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Biomedical subjects

D L Aronson

Publications and source records attributed to D L Aronson.

At least 19 recordsLinked to original sources
PubMed1992

Platelet-dependent thrombin generation after in vitro fibrinolytic treatment.

BACKGROUND: Fibrinolytic therapy is associated with frequent rethrombosis. There is evidence of both increased coagulation and platelet activation. METHODS AND RESULTS: Platelet-rich plasma (PRP) or washed platelets were incubated with the fibrinolytic agents urokinase, recombinant tissue-type plasminogen activator (rt-PA), or plasmin at concentrations consistent with those in the plasma of patients treated for myocardial infarction. All of the fibrinolytic agents induced a more rapid generation of thrombin and decreased the clotting times of non-contact-activated PRP than in untreated PRP. This effect was not blocked by the inclusion of thrombin inhibitors during the fibrinolytic treatment. Washed platelets derived from rt-PA-treated PRP induced more rapid thrombin generation when resuspended in untreated plasma or treated plasma. Washed platelets were treated with plasmin, rt-PA, and urokinase and added to platelet-poor plasma. Platelets treated with either plasmin or rt-PA increased the ability of washed platelets to support thrombin generation, but urokinase was without significant effect. CONCLUSIONS: These results indicate not only that plasmin can cause increased platelet support of prothrombin activation but also that rt-PA in the absence of plasminogen can have a direct effect on the platelet, which increases thrombin generation.

Blood Platelets↗
PubMed1988

Turnover of tPA in rabbits: influence of carbohydrate moieties.

The turnover of tissue plasminogen activator (tPA) was studied in rabbits using a double-label technique which allowed the comparison of various tPA derivatives with a standard tPA in individual animals. Purified recombinant tPA (Alteplase) was labelled with 125I and used as a standard for each experiment. Various tPA preparations which lacked specific carbohydrate structures were labelled with 131I (in separate experiments) and injected along with the 125I-tPA standard into rabbits. The clearance of standard tPA was biphasic with an average T 1/2 alpha and T 1/2 beta of 0.85 min and 12 min respectively. Type II tPA which lacks a portion of carbohydrate associated with Type I tPA as well as desialated tPA demonstrated a longer T 1/2 beta than standard tPA.

Animals↗
PubMed1988

Cause of death in hemophilia A patients in the United States from 1968 to 1979.

Death data on 949 hemophiliacs for the years 1968-1979 have been analyzed. The median age at death has increased from 33 to 55 years. There was no evidence of new diseases caused by the more intensive therapy during this time interval. The leading infectious disease was hepatitis, accounting for eight deaths. Only one acute hepatitis death was listed after 1974, when sensitive tests for hepatitis B antigen screening of plasma were implemented. Cirrhosis was a primary or associated cause of death in 76 cases (8%) and pneumonia was a primary or associated cause of death in 62 deaths (6.5%). The types of malignancies in hemophiliacs were similar to those in the male US population with no evidence of excessive retrovirus malignancies prior to infection with HIV-1.

Adolescent↗
PubMed1987

Thrombogenicity of factor IX complex: in vivo investigation.

Factor IX Complex therapy has been associated with thrombosis when used in patients with liver disease, hemophilia B and hemophilia A with inhibitors to Factor VIII when administered repetitively and in high doses. Three mechanisms for inducing thrombogenicity have been proposed: activated coagulants, coagulant-active phospholipid content and/or the high zymogen level attained in recipients. A new animal model using Russel Viper Venom (RVV) as an in vivo stimulus of coagulation has been used to investigate the role of high levels of zymogens in the induction of thrombosis. The quantity of RVV tolerated by rabbits infused with Factor IX Complex is reduced 100-fold. Infusion of Factor X or prothrombin also reduces the lethal dose of RVV. In contrast, Coagulation Factor IX devoid of other coagulants has little effect. However other animal data indicate that the amount of activated coagulants can play a role in the in vivo thrombogenicity of Factor IX Complex.

Animals↗
PubMed1986

Turnover of human tissue plasminogen activator (tPA) in rabbits.

The turnover of purified tissue plasminogen activator (tPA) from two different manufacturers was compared in rabbits. The first was melanoma derived one-chain tPA and the second was recombinant two-chain tPA. No differences were noted between the two products. A biphasic disappearance curve was observed for the protein (125Iodine labelled). The first phase was extremely rapid with a T1/2 of 0.59-0.89 min; the secondary phase had a T1/2 of 10-12 min. tPA accumulated rapidly in the liver (44% at twenty min) and appeared to be degraded as demonstrated by the increase in plasma of low molecular weight material which was also TCA soluble. Fractionation of purified recombinant two-chain tPA on a Dupont GF-250 column yielded two peaks of protein (Peak 1 and Peak 2) and the turnover of each in rabbits was compared.

Animals↗
PubMed1985

Experimental studies on venous thrombosis: effect of coagulants, procoagulants and vessel contusion.

We have examined the relative contribution of stasis, activated coagulants, procoagulants and vessel wall damage in the pathogenesis of experimental venous thrombosis. Using a Wessler stasis model in rabbits, we found an inverse correlation between duration of stasis and the amount of Contact Factor and Factor Xa required to produce a stasis thrombus. However, the slope of the dose-response curve for producing thrombi was different with these two coagulants. The infusion of Factor IX complex was also thrombogenic in this model despite prolonged circulation prior to stasis, implying that high levels of multiple procoagulants may be thrombogenic. In contrast, Factor VIII concentrates or a purified Factor IX preparation did not give thrombi under these conditions. When the vessel wall was crushed mechanically, followed by restored blood flow and subsequent stasis, there was essentially no formation of thrombi over the time course of the experiments. Scanning electron microscopy demonstrated that although the endothelium was swollen and damaged, there was usually no exposure of sub-endothelium and no adherence platelets. Where there was definite disruption of the endothelium, activated platelets could be seen adhering to the vessel wall. However, the blood in the segments remained fluid over a period of 30 min, despite the presence of adherent platelets. Our experiments demonstrated that the combination of vessel wall damage and stasis was relatively ineffective in producing venous thrombosis. In contrast, high levels of zymogens or small amounts of activated clotting factors, combined with local stasis, is a very effective thrombogenic stimulus in the venous system.

Animals↗
PubMed1985

Measures to inactivate viral contaminants of pooled plasma products.

In order to produce safer plasma products all possible methods of virus inactivation and reduction must be investigated systematically. Since the number and types of viruses are unknown and could change with time, a general viricidal approach is necessary. While heating has been the standard, a variety of methods are available for reducing the transmission of virus infection by blood products. Satisfactory development of these methods is limited by the cumbersome, expensive and imprecise experimental tools being used, i.e., the chimpanzee or human clinical trials.

Animals↗
PubMed1979

Physical studies on isolated human prothrombin fragment-2. Comparisons with human prothrombin fragment-1.

Variation of pH strongly affects the fluorescence intensity of human prothrombin fragment-1 in a manner suggesting contributions from a number of protropic equilibria including groups with apparent pKa values near 3.0. These results suggest a structural role for pK1a of gamma-carboxyglutamic acid noieties. Added calcium ions (9 mM calcium chloride) quench the fluorescence titration curve uniformly above pH 4. Below pH 4, however, the titration curve in the presence of calcium ions suggests that calcium-ion-dependent processes leading to fluorescence quenching are pH-dependent. Upon back titration of human fragment-1, from pH 9, hysteresis is observed. Human prothrombin fragment-2 fluorescence titration curves are relatively broad at low pH suggesting the titration of normal carboxyl groups. The titration curves of fragment-2 are not affected by the presence of calcium ions, and hysteresis occurs upon back titration from low pH values. Circular dichroism (CD) Cotton effects appear at 232 nm and 280 nm and a trough appears at 203 nm in the CD spectrum of human prothrombin fragment-2. The Cotton effects in the region from 230 nm to 300 nm are sensitive to pH, ellipticity values at 232 nm increasing from approximately 300 at pH 2.5 to 1300 (degree-cm/decimole) at neutral pH and finally become negative at high pH values. In contrast to fragment-1, at neutral pH the fragment-2 Cotton effect at 232 nm is insensitive to the presence of 8 mM calcium chloride.

Calcium↗