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J M Walenga

Publications and source records attributed to J M Walenga.

At least 73 records · Page 4Linked to original sources
PubMed1998

Low molecular weight heparins: are they different?

In addition to their use in postsurgical and medical prophylaxis of deep vein thrombosis (DVT), low molecular weight heparins (LMWHs) are being developed for cardiovascular and cerebrovascular indications. Because of manufacturing differences, each LMWH exhibits distinct pharmacological and biochemical profiles that may influence clinical performance. The specific activity of these agents in anticoagulant assays ranges from 35 to 45 anti-IIa U/mg or 80 to 120 anti-Xa U/mg. 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 antithrombotic doses, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects. However, the hemorrhagic responses vary and are largely product dependent. The product-dependent release of TFPI following intravenous and subcutaneous administration in a primate model also demonstrates the relevance of this inhibitor to the actions of LMWHs. The effect of repeated administration of LMWH mimicking the postsurgical prophylaxis of DVT exhibited product-based augmentation of the antithrombotic or hemorrhagic effects.

Animals↗
PubMed1997

Effect of glycoprotein IIb/IIIa antagonists on the HIT serum induced activation of platelets.

Heparin-induced thrombocytopenia is an increasingly common side effect associated with heparin usage. In the more severe manifestation of the syndrome, patients can develop thrombosis; a 10% mortality is associated with heparin induced thrombocytopenia. To date, the therapeutic options for patients with heparin-induced thrombocytopenia are limited. Glycoprotein IIb/IIIa inhibitors have been shown to block platelet aggregation induced by a wide variety of agonists. The ability of antibody and synthetic small molecule inhibitors of glycoprotein IIb/IIIa to block in vitro activation and aggregation of platelets in response to heparin-induced thrombocytopenia positive serum/heparin was examined using flow cytometry, platelet aggregometry, and luminescence aggregometry. Abciximab, YM 337, and SR 121566A were each found to inhibit platelet microparticle formation and P-selectin expression in whole blood, in response to heparin-induced thrombocytopenia positive serum/heparin. In a platelet rich plasma system, the platelet aggregation response was inhibited by all three agents. The IC50 for inhibition of heparin-induced thrombocytopenia positive serum/heparin induced platelet aggregation by SR 121566A was 18 nM, a concentration which was 4 to 8 fold lower than that observed for collagen and arachidonic acid induced aggregation. Adenosine triphosphate release from activated platelets, as measured by luminescence aggregometry, was concentration-dependently inhibited by SR 121566A. These results suggest that glycoprotein Ilb/IIIa inhibitors may be beneficial in the management of heparin-induced thrombocytopenia and warrant further investigation.

Benzylamines↗
PubMed1997

Efficacy of pentasaccharide in a dog model of hemodialysis.

A synthetic heparin pentasaccharide with sole anti-Xa actions has been evaluated for its antithrombotic efficacy in a dog model of hemodialysis. Various dosages of pentasaccharide, 400-800 nmol/kg, were compared with a single bolus dose of unfractionated heparin (250 U/kg). The primary endpoint in these studies was the duration of dialysis time. In addition, dialyzer filter content, venous trap protein, celite and saline ACT and hematocrit measurement. Pentasaccharide at dosages of 600 and 800 nmol/kg produced an extension of dialysis time (> 180 minutes) in contrast to unfractionated heparin at 250 U/kg which only produced antithrombotic effects for periods of up to 150 +/- 42 minutes (n = 5). At a lower dosage of 400 nmol/kg pentasaccharide produced weaker effects and the dialysis circuit was patent for periods of 122 +/- 14.8 (n = 5) minutes. The saline and celite ACT times were not extended at any dosage of pentasaccharide; however, at 250 U/kg, a strong effect was noted with unfractionated heparin (> 800 secs, 647 +/- 211 secs.), respectively. A dose dependent antithrombotic effect was also evident in the studies on the filter clots and venous trap protein content. No difference in the hematocrit was noted in any group. These results clearly suggest that despite the fact that pentasaccharide does not produce any prolongation of the coagulation times, it produces a dose dependent antithrombotic effect in this model of dog hemodialysis. Furthermore, these results also suggest that pentasaccharide at an appropriate dosage can be used as an alternate antithrombotic agent during hemodialysis.

Animals↗
PubMed1997

In vitro studies on the effect of activated protein C on platelet activation and thrombin generation.

The effect of activated protein C (APC) on agonist-induced platelet activation and on thrombin generation after intrinsic (IA) and extrinsic (EA) activation of the coagulation system was studied by flow cytometry and by measuring levels of prothrombin fragment F1+2. In platelet activation studies blood drawn from healthy volunteers was anticoagulated with 10 micrograms/ml APC and incubated at 37 degrees C either with saline, recombinant tissue factor (r-TF), arachidonic acid (AA), ADP or collagen. At definite times aliquots were taken and processed for flow studies. Platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed platelet activation after all agonists used. APC did not influence AA-, ADP- and collagen-induced platelet activation but completely inhibited activation of platelets induced by r-TF. The effect of APC on r-TF-mediated platelet activation was concentration-dependent in the range of 0.5 to 20 micrograms/ml showing an increase in CD-62 expression at lower concentrations. In citrated and APC-anticoagulated blood the generation of thrombin was studied after IA and EA. At 10 and 20 micrograms/ml APC effectively prevented blood clotting which rapidly occurred especially after EA. The amount of thrombin generated via the extrinsic pathway was reduced by APC whereas after IA F1+2 levels measured in the presence of APC were still strongly increased. These results indicate that small amounts of thrombin generated by r-TF are sufficient to activate platelets as well as blood coagulation. APC exerts strong concentration-dependent anticoagulant actions and effectively prevents activation of platelets.

Cells, Cultured↗
PubMed1997

Anticoagulation with Novastan (argatroban) in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome.

Heparin-induced thrombocytopenia (HIT) is a syndrome that has been identified with increased frequency. The mortality associated with HIT approaches 35%. Previous strategies for treatment of the associated thrombosis with HIT have frustrated clinicians with poor outcomes. Recent awareness of the complex pathophysiology of HIT combined with the availability of new anticoagulants has led to the development of a rational therapeutic strategy for this group of patients. The foundation of this strategy involves thrombin inhibition and careful patient monitoring. Our preliminary results with the thrombin inhibitor argatroban (Novastan) have been favorable and warrant continued investigation.

Antibodies↗
PubMed1997

Current status on new anticoagulant and antithrombotic drugs and devices.

Several new drugs for the management of thromboembolic disorders have recently become available. Low-molecular-weight heparins are being evaluated for the prophylaxis of medical and surgical deep venous thrombosis and pulmonary embolism; for the treatment of pre-existing thrombosis; and for cases of coronary syndrome (unstable angina, myocardial infarction), thrombotic and ischemic stroke, interventional cardiology, pregnancy, cancer, and transplantation-associated thrombosis. A chemically synthesized heparin pentasaccharide, which has purely anti-factor Xa activity and does not induce thrombocytopenia, is also in clinical trial. Thrombin inhibitors, such as hirudin and argatroban, are a practical anticoagulant substitute where heparin cannot be used. They are also useful for the management of coronary syndrome and as adjunct therapy. The antiplatelet agent ticlopidine and its analogue, clopidogrel, which does not produce blood dyscrasia, are effective for the secondary prevention of thrombotic stroke and the management of combined arterial thrombotic syndromes. Glycoprotein-targeting antibodies, synthetic derivatives, and peptides (some of which are orally bioavailable) have added a new dimension to the management of arterial thrombosis and high-risk patients having angioplasty. Plasma-derived agents, such as antithrombin III, are available for the management of thrombophilia and disseminated intravascular coagulation. Compression devices and the foot pump, alone and in combination with pharmacologic agents, have been used successfully. Combination therapy using various agents in different proportions have also been found useful. Although there is much enthusiasm in this quickly developing area and clinical trials are demonstrating the antithrombotic efficacy of the new drugs, safety considerations require additional clinical validation. Long-term outcomes and costs also need to be addressed objectively.

Adult↗
PubMed1997

Low molecular weight heparins: a developmental perspective.

Low molecular weight heparins (LMWHs) are now universally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently these agents are also being developed for the treatment of thrombosis and various cardiovascular indications. Due to manufacturing differences, each of the LMWHs exhibits a distinct pharmacological and biochemical profile. The specific activity of these agents in the anticoagulant assays ranges from 35 - 45 anti-IIa U/mg, whereas the specific activity in terms of anti-Xa units is designated as 80 - 145 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 doses that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both iv. and sc. administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects; however, the haemorrhagic responses vary and are largely dependent on the product used. The release of TFPI following iv. and sc. administration in a primate model also demonstrates product individuality and the relevance of this inhibitor to the actions of LMWHs. Furthermore, repeated administration, mimicking the post-surgical prophylaxis of DVT, leads to product-based augmentation of the antithrombotic or haemorrhagic effects. Antithrombotic and haemorrhagic studies are discussed, comparing the pharmacological profile of some of the available LMWHs. Product individuality, in terms of relative potency in different assays and the failure of standardisation protocols to provide any guidelines for product substitution and prediction of the clinical effects, is also addressed.

Journal Article↗
PubMed1996

Flow cytometric evaluation of the effect of various thrombin inhibitors on platelet activation in whole blood.

In an in vitro study the effect of various thrombin inhibitors (argatroban, efegatran, DuP 714, recombinant hirudin and PEG-hirudin) on platelet activation in whole blood was investigated. Blood was drawn from normal human volunteers using the double syringe technique without use of a tourniquet to avoid autoaggregation of platelets. Blood was anticoagulated with either argatroban, efegatran, DuP 714, hirudin or PEG-hirudin at final concentrations of 10 micrograms/ml. Blood samples were then incubated at 37 degrees C either with saline, r-tissue factor, arachidonic acid, adenosine diphosphate or collagen. At definite times (1, 2.5, 5, 10 min) aliquots were taken and after various steps of fixative procedure the percentage of platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed a platelet activation after all agonists used. All thrombin inhibitors studied caused a nearly complete inhibition of r-tissue factor-mediated platelet activation. In contrast, after activation with the other agonists an increased percent CD-62 expression was found with a maximum after 2.5 to 5 min. The results show that in whole blood thrombin inhibitors are effective in preventing platelet activation induced by r-tissue factor. The formation of active serine proteases including thrombin may be effectively inhibited by these agents. The observations further suggest that while thrombin inhibitors may control serine proteases, these agents do not inhibit the activation of platelets mediated by other agonists.

Adenosine Diphosphate↗
PubMed1996

Aprotinin modulation of platelet activation in patients undergoing cardiopulmonary bypass operations.

BACKGROUND: Aprotinin significantly decreases postoperative blood loss, yet its exact mechanism of action remains unproven. METHODS: To study the cytoprotective effect on platelets, we collected blood samples from patients during cardiopulmonary bypass (CPB) operations performed with or without aprotinin. Analysis included whole-blood flow cytometry. RESULTS: The highest percentages of activated platelets (positive for GMP-140 expression) were bound to leukocytes and erythrocytes in all CPB patients. Platelet-platelet activation did not reveal any marked differences between groups. However, in the platelet-cell bound region, increased ristocetin-stimulated platelet activation was observed from 30 minutes on CPB to 90 minutes after CPB with aprotinin (11.9% +/- 5.1% to 33.1% +/- 8.6%; p < 0.05), but not without aprotinin (17.5% +/- 0.1% to 17.9% +/- 2.3%). Platelet autoactivation increased more in the untreated group with time on CPB. CONCLUSIONS: This study demonstrates that in the presence of aprotinin, platelets remain unstimulated during CPB and the von Willebrand GPIb-mediated activatability of platelets is preserved, thus maintaining a viable platelet population. Most important, this study reveals that these mechanisms are more related to platelet-leukocyte than to platelet-platelet interactions.

Adult↗
PubMed1996

Efficacy of aprotinin with various anticoagulant agents in cardiopulmonary bypass.

BACKGROUND: Aprotinin has recently been approved for clinical use in cardiopulmonary bypass. Although unfractionated heparin has been the only anticoagulant widely used for cardiopulmonary bypass, disadvantages involving heparin have led to ongoing investigations of alternative anticoagulant agents. METHODS: The objective of this study was to evaluate the efficacy of aprotinin in combination with other anticoagulant agents, specifically low molecular weight heparin and recombinant hirudin, using a dog model of cardiopulmonary bypass. RESULTS: The blood conservation resulting from the use of aprotinin was observed only with unfractionated heparin. Efficacy of anticoagulation as measured by protein deposits in the bypass circuit filter revealed an unexpected reduction in the quantity of deposits when aprotinin was used in combination with low molecular weight heparin. CONCLUSIONS: As alternative anticoagulant agents are sought, the potential benefits of aprotinin in the reduction of operative blood loss must be evaluated independently for each anticoagulant agent.

Animals↗
PubMed1996

Plasma levels of the molecular markers of coagulation and fibrinolysis in patients with peripheral arterial disease.

In 103 patients with peripheral arterial disease (PAD) of the lower limbs, coagulation and fibrinolytic parameters were evaluated to identify hemostatic abnormalities characteristic of this patient population. PAD was defined as clinically stable Leriche stage 2 (based on clinical history, peripheral pulses, ankle-arm index, and treadmill test) for at least 3 months, walking distance > 100 m, and no other major illnesses, rest pain, or trophic lesions. Defibrotide, a polydeoxyribonucleotide derivative with vascular effects, was administered to the patients as part of a multicenter trial. The PAD patients exhibited a prothrombotic state as evidenced by high D-dimer in all but 24% of the patients (average 797 +/- 802 vs. 163 +/- 54 ng/mL normal population; p < 0.001) and high thrombin-antithrombin III complex (TAT) levels (10.2 +/- 8.9 vs. 2.5 + 1.5 ng/mL; p < 0.001) with low to normal levels of protein C (86 +/- 25 vs. 102 +/- 18%; p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) antigen (5.9 +/- 4.5 vs. 1.3 + 0.7 ng/mL; p < 0.001) were elevated in 79% of the patients. These results suggest that there is ongoing thrombosis in the majority of PAD patients. Differences from normal controls were observed for t-PA, PAI-1, protein C, and protein S; however, it is not certain that the thrombosis in patients with PAD is due to these factors.

Adult↗
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↗
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

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

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↗