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Byline: Torun Clausen, Srdjan Djurovic, Frank R. Brosstad, KA[yen]re Berg, Tore Henriksen Keywords: Adhesion molecules; endothelial dysfunction; placentation; preeclampsia; von Willebrand factor Abstract: Objective: The purpose of this study was to investigate whether indications of activation of the maternal endothelium were present at 18 weeks' gestation in women in whom preeclampsia eventually developed. Study Design: A total of 2190 blood samples were obtained at 18 weeks' gestation. Circulating levels of von Willebrand factor and soluble vascular adhesion molecule 1, soluble intercellular adhesion molecule 1, and E-selectin were assayed in 71 women with eventual preeclampsia and 71 control subjects. Results: E-selectin and von Willebrand factor levels were similar between the 2 groups. Soluble vascular adhesion molecule 1 concentration was significantly lower in the women with eventual preeclampsia (median, 649.0 ng/mL vs 762.4 ng/mL; P < .001), whereas soluble intercellular adhesion molecule 1 concentration was significantly higher (median, 239.8 ng/mL vs 178.3 ng/mL; P < .001). Conclusion: We found no indications of endothelial activation at 18 weeks' gestation in women in whom preeclampsia later developed. However, decreased serum concentration of soluble vascular adhesion molecule 1 and increased serum concentration of soluble intercellular adhesion molecule 1 may reflect the disturbed placentation known to be associated with the development of preeclampsia. (Am J Obstet Gynecol 2000;182:321-5.) Author Affiliation: Oslo, Norway From the Department of Obstetrics and Gynecology, Aker University Hospital,.sup.a the Institute for Medical Genetics and the Department of Medical Genetics, UllevA[yen]l University Hospital,.sup.b the Research Institute for Internal Medicine, National Hospital,.sup.c and the Department of Obstetrics and Gynecology, National Hospital and Institute for Nutrition Research,.sup.d University of Oslo Article History: Received 15 April 1999; Revised 5 August 1999; Accepted 23 September 1999 Article Note: (footnote) [star] Supported by the Throne Hoist Fond for Nutrition Research and Eckbos Legat., [star][star] Reprint requests: Tore Henriksen, MD, PhD, Department of Obstetrics and Gynecology, National Hospital, 0027 Oslo, Norway.

Byline: Hanne I. Flom-Halvorsen, Eivind Avrum, Geir Tangen, Frank Brosstad, Mari-Anne L. Ringdal, Rolf Aystese Abstract: Objective: Autotransfusion during and after cardiac surgery is widely performed, but its effects on coagulation, fibrinolysis, and inflammatory response have not been known in detail. Methods: Hemostatic and inflammatory markers were extensively studied in 40 coronary artery bypass patients undergoing a consistent intraoperative and postoperative autotransfusion protocol. An identical autotransfusion protocol was applied to 4916 consecutive coronary patients and the overall clinical results were evaluated in this large patient population. Results: The autologous blood pooled before bypass remained nearly inactivated after storage. A slight elevation of thrombin-antithrombin complex and prothrombin fragment 1.2, as well as plasmin/[alpha].sub.2-antiplasmin complex was found in the content of the extracorporeal circuit after surgery, indicating thrombin formation and fibrinolytic activity. Also some increase of [beta]-thromboglobulin was present. In the mediastinal shed blood, complete coagulation, as evidenced by the absence of fibrinogen, had taken place and all parameters described above were extremely elevated. However, no thrombin activity was detected. As for the inflammatory response, moderately increased levels of complement activation products, terminal complement complex, and interleukin-6 traced in the extracorporeal circuit reached very high levels in mediastinal shed blood. Autotransfusion of the residual extracorporeal circuit blood and the mediastinal drainage was followed by elevation of most of these markers in circulating plasma. On the other hand, no correlating harmful effects were recorded in the study patients or in the consecutive 4916 patients. Coagulation disturbances were rare and allogeneic transfusions were required in fewer than 4% of all patients. Conclusions: The hemostatic and immunologic systems were moderately activated in the autologous blood remaining in the extracorporeal circuit, whereas the mediastinal shed blood was highly activated in all aspects. However, autotransfusion had no correlating clinical side-effects and the subsequent exposure to allogeneic blood products was minimal. (J Thorac Cardiovasc Surg 1999;118:610-7) Author Affiliation: From the Department of Cardiac Surgery, Oslo Heart Center,.sup.a Research Institute for Internal Medicine, University of Oslo, Rikshospitalet,.sup.b Oslo, Norway Article History: Received 20 October 1998; Revised 16 December 1998; Revised 14 June 1999; Accepted 15 June 1999 Article Note: (footnote) [star] Address for reprints: Eivind Avrum, MD, PhD, Oslo Heart Center, Pilestredet 32, N-0027 Oslo, Norway., [star][star] 0022-5223/99 $8.00 + 0 12/1/100742

Although cerebral microemboli are often detected by transcranial Doppler ultrasonography in mechanical heart valve patients, the clinical significance of such microemboli is unclear. The aim of this study was to determine the frequency and composition of cerebral microemboli in a prosthetic heart valve population and to correlate these findings to cerebrovascular symptoms, blood inflammation, and coagulation parameters.

Heparin-free haemodialysis (HD) with intermittent saline flushes (ISF) in patients with bleeding risk is widely used. The aim of this study was to investigate if ISF reduce coagulation and clotting in stable patients receiving reduced doses of dalteparin.

Background. A single bolus of dalteparin at the start of haemodialysis (HD) may prevent clot formation, but subclinical activation of platelets and coagulation may still occur. Consequently, the relationship between clinical clotting events and activation markers of platelets and coagulation before and during HD is of interest.Methods. The effect of tapered doses of dalteparin during 84 HD sessions (4–4.5 h) was prospectively examined in 12 patients. Six of the patients were treated with warfarin. The initial dalteparin dose was reduced to 50% if no clotting was observed. Clinical clotting was evaluated by inspection of the air trap every hour and by inspection of the dialyser after each session. Anti‐FXa activity was measured for assessment of dalteparin activity. Markers of activated plasma coagulation, (thrombin‐antithrombin (TAT) and prothrombin fragment 1+2 (PF1+2)) and a marker of platelet activation (β‐thromboglobulin, β‐TG), were measured before the start of and after 3 and 4 h of dialysis. Ten pre‐dialytic patients with chronic renal failure served as a control group. A total sof 230 measurements of each parameter were performed.Results. An anti‐FXa activity above 0.4 IU/ml at the end of HD inhibits overt clot formation for 4 h. This was obtained by an intravenous dalteparin dose of about 5000 IU. TAT and PF1+2 correlated to clinical clotting episodes (r=0.50 and 0.47, P<0.001). β‐TG was not significantly correlated to clinical clotting. All parameters increased during the sessions (TAT, PF1+2, β‐TG, P<0.001). When measurements during clinical clotting episodes were disregarded, all parameters were still markedly increased. Warfarin‐treated patients had lower TAT and PF1+2. Dialysis patients had higher β‐TG values than pre‐dialytic patients.Conclusion. Despite clinically effective anticoagulation, obtained by dalteparin administration, platelets and coagulation are activated by HD, resulting in a potentially thrombophilic state. Warfarin treatment reduces clinical clot formation and subclinical activation of coagulation.

Purpose:Lysis of a thrombus is a function of the local concentration of thrombolytic enzymes. This study was designed to determine in a porcine model of acute deep vein thrombosis (DVT) whether perithrombic sequestration of small volumes of a concentrated enzyme solution can accelerate the process of thrombolysis.

Purpose:To evaluate in a porcine model of acute deep vein thrombosis (DVT) the efficacy of dalteparin and antithrombin with respect to heparin for local adjuvant therapy during selective thrombolysis, and the utility of nitroglycerin and iloprost as heparin supplements.

Fibrinogen from plasma was compared with fibrinogen from platelets using two-dimensional electrophoresis. The source of platelet fibrinogen was isolated α-granules, thrombin- and collagen-released platelet material. The Bβ- and γ-chains from the different sources showed similar two-dimensional patterns, while γ'-chains were not observed in platelet fibrinogen preparations. Furthermore, the Aα-chain could hardly be identified in platelet preparations. When individual fibrinogen was studied in persons heterozygous for genetic Bβ- and γ-chain variants, the two-dimensional variant pattern could be demonstrated in plasma fibrinogen as well as in platelet fibrinogen. This observation strongly indicates that the structural genes for plasma and platelet fibrinogen Bβ- and γ-chains are identical.

Besides their role in hemostasis, platelets are involved in inflammatory and immunological processes, and we hypothezise that platelet activation may play an immunopathogenetic role in HIV‐1 infection. Blood was drawn from 15 controls and 20 HIv‐1‐infected patients with normal platelet counts, classified into groups of non‐AIDS and AIDS. Platelet activation was detected using flow cytometry with mAbs against the release markers P‐selectin and CD63, mAb against GPIb, and the probe annexin V detecting surface exposure of aminophospholipids. The amount of microvesicles was measured using mAb against GβIIIa. Compared to controls, blood samples from HIV‐1‐infected patients showed significantly enhanced levels of microvesicles and activated platelets as detected by their exposure of P‐selectin, CD63, and aminophospholipids, as well as reduction in GPIb expression. Increased expression of P‐selectin and amounts of microvesicles were most pronounced in advanced clinical and immunological disease. When studying the effect of HIV‐1 protease inhibitor therapy (indinavir) on platelet activation, we found that concomitant with a profound decrease in plasma viral load, there was a near normalization of several of the parameters reflecting enhanced platelet activation. Finally, we demonstrated that platelets may be an important source of the chemokine RANTES in HIV‐1‐infected patients. Although both unstimulated and SFLLRN‐stimulated platelets from asymptomatic patients had enhanced release of RANTES, platelets from AIDS patients were characterized by markedly enhanced spontaneous, but decreased SFLLRN‐stimulated release of this chemokine. Taken together, these results, which demonstrate for the first time increased platelet activation in HIV‐1‐infected patients with normal platelet counts, may represent a previously unrecognized immunopathogenic factor in HIV‐1 infection.—Holme, P. A., Müller, F., Solum, N. O., Brosstad, F., Frøland, S. S., Aukrust, P Enhanced activation of platelets with abnormal release of RANTES in human immunodeficiency virus type 1 infection. FASEB J.12, 79–90 (1998)

Shear-induced platelet activation and platelet microparticle formation are triggered in native human blood by high arterial shear or by a sudden increase in shear as introduced by a stenosis with potential consequences for collagen-induced platelet thrombus formation. Blood was drawn from healthy volunteers and directly perfused ex vivo over various well-defined eccentric stenoses. Shear-induced platelet activation was determined by using flow cytometry to assess: 1) GPIIb-IIIa activation by fluorescein isothiocyanate (FITC)-labeled Mab PAC-1; and 2) translocation of membrane aminophospholipids (procoagulant activity) by FITC-labeled Annexin V. Microparticle formation was measured by flow cytometry and FITC-labeled Mab Y2/51 directed against GPIIIa. Significant platelet activation and platelet microparticle formation were elicited when the wall shear rate reached 10,500 sec−1 for a period of 0.075 sec. Prolonged exposure to or a rapid increase in shear further enhanced activation and microparticle formation. Shear-induced platelet activation was associated with significantly increased collagen-induced platelet thrombus formation that was insensitive to aspirin ingestion. Exposure of native blood to very high shear thus activates platelets to express GPIIb-IIIa, renders the platelet membrane procoagulant and stimulates microparticle formation. These responses are associated with enhanced collagen-induced thrombus formation by prostaglandin-independent mechanisms.

Fibrinogen-binding platelet proteins have been examined by crossed-immunoeloctrophoresis of solubilized, washed platelets followed by the incubation of the immunoplates with 125l-fibrinogen and exposure to x-ray films. Incubation with 0.1 mg/ml of 125l-fibrinogen revealed the binding of fibrinogen to the immunoprecipitates representing the glycoprotein IIb–IIIa complex, factor XIIIa chain, a granule membrane protein termed G4, fibrinogen, and albumin. Only the glycoprotein IIb–IIIa precipitate and the fibrinogen precipitate showed significant binding when the concentration of 125l-fibrinogen was lowered to 0.01 mg/ml. The binding to all the immunoprecipitates was completely abolished in the presence of a 20 fold excess of unlabeled fibrinogen, but not when unlabeled fibrinogen was replaced by the same amounts of bovine serum albumin or human hemoglobin. This indicates that the binding of fibrinogen is specific. Furthermore, 125l-fibronectin and 125l-thrombin did not bind to the glycoprotein IIb–IIIa precipitate. The binding of 125l-fibrinogen to the precipitates representing the glycoprotein IIb–IIIa complex, the factor XIIIa chain, and G4, but not to the albumin precipitate, was significantly lowered in the presence of EDTA. This effect of EDTA increased with increasing pH, with no binding at pH 8.7. Immunoprecipitates of dissociated glycoprotein lIb and IIIa did not bind 125l-fibrinogen. Binding of 125l-fibrinogen to the glycoprotein IIb–IIIa precipitate was dependent on the presence of either Ca2+or Mg2+, the binding to the factor XIIIa chain required Ca2+, and the binding to G4 required Mg2+. The results indicate that the glycoprotein IIb–IIIa complex, but not the separate glycoproteins IIb and IIIa, can act as Ca2+or Mg2+-dependent fibrinogen receptor, under proper physiologic conditions.

Radiologic contrast media (CM) may influence processes of coagulation and fibrinolysis. In the current study, the effects of various CM on the formation of plasmin were examined in an in vitro buffer system.

Purpose:To develop an animal model of acute deep vein thrombosis (DVT).Purpose:To develop an animal model of acute deep vein thrombosis (DVT).

The molecular basis of a novel congenital afibrinogenemia has been determined. The proposita, the only affected member in a consanguineous Norwegian family, suffers from a moderate to severe bleeding disorder due to the total absence of any detectable fibrinogen. Dot blots of solubilized platelets revealed a small amount of γ chain but no A or Bβ chains, whereas no chains were detected in plasma dot blots. DNA sequencing of the A chain gene revealed a homozygous C→T transversion 557 nucleotides from the transcription initiation site. This nucleotide change predicts the nonsense mutation A 149 Arg (CGA)→stop (TGA). Early truncation of the A chain appears to result in defective assembly or secretion of fibrinogen, probably due to the removal of the C-terminal disulfide ring residues that are critically required for the formation of a stable 3-chained half molecule.

SammendragIntoksikasjoner med tricykliske antidepressiva er p.g.a. deres cardiodepressive effekt og tendens til å gi alvorlige fatale arrytmier hetraktet sotn intoksikasjoner med betydelig alvorlighetsgrad.Man har derfor foretatt en retrospektiv undersekelse av samtlige intoksikasjoner innlagt i avdeling IX Ullevål sykehus i tiden 1966-73.Av alle intoksikasjoner i perioden representerte tricyliske antidepressiva 6,8. Ingen av de intoksikasjoner med tricykliske antidepressiva førte til mors. Alle alvorlige bivirkninger sotn ble registrert er assosiert med andre tricykliske antidepressiva enn Sinequan.