Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.2.7 (heparinase)
 1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant hirudin (r-hirudin) is currently under development as an anticoagulant for use in surgery, therapeutic anticoagulation, disseminated intravascular coagulation and other pathologic states involving the generation of thrombin. Circulating levels of r-hirudin as an antithrombotic agent range from 2 to 20 micrograms/ml (0.1-1.0 mg/kg) as determined in an animal model of stasis thrombosis. In order to establish a relationship between the r-hirudin circulating level and bleeding, we utilized a rabbit ear blood loss model. r-Hirudin did not produce any loss of blood at dosages up to 20 micrograms/ml i.v. (1.0 mg/kg). When the circulating levels were maintained at 20 micrograms/ml for periods of up to 3 h, no increase in blood loss was observed. At 50 and 100 micrograms/ml initial circulating levels (2.5 and 5.0 mg/kg) a dose-dependent increase in the blood loss was observed which was equivalent to that observed with 1.25 and 2.5 mg/kg i.v. heparin. Such levels of r-hirudin are not expected in clinical usage. In contrast to heparin, the anticoagulant actions of r-hirudin were not neutralized by protamine sulfate, platelet factor 4, other polycationic agents and heparinase. In our studies, the blood loss induced by greater than 2.0 mg/kg i.v. dosages of r-hirudin in an animal model was neutralized by the administration of an activated prothrombin complex concentrate at 25 U/kg. In a similar experimental setting, r-factor VIIa was also partially effective. These studies suggest that r-hirudin anticoagulation may not require neutralization, since bleeding effects are not observed at effective antithrombotic dosages in individuals with normal hemostatic status.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin. 189 98

Patients undergoing extracorporeal membrane oxygenation (ECMO) are at an increased risk for developing coagulopathies due to the adverse effects of extracorporeal circulation on the hemostatic mechanism. Methods of determining causative factors of bleeding diathesis are often inconsistent and non-specific. ECMO patients require aggressive transfusion therapy with autogenic blood products to stabilize and maintain hemostasis. The present study evaluated the coagulation status of newborn patients undergoing ECMO therapy, using a viscoelastic monitor (Thrombelastograph -TEG) that measures functional aspects of clot development and stabilization. Seventeen neonatal patients undergoing ECMO for severe respiratory dysfunction were entered into this study. Serial blood samples were obtained and routine coagulation assessment including fibrinogen concentration, platelet count and ionized calcium was performed. In addition, fibrin(ogen) degradation products (FDP), d-Dimers, antithrombin III and plasma free hemoglobin were measured. Transfusion indicators were established and total transfusion requirements recorded. TEG profiles were determined with the use of heparinase, an enzyme that degrades heparin but has little effect on other coagulation factors. The most commonly encountered complication was hemorrhaging which was diagnosed by laboratory and clinical assessment in 11 of 17 patients. Transfusion requirements (measured in ml/kg/ECMO hour) were the following: packed red blood cells--1.34 +/- 0.5; platelets--0.71 +/- 0.57; fresh frozen plasma--0.09 +/- 0.12; cryoprecipitate 0.05 +/- 0.05. Thrombelastograph profiles reflected hemostatic conditions that ranged from severe coagulopathies (DIC) to hypercoagulability. Interpretation of TEG profiles identified hemostatic abnormalities in 57 of 101 profiles (46.5%), with the most common etiology related to platelet dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coagulation monitoring during extracorporeal membrane oxygenation: the role of thrombelastography. 1015 58

As the spherical diameter of pulmonary capillaries is smaller than that of neutrophils, increased neutrophil stiffness or conversely, decreased neutrophil deformability is a key step in the initial sequestration of neutrophils within the lungs during inflammatory processes. Antithrombin III (AT) is known to exert a therapeutic effect against disseminated intravascular coagulation, and accumulating evidence suggests that AT also has anti-inflammatory properties. The mechanisms of its anti-inflammatory effects remain unclear, but in a rat endotoxin model, AT apparently inhibited neutrophil sequestration in the lung. In the present in vitro study, therefore, we examined the effect of AT on the deformability of human neutrophils and correlated those findings with their F-actin content. Isolated human neutrophils were stimulated with formyl-Met-Leu-Phe (1 muM, 2 min) in the presence or absence of the alpha, beta, or low heparin-affinity isoforms of AT (1 IU/ml, 20 min), and deformability was evaluated using a filter assay system. Neutrophils were also stained with fluorescein isothiocyanate-phalloidin and subjected to a fluorescein-activated cell sorter scan to assess F-actin content. The results showed that pretreatment with any of the three AT isoforms similarly inhibited the decreased neutrophil deformability and increased F-actin content of stimulated cells. Notably, heparinase had no effect on deformability or F-actin content in the presence or absence of AT, which was somewhat unexpected, as heparin sulfate proteoglycans likely function as AT receptors. These findings suggested that AT inhibits the increase in neutrophil stiffness seen during inflammatory processes by inhibiting actin polymerization via a heparin-independent pathway.
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PMID:Effect of antithrombin III on neutrophil deformability. 1600 Mar 88