumference. The proximal vessel edge was inverted by two 10-0 Nylon sutures exposing full thickness of the vessel wall to the lumen. After clamp release, a thrombus would build up at the arteriotomy site, and fragments of thrombus were seen to detach and embolize downstream. This model of a thrombogenic anastomosis is well established in rats [6,7] and pigs [8].The right femoral artery was placed in a trans-illuminator projecting a light beam through the vessel [8,9]. Recordings with a digital recorder were performed through the microscope for 30 min after clamp release and were analyzed offline in a blinded fashion. The thrombus area was measured as the number of pixels every minute, using special ImageJ based software. (ImageJ 1.45s, NIH, USA). The area was measured for 20 min while the number of emboli was counted manually every minute for 30 min. The area of the thrombus and number of emboli were displayed versus time in a graph. The area under the curve (AUC) for thrombus formation over time was determined. Two independent investigators analyzed 10 random videos (coefficient of variation was 21% for counting emboli and 8% for area measurement).Data were consistent with a Gaussian distribution, and the unpaired t-test was used for comparison of the two g...

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

“…For example, an examination of thrombus formation in large arteries (coronary and femoral) subjected to either local or remote (distant tissue) IPC have revealed improved vessel patency, the generation of small thrombi and fewer emboli after a subsequent insult (Hata et al 1998, Ropcke et al 2012). The anti-thrombogenic response of larger arteries to IPC is supported by a report describing attenuation of different molecular indices of platelet activation, including fibrinogen binding and aggregation with neutrophils (Linden et al 2006).…”

Chronic Remote Ischemic Conditioning Is Cerebroprotective and Induces Vascular Remodeling in a VCID Model

“…Non-invasive RIC therapy method was performed as published elsewhere [ 18 , 19 ] with a programmable cuff or its sham procedure with a cuff that did not inflate or deflate ( see detail in “ Supplemental Methods ” ) [ 15 ]. Bilateral RIC therapy was performed in both hind limbs simultaneously (4 cycles × 5 min duration of each cycle inflate and deflate × 5 min interval between each cycle) daily for 1 month (BCAS+RIC-1MO) or 4 months (BCAS+RIC-4MO) after 1 week from BCAS surgery.…”

Remote Ischemic Conditioning in Cerebral Diseases and Neurointerventional Procedures: Recent Research Progress

“…Moncada found that preconditioning increases expression of cyclooxygenase 1 and prostacyclin synthase; these enzymes act successively to produce prostacyclin, which inhibits platelet aggregation and vasoconstriction ( 50 ). Røpcke et al also demonstrated that RIPreC reduces arterial thrombus formation and embolization in rats ( 51 ). Several clinical trials are underway to test the safety and efficacy of RIPreC for protecting the brain against anticipated damage ( 52 , 53 ), and its procedural simplicity makes it an excellent candidate for study in future clinical trials.…”

“…The humoral pathway has been most extensively studied. Some studies have identified specific factors, such as stromal cell-derived factor-1 α, interleukin, nitrite, cysteine-rich secretory protein 3, and microRNA-144 as possible candidate transfer factors ( 51 , 79 , 80 ). Ueno et al suggest that RIPreC transiently increases plasma VEGF levels by downregulating miR-762 and miR-3072-5p in CD34-positive bone marrow cells, leading to protection against organ ischemia ( 81 ).…”