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Biomedical subjects

Victor J Marder

Publications and source records attributed to Victor J Marder.

17 recordsLinked to original sources
PubMed2006

Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Information regarding the histological structure of thromboemboli that cause acute stroke provides insight into pathogenesis and clinical management. METHODS: This report describes the histological analysis of thromboemboli retrieved by endovascular mechanical extraction from the middle cerebral artery (MCA) and intracranial carotid artery (ICA) of 25 patients with acute ischemic stroke. RESULTS: The large majority (75%) of thromboemboli shared architectural features of random fibrin:platelet deposits interspersed with linear collections of nucleated cells (monocytes and neutrophils) and confined erythrocyte-rich regions. This histology was prevalent with both cardioembolic and atherosclerotic sources of embolism. "Red" clots composed uniquely of erythrocytes were uncommon and observed only with incomplete extractions, and cholesterol crystals were notably absent. The histology of thromboemboli that could not be retrieved from 29 concurrent patients may be different. No thrombus >3 mm wide caused stroke limited to the MCA, and no thrombus >5 mm wide was removed from the ICA. A mycotic embolus was successfully removed in 1 case, and a small atheroma and attached intima were removed without clinical consequence from another. CONCLUSIONS: Thromboemboli retrieved from the MCA or intracranial ICA of patients with acute ischemic stroke have similar histological components, whether derived from cardiac or arterial sources. Embolus size determines ultimate destination, those >5 mm wide likely bypassing the cerebral vessels entirely. The fibrin:platelet pattern that dominates thromboembolic structure provides a foundation for both antiplatelet and anticoagulant treatment strategies in stroke prevention.

Adolescent↗
PubMed2005

Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

Anticoagulants↗
PubMed2005

Quantitative assessment of thrombus burden predicts the outcome of treatment for venous thrombosis: a systematic review.

PURPOSE: Clot-burden change in patients receiving anticoagulant therapy, by predicting subsequent recurrent venous thromboembolism, may provide a clinically relevant surrogate endpoint of prognostic importance. The validity of this objective measure is yet to be established. METHODS: A PubMed search was performed to retrieve articles published up to December 2003. We identified 11 randomized trials reported from 1990 to 2003 that met our study identification and selection criteria. Anticoagulant therapy subsequently approved by regulatory affairs was assessed by clot-burden change and the validated outcome measure, long-term venous thromboembolism. Two additional randomized trials, partly meeting the inclusion criteria, were included in the sensitivity analysis. RESULTS: Individual studies suggested a predictive relationship between clot-burden change and likelihood of recurrent venous thromboembolism irrespective of the particular anticoagulant. The summary treatment effects strongly favored the therapy under evaluation and were in harmony for improved clot-burden (relative risk 0.82; 95% CI, 0.76-0.88; P <0.001) and for recurrent venous thromboembolism (relative risk 0.56; 95% CI, 0.42-0.76; P <0.001). The aggregate data show a striking predictive correlation for clot-burden change and subsequent recurrent venous thromboembolism using meta-regression analysis; (correlation = 0.81, P = 0.005) validating quantitative clot-burden assessment. CONCLUSION: Clot-burden change predicts long-term outcome, providing clinically relevant, patient-specific prognostic findings that may guide duration of anticoagulant therapy as well as provide a valid surrogate endpoint for clinical trials of innovative antithrombotic therapy, allowing more efficient trials exposing far fewer patients to the hazards of ineffective therapy than is required for outcome studies. Noninvasive assessment (duplex ultrasonography) of clot-burden change is currently being deployed for use in clinical trials.

Anticoagulants↗
PubMed2004

Relationship between intermittent claudication, inflammation, thrombosis, and recurrent cardiac events among survivors of myocardial infarction.

BACKGROUND: Among coronary disease patients, concomitant peripheral arterial disease is a potent risk factor for future cardiac events and mortality. We sought to determine clinical and biochemical markers that might better elucidate the relationship between coronary and peripheral arterial disease. METHODS: Two months after an index myocardial infarction, 1045 patients provided detailed medical histories and underwent blood testing for selected hemostatic, lipid, and inflammatory markers. Patients were then followed up prospectively for a mean of 26 months. RESULTS: Compared with individuals without intermittent claudication (n = 966), those with claudication (n = 78) (information was unavailable for 1 individual) were significantly older and demonstrated an increased frequency of diabetes mellitus, tobacco use, prior cardiac and cerebrovascular events, and depressed left ventricular function. Individuals with claudication were less likely to receive beta-blocker therapy after the index infarction. Individuals with claudication had evidence of enhanced procoagulant and proinflammatory states manifested by relative elevations in plasma fibrinogen, D-dimer, C-reactive protein, and serum amyloid A concentrations. During follow-up, the presence of claudication was associated with an independent 2-fold increase in the combined end point of death or nonfatal cardiac event (38.5% vs 17.8%, P =.001) and a 5-fold increase in cardiac mortality (19.2% vs 3.6%, P =.001). Patients with intermittent claudication who were not treated with beta-blockers had a significant 3-fold mortality excess relative to those receiving beta-blockers. CONCLUSIONS: Following myocardial infarction, the added presence of intermittent claudication is associated with heightened procoagulant and proinflammatory states and an underuse of beta-blocker therapy and is a strong independent predictor of recurrent cardiovascular events.

Comorbidity↗
PubMed2004

Foundation and sites of action of antithrombotic agents.

Thromboembolic disorders are a major cause of morbidity and mortality. As knowledge of the complex interactions between the vessel wall, platelets and coagulation and fibrinolytic enzyme systems increases, new avenues for more effective and safer therapies become evident. In this review, we discuss mechanisms of hemostasis in relation to antithrombotic agents and results of clinical trials using these drugs.

Blood Coagulation Factors↗
PubMed2004

Locally delivered plasmin: why should it be superior to plasminogen activators for direct thrombolysis?

With advances in the field of thrombolytic therapy, whereby clots are routinely treated locally via a catheter, traditional systemic thrombolytics such as plasminogen activators might not be the best drugs for this task. Plasmin represents a new class of thrombolytic agents that exhibit direct fibrinolytic activity, without the need for either plasminogen or a plasminogen activator. In contrast to plasminogen activators, this independence from plasminogen allows plasmin to efficiently dissolve long, retracted blood clots that are inherently deficient in plasminogen. Preclinical safety studies in rabbits demonstrate that plasmin, in contrast to tissue-type plasminogen activator, does not cause re-bleeding from preformed hemostatic plugs. These results predict that plasmin will prove to be both superior to, and safer than, plasminogen activators in the dissolution of long, retracted blood clots in humans.

Animals↗
PubMed2003

History of hypertension and enhanced thrombogenic activity in postinfarction patients.

Hypertension is a risk factor for coronary thrombosis and death in cardiac patients mediated in part by endothelial damage or dysfunction and increased thrombogenicity. However, there are no data regarding the association between hypertension and thrombogenic activity in stable patients after myocardial infarction and limited data about the prognostic significance of thrombogenic factors in hypertensive patients after infarction. Therefore, levels of thrombogenic, lipid, and inflammatory factors were measured 2 months after an acute myocardial infarction in 461 hypertensive and 582 nonhypertensive patients. Thrombogenic factors included d-dimer, fibrinogen, plasminogen activator inhibitor-1, von Willebrand factor, factor VII, and factor VIIa. Lipid variables included cholesterol (total, HDL, LDL), triglyceride, lipoprotein (a), apolipoprotein-A1, and apolipoprotein-B. The prognostic significance of these factors for predicting cardiac events during a 2-year follow-up was evaluated in hypertensive and nonhypertensive patients. In comparison with nonhypertensive patients, those with hypertension had higher levels of d-dimer (607 versus 453 mg/L, P<0.001), fibrinogen (3.64 versus 3.43 g/L, P<0.001), plasminogen activator inhibitor-1 (29.7 versus 27.3 ng/mL, P=0.01), von Willebrand factor (159 versus 141 IU/dL; P<0.001), and higher levels of inflammatory markers (hsCRP and SAA). In multivariate analysis after adjustment for clinical covariates, elevated d-dimer was the only factor independently associated with a history of hypertension (OR, 1.38, P=0.05). d-Dimer was associated with an increased risk of recurrent cardiac events in both hypertensive (hazard ratio=3.02, P=0.005) and nonhypertensive (hazard ratio=2.42, P=0.02) patients. Thus, patients after infarction with a history of hypertension have enhanced thrombogenic activity, which predisposes them to recurrent cardiac events.

Apolipoproteins↗
PubMed2003

Metabolic syndrome best defines the multivariate distribution of blood variables in postinfarction patients.

The hypothesis was tested that metabolic syndrome (MS) plays a leading role in approximating the multivariate distribution of thrombogenic and metabolic blood variables in a population of postinfarction patients. The multivariate statistical technique of factor analysis was used to determine blood variable clustering 2 months after myocardial infarction. Five clusters resulted in two separate independent factors, dyslipidemia and metabolic, reflecting MS and the remaining interpreted as cholesterol-lipoprotein, vascular-inflammatory, and coagulation. All five factors accounted for 55% of total variance with MS-associated factors accounting for 20% and individual factor contributions as follows: 11.6, 8.6, 12.9, 11.9, and 9.6%, respectively. There were no interactions of metabolic variables with thrombogenic variables or CRP in any factor. Results of subgroup analysis in males and females and in patients on and not on statins were all similar to the total group. We conclude there is no interaction of variables of MS or cholesterol-lipoprotein factors with those of thrombogenic factors. This independence yields the potential for use of factors in evaluating CVD risk. Further, the importance of MS in this group of postinfarction patients is emphasized, as the largest contribution to total variance was from MS factors, meaning that these variables best approximate the original multivariate distribution.

Aged↗
PubMed2002

Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage.

All thrombolytic agents in current clinical usage are plasminogen activators. Although effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. We report results of a randomized, blinded, dose-ranging comparison of tissue-type plasminogen activator (TPA) with a direct-acting thrombolytic agent, plasmin, in an animal model of fibrinolytic hemorrhage. This study focuses on the role of plasma coagulation factors in hemostatic competence. Plasmin at 4-fold, 6-fold, and 8-fold the thrombolytic dose (1 mg/kg) induced a dose-dependent effect on coagulation, depleting antiplasmin activity completely, then degrading fibrinogen and factor VIII. However, even with complete consumption of antiplasmin and decreases in fibrinogen and factor VIII to 20% of initial activity, excessive bleeding did not occur. Bleeding occurred only at 8-fold the thrombolytic dose, on complete depletion of fibrinogen and factor VIII, manifest as prolonged primary bleeding, but with minimal effect on stable hemostatic sites. Although TPA had minimal effect on coagulation, hemostasis was disrupted in a dose-dependent manner, even at 25% of the thrombolytic dose (1 mg/kg), manifest as rebleeding from hemostatically stable ear puncture sites. Plasmin degrades plasma fibrinogen and factor VIII in a dose-dependent manner, but it does not disrupt hemostasis until clotting factors are completely depleted, at an 8-fold higher dose than is needed for thrombolysis. Plasmin has a 6-fold margin of safety, in contrast with TPA, which causes hemorrhage at thrombolytic dosages.

Animals↗
PubMed2002

Use of thrombolytic therapy for acute myocardial infarction: effects of gender and age on treatment rates.

BACKGROUND: Although there have been efforts to increase the utilization of thrombolytic therapy, there are still many patients who might benefit from this treatment who do not receive it. Women and the elderly have been particularly undertreated, despite evidence that their survival can be improved with thrombolysis. This study was undertaken to determine the relative rates of treatment of women vs. men and the elderly vs. younger subjects and to examine factors that might explain differences in treatment frequency. METHODS AND RESULTS: This is a retrospective study of patients who presented to the Emergency Departments of four local hospitals in 1993 and 1994 with evidence for acute ST-elevation myocardial infarction. Demographic data, past medical history, information on co-morbid illnesses, and times to hospital arrival, first electrocardiogram, physician notification, and thrombolytic therapy were recorded as was survival to hospital discharge. Data for patients who did or did not receive thrombolytic therapy were compared. Men were treated more frequently in both tertiary and community hospitals. Women were older, but within each age bracket, men were treated more often. The time of arrival was similar for men and women, but men who arrived within 6 hours or 6-12 hours after pain onset were treated at a higher rate than women. For patients without contraindications, treatment was not affected by gender or age. However, treatment rates decreased with increased prevalence of exclusionary factors, and since both women and the elderly tended to have more such factors, elderly women were treated at a markedly lower rate. The single clinical factor that increased thrombolytic usage in women compared to men was a history of prior myocardial infarction. CONCLUSION: Despite convincing evidence that thrombolytic therapy is beneficial in women and the elderly, these groups have been relatively neglected unless attention is called to clinical risk, for example, by history of prior myocardial infarction.

Age Factors↗
PubMed2002

Towards safer thrombolytic therapy.

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment.

Cardiovascular Diseases↗