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Biomedical subjects

V J Marder

Publications and source records attributed to V J Marder.

At least 19 recordsLinked to original sources
PubMed2006

Risk of excessive bleeding associated with marginally low von Willebrand factor and mild platelet dysfunction.

BACKGROUND: Bleeding symptoms are so commonly reported that it is not known whether they associate causally or coincidentally with mild but measurable primary hemostatic defects. OBJECTIVES/PATIENTS/METHODS: In order to evaluate if the mild primary hemostatic defects are truly causative of increased bleeding symptoms, we surveyed a population of healthy teenagers for bleeding symptoms. Using a case-control approach, we then estimated the risk of excessive bleeding associated with low von Willebrand factor (defined as VWF below the 5th percentile of a normal reference population), and with mild platelet dysfunction [PD, defined as concurrent reduced platelet aggregation responses to two agonists (adenosine diphosphate and epinephrine)]. RESULTS: Excessive bleeding was present in 63 out of 809 teenagers (7.8%). Among the 49 cases who were tested for VWF, low values by three measures were more commonly present than in 166 controls, specifically, ristocetin cofactor (RCo) activity [20.4% vs. 5.4%, odds ratio (OR) 4.5], collagen binding (14.3% vs. 4.2%, OR 3.8), and antigen level (20.4% vs. 6.0%, OR 4.0). The low RCo values ranged from 35 to 45 U dL(-1) except for a single case with 26 U dL(-1). Of the 47 teenagers with excessive bleeding who underwent platelet aggregation studies, reduced responses were more common than in controls (12.8% vs. 4.4%, OR 3.2). Twenty-nine per cent of cases with excessive bleeding had either low RCo or PD. CONCLUSION: Almost one in three teenagers who report excessive bleeding is likely to have a measurable hemostatic disturbance manifested either by marginally low VWF (by three measures) or by mild PD.

Adolescent↗
PubMed2006

Magnesium sulfate neither potentiates nor inhibits tissue plasminogen activator-induced thrombolysis.

BACKGROUND: Increasing circulating magnesium concentrations to 2-fold over normal baseline may afford a neuroprotective effect in patients with acute cerebral ischemia. OBJECTIVES: As patients receiving magnesium sulfate (MgSO(4)) in human clinical trials may also be candidates for subsequent thrombolytic therapy with tissue plasminogen activator (t-PA), preclinical assessment of possible inhibition or potentiation of fibrinolytic activity by MgSO(4) has important clinical relevance. METHODS: We utilized an in vitro system, in which D-dimer release served as a reflection of t-PA-induced clot lysis, to measure the effect of magnesium at the target concentration being tested in human stroke clinical trials, and at 2- and 3-fold higher levels. Clots from normal volunteers were exposed to t-PA at concentrations that correspond to therapeutic or endogenous plasma t-PA levels. RESULTS: MgSO(4) had no effect on t-PA-induced clot lysis at up to 3-fold target magnesium concentration (6x normal serum concentration). CONCLUSIONS: MgSO(4) concentrations well above the targeted level in therapeutic stroke trials does not affect t-PA-induced fibrinolytic activity, and therefore is a suitable agent for trials of combined neuroprotective and thrombolytic therapy in patients with acute ischemic stroke.

Dose-Response Relationship, Drug↗
PubMed2003

Life-threatening thrombotic thrombocytopenic purpura (TTP) in a patient with sickle cell-hemoglobin C disease.

We report a patient with hemoglobin sickle cell-hemoglobin C disease who developed the clinical syndrome of thrombotic thrombocytopenic purpura (TTP) during admission for typical acute pain crisis. The potential for multiorgan involvement secondary to vaso-occlusive crisis complicated the diagnosis and overlapped with the patient's clinical presentation of chronic bone pain and hemolytic anemia. Clinical improvement and normalization of laboratory parameters followed rapidly in response to plasma exchange therapy.

Adult↗
PubMed2003

Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin.

While protamine sulfate reverses the anticoagulant effect of standard heparin, there currently is no effective antidote for low molecular weight heparin (LMWH)-induced bleeding. Recently, recombinant activated factor VII (rFVIIa) was approved by the FDA for use in hemophilia patients with factor (F)VIII or FIX inhibitors. However, this new pro-hemostatic agent has potential utility in other clinical scenarios. In this study, we utilized a well-characterized rabbit ear puncture model to test the efficacy of rFVIIa to reverse LMWH-induced prolonged bleeding. Animals were first treated with bolus intravenous LMWH (1800 anti-FXa U kg(-1)) which increased the primary bleeding time approximately fourfold and raised the plasma anti-FXa activity immediately and continuously throughout the 90-min experiment. In a randomized and blinded fashion, animals then received either rFVIIa (400 microg kg(-1)) or placebo by bolus intravenous injection, following which the ear puncture bleeding times were measured, along with blood levels of heparin (anti-FXa activity) and FVII. FVII activity increased 5.3-fold over baseline in treated animals, decreasing by only 24% over the full observation period. The rFVIIa-treated animals showed a slight decrease in bleeding time immediately after injection, but there was no statistically significant difference in bleeding after rFVIIa or placebo administration. In this study using a rabbit ear bleeding model, rFVIIa was not an effective antidote to LMWH-induced bleeding. However, the bolus injection of LMWH produced a very high blood anti-FXa level, which may have precluded rFVIIa effectiveness.

Animals↗
PubMed2003

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty.

BACKGROUND: Unfractionated heparin (UFH) is safe and effective for thromboprophylaxis, but its use is limited to parenteral administration. A novel drug delivery agent (SNAC) has been developed to accomplish the oral delivery of heparin. OBJECTIVE: This report describes the foundation for dose selection and use of oral heparin/SNAC in patients undergoing elective total hip arthroplasty (THA). PATIENTS AND METHODS: To develop a treatment regimen for clinical study, a multiple dose Phase I pharmacokinetic (PK) study in healthy volunteers compared oral heparin/SNAC (90 000 U heparin) with subcutaneous UFH (5000 U). On this basis, we carried out a double-blind, randomized, multicenter study comparing subcutaneous UFH (5000 U) with oral heparin/SNAC at either 60 000 or 90 000 U heparin in 123 patients undergoing elective THA. Patients received, postoperatively, one of the three treatments every 8 h for a total of 12 doses and were followed for 35 days post surgery. RESULTS: In the Phase I study, anti-factor Xa activity peaked at 45-60 min following oral heparin/SNAC, returning to baseline at 4 h. RESULTS of the randomized trial in THA patients showed that venous thromboembolic events (n = 6), major bleeding events (n = 5) and need for transfusion (n = 23) were distributed evenly among the three treatment groups, UFH and both doses of oral heparin/SNAC. CONCLUSION: This is the first demonstration that oral heparin/SNAC can be safely delivered to the postoperative THA patient, and provides the basis for a larger clinical trial to assess the prophylactic efficacy of heparin/SNAC.

Adolescent↗
PubMed2003

Safety of plasmin in the setting of concomitant aspirin and heparin administration in an animal model of bleeding.

Plasmin is a direct thrombolytic which has been shown to have a strikingly favorable benefit to risk profile in comparison with plasminogen activators, notably tissue plasminogen activator (t-PA). As heparin is known to increase the risk of hemorrhage when co-administered with a plasminogen activator, we asked whether adjunct antithrombotic agents such as aspirin and heparin would affect the safety of plasmin. Three groups of rabbits were administered plasmin at a dose (4 mg kg-1) designed to induce significant decreases in antiplasmin, fibrinogen and factor (F)VIII, to about 25, 40 and 40%, respectively, of baseline values, but not cause prolongation of the ear puncture bleeding time. In a blinded and randomized trial, the results show that an intravenous aspirin bolus plus heparin administered as a bolus followed by a maintenance continuous infusion did not significantly prolong the bleeding time during plasmin infusion. These data indicate that in the rabbit, concomitant use of aspirin plus heparin does not affect the safety of a therapeutic dose of plasmin.

Animals↗
PubMed2001

Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.

BACKGROUND: Perioperative and postoperative venous thrombosis are common in patients undergoing elective hip surgery. Prophylactic regimens include subcutaneous low-molecular-weight heparin 12 hours or more before or after surgery and oral anticoagulants. Recent clinical trials suggest that low-molecular-weight heparin initiated in closer proximity to surgery is more effective than the present clinical practice. We performed a systematic review of the literature to assess the efficacy and safety of low-molecular-weight heparin administered at different times in relation to surgery vs oral anticoagulant prophylaxis. METHODS: Reviewers (A.F.M. and S.M.M.) identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Randomized trials comparing low-molecular-weight heparin administered at different times relative to surgery with oral anticoagulants in patients undergoing elective hip arthroplasty, evaluated using contrast phlebography, were selected. Two reviewers (A.F.M. and S.M.M.) extracted data independently. RESULTS: The literature review identified 4 randomized trials meeting predefined inclusion criteria. The results indicate that low-molecular-weight heparin initiated in close proximity to surgery resulted in absolute risk reductions of 11% to 13% for deep vein thrombosis, corresponding to relative risk reductions of 43% to 55% compared with oral anticoagulants. Low-molecular-weight heparin initiated 12 hours before surgery or 12 to 24 hours postoperatively was not more effective than oral anticoagulants. Low-molecular-weight heparin initiated postoperatively in close proximity to surgery at half the usual dose was not associated with a clinically or statistically significant increase in major bleeding rates (P =.16). CONCLUSIONS: The timing of initiating low-molecular-weight heparin significantly influences antithrombotic effectiveness. The practice of delayed initiation of low-molecular-weight heparin prophylaxis results in suboptimal antithrombotic effectiveness without a substantive safety advantage.

Administration, Oral↗
PubMed2001

Acquired thrombophilic syndromes.

As the biochemical mechanisms of hypercoagulable states are revealed, the syndromes of venous thromboembolism have been increasingly associated with specific aberrations. Most of these changes involve an increase in procoagulant potential, for example, by activation of the coagulation cascade, or by a defect or decrease in natural inhibitors of clotting. Similar abnormalities of the fibrinolytic pathways may contribute, as can loss of inhibitory mechanisms of endothelial cells, as well as changes in vascular anatomy and rheologic patterns of blood flow. All of these factors can directly influence thrombus formation and/or the physiologic response to the thrombus.(1)

Humans↗
PubMed2001

Orally active heparin and low-molecular-weight heparin.

The heparins, (unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH)) given by subcutaneous or intravenous injection have been used extensively in the prevention and treatment of both venous and arterial thromboembolic disorders. The increasing use of the heparins, LMWHs in particular, in the out of hospital setting has stimulated interest in the development of orally absorbable antithrombotic agents that require little or no monitoring, and this includes the heparins. UFH or LMWH delivered orally has been shown to have an antithrombotic effect in animal thrombosis models although there is little change in plasma coagulation tests. The addition of a simple organic chemical N -(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to UFH markedly enhances its absorption. A phase II study in patients undergoing total hip replacement indicated that SNAC heparin in two different doses was as effective and safe as UFH given subcutaneously. A phase III clinical trial comparing two doses of SNAC heparin given orally with LMWH by subcutaneous injection for the prevention of venous thromboembolism in patients undergoing total hip replacement is currently underway.

Administration, Oral↗
PubMed2001

Plasmin induces local thrombolysis without causing hemorrhage: a comparison with tissue plasminogen activator in the rabbit.

The direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites. These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.

Animals↗
PubMed2001

Increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients. THROMBO Investigators.

Diabetes is an established risk factor for reinfarction and cardiac death in postinfarction patients. Since the underlying mechanism of diabetes-related risk is not fully understood we aimed to evaluate the association between lipids, thrombogenic factors and diabetes in postinfarction patients. The study population consisted of 1,045 postinfarction patients (846 non-diabetic, 125 non-insulin- and 74 insulin-requiring diabetics) with the following blood tests performed 2 months after an index myocardial infarction: lipoprotein (a), apolipoprotein-B, apolipoprotein-A, cholesterol, HDL cholesterol, triglycerides, insulin, von Willebrand factor (vWF), fibrinogen, factor VII, D-dimer, and plasminogen activator inhibitor (PAI-1). After adjustment for relevant clinical covariates, non-insulin-requiring diabetes was significantly (p < 0.05) associated with elevated levels of (odd ratios per 1 log unit increase in parenthesis) vWF (1.74) and PAI-1 (1.42) whereas insulin requiring diabetes was associated with even more elevated levels of vWF (4.68), but not with increased levels of PAI-1. No significant differences in lipid levels were observed among three groups. In conclusion, increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients, suggesting that endothelial damage is the primary mechanisms contributing to an increased occurrence of vascular and cardiac events in diabetic postinfarction patients.

Adult↗
PubMed2000

Effect of smoking on lipid and thrombogenic factors two months after acute myocardial infarction.

Cigarette smoking is linked to increased cardiac morbidity and mortality, and has been shown to affect both lipid profiles and thrombotic factors in healthy subjects. However, the influence of smoking on the atherothrombotic environment has not been studied in a large population of patients after acute myocardial infarction (AMI). Blood samples and medical history, including smoking status, were obtained from 1,045 patients at a 2-month visit after AMI. Smokers were asked to refrain 24 hours before the visit, but not all complied. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein-B, apolipoprotein-A, triglycerides, factor VII, factor VIIa, von Willebrand factor, D-dimer, and plasminogen activator inhibitor. There were 247 current, 443 past, and 349 nonsmokers. After adjustment for clinical variables, current smokers had higher levels of total cholesterol and apolipoprotein-B than past and nonsmokers (p <0.01). High-density lipoprotein cholesterol and apolipoprotein-A levels were similar between groups. Fibrinogen was elevated in current (p = 0.001) and past (p = 0.029) smokers, compared with nonsmokers. Smokers who smoked within 24 hours of blood sampling had higher apolipoprotein-B (p = 0.005), total cholesterol (p = 0.001), and fibrinogen (p = 0.015) levels than those who refrained from smoking. In conclusion, postinfarction patients, who historically have higher levels of atherogenic lipids than healthy subjects, have increased levels of these lipids attributed to active smoking. After smoking cessation, lipid profiles approach nonsmoker levels, but fibrinogen remains elevated. Smoking within 24 hours of blood sampling was associated with further adverse prothrombotic and lipogenic effects.

Aged↗
PubMed2000

Cocaine and Buerger disease: is there a pathogenetic association?

A patient with a diagnosis of Buerger disease is described with peripheral limb ischemia and toe amputations, 2 recent small myocardial infarctions, and a long history of cigarette use. Peripheral angiography findings were incompatible with the clinical impression, and further workup revealed heavy recreational use of cocaine. A literature review of the clinical and pathologic manifestations of Buerger disease and of cocaine exposure shows them to have remarkable similarities. Based on our case observation and suggestive evidence from the literature, we propose that cocaine exposure may masquerade as Buerger disease, and further, that unrecognized cocaine exposure may underlie such cases, even including those originally described by Buerger in 1908.

Adult↗
PubMed2000

Gender-related differences in thrombogenic factors predicting recurrent cardiac events in patients after acute myocardial infarction. The THROMBO Investigators.

Thrombosis contributes to recurrent coronary events in patients after acute myocardial infarction (AMI), but prognostic significance of thrombogenic factors by gender is unknown. This study aimed to determine gender-related differences in the prognostic significance of thrombogenic factors for predicting cardiac events (nonfatal reinfarction or cardiac death) in postinfarction patients. Blood levels of the following factors were measured 2 months after AMI in 791 men and 254 women: fibrinogen, von Willebrand factor, factor VII and VIIa, plasminogen activator inhibitor, D-dimer, cholesterol, apolipoprotein A-1, apolipoprotein B, lipoprotein(a), triglycerides, and high-density lipoprotein cholesterol. After adjustment for clinical covariates, levels of apolipoprotein A, high-density lipoprotein cholesterol, fibrinogen, and factor VIIa were significantly higher in postinfarction women than men. During a mean 26-month follow-up, there were 67 cardiac events (8.5%) in men and 14 (5.5%) in women (p = 0.11). In the multivariate Cox model, elevated levels of factor VIIa were a significant predictor of cardiac events in women (p = 0.022) but not in men (p = 0.80), with significant gender-related effect (hazard ratio 2.80 vs 0.92, respectively; p <0.05). D-dimer had prognostic value in men (p = 0. 006) but not in women (p = 0.36), although the difference between hazard ratios for men and women was not significant (2.35 vs 1.58, respectively; p = 0.49). In conclusion, elevated levels of factor VIIa are associated with an increased risk of recurrent cardiac events in postinfarction women, but not in men. D-dimer is more predictive for cardiac events in postinfarction men than women. These observations indicate possible gender-related differences in the pathophysiologic mechanisms of recurrent cardiac events.

Apolipoproteins↗
PubMed2000

Post-transcriptional regulation of endothelial cell plasminogen activator inhibitor-1 expression during R. rickettsii infection.

Intracellular infection of endothelial cells with Rickettsia rickettsii results in increased steady-state levels of plasminogen activator inhibitor-1 (PAI-1) mRNA. Control mechanisms governing such increased expression in response to this novel stimulus have not been defined. In this study, we compared the stability of PAI-1 mRNA in infected and uninfected endothelial cells (EC) and explored the requirement for de novo host cell protein synthesis in the infection-induced increase of steady-state levels. The half-life of PAI-1 mRNA, which is constitutively expressed in cultured EC, increased from 18 h in uninfected EC to greater than 30 h in EC infected for 24 h, a time point at which increases in steady-state PAI-1 mRNA levels are noted. There was no change in stability of gamma-actin due to infection. Nuclear run-on studies revealed no apparent increase in transcription rate at 4, 18 and 24 h. R. rickettsii -induced increase in PAI-1 mRNA was blocked by the eukaryotic protein synthesis inhibitor, cycloheximide, which suggests that this response requires de novo host cell protein synthesis. These results provide evidence that post-transcriptional control mechanisms are operative in the regulation of PAI-1 during R. rickettsii infection.

Actins↗
PubMed2000

Cloning of guinea pig tissue factor cDNA: comparison of primary structure among six mammalian species.

Tissue factor (TF) is a transmembrane glycoprotein that serves as an essential cofactor for plasma coagulation factor VII. TF procoagulant activity exhibits varying species specificity. In particular, guinea pig (GP) TF is unable to activate clotting in heterologous plasma systems, but the molecular basis for this phenomenon is not yet understood. The full-length GP TF cDNA was cloned and sequenced. The open reading frame encoded a predicted precursor protein of 289 amino acids (aa) which was expressed in a reticulocyte lysate system as a protein of apparent molecular weight of 34 kD. The identity of the predicted aa sequence of mature GP TF with rabbit, human, bovine, rat and mouse TF was 66.4, 64.4, 60.6, 53.2 and 52.2%, respectively. With a focus on sites of potential functional significance, we compared sequences within the known binding regions. The eleven residues at the interface region between the TF1 and TF2 modules, which bind to the EGF domain of VIIa, were perfectly conserved among the six species, with the exception of an isoleucine replacing a lysine in the guinea pig sequence. However, only four of the eleven binding residues in the TF1 module, known to interact with the catalytic domain of factor VII, and three of the five residues in the TF2 module, involved in binding the factor VII Gla domain, were conserved among species. We hypothesize that divergence at these regions contributes to the specificity and non-reciprocity of TF procoagulant activity between species.

Amino Acid Sequence↗