Koichiro Aihara

Recombinant thrombomodulin improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat LPS model.

INTRODUCTION Abnormalities in vascular endothelial function play an important role in the development of septic organ dysfunction. The aim of this study was to examine the effect of recombinant thrombomodulin (rTM) on leukocyte-endothelial interaction and subsequent malcirculation in endotoxemia. MATERIALS AND METHODS Wistar rats were administered with either low, medium or high dose of rTM (n=7 each) 2hours after lipopolysaccharide (LPS) infusion. Mesenteric microcirculation after the treatment was observed under the intravital microscopy. In another series (n=5 each), plasma levels of high-mobility group box 1 (HMGB1) levels were measured at 5hours after LPS infusion. RESULTS Microscopic findings revealed suppression in leukocyte adhesion, thrombus formation and endothelial damage with the treatment by rTM. However, high-dose rTM tended to increase the bleeding events. Thus, blood flow was better maintained with medium-dose rTM (P<0.05). The increase in HMGB1 level was significantly suppressed by medium and high-dose rTM (P<0.05, respectively). CONCLUSIONS rTM demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of HMGB1.

Enoxaparin and fondaparinux attenuates endothelial damage in endotoxemic rats.

Background: Prophylactic use of anticoagulants for septic patients in intensive care unit is a standard therapy for the prevention of venous thrombosis. Moreover, recent studies have demonstrated the anti-inflammatory effects of anticoagulants such as Factor Xa inhibitors and heparins. However, there have been no studies to examine the effects of fondaparinux and enoxaparin when applied in a sepsis model. Therefore, we examined the anti-inflammatory effects and bleeding events when these agents are applied in a lipopolysaccharide challenge model. Methods: Wistar rats received lipopolysaccharides followed by a bolus infusion of fondaparinux, enoxaparin, or placebo. Microscopic observation of the mesenteric microcirculation for endothelial damage and measurement of bleeding area after vascular puncture was performed (n = 6 in each group). In another series, blood samples were taken, and blood cell counts, coagulation markers, and organ damage markers were measured (n = 6 in each). Results: Both leukocyte adherence to vascular endothelium and endothelial damage were reduced in fondaparinux and enoxaparin groups. The bleeding area was markedly increased in the fondaparinux group. Coagulation markers were maintained better in the enoxaparin group. Levels of organ damage markers were significantly suppressed in both fondaparinux and enoxaparin groups (p < 0.01, compared with control, each). Conclusions: Fondaparinux and enoxaparin reduce organ dysfunction by decreasing endothelial damage. However, bleeding was more prominent in the fondaparinux group compared with the enoxaparin group at an equipotent dose for anti-Xa activity. Because the setting of this experiment is different from the clinical use, further study is required for the comparison of both pharmaceuticals.

Estimated glomerular filtration rate is an independent predictor for mortality of patients with acute heart failure.

BACKGROUND Heart failure is a major public health problem in developed countries including Japan, therefore it is important to estimate the future risk in patients with heart failure. Recently, it has been reported that chronic kidney disease (CKD) is an independent predictor for mortality in chronic heart failure. However, it is unknown whether CKD is an independent predictor for mortality in acute heart failure. We retrospectively investigated the relationship between estimated glomerular filtration rate (eGFR) on admission for acute heart failure and long-term mortality. METHODS We analyzed 194 patients who were admitted for acute heart failure from January, 2002 to February, 2005. Patients were divided into two groups, high-eGFR group (eGFR <60 ml/min, n=75) and low-eGFR group (eGFR > or =60 ml/min, n=119). eGFR was calculated by equation of MDRD (modification of the diet in renal disease) study. eGFR level <60 ml/min/1.73 m(2) is impaired renal function according to the guidelines of the Japanese Society of Nephrology and of the National Kidney Foundation. Serum B-type natriuretic peptide (BNP) level and left ventricular ejection fraction (LVEF), anemia, age, gender, and etiology of heart failure were also evaluated. Median observation period was 609 days (range: 30-1627). Mean age was 69 years and 138 patients were male. RESULTS Median eGFR on admission was 74.2 ml/min (range: 5.48-238.7), median BNP level was 840 pg/ml (range: 200-4800), and median LVEF was 36% (range: 11-81%). Forty-two percent of patients had eGFR <60 ml/min of eGFR at the time of coronary care unit admission. Patients with low-eGFR had a significantly lower mortality rate by Kaplan-Meier analysis (log rank test, p=0.013). By Coxs proportional-hazard analysis, eGFR was an independent factor for long-term mortality of acute heart failure (p=0.039). CONCLUSIONS Lower eGFR at the time of admission could be an independent predictor for mortality of acute heart failure.

Factor Xa inhibitor attenuates leukocyte adhesion and thrombus formation in an experimental mouse model of the metabolic syndrome.

AIMS In a model of acute inflammation, Factor Xa inhibitors have been reported not only to suppress the coagulation system but also to exert anti-inflammatory effects. However, this has not been experimentally demonstrated in a model of chronic inflammation. Recent studies demonstrated that vascular inflammation in the metabolic syndrome plays major roles in the development of thrombotic diseases. Therefore, we examined the anti-inflammatory effects of fondaparinux, a Factor Xa inhibitor, in a mouse model of the metabolic syndrome, looking at both leukocyte adhesion on the vascular endothelium and thrombus formation. METHODS Following clamping of the mesenteric vein for 20 min in the KK-A(y) mouse, mice were administered by subcutaneous injection either low-dose or high-dose fondaparinux or placebo (n = 10 in each group. Microscopic observation of the intestinal microcirculation was carried out. In another series, blood samples were taken and measured for blood cell counts and organ damage markers (n = 6 in each). RESULTS Both leukocyte adherence and thrombus formation were inhibited by treatment with fondaparinux. Red blood cell and white blood cell counts were maintained better in high-dose group. Levels of alanine aminotransferase (ALT) were significantly reduced in both low-dose and high-dose groups (P < 0.05 and 0.01, compared with control, respectively). CONCLUSIONS Factor Xa inhibitor attenuates leukocyte adhesion and leukocyte-platelet conjugate formation in a mouse model of the metabolic syndrome. These effects appeared to be related to both inhibition of thrombus formation and reduction in markers of organ damage.

Formation of the venous thrombus after venous occlusion in the experimental mouse model of metabolic syndrome

INTRODUCTION The metabolic syndrome is considered to be a risk factor for the venous thromboembolism (VTE) as well as arterial thrombosis. Although obesity, hyperglycemia and dyslipidemia are considered to be important triggering factors, it is difficult to evaluate the relationship between VTE and the metabolic syndrome in a clinical study. Furthermore the mechanism of venous thrombosis initiation still remains elusive. MATERIALS AND METHODS 20 min clamp of superior mesenteric vein was applied to 7 w, 16 w-old KK-A(y) mouse and 16 w-old B6J mouse (n = 6 in each group), after de-clamp, the view of the mesenteric vein and intestinal submucosal venule were observed by the intravital microscopy. RESULTS Massive thrombi formed in the mesenteric vein in 16 w-old KK-A(y) mice, moderate thrombi formation was observed in 7 w-old KK-A(y) mice, while very few thrombi were observed in B6 J mice. The first event in submucosal venule after de-clamp was the adhesion of leukocytes to the endothelium. Subsequently, leukocytes assembled and platelets covered the leukocyte cluster. These leukocyte-platelet aggregates move from the venule to the vein and finally formed a venous thrombus. CONCLUSION Metabolic syndrome is a risk factor for venous thrombosis. Intravital microscopic examination revealed leukocyte and platelet recruitment to the venule in the early stages of venous thrombosis formation.

Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes mellitus

INTRODUCTION Thrombosis is a major complication in diabetes mellitus. Since Factor Xa inhibitors are not only inhibit the coagulation system but also attenuate the leukocyte-endothelial interaction in acute inflammation models, the purpose of this study is to confirm the similar effects of rivaroxaban in a mouse model of type 2 diabetes mellitus. MATERIALS AND METHODS In the treatment groups, either 5 or 10mg/kg of rivaroxaban dissolved in DMSO was orally given to KK-A(y) mice for 7 weeks (n=6 in each group). KK-A(y) mice fed by chow containing DMSO without rivaroxaban for 7 weeks were served for the control group (n=6). Following clamping of the mesenteric vein for 20 minutes, intravital microscopic observation of the intestinal microcirculation and the measurement of bleeding time after the needle puncture were carried-out. In another series, the calculation for blood cell counts and the measurement of blood fluidity using micro channel array flow analyzer (MC-FAN) were performed. RESULTS The initial event in the microvasculature is the leukocyte adhesion on endothelium. Then, the leukocytes make clusters and the platelets are involved in. These leukocyte-platelet conjugates aggregate and form thrombus. The leukocyte adherence and the microthrombus formation was significantly suppressed with the treatment of 10 mg/kg of rivaroxaban compared to the control group (P<0.05). While, the bleeding time was significantly extended with the treatment with 10mg/kg of rivaroxaban (P<0.01). The blood fluidity was maintained best with the treatment of 10 mg/kg rivaroxaban. CONCLUSIONS Rivaroxaban attenuates the leukocyte-platelet-endothelial interaction, which leads to the attenuation of microthrombus formation in a mouse model of diabetes mellitus.

A case of cardiac arrest with ST elevation induced by contrast medium

A 62-year-old man with local recurrence of pancreatic cancer underwent his 17th infusion of contrast medium. He had no history of allergy and had not experienced any side effects from the contrast medium during any of the previous examinations. During infusion, he complained of nausea, followed by a loss of consciousness. He was injected intramuscularly with 0.3 mg adrenalin; however, he temporally went into cardiopulmonary arrest. He was therefore injected with 100 mg hydrocortisone and the continuous infusion of dopamine for shock. His electrocardiogram revealed ST elevation. An urgent cardiac echo evaluation revealed hyperkinetic wall motion. As his blood pressure increased after the initiation of the treatment, the ST elevation started to normalize. After transportation to an intensive care unit, the patient did not show chest pain, ST elevation on cardiograms, or any increase in the levels of cardiac markers. Based on his clinical course, the cause of the patients ST elevation was considered to be coronary vasospasm. Kounis syndrome is the concurrence of acute coronary syndromes with conditions associated with mast cell activation, including allergic or hypersensitivity and anaphylactic or anaphylactoid insults. In cases of coronary vasospasm with shock due to contrast medium, supportive therapy using catecholamine, which has coronary vasodilator activity, and a steroid might be effective to treat the coronary vasospasm. Attention should therefore be paid to the patients complaints, the findings of real-time cardiosonography, electrocardiograms, and the levels of cardiac markers to ensure a correct diagnosis and to achieve a good treatment outcome.

Analysis of non-traumatic truncal back pain in patients who visited an emergency room

To investigate epidemiology of acute non‐traumatic back pain using modern diagnostic methods in patients who visited an emergency room.