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Biomedical subjects

R Lassila

Publications and source records attributed to R Lassila.

At least 19 recordsLinked to original sources
PubMed2003

Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis.

BACKGROUND: Prior studies have suggested a central role for cellular adhesion molecules (CAMs) in the pathophysiology and symptoms of atherosclerotic carotid plaques (CPs). OBJECTIVE: This study examined the role of CAMs in symptom generation in patients with advanced carotid artery disease. METHODS: Ninety-two consecutive patients underwent carotid endarterectomy, six for both sides (54 symptomatic and 41 asymptomatic CPs). Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin were immunostained in fresh-frozen CP specimens and examined semiquantitatively in the endothelium and intima-media. Plasma concentrations of soluble ICAM-1 and sVCAM-1 were analyzed by ELISA. RESULTS: Endothelial expression of ICAM-1, VCAM-1, P-selectin, and E-selectin did not differ between symptomatic and asymptomatic CPs, but endothelial ICAM-1 was associated with serum sensitized C-reactive protein levels (p = 0.026). However, there was less ICAM-1 expression in the intima-media of the symptomatic CPs (p = 0.022), and there was a similar, but nonsignificant tendency for VCAM-1. Soluble ICAM-1 and soluble VCAM-1 were not associated with the symptom status. CONCLUSIONS: In contrast to earlier studies, it was found that symptomatic carotid disease is not associated with increased expression of adhesion molecules in the endothelium of advanced carotid plaques or in circulation. Rather, there was less expression of adhesion molecules in the intima-media of symptomatic carotid plaques.

Aged↗
PubMed2003

Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects.

OBJECTIVE: Platelet aggregation responses to acetylsalicylic acid (ASA) show considerable interindividual variation, the causes of which are largely unknown. We determined whether variation in insulin action is associated with that of ASA on platelets. SUBJECTS: In all, 10 nonobese (age 50+/-3 y, BMI 25+/-1 kg/m(2)) and 11 obese (age 52+/-2 y, BMI 32+/-1 kg/m(2)) subjects. MEASUREMENTS: Insulin sensitivity of glucose uptake was determined by the euglycemic insulin clamp technique. Platelet aggregation responses to four doses of arachidonic acid (AA) and adenosine diphosphate (ADP) were assessed in platelet-rich plasma before and 1 h after ingestion of 50 mg ASA using Born's turbidometric aggregometer. RESULTS: Whole-body insulin sensitivity (M-value 0-180 min) was 36% lower in the obese (4.5+/-0.6) than the nonobese (7.1+/-0.6 mg/kg min, P<0.01) group. Before ASA, all doses of AA induced complete aggregation. After ASA ingestion, ASA inhibited maximal aggregation more in the nonobese than the obese group at AA concentrations of 0.75, 1 and 1.5 mmol/l (P=0.016 for ANOVA). ADP-induced aggregation at high doses (2 and 3 micromol/l) was also less inhibited in the obese group. In vivo insulin sensitivity (r=-0.68, P<0.001 for 1 mmol/l AA) and BMI (r=0.58, P<0.01 for 1 mmol/l AA) were closely correlated with residual aggregation after ASA administration. CONCLUSION: These data demonstrate that obese insulin-resistant subjects have a blunted response to platelet-inhibitory effect of ASA. If this blunted effect is of a single dose of ASA preserved in continuous use, it could contribute to the increased risk of atherothrombosis in insulin-resistant individuals.

Adenosine Diphosphate↗
PubMed2003

Abciximab inhibits procoagulant activity but not the release reaction upon collagen- or clot-adherent platelets.

In addition to inhibiting platelet (plt) aggregation abciximab, a glycoprotein (GP) IIb/IIIa antagonist, reduces coagulation in blood or platelet-rich plasma. We assessed the effects of abciximab (10 micro g mL(-1)) on adhesion-dependent procoagulant activity (PCA) of plt upon: (i) collagen to model initial adhesion; or (ii) plasma clot or fibrin to model a preformed thrombus with retained thrombin activity. In a two-stage assay gel-filtered plt (GFP) first adhered on collagen, plasma clot, or fibrin, and plt activation was traced with platelet factor 4 (PF 4) release. Second, PCA was measured on adherent plt (i) by soluble prothrombin fragments (F1 + 2); and (ii) chromogenically by adding defibrinated plasma and thromboplastin. Abciximab inhibited aggregation upon collagen-adherent plt both in the absence and presence of plasma. In contrast, without plasma abciximab enhanced plt deposition to fibrin surfaces depending on thrombin generation and fibrin polymerization. However, abciximab reduced PCA and generation of F1 + 2 on adherent plt surface-independently by 35%, whereas PF 4 release persisted. Also, a GP Ib inhibitor, mAb SZ2, attenuated PCA by 40% alone, and by 65% together with abciximab, leaving 35% of PCA unaltered. Abciximab decreased generation of new thrombin on both collagen- and clot-adherent plt. However, abciximab did not inhibit alpha-granule release, suggesting distinct pathways for PCA and release reaction. Deposition of isolated plt on clots in the presence of abciximab was dependent on thrombin and polymerizing plt-derived fibrin(ogen). Due to local consumption of natural anticoagulants adjacent to a preformed thrombus the antithrombotic effect of abciximab benefits from additional inhibition of thrombin.

Abciximab↗
PubMed2001

Epinephrine--via activation of p38-MAPK--abolishes the effect of aspirin on platelet deposition to collagen.

The mechanism by which epinephrine enhances experimental thrombosis in the presence of aspirin is poorly understood. In this study, we set to explore, in aspirinised platelet-rich plasma (PRP), the effect of epinephrine (100 nmol/l) on platelet deposition to immobilised collagen and the subsequent involvement of several intracellular pathways. Under these experimental conditions, which allow platelet aggregation on top of the collagen-adherent platelets, epinephrine increased platelet deposition by 55-86%. This enhancement could be specifically prohibited by the alpha(2A)-adrenoceptor antagonist, atipamezole, the p38 mitogen-activated protein kinase (p38MAPK) inhibitor SB203580, and the cytosolic phospholipase A(2) (cPLA(2)) inhibitor, mepacrine. The effect of epinephrine coincided with increased phosphorylation of p38MAPK and cPLA(2) and with arachidonic acid (AA) release from platelet membrane. We conclude that epinephrine enhanced platelet deposition on collagen in aspirinised PRP via a mechanism dependent on both free AA in platelet cytosol (released by cPLA(2)) and p38MAPK.

Adult↗
PubMed2001

Variability in platelet responses to collagen--comparison between whole blood perfusions, traditional platelet function tests and PFA-100.

The purpose of this study was to determine if the results obtained in platelet function tests and whole blood perfusions are associated with those in platelet function analyser (PFA)-100. We used collagen type I monomers and fibrils to analyse the distinct roles of glycoprotein (GP) Ia/IIa and other collagen receptors in flowing blood under a high shear rate (1600/s) and in aggregation studies. Also, anticoagulation [citrate vs. D-phenylalanyl-1-prolyl-1 arginine chloromethyl ketone (PPACK)] was varied to enhance the functions of GP Ia/IIa, since it has been shown that the cation-poor environment of citrated blood impairs GP Ia/IIa-dependent platelet recruitment. Large interindividual variability (45-fold) was detected in deposition of platelets in whole blood perfusions over collagen monomers, whereas this variation was only fourfold in fibrils. In PFA, this variation was reduced to 2.5-fold. However, platelet deposition on monomers is associated with epinephrine-enhanced PFA (r=-.49, P<.03), whereas platelet deposition on fibrils is correlated with adenosine diphosphate (ADP)-enhanced PFA (r=-.47, P<.05), suggesting a distinct synergism between epinephrine and monomers (GP Ia/IIa) as well as ADP with fibrils (other collagen receptors). Donors with 807 C/C polymorphism of GP Ia (n=14) had longer lag phase in aggregation experiments compared with C/T (n=7) both by monomers and fibrils (P<.04), but these polymorphisms with their mild impact on GP Ia/IIa activity did not markedly differ in other tests. In conclusion, the results obtained in perfusion studies and PFA experiments correlated, but PFA fails to reveal the large-scale variability related to collagen-induced platelet responses.

Adenosine Diphosphate↗
PubMed2001

Activation of coagulation and fibrinolysis during reconstructive microsurgery in patients with cancer.

Cancer patients are subjected to increased systemic risk of thrombotic events and may therefore be at higher risk of even local thrombosis compromising the outcome of reconstructive microsurgery. Coagulation and fibrinolysis activities were studied serially during and after reconstructive microsurgery in seven patients with oropharyngeal cancer or sarcoma in the extremities. A preoperative hypercoagulable state was found in four patients (elevated fibrinogen, TAT, F1+2, or D-dimer); two of these patients also had a local thrombotic event. In all patients, the plasma markers generally varied perioperatively: fibrinogen decreased, whereas TAT and subsequently D-dimer increased at the end of the operation. However, tPA and PAI-1 remained unaltered, except in the patients with thrombosis in whom PAI-1 activity increased progressively during the operation. F1+2 was also clearly elevated in these two patients at the time of thrombosis. Preoperative assessment of hypercoagulability for this group of patients could be helpful in targeting meticulous antithrombotic protection.

Adult↗
PubMed2001

Activation of coagulation and fibrinolysis in microsurgical reconstructions in the lower extremities.

Coagulation and fibrinolysis activities in relation to trauma, surgery and thrombosed microanastomoses were studied during free-flap surgery in eight patients with lower-extremity defects due to recent trauma or chronic ulcers. One patient had an intraoperative thrombosis, and three more patients required reoperations on the same day due to postoperative thromboses; one of these also required a second reoperation due to flap failure. The baseline level of fibrinogen was slightly elevated in all patients except one, and was significantly higher in the patients who underwent reoperation. At the end of the primary surgery, distinct thrombin generation (TAT and F1+2) was seen in three patients with excessive bleeding, and all three later underwent reoperations. One of these patients generated excessive thrombin on the eighth postoperative day, upon removal of a necrotic flap. Thrombin generation (F1+2) was also seen at baseline in the patient with the intraoperative thrombosis, and persisted on the first postoperative day. D-dimer at baseline was higher in patients with recent trauma, and in two of these, both of whom underwent reoperations on the same day, D-dimer remained high perioperatively. Resistance to fibrinolysis with increased PAI-1 levels was seen in these two patients at the time of reoperation. In all, TAT and F1+2 were associated with the threat of flap failure. A preoperative hypercoagulable state and excessive bleeding during the operation were predictors of reoperation. The markers for coagulation and fibrinolysis could be used preoperatively to target antithrombotic control, and postoperatively to detect the threat of flap failure. Meticulous haemostasis during surgery might help to diminish the need for reoperations.

Adult↗
PubMed2001

Intraoperative flow predicts the development of stenosis in infrainguinal vein grafts.

OBJECTIVE: There are data to suggest that the development of myointimal hyperplasia is affected by long-term alterations in blood flow. However, the clinical relevance of these findings has not been demonstrated. METHODS: In this retrospective clinical study, intraoperative volume flow measurement with transit time flowmeter was performed in 257 infrainguinal vein grafts carried out in 241 patients. The patients were enrolled in an intensive duplex scanning-based surveillance program. The relationship between the intraoperative graft flow and subsequent occlusion or development of stenosis was evaluated and controlled for other pertinent risk factors. RESULTS: The median follow-up time was 13.6 months. A graft stenosis was found in 58 grafts. The mean graft flow for event-free grafts was 98 mL/min, which was significantly higher compared with 78 mL/min for stenosed or 69 mL/min for occluded grafts. The patients were divided into four groups according to quartiles of the sample distribution of graft flow measurements. The respective 2-year primary and assisted primary patency rates in the lowest to the highest graft flow groups were 39%, 49%, 47%, and 72% (P =.003) and 55%, 67%, 71%, and 84% (P =.01). Analogous significant differences were observed for maximal flow capacity measurements. Female sex (P =.009) and low graft flow in maximal flow capacity measurements (P =.003) were independent predictors of stenosis development in the multiple regression model. CONCLUSION: Intraoperative graft volume flow is a predictor of bypass occlusion after infrainguinal bypass. In addition, this study verifies an association between the development of clinically evident graft stenoses and low graft flow.

Adult↗
PubMed2001

Procoagulant activity on platelets adhered to collagen or plasma clot.

In a new 2-stage assay of platelet procoagulant activity (PCA), we first subjected gel-filtered platelets to adhesion on collagen (as a model of primary hemostasis) or plasma clots (as a model of preformed thrombus) for 30 minutes, and then the adherent platelets were supplemented with pooled, reptilase-treated, diluted plasma. Defibrinated plasma provided coagulation factors for assembly on platelet membranes without uncontrolled binding of thrombin to fibrin(ogen). Platelet adhesion to both surfaces showed modest individual variation, which increased at platelet densities that allowed aggregation. However, adhesion-induced PCA varied individually and surface-independently >3-fold, suggesting a uniform platelet procoagulant mechanism. Permanently adhered platelets showed markedly enhanced PCA when compared with the platelet pool in suspension, even after strong activation. The rate of thrombin generation induced by clot-adherent platelets was markedly faster than on collagen-adherent platelets during the initial phase of coagulation, whereas collagen-induced PCA proceeded slowly, strongly promoted by tissue thromboplastin. Therefore at 10 minutes, after adjustment for adhered platelets, collagen supported soluble thrombin formation as much as 5 times that of the thrombin-retaining clots. Activation of platelets by their firm adhesion was accompanied by formation of microparticles, representing about one third of the total soluble PCA. Collagen-adhered platelets provide soluble thrombin and microparticles, whereas the preformed clot serves to localize and accelerate hemostasis at the injury site, with the contribution of retained thrombin and microparticles.

Blood Coagulation↗
PubMed2001

Immunologic and hematologic properties of antibodies to prothrombin and plasminogen in a mouse model.

Antibodies to prothrombin have been associated with venous and arterial thrombosis, and they cross-react with a structurally closely related protein plasminogen. We immunised 16 mice with human prothrombin and 15 mice with human plasminogen. Mice immunised with prothrombin developed cross-reactive antibodies to plasminogen (12/16), beta2-glycoprotein I (4/16), tissue-type plasminogen activator (6/16) and cardiolipin (11/16). Mice immunised with plasminogen developed cross-reactive antibodies to prothrombin (8/15), tissue-type plasminogen activator (2/12) and cardiolipin (5/12). Functional effects of antibodies were examined. Immunisation with prothrombin induced lupus anticoagulant activity in 9/14 mice. In mice immunised with plasminogen, radial fibrinolysis was inhibited in 8/10 and plasminogen activation in the chromogenic assay was inhibited in 9/11. No cross-functionality was observed. In conclusion, antibodies to prothrombin and plasminogen cross-react in vivo. Antibodies to prothrombin and plasminogen have different functional profiles, immunisation with prothrombin leads to prolonged blood clotting time, and immunisation with plasminogen induces antibodies interfering with fibrinolysis.

Animals↗
PubMed2000

Atipamezole, an imidazoline-type alpha(2)-adrenoceptor inhibitor, binds to human platelets and inhibits their adrenaline-induced aggregation more effectively than yohimbine.

To investigate the usefulness of atipamezole [MPV-1248, 4-(2-ethyl-2, 3-dihydro-1H-inden-2-yl)-1H-imidazole], a novel alpha(2)-adrenoceptor-specific antagonist, as a tool in platelet studies, the ability of this antagonist: (1) to bind to platelet alpha(2)-adrenoceptors, and (2) to inhibit adrenaline-induced platelet aggregation was compared to that of yohimbine, another commonly used alpha(2)-adrenoceptor antagonist. It was found that atipamezole binds to platelet alpha(2)-adrenoceptors more effectively than yohimbine: [3H]atipamezole has more than three times higher alpha(2)-adrenoceptor binding affinity in intact gel-filtered human platelets (equilibrium dissociation constant (K(d)) 0.7+/-0.21 vs. 2.9+/-0.77 nM, p<0.05), but only one-third of the binding capacity of [3H]yohimbine (B(max) 27.0+/-3.8 vs. 100+/-19 pM/10(5) cells, p<0.01). Functionally, in comparison with yohimbine, an almost threefold lower concentration of atipamezole inhibited adrenaline (5 microM)-induced platelet aggregation. A concentration of atipamezole, which inhibited this aggregation by 50% (IC(50)), was 0.37+/-0.07 microM, whereas IC(50) for yohimbine was 0.98+/-0.12 microM, p<0.0001. Thus, atipamezole represents a functionally undisputed alpha(2)-adrenoceptor antagonist, more effective than yohimbine. Its distinct binding profile as a radioligand also suggests the presence of imidazol(in)e binding sites in platelets.

Adrenergic alpha-Agonists↗
PubMed2000

Immunohistochemical evaluation of failed vessel anastomoses in clinical microsurgery.

Failed vessel anastomoses collected from 12 patients during elective free flap surgery, and from one patient after failed mid-hand replantation were subjected to immunohistochemical analysis. The anastomotic failure was due to an obvious thrombosis, poor flow, an excessively sharp pulse or some other reason causing a non-functioning anastomosis. A total of 17 samples were obtained, 13 of them arterial, three between the artery and vein graft, and one venous. The majority of samples were resected during primary surgery and four of them at reoperation. Variables of coagulation and fibrinolysis were analysed repeatedly during the operation in 7/13 patients. Total occlusion was seen in 6/17 samples and a non-occlusive thrombus in 4/17; two of these were due to suture error. Immunohistochemistry showed that, overall, the endothelial cells (PECAM-l, CD 31) were absent and that the staining pattern for platelets (CD 42b and CD 31) and fibrin (fibrin II, T2G1) correlated. In the absence of a thrombus, however, adherent platelets were positive only for CD 42b, not for PECAM-1. Vessel inflammation was a prominent feature at reoperations. Analysis of coagulation and fibrinolytic markers (thrombin-antithrombin III complex, prothrombin fragment 1 + 2 and D-dimer) confirmed the occurrence of thrombosis in three patients undergoing breast reconstruction with clinically obvious thrombosis during primary surgery or at reoperation. Moreover, the patients with active cancer (2/7) were clearly hypercoagulable compared with the other patients. In short, the primary anastomotic failure was associated with loss of endothelial cells, and with co-localised platelet recruitment and fibrin formation at these sites. At reoperation, inflammation was a prominent feature at the vessel site of thrombi.

Adult↗
PubMed2000

Coimmobilized native macromolecular heparin proteoglycans strongly inhibit platelet-collagen interactions in flowing blood.

We coimmobilized mast cell-derived heparin proteoglycans (HEP-PGs) of very high molecular weight (750 kDa) or unfractionated heparin (UFH) on coverslips together with collagen without altering the amount of immobilized collagen. Subsequently, platelet-collagen interactions were studied under both flowing and static conditions in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone-anticoagulated blood and platelet-rich plasma (PRP), respectively. At a high shear rate (1600 1/s), the mean platelet deposition (PD) on collagen monomers was 7.5+/-6.1x10(6)/cm(2) (n=5). When the monomers were coimmobilized with UFH, PD was inhibited by 73% (2.0+/-1.2x10(6)/cm(2)), whereas HEP-PG completely blocked it (0. 42+/-0.38x10(6)/cm(2); P<0.05). Also, when collagen fibrils were used for coating, HEP-PG significantly inhibited PD. At a low shear rate (200 1/s) and under static conditions in PRP, the inhibitory effect of HEP-PG on PD was less marked. Inhibition of glycoprotein IIb/IIIa did not affect PD on coimmobilized HEP-PG in contrast to coimmobilized UFH or collagen alone. As a sign of inactivation, platelets adhering to the HEP-PG surface released considerably less beta-thromboglobulin than did those adhering to pure collagen. In summary, immobilized HEP-PG strongly inhibited PD on collagen by attenuating adhesion-induced platelet activation. The stronger effect on collagen monomers suggests the inhibition of glycoprotein Ia/IIa-mediated activation.

Animals↗
PubMed2000

Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A.

Coagulation factor XIII (FXIII) is a protransglutaminase involved in the last step of the coagulation cascade by stabilising the fibrin clot. Recently, a common variation (FXIII Val34Leu) has been associated with a decreased risk of myocardial infarction and deep venous thrombosis. Val34Leu is critically located near the thrombin activation site of FXIII-A. In this study we investigated its effects on the activation of FXIII. Both recombinant and platelet-derived FXIII Val34Leu variants were shown to be more susceptible to thrombin cleavage than the wild type FXIII. The rate of enzymatic activation of FXIII Val34Leu was found increased, however, the specific activity of fully activated wild type FXIII and the Val34Leu mutant did not differ. During the course of thrombin-induced activation of FXIII fibrin gamma-chain dimerisation and alpha-chain polymerisation developed more rapidly with the Val34Leu mutant. The increased rate of fibrin stabilisation brought about by the Val34Leu FXIII seems to be paradoxically associated with a protective effect against pathological thrombosis.

Animals↗
PubMed1999

Studies of adhesion-dependent platelet activation: distinct roles for different participating receptors can be dissociated by proteolysis of collagen.

The molecular differences between native-type collagen type I fibrils (NC) and their pepsinated monomers (PC) were used to uncover receptors involved in platelet-collagen interaction along the adhesion-activation axis. The platelet-depositing capacity of NC and PC under blood flow and their adhesive properties and respective morphologies, aggregation, procoagulant capacity, and tyrosine phosphorylation were compared under different cationic milieus, including or excluding the glycoprotein (GP) Ia/IIa. NC was consistently a more preferable and activating substrate than PC during flow (5 minutes) and in platelet aggregation. In PPACK-treated blood, both NC (3.3-fold) and PC (2.7-fold) increased platelet attachment on elevation of the shear rate from 500 to 1640 s(-1), whereas in citrated blood, adhesion and thrombus growth on PC were negligible under the high shear rate, unlike on NC (1.9-fold increase). The complete lack of platelet deposition on PC in citrated blood could be overcome by restoring physiological Mg(2+) concentration, and in contrast to NC, platelets interacting with PC were highly dependent on Mg(2+) during adhesion, aggregation, and procoagulant response. Monoclonal antibody (mAb 131.7) against GP IV inhibited platelet deposition to NC in citrated blood (2 minutes) by 49%, which was not further increased by coincubation with mAb against GP Ia (6F1). These results stress the importance of GP Ia/IIa in shear-resistant platelet deposition on collagen monomers. In native fibers, however, the preserved quaternary structure with telopeptides activates additional platelet receptors capable of substituting GP Ia/IIa and GP IV.

Animals↗