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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 145 records · Page 8Linked to original sources
PubMed1996

Thromboembolic diseases: biochemical mechanisms and new possibilities of biological diagnosis.

The diagnosis of thromboembolic diseases is still difficult to establish before the occurrence of the pathological event, although it is now known that they are the result of a progressive alteration of the cardiovascular system. Introduction of new diagnostic tools for the evaluation of the thromboresistance capacity of the body or for the measurement of molecular markers allows the testing of the body defenses against thrombosis which is becoming a routine clinical diagnosis. Antithrombin III (AT III), protein C, protein S, and parameters of fibrinolysis have been recognized to be very important anticoagulant proteins and regulators of thrombin formation and thrombus extension. Furthermore, a normal factor V is necessary for the normal function of the protein C pathway. The presence of a factor V mutation leads to the activated protein C resistance syndrome. However, the major incidence of thrombotic events concerns the overall population. It has been epidemiologically related to the existence of risk factors producing blood activation, which progressively saturates the body's thromboresistance. This period is clinically silent for a long time. The new molecular markers recently introduced can show the existence of a preclinical state of blood activation at the plasma level (fibrinopeptide A, thrombin-antithrombin complexes, modified antithrombin III, fragments 1 + 2 of prothrombin, D-dimer) or at the platelet level (B-thromboglobulin, platelet factor 4, and thrombospondin), and promising developments concern the endothelial level (soluble thrombomodulin). The most universally used blood activation test is the D-dimer assay. This analyte has become very popular in past years for its high sensitivity, its long half-life, and its easy detection directly on citrated plasma. Its negative predictive value (in deep venous thrombosis or pulmonary embolism) as well as its use for monitoring of thrombotic risk in the post-operative period have been well documented clinically. New investigations are initiated to find analytes reflecting endothelial damage, an early platelet activation, or the involvement of blood cells (mainly monocytes and neutrophils) in abnormal processes. It also becomes possible to evaluate directly pathological causes inducing blood activation, such as the presence of antiphospholipid antibodies or other autoimmune antibodies.

Biomarkers↗
PubMed1996

Are the available low-molecular-weight heparin preparations the same?

Low molecular weight heparins (LMWHs) are now universally accepted as drugs of choice for post-surgical prophylaxis of DVT. Currently these agents are also being developed for therapeutic and cardiovascular indications. Because of manufacturing differences, each of the LMWHs exhibit distinct pharmacologic and biochemical profiles. The specific activity of these agents in the anticoagulant assays ranges from 35 to 45 anti-IIa U/mg whereas the specific activity in terms of anti-Xa units is designated as 80 to 120 anti-Xa U/mg. These LMWHs are capable of producing product specific dose and time dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at dosages that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In the experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous (i.v.) and subcutaneous (s.c.) administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects; however, the hemorrhagic responses vary and are largely dependent on products. The release of TFPI following i.v. and s.c. administration in a primate model also demonstrated the product individuality and the relevance of this inhibitor to the actions of LMWHs. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT also exhibited product based augmentation of the antithrombotic or hemorrhagic effects. Antithrombotic and hemorrhagic studies are reported that compare the pharmacologic profile of some of the available LMWHs. Product individuality in terms of relative potency in different assays and the failure of standardization protocols to provide any guidelines for product substitution and prediction of the clinical effects is also addressed.

Animals↗
PubMed1996

Recombinant full-length tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis.

In the jugular vein of rabbits thrombus formation was induced by vessel wall damage using a balloon catheter and following reduction of blood flow by 80-90% for 60 min (partial stasis). The blood flow in the vein was measured continuously and the incidence of primary thrombus formation, the time until lysis with recombinant tissue-type plasminogen activator (rt-PA) as well as the incidence of rethrombosis after lysis were determined. At the end of the experiment the wet weight of the thrombus formed inside the vessel was measured. For the determination of haemostaseological parameters blood was drawn from the cannulated femoral artery. Recombinant full-length tissue factor pathway inhibitor (TFPI) was studied with regard to its effect both on primary thrombus formation and on rethrombosis after lysis. In control animals damage of the vessel wall combined with partial stasis led to the formation of occlusive venous thrombi. In vitro bolus injection of TFPI (5, 10, 20 micrograms/kg) at the time of thrombus induction prevented the formation of venous thrombi during the 1 h period of partial stasis. In the subsequent observation period a dose-dependent inhibition of later occurring partial or complete thrombotic occlusion was found. At the dose of 20 micrograms/kg i.v. in all animals TFPI prevented a complete thrombotic occlusion of the vein up to 3 h after stasis. To study the effectiveness of TFPI on rethrombosis after lysis TFPI was injected i.v. after lysis of the thrombus with rt-PA (600 micrograms/kg i.v. bolus + 600 micrograms/kg i.v. infusion over 60 min). In saline treated control rabbits a reocclusion of the vessel was seen in 8 of 10 animals. TFPI (10, 20, 40 micrograms/kg i.v.) injected at the end of rt-PA administration caused a dose-dependent inhibition of thrombotic reocclusion after lysis. At 40 micrograms/kg i.v. the formation of occlusive thrombi was prevented up to 3 h after lysis. TFPI at the doses used caused modest anticoagulant effects in global clotting assays; activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) were only slightly prolonged. A clear and dose-dependent prolongation of clotting times was only seen in the Heptest assay. The results show that the physiologic coagulation inhibitor TFPI acts as a strong antithrombotic agent in an experimental model of venous thrombus formation and thrombotic reocclusion after lysis in rabbits.

Animals↗
PubMed1995

Comparative study on the use of anticoagulants heparin and recombinant hirudin in a rabbit traumatic anastomosis model.

Antithrombotic drugs, such as heparin, have been used in the clinics for a long time. Heparin acts by binding with antithrombin III to form a complex thereby enhancing the activity of antithrombin III to inactivate coagulation factors IIa, IXa, Xa, XIa and XIIa. Hirudin is a new antithrombotic agent and is reported to be much more powerful than heparin on a gravimetric basis. When both are administered systemically, one of the common complications seen is bleeding. Some previous studies have shown that local vascular endothelial concentrations of heparin are 30 to 7500 times greater than those found in the circulating blood. In order to avoid such complications, topical administration of antithrombotic drugs may be an ideal route of administration. The rabbit ear arterial crush-avulsion thrombosis model was used in this study. The animals were divided into five groups: one control group and four treatment groups which received varying concentrations of heparin and hirudin. In the saline control group, the patency rate was 19.23% at 24 hrs and 15.38% at 7 days. A higher patency rate at 7 days was obtained in groups treated with high concentration of heparin and hirudin. ACT, PT and APTT performed on samples drawn one hour after drug administration were within the normal range in both the control and the treatment groups. Scanning electron microscopy revealed the different extent of the clots on the injured intimal surfaces of the vessels in different groups. The results indicate that high concentrations of topically administered heparin or hirudin minimize the systemic complications and maximize the antithrombotic effects.

Administration, Topical↗
PubMed1995

Anticoagulant and antithrombotic actions of a semisynthetic beta-1,3-glucan sulfate.

Sulfation of the natural polysaccharide curdlan results in anticoagulantly active beta-1,3-glucan sulfates whose activity depends on various structural parameters. In this study the anticoagulant and antithrombotic effects of one of these beta-1,3-glucan sulfates (GS) were compared with those of a porcine mucosal heparin. GS produced a concentration dependent anticoagulant effect in all the global coagulation assays with the exception of the anti-Xa assay. The best activity was found in the APTT and the thrombin time assays indicating that protease generation and the direct inhibition of thrombin may be sites of actions of this agent. Whereas the anticoagulant activity of GS was approximately 5 fold lower compared to heparin, a 32 fold higher concentration (ED50 = 550 micrograms/kg) was needed for an antithrombotic effect similar to heparin (ED50 = 17.2 micrograms/kg) in a rabbit model of stasis thrombosis. In contrast to this, when a rat model of clamping induced jugular vein occlusion was used to produce vascular obstruction, GS produced similar antithrombotic actions to heparin. At a 250 micrograms/kg dosage, both agents doubled the number of clampings required for complete vascular obstruction. Since the mechanical injury to the blood vessel is the primary determinant of the thrombogenic response, GS may inhibit some of the pathophysiologic mechanisms responsible for the occlusion of the blood vessel. The current study also points to the fact that the global anticoagulant effects may not reflect the antithrombotic potential of newer sulfated carbohydrate derived drugs.

Animals↗
PubMed1995

TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin.

Tissue factor pathway inhibitor (TFPI) is an important mediator of the in vivo anticoagulant/antithrombotic properties of unfractionated heparin (UFH) and low molecular weight heparin (LMWH). The vascular pool of TFPI is released into the circulation after intravenous and subcutaneous administration of both UFH and LMWH. We have administered LMWH (Ardeparin) and UFH to normal human volunteers in a dose dependent manner. Our results demonstrate that the TFPI antigen levels increase upon the intravenous and subcutaneous administration of UFH and Ardeparin. Because of the better bioavailability of LMWH by the subcutaneous route at equigravimetric dosages, Ardeparin released more TFPI than UFH. However, when given intravenously an identical release of TFPI from the vasculature has been observed. The plasma concentration of TFPI was increased 0.5-2 fold when UFH or Ardeparin was administered subcutaneously and was 3 fold higher when administered intravenously. This profound increase in TFPI antigen levels was dependent on the dosage of Ardeparin administered. This release in TFPI correlates with prolongation of the Heptest clotting assay. However, it appears from this study that TFPI release precedes the elevation of the Heptest clotting time.

Adult↗
PubMed1995

Molecular profiling and weight determination of heparins and depolymerized heparins.

The recently proposed calibrant LHN-1 (lot F537; henceforth designated F537), for the molecular weight (MW) determination by high-performance size-exclusion chromatography of heparins, is shown here to have a range too narrow to allow for the accurate MW determination of all low molecular weight heparins (LMWHs). We have recently demonstrated, by this same methodology, that a chemically degraded benzyl ester of unfractionated heparin, heparin mass calibrator (HMC), is a better calibrant. Weight-average MW, number-average MW, peak MW, and dispersity values were calculated with F537, HMC, and by a reference narrow-range-calibration method for various LMWHs and unfractionated heparins. Values for these parameters determined with HMC were not significantly different from those determined by the reference method until the MW of the substance exceeded 15.0 kDa. In contrast, the MW profile obtained with F537 was appreciably different from that obtained by the reference method for samples with MWs > 7.5 kDa. The range exhibited by HMC should allow this calibrant to be used for both LMWHs and unfractionated heparins.

Heparin↗
PubMed1995

Modified crush-avulsion anastomosis model on the rat femoral vein.

A crush-avulsion anastomosis model was established on the rat femoral vein. Saline or heparin was used as a luminal topical agent and was allowed to contact the damaged endothelium for 10 min. Patency and coagulation parameters were investigated for 1 week. The heparin treated group had a patency rate of 93% at 1 hr vs. 13% for the saline treated group (P < 0.001). At 7 days, the heparin treated group had an 87% patency vs. 7% for the saline-treated group (P < 0.001). Scanning electron micrography (SEM) provided evidence of the deposition of the components of early thrombosis in the crushed venous wall. In contrast, the SEM of the heparin treated group shows a paucity of any evidence of thrombus. These results indicate that the rat vein crush-avulsion model is a reliable and reproducible thrombosis model with low patency. The methods used with the topical agent may improve the patency rate in crush avulsion injuries.

Anastomosis, Surgical↗
PubMed1995

Impact of biotechnology in the diagnostic and therapeutic management of cardiovascular disorders.

Although biotechnology has been useful in the development of new diagnostic methods and drugs for the management of cardiovascular disorders, there are several issues which raise certain questions on the global use of biotechnology based drugs and diagnostic methods (Piascik, 1991; Fareed, 1993a; Fareed, 1994a). The cost is rather prohibitive in the development of this type of technology. Most diagnostic methods and drugs developed utilizing biotechnology based methods are relatively expensive. The second important consideration is the equivalence of the newer biotechnology derived drugs to the natural products. Many of the biotechnology derived drugs are obtained in prokaryotic systems (E. coli). Post-transcriptional modifications such as glycosylation are often important in determining the function of various proteins. On the other hand, biotechnology based diagnostic methods exhibit somewhat different specificity in comparison to conventional methods. Thus, it is rather important to assess the developments in this area in a careful manner. Furthermore, validation of the clinical, diagnostic and therapeutic efficacy of biotechnology derived diagnostic devices and drugs is a prerequisite for their use in cardiovascular medicine.

Amino Acid Sequence↗
PubMed1995

A comparative study on the mechanism of the anticoagulant action of mollusc and mammalian heparins.

The anticlotting activities on some steps of the coagulation cascade of mollusc and mammalian heparins were studied. AT III-high affinity heparin is a more potent inhibitor than unfractionated heparin and mollusc heparin in the intrinsic and extrinsic pathways of thrombin and factor Xa generation. Mollusan heparin has about the same activity as the AT III high affinity-heparin on the inhibition of factor Xa and thrombin in the presence of antithrombin III and four times more inhibitory activity than unfractionated heparin on the heparin cofactor II mediated inhibition of thrombin.

Animals↗
PubMed1995

Modifications of plasma levels of tissue factor pathway inhibitor and endothelin-1 induced by a reverse Trendelenburg position: influence of elastic compression--preliminary results.

PURPOSE: The purpose of this study was to assess the effects of the passive 45-degree reverse Trendelenburg position and graduated compression stockings (GCS) on plasma tissue factor pathway inhibitor (TFPI) and endothelin-1 levels in a group of volunteers. METHODS: Ten healthy subjects lay on an examining table for 30 minutes while baseline measurements were made. The table was then tilted to a 45-degree upright position for 60 minutes, and measurements were repeated. On a different day, subjects were tilted again, but on this occasion they wore thigh-length GCS. Blood was drawn before and 60 minutes after tilting during both sessions, and plasma TFPI and endothelin-1 were obtained. Cross-sectional areas of the calf medial gastrocnemius vein, before and after tilting, were measured by a duplex scanner. RESULTS: Upright tilting induced a significant dilation of the medial gastrocnemius veins that was partially corrected by the use of elastic stockings. Similarly, endothelin-1 levels significantly increased after tilting. The use of GCS did not modify these differences. On the other hand, although TFPI levels were not affected by tilting without stockings, they were significantly elevated after tilting when GCS were used. CONCLUSIONS: Upright passive tilting induces significant dilation of the deep calf veins and is associated with a significant increase in plasma levels of endothelin-1, whereas TFPI levels remain unchanged. The use of elastic stockings reduces the degree of calf distention but does not prevent an increase in endothelin-1. TFPI levels are significantly increased after tilting when GCS are used. This might represent a previously unknown mechanism of action of elastic stockings with interesting potential for deep vein thrombosis prophylaxis. More studies are warranted in a larger series to confirm these results.

Adult↗