Quantification of the effects of thrombin activatable fibrinolysis inhibitor and α2-antiplasmin on fibrinolysis in normal human plasma
Department of Anesthesiology, The University of Alabama at Birmingham, Alabama 35249-6810, USA.Blood Coagulation and Fibrinolysis (Impact Factor: 1.4). 01/2007; 18(1):29-33. DOI: 10.1097/MBC.0b013e3280129afe
Two major proteins that inhibit fibrinolysis include thrombin activatable fibrinolysis inhibitor (TAFI) and alpha2-antiplasmin. Our goal was to quantify the contribution of TAFI and alpha2-antiplasmin to antifibrinolytic defenses with thrombelastography. Plasma activated with tissue factor/kaolin was subjected to fibrinolysis with tissue-type plasminogen activator (100 U/ml). Prior to activation, TAFI activity was inhibited with either potato carboxypeptidase inhibitor (25 microg/ml) or an anti-TAFI antibody, and alpha2-antiplasmin activity was inhibited with an anti-alpha2-antiplasmin antibody. Data were collected for 30 min, with the time of onset and rate of fibrinolysis determined. Compared with uninhibited samples, TAFI inhibition significantly (P < 0.05) decreased the time of onset of fibrinolysis by 70% and increased the rate of lysis by 70%. There was no difference between potato carboxypeptidase inhibitor and anti-TAFI antibody inhibition. Inhibition of alpha2-antiplasmin resulted in a significantly (P < 0.05) decreased time of onset (85%) and increased the rate of lysis (557%) compared with uninhibited samples. Inhibition of alpha2-antiplasmin activity resulted in a significantly (P < 0.05) greater fibrinolytic response than TAFI inhibition. In conclusion, utilization of standard inhibitors and thrombelastography permitted quantification of the effects of TAFI and alpha2-antiplasmin on fibrinolysis in plasma. Future investigation of diseases involving hypofibrinolysis (e.g. left ventricular assist devices) could be conducted using this assay system.
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ABSTRACT: Hydroxyethyl starch (HES) solutions are effective volume expanders but are also associated with poorly understood coagulopathy. Enhanced fibrinolysis following dilution with HES has been demonstrated. This investigation sought to identify the interactions of HES with critical fibrinolytic/antifibrinolytic enzymes. Normal plasma or plasmas deficient in factor XIII, thrombin activatable fibrinolysis inhibitor or alpha2-antiplasmin were either not diluted or were diluted 20% with 0.9% NaCl, 5% human albumin, high-molecular-weight HES (HES 450) or low-molecular-weight HES (HES 130). Plasma was activated with celite and exposed to 75 IU/ml tissue-type plasminogen activator. Coagulation growth/disintegration kinetics were determined with thrombelastography. Compared with undiluted plasma, diluted plasma had a significant decrease in the clot lysis time and the time to maximum rate of lysis in all plasma types except in alpha2-antiplasmin-deficient plasma. The hierarchy of the decrease in clot lysis time and time to maximum rate of lysis was HES 450 = HES 130 > 5% human albumin = 0.9% NaCl. In conclusion, HES dilution enhances fibrinolysis by diminishing alpha2-antiplasmin-plasmin interactions. Further laboratory and clinical investigation is warranted to better define the mechanisms by which HES enhances clot disintegration and to find new therapeutic roles for HES to either prevent or treat thrombosis.
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ABSTRACT: Antiphospholipid syndrome is an autoimmune thrombophilic disorder that is uncommon in adults and remarkably rare in children. Thrombotic etiological factors are variable in antiphospholipid syndrome, including antibody-antigen complex-mediated platelet activation, inhibition of anticoagulants, or attenuation of fibrinolysis. We present the case of a child with antiphospholipid syndrome presenting with syncope, constrictive pericarditis and hepatic enlargement that was found to have platelet-mediated hypercoagulability and marked clot lysis via thrombelastography in the preoperative period. Restoration of circulation following pericardectomy and inotropic support was associated with attenuation of hypercoagulability and fibrinolysis. It is concluded that the etiological factors responsible for antiphospholipid syndrome-mediated hemostatic abnormalities and the probable effects of hepatic hypoperfusion on clot lysis in this patient were detected with thrombelastography, and similar thrombelastographic analyses are recommended to compliment standard coagulation assessments of patients with antiphospholipid syndrome.
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