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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 289 records · Page 16Linked to original sources
PubMed1988

Relationship between postsurgical fibrinolytic parameters and deep vein thrombosis in surgical patients treated with compression devices.

This study consisted of 52 patients admitted for orthopedic surgery and 28 patients admitted for general surgery, who were treated with Sequential Compression Devices (SCD) and Thromboembolic Deterrent Stockings (TEDS) and monitored for the development of deep vein thrombosis (DVT). Coagulation and fibrinolytic profiles were carried out on these patients preoperatively, and on days one, three, and six postoperatively. All patients were followed by I-125-Fibrinogen scanning, Venous Doppler, and Impedance Plethysmography studies for clot detection. In the orthopedic surgery group, six (11.5%) developed DVT, and in the general surgery group, one (3.6%) developed DVT. No patients developed pulmonary embolism. The combined incidence of DVT was 8.8 per cent. A variety of parameters was measured in order to determine whether compression devices prevent a fibrinolytic shut-down commonly seen in the postsurgical patient. A combination of three assays was found to be significant in demonstrating a fibrinolytic response. These parameters were a post-surgical decrease in the plasminogen level, an increase in the level of free protease activity postoperatively, and an increase in the level of tissue plasminogen activator after surgery. 56.3 per cent of all patients treated with SCD and TEDS showed a fibrinolytic response on postoperative day one by a combination of all three of these parameters. In the group of patients that developed DVT none showed an increase in free protease activity, and five of seven showed no significant decrease in plasminogen and no increase in tissue plasminogen activator. Patients who developed thrombosis had measurable differences in their fibrinolytic system compared to those without postoperative thrombosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Clothing↗
PubMed1987

Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges.

A synthetic pentasaccharide, representing the critical sequence required in heparin for binding to antithrombin III (AT III), produces strong anti-factor Xa activity in vitro in the presence of AT III and is devoid of any activity directed towards thrombin. This pentasaccharide provides a unique tool to study the question of whether an agent capable of inhibiting factor Xa but devoid of anti-factor IIa activity in vitro, has the capacity to produce an antithrombotic effect in vivo. We have previously demonstrated in a rabbit stasis thrombosis model using a human serum challenge, a significant antithrombotic effect of the pentasaccharide. This finding and discrepancies with some earlier reports on the antithrombotic actions of other oligosaccharide fragments, led us to extend these studies. Four modifications of the stasis thrombosis model were developed using the following thrombogenic challenges selected for their specified induction sites of thrombosis, thromboplastin, an activated prothrombin complex concentrate, a non-activated prothrombin complex concentrate administered simultaneously with Russell's viper venom, and factor Xa. Dose-dependent antithrombotic responses were obtained in all four systems with ED50 values between 25-43 ug/kg for pentasaccharide as compared to 16-47 ug/kg for heparin. Complete inhibition of induced thrombosis was obtained in all four systems for pentasaccharide. Ex vivo analysis revealed expected anti-factor Xa levels but no anti-factor IIa activity. It is concluded that an oligosaccharide with high anti-factor Xa activity and devoid of anti-factor IIa activity is capable of inhibiting thrombosis induced in rabbit stasis models, but that higher dosages than heparin are required for this effect.

Animals↗
PubMed1987

[Low molecular weight heparin fractions. Comparative preclinical study of various parameters].

Preliminary results of the use of heparin fractions of low molecular weight showed improved bioavailability, sustained pharmacological actions and less bleeding than with non-fractionated heparin. Although prepared by different chemical and enzymatic processes, low molecular weight heparin fractions (LMWHF) possess remarkably similar chemical properties but differ in their pharmacological activity. Significant variations have been noted in tests for anti-Xa activity using reagents of USP or European standards. A study was carried out with eight heparin fractions of low molecular weight: CY 216 and CY 222 (Choay, France), Kabi 2165 (Sweden), PK 10169 (Pharmuka, France), RD 11885 (Wyeth, USA), OP 2123 (Opocrin, Italy), ORG 10172 (Organon, low countries) and heparinase depolymerization products. Numerous biochemical and pharmacological tests were carried out. In protease generation tests these agents can exert antiprotease activity when anti-Xa and anti-IIa functional activities are totally absent: it can therefore be suggested that compounds that lack affinity for anti-III contribute to the biological activities of these agents. The LMWHF possess different profiles of platelet factor, protamine and polybrene neutralization. These agents produce platelet activation to various degrees and can produce heparins able to induce thrombocytopenia. Since heparin was chosen as reference products for LMWHF, numerous dosage problems were encountered. These agents also exhibit wide variations in hemorrhagic index in animal studies. Taking previous studies into account, these products could be improved to show a greater efficacy and safety level in clinical practice.

Blood Coagulation↗
PubMed1986

Heparin-induced platelet aggregation: dose/response relationships for a low molecular weight heparin derivative (PK 10169) and its subfractions.

Addition of heparin or heparin derivatives to citrate anticoagulated platelet-rich plasma caused platelet aggregation in a dose-dependent manner. Utilizing heparin, a low molecular weight heparin derivative (PK 10169) and its various subfractions, we determined dose/response relationships for platelet aggregation and found that the ability of these agents to cause platelet aggregation was dependent upon the molecular weight of the individual subfraction used. In comparison to unmodified porcine mucosal heparin, the lower molecular weight derivative (PK 10169) yielded a dose/response curve that was shifted down and to the right, and indicated that this agent was less potent in causing platelet aggregation. In addition, as the molecular weight of PK 10169 subfractions decreased, their dose/response curves were progressively shifted down and to the right. The lowest molecular weight subfraction was essentially without platelet aggregating activity. We also measured the anti IIa and anti Xa activities of these agents and concluded that these activities did not appear to correlate with platelet aggregating activity. Platelet aggregation studies with PK 10169 subfractions of high and low affinity for antithrombin III (AT III) indicated that the platelet aggregating activity of these compounds may not be related to their affinity for AT III, but results were not definitive.

Antithrombin III↗
PubMed1986

Effect of heparin and heparin fractions on experimental abscess formation.

To evaluate the effectiveness of heparin and heparin fractions in decreasing abscess formation, rats were divided into six groups. A fibrin clot containing 10(9) live Escherichia coli was placed in the peritoneal cavity of each rat. Group 1 (controls) received daily subcutaneous (SQ) injections of 0.1 mL of saline solution. Group 2 received daily intramuscular injections of gentamicin, 12.5 mg/kg. Group 3 received a daily SQ dose of 30 U of porcine heparin. In addition to gentamicin, group 4 received heparin, group 5 received heparin fraction PK10169, and group 6 received heparin fraction CY216, all in daily SQ doses of 30 U. Survivors were killed at ten days and examined for intra-abdominal abscesses. All group 1 animals developed abscesses. Abscess formation was significantly decreased in all groups receiving gentamicin. When used with gentamicin, neither heparin nor heparin fractions decreased the number of abscesses formed when compared with gentamicin alone. Heparin or heparin fractions in combination with gentamicin did decrease abscess size significantly when compared with controls.

Abscess↗
PubMed1986

Molecular markers of hemostatic activation in atherosclerosis: a new concept in diagnostic profiling of endogenous pathophysiologic transition.

Molecular markers of hemostatic activation provide a reliable measure of the endogenous pathophysiologic state in atherosclerosis. Measurement of these markers before and after exercise provides a diagnostic probe for cellular-vascular interactions in patients with atherosclerosis. Molecular markers may possibly identify very early stages of atherosclerosis due to their inherent sensitivity. A high-risk cardiovascular population can be easily recognized by profiling molecular markers of hemostatic activation. Newly developed immunoassays can be used to quantitate these markers in routine laboratories. Additional clinical studies are needed to establish the diagnostic role of these molecular markers in patients with atherosclerosis and related disorders.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Modulation of smooth muscle responses by serine proteases and related enzymes.

Standard isolated smooth muscle tissue preparations were used to screen the musculotropic actions of serine proteases and other substances that are generated during hemostatic activation. Sera obtained from human, rabbit, and guinea pigs produced a dose-dependent contraction of these isolated tissue preparations. These sera also augmented the actions of epinephrine and other agonists on different tissue preparations. Both contractile and relaxant actions of proteases were observed with various serine proteases and their complexes. Thrombins (alpha, beta, and gamma) produced varying degrees of contractile actions of rabbit aortic strips; however, Factor Xa produced a marked relaxation of this preparation. Trypsin and kallikrein did not produce any action on the aortic strip and thrombin, however, produced contraction of the guinea pig ileum. Protease complexes produced varying musculotropic actions on the isolated tissue preparations, which may be related to their composition. The musculotropic actions of serum and thrombin were not blocked by conventional pharmacologic antagonists. However, protease inhibitors, such as hirudin, D-Phe-Pro-Arginal, and other derivatives, produced varying effects of the musculotropic actions of serum and thrombins. These results indicate that thrombin and related proteases generated during the activation of the hemostatic system are capable of producing direct musculotropic actions of various smooth muscles. Various serine proteases and serine protease complexes were found to produce strong hemodynamic effects in a rabbit model for the study of blood plasma. The smooth muscle modulant actions of serine proteases should be taken into account to clarify the vascular pathologic changes in relation to spasmogenic and spasmolytic syndromes observed during hemostasis disorders.

Animals↗
PubMed1986

Coagulant versus amidolytic properties of human and bovine thrombins: implications in standardization and diagnostic usage.

Since the introduction of synthetic peptide substrates for thrombin, many amidolytic methods for the determination of AT III, heparin cofactor II, prothrombin, thrombin, platelet factor 4, and absolute levels of heparin have been proposed. All of these methods utilize thrombin that has been standardized in coagulant assays using either fibrinogen (human or bovine) or citrated plasma substrates. These thrombin preparations may contain noncoagulant forms of thrombin, prothrombin fragments, and other serine protease enzymes. Impurities other than variant forms of thrombin in commercial preparations may interact with antithrombin and other reagents altering the results of an assay. Similarly, the noncoagulant forms of thrombin contribute to amidolytic but not coagulant activity. If these parameters are not properly controlled, the assays based on amidolysis are seriously affected. Our studies on the amidolytic and coagulant properties of commercial thrombins suggest that, although these preparations are assigned their potency in NIH units, they vary greatly and do not truly exhibit the same potency as designated in the coagulant assays. In addition, these thrombin preparations show wide variations in their amidolytic actions toward synthetic chromogenic and fluorogenic peptide substrates. We propose that thrombin preparations for chromogenic and fluorogenic peptide assays should be standardized in terms of their amidolytic activity under defined conditions. In addition, further studies should be conducted to prove their efficacy in providing reliable diagnostic information in clinical laboratory assays.

Amidohydrolases↗
PubMed1986

Protein C antigen deficiency and warfarin necrosis.

Recent reports have suggested a correlation between congenital protein C deficiency and tissue necrosis complicating oral anticoagulants (warfarin necrosis). The authors studied blood samples of 13 patients, obtained two weeks to more than six months after warfarin necrosis. Protein C antigen levels were assayed by an enzyme-linked immunosorbent assay method (Diagnostica Stago, France). Factors II, VII, IX, and X were assayed by functional methods, and IX and X additionally by immunologic methods. The results show that 11 of 13 patients with a history of tissue necrosis had low protein C levels, ranging from 23 to 69%, with the normal range being 70-140%. These results confirm that low protein C antigen levels are implicated in the pathogenesis of warfarin necrosis.

Administration, Oral↗
PubMed1986

Biochemical and pharmacological studies on the interaction of PK 10169 and its subfractions with human platelets.

The interactions of heparin or its fractions with platelets that cause heparin-induced thrombocytopenia or in vitro platelet activation are poorly understood. We have shown that a low molecular weight derivative of heparin (PK 10169) and its subfractions can cause in vitro activation of platelets from normal human donors. This activation process is molecular-weight-dependent and involves the generation of thromboxane. We have also examined the effect of the serum from a patient with immune heparin-induced thrombocytopenia on normal donors' platelets incubated with heparin, PK 10169 or subfractions of PK 10169. It was found that the patient's serum induced aggregation of normal donor platelets in the presence of heparin, PK 10169 or certain subfractions of PK 10169. This process also appears to be mediated by thromboxane generation.

Antithrombin III↗
PubMed1986

Laboratory studies on the intravenous and subcutaneous administration of PK 10169 in man.

Intravenous and subcutaneous administration of PK 10169 in healthy human volunteers were studied utilizing numerous old and new laboratory methods for the monitoring of the effects of this agent. In the intravenous studies, individual groups of 10 healthy volunteers were administered with 2,500-12,500 anti-Xa units (25-125 mg) PK 10169 as a single bolus, and blood samples were drawn at 30 min, 1, 4 and 24 h after the administration of the drug. In the subcutaneous studies, 4,000 anti-Xa units (40 mg) b.i.d. of PK 10169 were administered to a group of 10 healthy individuals for 7 consecutive days, and blood samples were drawn 6 h after each dose. Citrated blood samples collected from both studies were centrifuged, plasma was frozen at -70 degrees C in aliquots, and various laboratory parameters were determined in batches. In the intravenous studies, the global clotting assays (activated partial thromboplastin time and thrombin time) were only prolonged at initial stages of treatment, whereas a marked increase in the antiprotease and antifibrinopeptide A generation activity titer was observed for periods of up to 24 h. In the subcutaneous studies, no significant prolongation of the global clotting assays was noted; however, the anti-Xa levels were significantly increased throughout the study period (7 days). Only a trace of anti-IIa activity was observed. In contrast, a strong antifibrinopeptide A generation activity was observed in all samples which persisted after the discontinuation of PK 10169. These studies suggest that PK 10169 may exert its clinical effects by multiple mechanisms which are only partially assessable by routine laboratory methods.

Blood Coagulation↗
PubMed1986

In vitro evaluation of heparin fractions: old vs. new methods.

Conventionally, heparin has been evaluated for its anticoagulant effect by various nonspecific, poorly standardized coagulant methods such as the U.S. Pharmacopeial and other global (APTT) tests. However, these assays are relatively insensitive to heparin fractions and fragments, and give varying with the newer modes of heparin administration. It has become necessary, therefore, to develop other methods able to detect a proper therapeutic/prophylactic level and to evaluate a standard potency for these agents. Newer amidolytic assays utilizing synthetic substrates provide for specific anti-factor Xa or anti-factor IIa evaluation. Although these factors are believed to reflect the antithrombotic effect of heparin and its fractions/fragments, conclusive clinical studies are not available at this time. Interactions with non-AT-III-mediated pathways, the contact, kallikrein-kinin, and fibrinolytic system, other coagulant factors, endothelium, and eicosanoid system all can contribute to the overall antithrombotic response of heparin. Some of these actions are not measurable by current in vitro test methods. Amidolytic, immunochemical, and physical assays using various activators to generate endogenous factor Xa, as well as assays for the detection of metabolic or release products of each of these systems, may be more relevant to in vivo conditions. Specific low molecular weight markers such as fibrinopeptide A, which provide the earliest detection of hemostatic activation, can be measured directly, or an in vitro system can be developed to quantitate the relative generation of these markers. These methods can then be modified to assay the in vitro potency of heparin preparations. With proper consideration of reagent specificity and concentration, molecular interactions, reaction time and temperature, ionic type and concentration, reliable accurate methods for a true in vitro representation of in vivo events may be developed. Clinical assays must measure an endogenous response to therapy and not merely an absolute circulating level of drug. However, a standardized pure enzyme system may be ideal to evaluate the potency of these agents. The development of heparin derivatives necessitates a reassessment of currently practiced laboratory technology. Furthermore, well-defined biochemical methods are required for a standardized evaluation of potency and clinical monitoring of these agents.

Blood Coagulation↗
PubMed1986

Assessment of thrombogenicity of activated and non-activated prothrombin concentrates in a rat model.

In vitro clotting activity of rats injected with different preparations of prothrombin concentrates was measured. Animals rendered deficient in vitamin K-dependent coagulation factors by early coumadin (warfarin) pretreatment, followed by injections of concentrate preparations were also evaluated. Findings indicate a dose-related response in abnormal coagulation changes demonstrable with each preparation and lack of protection of intravascular coagulation by coumadin anticoagulation. Furthermore, a role for in vivo factor VII activation of haemostasis following concentrate administration could not be elicited.

Animals↗