Fibrinolytic Response Research Articles

Vasomotor and fibrinolytic responses to kinin receptor agonists in the atherosclerotic human lower limb

Upregulation of vascular B(1) kinin receptor expression has been reported in human atheroma, but its role remains unclear. We examined vasomotor and fibrinolytic responses to selective B(1) and B(2) kinin receptor agonism in the human femoral circulation and correlated responses with femoral arterial plaque load. Femoral arterial cross-sectional area, blood flow and plaque volume were determined using intravascular ultrasound and Doppler during selective arterial infusion of Lys-des-Arg(9)-bradykinin (B(1) agonist), bradykinin (B(2) agonist) and sodium nitroprusside in eleven patients undergoing diagnostic coronary angiography. Net release of tissue plasminogen activator was determined across the femoral vascular bed. Mean femoral arterial plaque load was 8.1 (±0.9)mm(3)/mm of vessel. Bradykinin and sodium nitroprusside caused dose-dependent increases in femoral blood flow (p<0.05 and p<0.005, respectively). Bradykinin caused a dose-dependent increase in net tissue plasminogen activator release (p<0.05), which was augmented by angiotensin-converting enzyme inhibition (p<0.05). There were no correlations between plaque load and bradykinin-mediated vasodilation or tissue plasminogen activator release. Lys-des-Arg(9)-bradykinin had no effect on blood flow or tissue plasminogen activator release. The vasomotor and fibrinolytic actions of bradykinin in the femoral circulation are mediated solely by the B(2) kinin receptor, irrespective of the presence of atheroma. In keeping with previous data, bradykinin-mediated tissue plasminogen activator release was augmented in the presence of angiotensin-converting enzyme inhibition consistent with its putative vascular protective effect.

Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes (LVT) or high tidal volumes (HVT). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with HVT as compared to LVT. In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.

The effects of whole body vibration and exercise on fibrinolysis in men

Whole body vibration (WBV) is a novel modality that has been demonstrated to enhance muscular and cardiovascular functions reported to increase fibrinolytic activity. The purpose of this study was to examine the fibrinolytic response to WBV and exercise in men. Twenty healthy males (23.8±0.9years, 25.6±0.2kgm(-2)) participated in the study. Each subject performed three trials in randomized order separated by 1week: exercise (X), vibration (V) and vibration+exercise (VX). Exercise sessions consisted of 15min of unloaded squatting at a rate of 20 per minute. Vibration sessions were conducted on a WBV platform vibrating for 15min. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) were assessed at baseline and immediately after each condition. The increase in tPA activity was significantly greater in VX (0.87±0.35 to 3.21±1.06IUml(-1)) compared to X (0.71±0.36 to 2.4±1.13IUml(-1)) or V (0.83±0.25 to 1.00±0.37IUml(-1)) conditions, and greater in the X condition compared to the V condition. PAI-1 activity decreased significantly more in the VX (6.54±5.53 to 4.89±4.13IUml(-1)) and X (9.76±8.19 to 7.48±7.11IUml(-1)) conditions compared to the V (5.68±3.53 to 5.84±3.52IUml(-1)) condition. WBV does not augment fibrinolytic activity in healthy men. However, WBV combined with squatting exercise increases fibrinolytic activity more than exercise alone.

Coagulation, fibrinolysis and cytokine responses to intramedullary nailing of the femur: An experimental study in pigs comparing traditional reaming and reaming with a one-step reamer-irrigator-aspirator system

Introduction Operations in trauma patients represent a second insult and the extent of the surgical procedures influences the magnitude of the inflammatory response. Our hypothesis was that a reamer-irrigator-aspirator (RIA) system would cause a lesser inflammatory response than traditional reaming (TR). Materials and methods Coagulation, fibrinolysis and cytokine responses were studied in Norwegian landrace pigs during and after intramedullary nailing (IMN) with two different reaming systems using ELISA and chromogenic peptide substrate assays. The TR ( n = 8) and the RIA ( n = 7) reaming systems were compared to a control group ( n = 7). The animals were followed for 72 h. Arterial, mixed venous and femoral vein blood were withdrawn simultaneously peroperatively and until 2 h after the nail was inserted for demonstration of local, pulmonary and systemic activation of the cascade systems. At 6 h, 24 h, 48 h and 72 h postoperatively arterial blood samples were withdrawn. Results Significantly procedure-related increased levels were found for thrombin–antithrombin (TAT) and tissue plasminogen activator (t-PA) in the TR group and TAT in the RIA group. The local and the pulmonary activation of coagulation and fibrinolysis were more pronounced in the TR than in the RIA group, the difference reached significance for plasminogen activator inhibitor-1 (PAI-1) (arterial blood). The cytokine response, mainly represented by IL-6 increase, was more pronounced in the TR than the RIA group, and was significant for IL-6 in femoral vein blood. The arterial levels of IL-6 exceeded the mixed venous levels indicating an additional pulmonary activation of IL-6. Two animals in the TR group, who died of pulmonary embolism (PE) prior to planned study end point, had a more pronounced response compared to the rest of the TR group. Conclusion A procedure-related coagulation and fibrinolytic response was demonstrated in both reaming groups, with more pronounced response in the TR than in the RIA group. Elevated levels of cytokines were demonstrated related to reaming and nailing, with significantly higher IL-6 levels in the TR than in the RIA group.

Fibrinolytic Responses of the Equine Peritoneum to Abdominal Surgery, Surgical Trauma, and Intraperitoneal Sodium Hyaluronate

Postoperative abdominal adhesions are known to present clinical challenges to the surgeon. Adhesion formation is a balance modulated by the fibrinolytic system. The key components involved are the tissue plasminogen activators (tPAs) and plasminogen activator inhibitors (PAI-1 and PAI-2). Sodium hyaluronate (HA) has been shown to reduce the incidence and severity of adhesions in horses. The objectives of this study were to measure tPA and PAI-1 activity in equine peritoneum and evaluate the effect of 0.4% HA solution on local tPA and PAI-1 activity. An exploratory laparotomy was performed and local serosal trauma was induced by using an established abrasion model. Our study involved two groups: in the first group (n = 6) 0.4% HA was used in all intestinal manipulations, whereas in the second group (n = 6) sterile saline was used. Parietal peritoneum, jejunal seromuscular biopsies at abraded sites (AJ) and nonabraded sites, and peritoneal fluid samples were taken at time 0- and at 30-minute intervals up to 120 minutes. Peritoneum tPA activity was significantly decreased at 60 and 90 minutes. Interestingly, AJ contained significantly higher tPA activity than nonabraded sites at 30-, 60-, 90-, and 120-minute intervals in control horses. The increase in tPA activity with AJ in treated (HA) horses was significantly attenuated as compared with the control (saline). Detectable levels of PAI-1 activity could not be identified in our samples. The results of our study indicate that exploratory celiotomy in horses is associated with a significant decrease in peritoneal tPA activity, and HA significantly decreases the fibrinolytic response of the jejunum to surgical trauma. Further characterization of these responses will hopefully lead to new pharmacologic strategies for adhesion prevention.

The Influence of Acute Resistance Training and Body Composition on Coagulation and Fibrinolytic Activity in Low-Risk Women

This study explored the coagulation and fibrinolytic responses to acute resistance training in young women and aimed to determine the influence of body composition on these variables. Healthy young women aged 23+/-5 yrs participated in the study. Body fat and fat distribution were assessed using DEXA. Each subject performed 6 sets of 10 leg extension repetitions at an intensity associated with 70% of 1-repetition maximum. Markers of coagulation (TAT), fibrinolytic stimulation (tPA) and inhibition (PAI-1) were assessed before and immediately after exercise. tPA activity increased in response to acute resistance exercise (p<0.05), however, there was no change in TAT or PAI-1 activity. Percent body fat was negatively correlated to the tPA response to exercise (r=-0.44), and positively related to PAI-1 at baseline (r=0.47) and post-exercise (r=0.47), and to post-exercise TAT (r=0.44). Android/gynoid fat ratio was negatively related to post-exercise tPA (r=-0.43), positively related to PAI-1 at baseline (r=0.61) and post-exercise (r=0.62) and to post-exercise TAT (r=0.43). These physiological responses suggest women with elevated body fat may be at increased risk of an adverse thrombosis-related event both at rest and during exercise compared to leaner women.

Urokinase Receptor Is Necessary for Bacterial Defense against Pneumonia-Derived Septic Melioidosis by Facilitating Phagocytosis

Urokinase receptor (urokinase-type plasminogen activator receptor [uPAR], CD87), a GPI-anchored protein, is considered to play an important role in inflammation and fibrinolysis. The Gram-negative bacterium Burkholderia pseudomallei is able to survive and replicate within leukocytes and causes melioidosis, an important cause of pneumonia-derived community-acquired sepsis in Southeast Asia. In this study, we investigated the expression and function of uPAR both in patients with septic melioidosis and in a murine model of experimental melioidosis. uPAR mRNA and surface expression was increased in patients with septic melioidosis in/on both peripheral blood monocytes and granulocytes as well as in the pulmonary compartment during experimental pneumonia-derived melioidosis in mice. uPAR-deficient mice intranasally infected with B. pseudomallei showed an enhanced growth and dissemination of B. pseudomallei when compared with wild-type mice, corresponding with increased pulmonary and hepatic inflammation. uPAR knockout mice demonstrated significantly reduced neutrophil migration toward the pulmonary compartment after inoculation with B. pseudomallei. Further in vitro experiments showed that uPAR-deficient macrophages and granulocytes display a markedly impaired phagocytosis of B. pseudomallei. Additional studies showed that uPAR deficiency did not influence hemostatic and fibrinolytic responses during severe melioidosis. These data suggest that uPAR is crucially involved in the host defense against sepsis caused by B. pseudomallei by facilitating the migration of neutrophils toward the primary site of infection and subsequently facilitating the phagocytosis of B. pseudomallei.

Coagulation and fibrinolytic responses at an early phase of trauma: The main issues in the world are reviewed and discussed

外傷急性期の凝固線溶系の変化に関してEducational Initiative on Critical Bleeding in Trauma（EICBT）から新しい病態概念である「Coagulopathy of Trauma」と「Acute Coagulopathy of Trauma-Shock（ACoTS）」が提唱された。しかし，これらの診断基準は存在せず，両者の本態は従来から独立した病態として存在する線溶亢進型DIC（disseminated intra vascular coagulation）に一致する。診断基準がないことが同概念と線溶亢進型DICおよび類似病態との鑑別を不可能としている。これらの理由により「Coagulopathy of Trauma and ACoTS」は，独立した疾患・病態概念ではなく定義不能な臨床状態として位置づけることが可能である。このような曖昧な概念を外傷急性期の凝固線溶系変化の病態生理解明のために使用すべきではない。外傷急性期の凝固線溶系異常は線溶亢進型DICで説明可能であり，線溶亢進型DICは従来どおり正しく線溶亢進型DICと呼称されるべきである。

Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study

IntroductionInfluenza accounts for 5 to 10% of community-acquired pneumonias and is a major cause of mortality. Sterile and bacterial lung injuries are associated with procoagulant and inflammatory derangements in the lungs. Activated protein C (APC) is an anticoagulant with anti-inflammatory properties that exert beneficial effects in models of lung injury. We determined the impact of lethal influenza A (H1N1) infection on systemic and pulmonary coagulation and inflammation, and the effect of recombinant mouse (rm-) APC hereon.MethodsMale C57BL/6 mice were intranasally infected with a lethal dose of a mouse adapted influenza A (H1N1) strain. Treatment with rm-APC (125 μg intraperitoneally every eight hours for a maximum of three days) or vehicle was initiated 24 hours after infection. Mice were euthanized 48 or 96 hours after infection, or observed for up to nine days.ResultsLethal H1N1 influenza resulted in systemic and pulmonary activation of coagulation, as reflected by elevated plasma and lung levels of thrombin-antithrombin complexes and fibrin degradation products. These procoagulant changes were accompanied by inhibition of the fibrinolytic response due to enhanced release of plasminogen activator inhibitor type-1. Rm-APC strongly inhibited coagulation activation in both plasma and lungs, and partially reversed the inhibition of fibrinolysis. Rm-APC temporarily reduced pulmonary viral loads, but did not impact on lung inflammation or survival.ConclusionsLethal influenza induces procoagulant and antifibrinolytic changes in the lung which can be partially prevented by rm-APC treatment.

Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular Tissue-Type Plasminogen Activator Release

Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.

Effects of Atenolol or Losartan on Fibrinolysis and von Willebrand Factor in Hypertensive Patients With Left Ventricular Hypertrophy

To compare the effects of the beta-blocker atenolol with the angiotensin receptor blocker (ARB) losartan on plasma tissue-type plasminogen activator (tPA) activity and mass concentration, plasminogen activator inhibitor-1 (PAI-1) activity, tPA/PAI-1 complex, and von Willebrand factor (VWF). A prespecified, explorative substudy in 22 patients with hypertension and left ventricular hypertrophy (LVH) performed within randomized multicenter, double-blind prospective study. After a median of 36 weeks of treatment, there were significant differences between the treatment groups, atenolol versus losartan, in plasma median levels of tPA mass (11.9 vs 7.3 ng/mL, P = .019), PAI-1 activity (20.7 vs 4.8 IU/mL, P = .030), and tPA/PAI-1 complex (7.1 vs 2.5 ng/mL, P = .015). In patients treated with atenolol, median levels of tPA mass (8.9-11.9 ng/mL, P = .021) and VWF (113.5%-134.3%, P = .021) increased significantly, indicating a change toward a more prothrombotic state. No significant changes occurred in the losartan group. Losartan treatment was associated with preserved fibrinolytic balance compared to a more prothrombotic fibrinolytic and hemostatic state in the atenolol group. These findings suggest different fibrinolytic and hemostatic responses to treatment in hypertensive patients with LVH.

The Peritoneal Fibrinolytic Response to Conventional and Laparoscopic Colonic Surgery

Laparoscopic surgery is considered to induce less peritoneal trauma than conventional surgery. The peritoneal plasmin system is important in the processes of peritoneal healing and adhesion formation. The present study assessed the peritoneal fibrinolytic response to laparoscopic and conventional colonic surgery. Twenty-four patients scheduled for a right colonic resection were enrolled in the trial. Twelve underwent conventional surgery and 12 were operated laparoscopically. Biopsies of the parietal peritoneum were taken at standardized moments during the procedure. Tissue concentrations of tissue-type plasminogen activator (tPA) and its specific activity (tPA-activity), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) were measured, using commercial assays. After mobilization of the colon, peritoneal levels of tPA antigen and activity were significantly higher in the laparoscopic group (p < 0.005) due to a decrease in the conventional group (p < 0.05). At the end of the procedure, the concentrations of tPA antigen and activity significantly (p < 0.05) decreased in the laparoscopic group to levels comparable with the conventional group. Neither uPA antigen nor PAI-1 antigen changed throughout the procedures. Both conventional and laparoscopic surgery inflict a decrease in tPA antigen and its specific activity. Peritoneal hypofibrinolysis initiates more rapidly during conventional, compared to laparoscopic, surgery, but at the conclusion of the surgery, the effect was the same.

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B(2) receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 +/- 5.9 versus 25.6 +/- 20.1 pg/ml, P = 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F(2)-isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B(2) receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.

Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention.

Most people with diabetes die from thrombotic complications superimposed to degenerative arterial vascular lesions, mostly myocardial infarction. Diabetes is a risk factor per se for such complications, but often clusters with dyslipoproteinemia, hypertension and obesity. In NIDDM (Type-II) patients this is referred to as "metabolic syndrome" and often operates on a genetically programmed susceptibility which accelerates the pathogenesis of coronary artery disease in front of a much wider diabetes specific cardiopathy. From a pathophysiological point of view none of these associated risk factors explains the pathogenetic series of events leading to the precipitation of an occlusive thrombus at sites of complicated coronary plaques. In patients with diabetes the coagulation system is switched towards a prethrombotic state, involving increased plasmatic coagulation, diminished fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperreactivity ("diabetic thrombocytopathy"). Some of these factors are associated with an increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also directly linked to the pathogenesis of "atherothrombosis". Altered cardiac remodelling together with adhesion and coagulation mechanisms appears suitable to explain decreased functional performance of infarcted organs, decreased success of acute (reduced fibrinolytic response, reperfusion injury) and longterm intervention strategies (PTCA, CABG) in diabetes. Glucose adjustment alone will not adequately neutralize these complex mechanisms. Particularly in diabetes a multidimensional interventional repertoire is required including antihypertensive, antidyslipoproteinemic and antithrombotic drugs, customized according to the individual patients needs as assessed by early diagnostic measures ("early secondary prevention").

What happens after venous thromboembolism?

Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) with or without symptomatic pulmonary embolus (PE). The incidence of a first episode of VTE is 1.5 per 1000 person-years [1] (J Thromb Haemost, 2007;5:692-9) with a per-person lifetime incidence of 5% [2] (Arch Intern Med 1998;158:585-93). The risk of recurrence after DVT and PE is similar but the pattern of recurrence tends to reflect the initial event, for example recurrence with PE is more common in patients with previous PE [3] (Circulation 2003;107:122-30). At least 50% of patients, who present with symptomatic DVT, have asymptomatic PE and conversely, a majority presenting with symptomatic PE have asymptomatic DVT [3] (Circulation 2003;107:122-30). This suggests that whilst DVT and PE are manifestations of the same pathology, the phenotypic expression of the disease is predetermined. This may be an important consideration for long-term anticoagulant therapy as the risk of fatal PE is the greatest in patients with previous PE [4] (Ann Intern Med 2007;147:766-74). At present, the only factor reported to be associated with the pattern of VTE is the factor V Leiden mutation [5] (Thromb Haemost 1999;81:345-8). This suggests that the kinetics of thrombin generation and the resulting fibrinolytic response may influence clot structure and likelihood of embolization.

Disseminated intravascular coagulation in obstetric disorders and its acute haematological management

As activation of the coagulation pathway is a physiological response to injury, the development of disseminated intravascular coagulation (DIC) is a warning signal to the clinician that the primary pathological disease state is decompensating. In pregnancy, DIC can occur in several settings, which include emergencies such as placental abruption and amniotic fluid embolism as well as complications such as pre-eclampsia. Whilst the acuteness of the event and the proportionality in the coagulant and fibrinolytic responses may vary between these different conditions, a common theme for pregnancy-associated DIC is the pivotal role played by the placenta. Removal of the placenta is the linchpin to treatment in most cases but appropriate blood product support is also key to management. This is necessary because DIC itself can have pathological consequences that translate clinically into a worse prognosis for affected patients. This article will describe how pregnancy-associated DIC can be diagnosed promptly and how treatment should be managed strategically. It also discusses the latest developments in our understanding of haemostatic mechanisms within the placenta and how these may have relevance to new diagnostic approaches as well as novel therapeutic modalities.

Effects Of Kaatsu Training On Haemostasis In Healthy Subjects

The KAATSU training is performed under the reduction of muscle blood flow by a specially-designed belt (KAATSU belt), which induces blood pooling in capacitance vessels by restricting venous return. However, no prior studies have examined the effects of KAATSU training on haemostasis. PURPOSE: We investigated acute effects of KAATSU training on haemostasis including fibrinolytic responses under several conditions. in healthy subjects. METHODS: Two protocols have been performed. (1) 6 healthy men (mean age, 48 ± 5 yr) performed KAATSU (160 mmHg) of both thighs for 15 minutes and then KAASTU training combined with low-intensity leg and foot aerobic exercises for ∼10 minutes in hypobaric chamber, which mimics 8000 feet in airflight. (2) Another 7 men (mean age, 30 ± 4 yr) performed leg press exercises (30 % 1 RM) with and without KAATSU of both thighs 24 h after bed rest. Blood samples were taken at rest, immediately after KAATSU, and exercises with or without KAATSU, and after exercise. For the investigation of blood fibrinolysis, determinations of tissue-type plasminogen activator (tPA) activity or antigen, plasminogen activator inhibitor (PAI)-1 activity or antigen, fibrin degradation product (FDP) and D-dimer were used. Prothrombin time (PT) and platelet counts were also measured. RESULTS: (1) In hypobaric chamber, KAATSU by itself significantly increased tPA activity, while PAI-1 activity was unchanged. Furthermore, immediately after the exercise, tPA activity increased significantly. (2) During the exercises combined with KAATSU 24 h after bed rest, tPA antigen significantly increased, compared with control exercises, but PAI-1 antigen was unchanged. In both cases, KAATSU training did not induce fibrin formation as assessed by fibrin D-dimer and FDP. CONCLUSIONS: This study indicates that potentially favorable changes occur in fibrinolytic factors after KAATSU and KAATSU training in healthy subjects.

Prothrombotic state at hospital discharge increases 1-year mortality in pneumonia and sepsis survivors

Prothrombotic conditions, like myocardial infarction and pulmonary embolism, are more common after respiratory infections, but underlying mechanisms are unclear. We hypothesized that the imbalance between procoagulant and fibrinolytic response during community-acquired pneumonia (CAP) persists at hospital discharge and increases the risk of 1-year mortality.

Thrombomodulin and GFC levels in Legg–Calve–Perthes disease

Legg–Calve–Perthes disease (LCPD) is a self-limited microvascular disorder leading to the occlusion of the femoral blood supply, which results in bone necrosis. Endothelial injury and hemostatic alterations may play a role in the microvascular compromise and decreased blood flow, which occur during the course of LCPD. Global fibrinolytic capacity (GFC) is a novel assay reflecting the overall fibrinolysis response resulting from the dynamic interactions of numerous stimulatory and inhibitory fibrinolytic molecules. Circulating soluble thrombomodulin (TM) reflects endothelial activation and/or injury. It is a cofactor in the clinically important protein C natural anticoagulant system. Beyond the coagulation pathway it is shown to have effects on biological events, especially inflammation. The aim of this study was to determine GFC and TM levels in LCPD patients. The study included 77 children in two groups. Group I consisted of 42 patients with LCPD and Group II (control) comprised 35 healthy children. Median (interquartile ratios) GFC and TM levels were significantly higher in the LCPD patients (Group I) (p<0·0001 and p=0·049, respectively). Circulating high levels of soluble TM may be associated with ongoing endothelial injury or ongoing inflammation during the disease course. Along with increased overall fibrinolytic response, increased TM may be a compensatory reaction to thrombosis. Further investigations are needed to elucidate the endothelial, anticoagulant, and fibrinolytic kinetics associated with the microvascular compromise and self-limiting nature of LCPD.

Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice

Type 2 diabetes mellitus results in a procoagulant and thrombogenic state that could predispose diabetic individuals to develop venous thrombosis. We sought to determine whether diet-induced type 2 diabetes mellitus affects deep venous thrombosis (DVT) resolution in a murine model. C57Bl/6 mice were fed a low-fat or a high-fat diet (n = 10) for 10 weeks, after which DVT was created in the inferior vena cava (IVC) by a combination of low flow and endothelial damage. The IVC and thrombus were harvested at 1 and 2 weeks. Thrombus resolution and neovascularization were investigated through transfemoral angiography (n = 10), thrombus size (n = 4) and weight (n = 10), and nitric oxide synthase 3 immunoquantification (n = 4). Macrophage content was assessed by CD68 immunoreactivity (n = 4). The fibrinolytic system (urokinase plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]) was analyzed by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Total collagen was stained by Sirius red. Matrix metalloproteinases (MMP)-2 and MMP-9 activities were evaluated by zymography and their expressions by Western immunoblotting (n = 6) and immunohistochemistry (n = 4). Diabetic mice had significantly larger and heavier thrombi at 1 and 2 weeks (P < .05), threefold less neovascularization (P < .05), and 35-fold increase in macrophage content (P < .01), than control mice 2 weeks after surgery. IVC recanalization was documented in 90% of 2-week control mice and in 10% of 2-week diabetic mice (P < .01). Increased vein wall collagen and less uPA and more PAI-1 expressions with a decreased uPA/PAI-1 ratio (31%, P < .01) were documented at 2 weeks in diabetic mice. MMP-2 and MMP-9 activities and expressions were significantly increased in diabetic mice at 1 and 2 weeks (P < .05) compared with control mice. Diet-induced type 2 diabetes may impair DVT resolution through altered inflammatory, fibrinolytic, and MMP responses.