Plasminogen Activity Research Articles

Hemostatic changes in gestational diabetes mellitus

The purpose was to characterize the hemostatic changes in women with gestational diabetes mellitus (GDM). In this case–control study, 50 women with newly diagnosed GDM at 24–28 weeks of pregnancy and 41 normal pregnant women, matched for age, body mass index, and gestational age, were enrolled. Anthropometric, metabolic patterns, coagulation parameters, and plasminogen were measured in each subject. Plasma fibrinogen levels, plasminogen, and von Willebrand factor (vWF) activities were significantly higher in patients with GDM as compared to normal pregnant women (p < 0.001, p < 0.001, and p < 0.05, respectively). Although protein S was significantly elevated in diabetic group (p < 0.05), free protein S was similar in both groups. Coagulation factors VIII and IXa were significantly higher in patients with GDM (p < 0.001 and p < 0.01, respectively). In the group with GDM, factor VIII was positively correlated with HbA1c (r = 0.192, p < 0.001). A weak but significant negative correlation was observed between protein S and fasting glucose (r =−0.006, p < 0.05). GDM potentiates the alteration in coagulation and fibrinolysis during normal pregnancy. The question of whether the hemostatic balance is unchanged or shifts toward a hypercoagulable status remains unanswered.

Targeted Inhibition of PAI-1 Activity Impairs Epithelial Migration and Wound Closure Following Cutaneous Injury.

Objective: Aberrant plasminogen activator inhibitor-1 (PAI-1) expression and activity have been implicated in bleeding disorders, multiorgan fibrosis, and wound healing anomalies. This study details the physiological consequences of targeted PAI-1 functional inhibition on cutaneous injury repair. Approach: Dorsal skin wounds from FVB/NJ mice, created with a 4 mm biopsy punch, were treated topically with the small-molecule PAI-1 antagonist tiplaxtinin (or vehicle control) for 5 days and then analyzed for markers of wound repair. Results: Compared to controls, tiplaxtinin-treated wounds displayed dramatic decreases in wound closure and re-epithelialization. PAI-1 immunoreactivity was evident at the migratory front in all injury sites indicating these effects were due to PAI-1 functional blockade and not PAI-1 expression changes. Stimulated HaCaT keratinocyte migration in response to recombinant PAI-1 in vitro was similarly attenuated by tiplaxtinin. While tiplaxtinin had no effect on keratinocyte proliferation, cell cycle progression, or apoptosis, it effectively reduced collagen deposition, the number of Ki-67+ fibroblasts, and incidence of differentiated myofibroblasts (i.e., smooth muscle α-actin immunoreactive cells), but not fibroblast apoptosis. Innovation: The role for PAI-1 in hemostasis and fibrinolysis is established; involvement of PAI-1 in cutaneous wound healing, however, remains unclear. This study tests the effect of a small-molecule PAI-1 inhibitor in a murine model of skin wound repair. Conclusion: Loss of PAI-1 activity significantly impaired wound closure. Re-epithelialization and fibroblast recruitment/differentiation were both reduced in tiplaxtinin-treated mice. Therapies directed at manipulation of PAI-1 expression and/or activity may have applicability as a treatment option for chronic wounds and scarring disorders.

Effect of Three Dimensional Culture of Porcine Endometrial Cells on Their Plasminogen Activity and Pre-implantation Embryo Development after Co-culture

Effect of Three Dimensional Culture of Porcine Endometrial Cells on Their Plasminogen Activity and Pre-implantation Embryo Development after Co-culture

Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients

IntroductionClot buster tissue plasminogen activator (tPA) and its end-product plasmin play a well-defined role in neurochemistry. They mediate a number of events that culminate in tolerance against excitotoxicity, hippocampal neurogenesis, synaptic remodeling, neuronal plasticity, cognitive and emotional processing. Abnormalities in these processes have been implicated in schizophrenia pathogenesis. MethodsLaboratory markers of low activity of tPA/plasmin were analyzed in 70 schizophrenia adults (DSM-IV), and 98 age-matched controls, consecutively selected at university hospitals. ResultsAll but two patients had positive markers (1–6, mean 2.1). Twenty-nine patients and 11 controls had hyperinsulinemia (44% vs. 11%) and 20 patients and 11 controls had hypertriglyceridemia (29% vs. 11%). Both insulin and triglycerides stimulate production of plasminogen activator inhibitor (PAI)-1, a major tPA inhibitor. Nineteen patients and six controls had hyperhomocysteinemia (27% vs. 6%), a condition that impairs tPA catalytic activity. Fifteen patients (22%) but no controls had free-protein S deficiency, a condition that reduces PAI-1 inhibition. Twenty-one patients (30%) but no controls had 1–3 antiphospholipid antibodies in medium or/high levels. Such antibodies are able to inhibit tPA/plasmin activity. Both PAI-1 polymorphism 4G/5G and heterozygous prothrombin G20210A were more prevalent in patients (60% vs. 48% and 2% vs. 1%, respectively), but difference lacked significance. PAI-1 polymorphism was synergistic with hyperinsulinemia. Protein C deficiency was not detected in patients or controls. ConclusionWe have found a high prevalence of markers of low tPA/plasmin activity in a sample of schizophrenia patients. Our findings should be validated in large studies, preferably in medication-naïve patients.

Thermoresponsive copolymer decorated surface enables controlling the adsorption of a target protein in plasma.

The control of protein/surface interactions by external stimuli is often required in bioapplications such as bioseparation and biosensors. Although regulation of protein adsorption has been achieved on the surfaces modified with stimuli-responsive polymers, controlled protein adsorption is still challenging for a target protein in a multiprotein system. The present study developed a concept of surface design for the controlled adsorption of a specific protein from plasma by combining a thermoresponsive polymer with an affinity ligand on the surface. In this regard, a polyurethane (PU) surface was modified with the copolymer of N-isopropylacrylamide (NIPAAm) and a ε-lysine-containing monomer (LysMA). ε-Lysine is a specific ligand for plasminogen that was used as the model "target protein" in this study. The PU-P(NIPAAm-co-Lys) surfaces exhibited distinct thermoresponsivity of plasminogen adsorption from plasma with a larger quantity adsorbed at 37 °C than at 23 °C. By contrast, the surfaces showed a low level of adsorption for other plasma proteins at both temperatures. In addition, plasminogen adsorbed on a PU-P(NIPAAm-co-Lys) surface could be partly desorbed by lowering the temperature, and the activity of plasminogen adsorbed was well preserved. We believe that the concept developed in this study can be extended to other proteins by combining PNIPAAm and specific ligands with affinities for the proteins of interest.

Higher dose of warfarin for patients with pulmonary embolism complicated by obstructive sleep apnea hypopnea syndrome

BackgroundThe concomitant prevalence of obstructive sleep apnea hypopnea syndrome (OSAHS) and pulmonary embolism (PE) is strikingly high, and therefore we studied the patients with PE to determine whether those who had OSHAS required greater warfarin doses to achieve a therapeutic international normalized ratio (INR). MethodsBy using computer tomographic pulmonary angiography or pulmonary angiography, we identified and recruited 97 patients with PE and all underwent polysomnography. Warfarin was initiated at a dose of 3 mg/day and modified to adjust the INR to the range of 2.0–3.0. ResultsOSAHS patients (n = 32) required a significantly higher dose of warfarin than their non-OSAHS counterparts (5.01 mg vs 3.61 mg, P < .001). This difference still existed between the two groups after adjusting for covariates (achieved INR value and weight). Logistic analysis suggested that OSAHS was an independent risk factor for high dose warfarin (OR 5.715, P < .001). On admission, OSAHS patients had a lower mean value of INR and prothrombin time but higher plasminogen (PLG) activity compared to non-OSAHS patients. Other coagulation indices were not significantly different between the two groups. Except for the PLG activity (r = .273, P = .026), the correlation between the warfarin dose and the baseline coagulating indices wasn't significant. ConclusionsOur findings indicate that factors associated with OSAHS, such as hypercoagulation, may explain the need for higher doses of warfarin in treating patients with PE.

Indicators of activation of plasminogen and growth factors in nevus and skin melanoma

Skin melanoma is believed to arise from the malignant development of congenital or acquired pigmented nevi under the action of various causative agents. A study of samples of skin melanoma tissues, as well as pigmented nevus tissues that were obtained from patients of both sexes, was carried out using enzymelinked immunosorbent assay. The study included a comparative analysis of activities of plasmin and plasminogen, as well as the activities and concentrations of urokinase type plasminogen activator, tissue-type plasminogen activator, and an inhibitor of plasminogen activator, as well as the levels of a number of growth factors, including vascular endothelial growth factor and its receptor, epidermal growth factor and its receptor, transforming growth factor, fibroblast growth factor, and finally insulin-like growth factors 1 and 2. The data underpin the possibility of malignant transformation of skin nevi and indicate provisional mechanisms of tumorigenesis. These results are useful for the development of preventive and risk evaluation methods for neoplastic transformation.

Interaction of surface molecules on Cryptococcus neoformans with plasminogen

Microbial pathogens are known to express molecules that interact with host proteins, leading to invasion and colonization. For example, some pathogenic microorganisms express proteins that bind to and enhance the activity of plasminogen. In this way, pathogens utilize the host fibrinolytic system to promote invasion. We found that triosephosphate isomerase (TPI), a glycolytic enzyme produced by Staphylococcus aureus, bound to mannooligosaccharides from the pathogenic capsulated fungus Cryptococcus neoformans and human plasminogen, suggesting that TPI is a moonlighting protein. Several C. neoformans surface proteins are thought to be plasminogen-binding proteins. Here, we examined the ability of surface polymers (including polysaccharides) to bind plasminogen. Heat-killed C. neoformans cells transformed plasminogen into plasmin in a dose-dependent manner in the presence of tissue plasminogen activator. Soluble polysaccharides were found to bind plasminogen based on surface plasmon resonance (SPR) analysis. Neutral polysaccharides fractionated using DEAE column chromatography bound and activated plasminogen. However, the fraction containing glucuronoxylomannan (the primary component of the capsule) did not activate plasminogen. In addition, binding between glucuronoxylomannan and plasminogen was weak. Components of the neutral polysaccharides were identified as mannose, galactose, glucose and xylose. In conclusion, neutral polysaccharides that may affect fibrinolysis were detected on the surface of C. neoformans.

Lp(a)/apo(a) Modulate MMP-9 Activation and Neutrophil Cytokines in Vivo in Inflammation to Regulate Leukocyte Recruitment

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular diseases, but the mechanism is unclear. The pathogenic risk of Lp(a) is associated with elevated plasma concentration, small isoforms of apolipoprotein [apo(a)], the unique apolipoprotein of Lp(a), and a mimic of plasminogen. Inflammation is associated with both the initiation and recovery of cardiovascular diseases, and plasminogen plays an important role in leukocyte recruitment. Because Lp(a)/apo(a) is expressed only in primates, transgenic mice were generated, apo(a)tg and Lp(a)tg mice, to determine whether Lp(a)/apo(a) modifies plasminogen-dependent leukocyte recruitment or whether apo(a) has an independent role in vivo. Plasminogen activation was markedly reduced in apo(a)tg and Lp(a)tg mice in both peritonitis and vascular injury inflammatory models, and was sufficient to reduce matrix metalloproteinase-9 activation and macrophage recruitment. Furthermore, neutrophil recruitment and the neutrophil cytokines, CXCL1/CXCL2, were suppressed in apo(a)tg mice in the abdominal aortic aneurysm model. Reconstitution of CXCL1 or CXCL2 restored neutrophil recruitment in apo(a)tg mice. Apo(a) in the plasminogen-deficient background and Lp(a)tg mice were resistant to inhibition of macrophage recruitment that was associated with an increased accumulation of apo(a) in the intimal layer of the vessel wall. These data indicate that, in inflammation, Lp(a)/apo(a) suppresses neutrophil recruitment by plasminogen-independent cytokine inhibition, and Lp(a)/apo(a) inhibits plasminogen activation and regulates matrix metalloproteinase-9 activation and macrophage recruitment.

Intravitreal Functional Plasminogen in Eyes with Branch Retinal Vein Occlusion

Purpose: To evaluate whether intravitreal functional plasminogen is elevated in eyes with branch retinal vein occlusion (BRVO) and to discover whether intravitreal plasminogen activities are correlated with the extent of blood-retina barrier (BRB) breakdown. Methods: Our study is a prospective case series of 20 consecutive patients with BRVO and 10 consecutive patients serving as controls. Vitreous taps were extracted from the central vitreous body and plasminogen was functionally determined in an innovative, ultrasensitive p-nitroanilide reaction after activation with streptokinase (100% of normal, %N = functional plasminogen in pooled normal citrated plasma). Intravitreal VEGF levels were assayed to estimate BRB breakdown. Results: Intravitreal functional plasminogen was detected in all analyzed samples (n = 30) and mean (±SD) plasminogen activities were found to be 0.97 ± 1.06%N (range: 0.03-3.9%N). Patients suffering from BRVO exhibited significantly higher intravitreal plasminogen (1.35 ± 1.11%N) in comparison with controls (0.20 ± 0.21%N, p < 0.001). Intravitreal VEGF concentrations in the BRVO group (576 ± 547 pg/ml) were significantly higher than these in controls (111 ± 120 pg/ml, p = 0.003). There was a significant correlation between intravitreal functional plasminogen and intravitreal VEGF levels (r = 0.519, p = 0.003). Conclusions: Intravitreal functional plasminogen is significantly elevated in eyes suffering from BRVO and correlates with the extent of BRB breakdown. The induction of posterior vitreous detachment by using intravitreally administered recombinant tissue plasminogen activator (enzymatic vitreolysis) should be explored in further investigations.

Routine tests of haemostasis and low-oestrogen oral contraceptives: what to expect?

Frequent requests from gynaecologists for testing of haemostatic parameters in women using hormonal contraception in order to predict development of thromboembolic disease, along with advancement of testing quality and accuracy, created the need to assess and compare the overall effect of oral contraceptives on today's routine haemostatic tests. This 6-month prospective study included 195 women, first time users of oral contraceptives or with at least a 3-month pause before their entry in the study. Haemostatic changes were assessed by the following tests performed at three study time-points: at baseline, after three and after six months of taking oral contraceptives: prothrombin time, activated partial thromboplastin time, fibrinogen, resistance to activated protein C ratio, protein C activity, protein S activity, FVIII activity, antithrombin activity, plasminogen activity, alpha2-antiplasmin activity, inhibitor of plasminogen activator type 1 (PAI-1), and D-dimers. In addition, study subjects underwent genetic testing for FV Leiden mutation, FII G20210A mutation, and PAI-1 4G/5G polymorphism. Significant changes were found in all haemostatic variables except for FVIII activity. With in-depth analysis, we showed that PAI-1 concentration decreased only in subjects with PAI-1 4G/5G genotype. None of the subjects developed venous thromboembolic disease during the study. As most changes were within reference ranges, routine laboratory testing still does not appear to be recommendable in women without a known risk of thromboembolic disease.

Plasminogen Activator Inhibitor-1 Levels and Activity Decrease After Intervention in Patients with Critical Limb Ischaemia

Patients with peripheral arterial occlusive disease (PAOD), in particular critical limb ischaemia (CLI), carry a high risk of thrombotic events. We hypothesised that patients undergoing conservative, endovascular, or open surgical treatment for CLI have increased levels of plasminogen activator inhibitor-1 (PAI-1), leading to a prothrombotic state. The objective was to determine levels of PAI-1 in patients with acute or chronic PAOD/CLI. Thirty-two patients with a median age of 74 (49-90) years were included. Three underwent thrombolysis for acute limb-threatening ischaemia. Twenty-six patients with chronic ischaemia received endovascular (n = 20) or open (n = 6) surgical treatment. Three were treated conservatively. Biomarkers and ankle brachial index (ABI) were measured before and up to 1 month after intervention. Patency was studied with repeated duplex ultrasound. Ankle pressure and ABI improved after intervention (p < .001). C-reactive protein (CRP) increased from a median of 7.90 mg/L at baseline to 31.5 on day 1 (p < .001), 28.0 on day 6 (p < .001), and returned to baseline levels on day 30. PAI-1 antigen and activity decreased from day 6 and onwards post-intervention compared with baseline (p < .05). A great individual variability in PAI-1 antigen and activity was observed. Although most actively treated patients had normal PAI-1 activity, 11/29 (38%) were above that level of normality at baseline, 10/24 (42%) on day 1, 3/23 (13%) on day 6, and 5/27 (19%) on day 30 after intervention. Endovascular and open surgical treatment resulted in improved ankle pressure and ABI. The intervention was followed by a transient increase in CRP and a sustained reduction in PAI-1 levels and activity.

Using certain indices of fibrinolytic system for forecasting the efficiency of neoajuvant chemotherapy in ovarian cancer.

e22022 Background: Using cell markers that characterize biological properties of a tumor, the relevance of treatment used can be determined for each patient, further ways of surveillance of the patients can be selected, and individual forecasts of the illness can be made. Methods: After 1 course of neoajuvant chemoterapy according to the scheme CAP, in the malign tumor tissue of 21 patients (T3a-c N0-1M0-1), the activity of plasminogen and plasmin was determined by ELISA. Then the ratio K of plasminogen (PG) and plasmin (P) was calculated. As a blank, tumor tissue of 18 patients having ovarian cancer without chemotherapy administered has been studied. On all patients, operations in full or cytoreductive surgery were performed. Results: With efficient treatment, ratio K increased (К=1,4±0,2) relative to indices in patients without neoajuvant chemotherapy (К=0,3±0,17), while it remained the same (К=0,2±0,09) or decreased relative to initial data if there was no clinical effect, which is confirmed by further development of ovarian cancer. Conclusions: Thus, determining of plasminogen and plasmin – fibrinolytic system indices – in the tumor tissue and calculating of their ratio allows detecting the patients who have effect from treatment and good forecast and ones without effect, having bad forecast, who need aggressive ajuvant treatment. It also allows determining individual sensitivity or resistance of malign tumors in patients to certain regimens of chemotherapy. At the same time, there is an opportunity to objectify the results of specific therapy.

Intracameral concentrations of the fibrinolytic system components in patients with age-related macular degeneration

To detect the intracameral concentrations and activities of plasminogen and other components of the fibrinolytic system, and to investigate whether those concentrations and activities are higher in patients with age-related macular degeneration (AMD) in comparison to healthy controls. Prospective case series of 93 patients scheduled for standard phacoemulsification. Mean plasminogen activity in patients with non-exsudative AMD (n = 24) revealed to be 0.06%N, in patients with exudative AMD (n = 7) 0.03%N and in healthy controls (n = 43) 0.02%N (p = 0.38, ANOVA). Plasminogen activator inhibitor I (PAI-1) was detected in neither group. Alpha2-antiplasmin activity was 1.61 U/ml in the non-exudative AMD group (n = 27), 0 U/ml in the exudative AMD group (n = 7) and 0.54 U/ml in the control group (n = 48) (p = 0.1, ANOVA). Concentrations of plasmin-a2-antiplasmin complex (PAP) were detected at levels of 17.91 ng/ml in the non-exudative AMD group (n = 11), of 16.6 ng/ml in the exudative AMD group (n = 5), and of 17.43 ng/ml in the control group (n = 14) (p = 0.92, ANOVA). Plasminogen is present with a very low activity in aqueous humor. There are no significant differences in aqueous humor concentrations or activities of plasminogen and other components of the fibrinolytic system between patients with non-exudative AMD, exudative AMD, and healthy controls. Further studies should investigate vitreous samples instead of aqueous humor samples. A careful and accurate workup of obtained intraocular fluids is needed to detect the low concentrations and activities of the parameters analyzed.

Вплив піоглітазону на гемостаз та протеоліз у хворих на гіпертонічну хворобу в поєднанні з цукровим діабетом другого типу

The authors have examined 30 patients with essential hypertension combined with diabetes mellitus of type 2 in the dynamics of treating with a combination of antihypertensive agents (S-amlodipine and lisinopril) with metformin or pioglitazon. It has been established that treating with antihypertensive drugs with metformin and pioglitazon is accompanied with a significant decrease of the fibrinogen level, an elevated activity of antitrhombin III and Hagemann’s dependent fibrinolysis, an increase of the potential activity of plasminogen (in the subgroup of metformin), a decrease of the indices of the lysis of low- and high-molecular proteins without changes of the blood collagenolytic activity.

The influence of pioglitazon on hemostasis and proteolysis in patients with essential hypertension combined with diabetes mellitus of type 2

The authors have examined 30 patients with essential hypertension combined with diabetes mellitus of type 2 in the dynamics of treating with a combination of antihypertensive agents (S-amlodipine and lisinopril) with metformin or pioglitazon. It has been established that treating with antihypertensive drugs with metformin and pioglitazon is accompanied with a significant decrease of the fibrinogen level, an elevated activity of antitrhombin III and Hagemann’s dependent fibrinolysis, an increase of the potential activity of plasminogen (in the subgroup of metformin), a decrease of the indices of the lysis of low- and high-molecular proteins without changes of the blood collagenolytic activity.

Acute CO Poisoning is Associated with Impaired Fibrinolysis and Increased Thrombin Generation

Carbon monoxide (CO) poisoning is a leading cause of unintentional poisoning deaths in many countries. In ex vivo studies, CO released from carbon monoxide-releasing molecules has been shown to attenuate fibrinolysis via increased alpha-2-antiplasmin activity. Hypofibrinolysis is associated with coronary ischaemia, which is also commonly observed in CO poisoning. We examined fibrin clot properties in acutely poisoned CO patients. Ex vivo plasma fibrin clot permeability, turbidimetry and efficiency of fibrinolysis were investigated in 48 patients and controls matched for age and sex. CO-poisoned patients had 11.6% longer clot lysis time than the controls (p < 0.0001). No intergroup differences in clot permeability or turbidimetric variables were observed. Plasma tissue-type plasminogen antigen (tPA), plasminogen activator inhibitor-1 (PAI-1) antigen and activity and F1.2 prothrombin fragments were higher in the patients than in the controls (all p < 0.0001). Plasma tPA activity was lower in the CO-poisoned group. Multiple linear regression showed that a thrombin generation marker, F1.2, is the strongest predictor of clot lysis time, followed by PAI-1 activity and carboxyhaemoglobin levels. In conclusion, this report is the first to demonstrate that acute CO poisoning in human beings is linked to increased thrombin generation and impaired fibrinolysis, which might contribute to ischaemic complications.

Short communication: Supplementing with vitamin E may alter the fibrinolytic capacity of cattle

Vitamin E supplementation has been reported to decrease the incidence of cystic ovarian disease (COD) and retained placenta (RP) in cattle however the mechanism of action is not known. In humans, vitamin E supplementation twofold the daily requirements decreases plasma plasminogen activator inhibitor-1 (PAI-1) activity. As proteolysis may be involved in both COD and RP, vitamin E may be reducing these disorders in cattle through its effects on PAI-1. To evaluate the effects of vitamin E on plasma PAI-1 activity in cattle, six non-lactating beef cows (n = 3 per treatment) were injected with 0 (Control) or 2750 IU of vitamin E (Vitamin E) IM once every four days for 24 days (Day 0 = first day of treatment). Blood samples were collected every two days for 28 days starting on Day 0 and plasma PAI-1 and tissue-type plasminogen activator (tPA) concentrations and activities were determined. No differences (P > 0.05) were observed due to vitamin E supplementation in plasma PAI-1 and tPA concentrations and activities or concentrations and activities adjusted relative to the Day 0 value for each cow. Day of treatment was a significant effect in all tPA measurements. The ratio of adjusted PAI-1 to tPA concentrations did not differ (P > 0.05) due to vitamin E supplementation however the ratio of PAI-1 to tPA activity tended to be greater (P = 0.097) in Control compared to Vitamin E cows (1.0 ± 0.1 and 0.7 ± 0.1, respectively). These data suggest vitamin E supplementation may contribute to the reduced incidence of COD and RP in cattle by shifting the ratio of plasma PAI-1 to tPA activity to a state favoring proteolysis.

A Case of Acute Pulmonary Embolism Associated with Dysplasminogenemia

The incidence of pulmonary embolism (PE) rises markedly with age, and only a few cases have been reported in younger adults. Thrombophilia has been reported as one of the predisposing factors for PE in younger adults. Here we report an extraordinary case of PE complicated with dysplasminogenemia, a rare genetic disorder resulting in hypercoagulability, in a young male. An 18-yr-old male visited an emergency room in the United States complaining chest discomfort. He was diagnosed as PE with deep vein thrombosis without apparent risk factors. Anticoagulation therapy with warfarin had been initiated and discontinued after 6 months of treatment. After returning to Korea he was tested for thrombophilia which revealed decreased activity of plasminogen and subsequent analysis of PLG gene showed heterozygous Ala620Thr mutation. He was diagnosed with PE complicated with dysplasminogenemia. Life-long anticoagulation therapy was initiated. He is currently under follow-up without clinical events for 2 yr.

Early Insulin Glycemic Control Combined With tPA Thrombolysis Reduces Acute Brain Tissue Damages in a Focal Embolic Stroke Model of Diabetic Rats

Therapeutic effects of early insulin glycemic control for poststroke hyperglycemia in combination with tissue-type plasminogen activator (tPA) thrombolytic therapy have not yet been studied but are of great clinical interest. In this study, we tested the effects of insulin plus tPA combination in a model of focal embolic stroke in Type I diabetic rats. Streptozotocin was used to produce Type I diabetes in male Wistar rats for 6 weeks and then embolic focal strokes were induced. All rats were treated with insulin or saline at 1 hour followed by tPA or saline at 1.5 hour after stroke. Mortality, infarction, hemispheric swelling, hemorrhagic transformation, and perfusion defects were examined at 24 hours after stroke. Total plasma plasminogen activator inhibitor-1 antigen and activity levels were measured before stroke and 1.5, 3, and 6 hours after stroke by ELISA. Early insulin glycemic control alone or tPA thrombolysis alone had no significant effects on ischemic infarction. However, early insulin glycemic control combined with tPA significantly reduced brain infarction and swelling, ameliorated tPA-associated hemorrhagic transformation, and improved plasma perfusion at 24 hours after stroke. We also found that the combination significantly decreased plasma plasminogen activator inhibitor-1 antigen level at 6 hours and plasminogen activator inhibitor-1 activity at 1.5 and 6 hours after stroke. Early insulin glycemic control may be beneficial in combination with tPA thrombolysis for ischemic stroke with diabetes mellitus or poststroke hyperglycemia.